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ISSN 2147-0634
MEDICINE ISSN 2147-0634
SCIENCE International Medical Journal
Volume 8, Number 2, June 2019, Pages 260-488
photo by photo Serhat by Karaman Osman Celbiş
E ditor-in-Chief Osman CELBIS
E ditors David O. CARPENTER Nevzat ERDIL Yuksel ERSOY Ədalət HƏSƏNOV Yunus KARAKOC Ronald S MacWALTER Selami Cagatay ONAL Ibrahim SAHIN
P ublishing E ditor Fatih BATI
Medicine Science International Medical Journal
EDITORIAL BOARD
Editor-in-Chief Osman CELBIS (MD, Professor), (editor.osmancelbis@gmail.com)
➢
Editors ➢
Yuksel ERSOY (MD, Professor) (editor.yukselersoy@gmail.com)
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Yunus KARAKOC (PhD, Professor) (editor.yunuskarakoc@gmail.com)
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Selami Cagatay ONAL (MD, Professor) (editor.cagatayonal@gmail.com)
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Ibrahim SAHIN (MD, Professor) (editor.ibrahimsahin@gmail.com)
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Nevzat ERDIL (MD, Professor) (editor.nevzaterdil@gmail.com)
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David O. CARPENTER (MD, Professor)
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Ronald S MacWalter (MD, FRCP)
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Ədalət Həsənov (MD, Professor)
Publishing Editor ➢
Fatih BATI (MD, Assistant Professor) (editor.fatihbati@gmail.com)
Medicine Science International Medical Journal
SCIENTIFIC ADVISORY BOARD (Alphabetical Order) •
Gökhan Akbulut, İzmir, Turkey
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Ferah Kızılay, MD, Antalya, Turkey
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Murat Alper, MD, Erzincan, Turkey
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Prakash Kinthada, PhD, Visakhapatnam, India
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Mustafa Altintas, MD, Antalya, Turkey
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Ozkan Kose, MD, Antalya, Turkey
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Sevil Atasoy, PhD, Istanbul, Turkey
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Zhiqiang Liu, MD, PhD, Houston, TX, USA
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Aysegul Atmaca, MD, Samsun, Turkey
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Liu Liu, MD, PhD, New Orleans, LA, USA
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Yasar Bayindir, MD, Malatya, Turkey
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Ronald S MacWalter, MD, Scotland, UK
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Turgay Bork, MD, Malatya,Turkey
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Bulent Mızrak, MD, Batumi, Georgia
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David O. Carpenter, MD, New York, USA
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Camal Musaev, MD, Azerbaycan
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Chang-Hwei Chen, PhD, New York, USA
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Musfiq Orucov, MD, Azerbaycan
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Gurkan Celebi, MD, Ankara, Turkey
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Ercument Olmez, MD, Manisa, Turkey
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Selcuk Cetin, MD, Tokat, Turkey
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Bedirhan Sezer Öner, MD, Malatya, Turkey
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Nefise Oztoprak Cuvalcı, MD, Antalya, Turkey
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Necdet Oz, MD, Antalya, Turkey
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Oguzhan Deyneli, MD, İstanbul, Turkey
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Abdullah Ozgonul, MD, Sanliurfa, Turkey
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Ahmet Hakan Dinc, Ankara, Turkey
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Hakan Parlakpinar, MD, Malatya, Turkey
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Ali Dogan, MD, Antalya, Turkey
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Erkan Pehlivan, PhD, Malatya, Turkey
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Teoman Dogru, MD, Balıkesir, Turkey
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Oguz Polat, MD, Cleveland , USA
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Nevzat Erdil, MD, Malatya, Turkey
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Nilufer Tulin Polat, PhD, Malatya, Turkey
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Bulent Eren, MD, Bursa, Turkey
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Nariman Safarli, MD, Baku, Azerbaijan
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Zerrin Erkol, MD, Bolu, Turkey
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Nusret Soylu, MD, Malatya, Turkey
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Kadir Ertem, MD, Malatya, Turkey
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Maryna Steyn, MD, South Africa
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Yasemin Ersoy, Malatya, Turkey
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Hülya Taskapan, MD, Malatya, Turkey
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Suraj K George, MD, USA
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Mehmet Tokdemir, MD, , Elazig, Turkey
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Mira R. Gökdoğan, PhD, Girne, North Cyprus
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Nilgun Ulutasdemir, PhD, Gaziantep, Turkey
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Ali Gunes, MD, Malatya, Turkey
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Ali Uzunkoy, MD, Sanliurfa, Turkey
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Hakan Gunen, MD, Istanbul, Turkey
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Yingjun Yan, MD, Nashville, TN 37232, USA
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Than Than Htwe, MD, Perak, Malaysia
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Dilek Yavuz, MD, İstanbul , Turkey
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S.Iqbal, MD, Kerala, India
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Ilhan Yetkin, MD, Ankara, Turkey
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Nur Efe Iris, MD, İstanbul, Turkey
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Tulay Öner Yıldırım, MD, Malatya, Turkey
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Servet Birgin Iritas, MD, Ankara, Turkey
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Oguzhan Yıldırım, MD, Malatya, Turkey
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Mehmet Yasar Işcan, PhD, Istanbul, Turkey
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Tuba Duygu Yılmaz, MD, Mersin, Turkey
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Om Prakash Jasuja, PhD, Patiala, India
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Eda Bengi Yılmaz, MD, Mersin, Turkey
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Kishore Kumar Jella, PhD, Atlanta GA, USA
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Saim Yologlu, PhD, Malatya, Turkey
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Mehmet Karaca, MD, Antalya, Turkey
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Menizibeya Osain Welcome, MD, Minsk, Belarus
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Abdullah Karaer, MD, Malatya, Turkey
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Ersoy Kekilli, MD, Malatya, Turkey
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Pavel Timonov, MD, Bulgaria
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Mehmet Kelles, MD, Malatya, Turkey
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Antoaneta Fasova, MD, Bulgaria
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Inam Danish Khan, MD, CH EC Kolkata, India
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Robert (Paweł) SUSŁO, MD, Poland
Ronald K Wright BS MD JD, FL , USA
Available online at www.medicinescience.org
ORIGINAL RESEARCH
Medicine Science International Medical Journal
Medicine Science 2019;8(2):260-2
Frequency of lysosomal acid lipase deficiency in patients with primary hyperlipidemia Bahri Evren1, Yılmaz Bilgic2, Feyza Firat Atay3, Ayse Nuransoy Cengiz4, Yasir Furkan Cagin2 1 Inonu Universty Faculty of Medicine, Department of Endocrinology Malatya Turkey Inonu Universty Faculty of Medicine, Department of Gastroenterology Malatya Turkey 3 Kovancilar State Hospital, Clinic of Internal Medicine, Elazig Turkey 4 Inonu Universty Faculty of Medicine, Department of Internal Medicine Malatya Turkey 2
Received 27 January 2019; Accepted 17 February 2019 Available online 10.05.2019 with doi:10.5455/medscience.2019.08.9025 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract The aim of our study was to investigate the prevalence of LAL (lysosomal acid lipase) deficiency in patients with primary hyperlipidemia. Twenty-four patients with primary hyperlipidemia were included in the study. The gender, age, height, weight, body mass index and waist circumference of the patients were recorded. Lipid profiles, glucose, transaminases and LAL enzyme profiles were evaluated. LAL enzyme deficiency was not detected in patients with primary hyperlipidemia. In our study, when we investigated LAL deficiency in primary hyperlipidemic patients, we could not find a relationship between them. As a result of our study, LAL deficiency was not detected in patients with primary hyperlipidemia. However, in this context, there is a need to work with a large number of patients. Keywords: Primary hyperlipidemia, lysosomal acid lipase deficiency
Introduction
Material and Methods
Lysosome is a membrane-associated, acidic organelle found in animal-related cells. Its lead to the breakdown of biological macromolecules (mucopolysaccharides, sphingolipids, glycoproteins, triglycerides, cholesterol esters) which are produced both from the outside and within the cell by the acid hydrolases ıts contain [1]. Lysosomal storage diseases (LSD), which the lack of enzymes involved in the catabolism of macromolecules is a group of diseases caused by the defect of the transports that cause the lysis of the lysosomes to function out of the cell due to the accumulation of specific substrates. Clinical findings vary according to the substance stored. Because the accumulated molecules are highly heterogeneous, clinical presentations are also heterogeneous [2]. Lysosomal Acid Lipase (LAL) deficiency is a rare autosomal recessive, lysosomal lipid storage group. It is characterized by progressive cholesterol ester and triglyceride accumulation in liver, spleen and other organs (central system, gis …) [3].
Twenty-four patients with primary hyperlipidemia who were admitted to the endocrinology and metabolism outpatient clinic of Inonu University between June 2016 and September 2017 and who were diagnosed with secondary hyperlipidemia such as type 2 diabetes mellitus, nephrotic syndrome, hypothyroidism and primary biliary cirrhosis were included in the study. The gender, age, height, weight, body mass index and waist circumference of the patients were recorded. Lipid profiles, glucose, transaminases and LAL enzyme profiles were evaluated. LAL enzyme deficiency was not detected in patients with primary hyperlipidemia. Exclusion criteria are given in the material method part of our study. LAL activity was measured by using Dried Blood Spot Test (DBS). The results are given in nanomol / punch / hour. In our study, the mean + standard deviations of the data were given as statistical analysis. Since there was no LAL deficiency in our patients, no specific statistical method was used. Results
*Coresponding Author: Yilmaz Bilgiç, Inonu Universty, Faculty of Medicine Department of Endocrinology Malatya Turkey E-mail: drybilgic1975@hotmail.com
When the laboratory and anthropometric results of the patients with primary hyperlipidemia were evaluated, the mean age was found to be 38.55 ± 10.7 years. The mean weight and body mass index of the patients were 72.42 ± 11.4 kg and 26.72 ± 5.2 kg 260
doi: 10.5455/medscience.2019.08.9025
/ m2, respectively. The waist circumference of the patients was calculated without gender discrimination and the mean was 84.41 ± 12.8 in both sexes. For the exclusion of diabetes mellitus, a cause of secondary hyperlipidemia, fasting blood glucose was also included in our study and mean fasting glucose was measured as 86 ± 9.5 mg / dl. Liver enzymes were also studied to determine whether there was a high liver enzyme elevation in LAL deficiency. The mean AST 27 ± 7.2 UI / L and ALT 24 ± 6.3 UI / L were determined. In our study, mean blood lipids were 244 ± 54.2 mg / dl for total cholesterol, 121 ± 44.7 mg / dl for triglyceride, 51.4 ± 10.3 mg / dl for HDL cholesterol and 182 ± 39.4 mg / dl for LDL cholesterol (Table 1). Table 1. Laboratory and anthropometric results of patients with primary hyperlipidemia Parameters
Patients with primary hyperlipidemia (n = 24)
Age (years)
38.55 ± 10.7
Height (cm)
157.2 ± 6.1
Weight (kg)
72.42 ± 11.4
BMI (kg/m2)
26.72 ± 5.2
Waist circumference
84.41 ± 12.8
Glucose (mg/dl)
86 ± 9.5
AST
27 ± 7.2
ALT Total cholesterol (mg/dl)
24 ± 6.3 244 ± 54.2
Triglyceride (mg/dl)
121 ± 44.7
HDL cholesterol (mg/dl)
51.4 ± 10.3
LDL cholesterol (mg/dl)
182 ± 39.4
LAL (nmol/punch/h.)
0.74 ± 0.68
Discussion LAL is a rare lipid storage disease and its prevalence is approximately 1 / 40.000 depolama1 / 350.000 in newborns. Diagnostic images such as liver ultrasound and biopsy are important, which show changes in hepatic morphology such as microvescular steatosis with Kupffer cell involvement, fibrosis and cholesterol-estercrystal accumulation. These findings should suggest LAL disease. Because the disease is manifested as idiopathic microvesicular hepatosteatosis disease [4]. As the disease progresses in patients with initially indeterminate complaints, some clinical symptoms, such as rough facial, skeletal dysplasia, and developmental delay, stimulate a lysosomal depot disorder. Different lysosomal storage disorders share common symptoms and symptoms [5]. LAL deficiency is a disease associated with progressive hepatic insufficiency accompanied by increased atherosclerosis, cardiovascular disease, hepatomegaly, and increased liver enzyme deficiency, with dyslipidemia frequently associated with. LAL deficiency in adults and children shows very different clinical features and heterogeneous course. While the age at onset may occur in late age as 44 years in men and 68 years in women, the mean age at which onset of symptoms is 5 years in both sexes [3]. Hepatomegaly is the most common clinical manifestation of lysosomal storage disease. High serum total cholesterol, LDL cholesterol, triglyceride high together with hepatomegaly are among the most characteristic findings [6]. Definitive diagnosis is the measurement of enzyme activity in leukocytes, cutaneous fibroblasts or dry blood samples from peripheral blood samples. The values below 0.03 (nmol / punch / h) in LAL activity were
Med Science 2019;8(2):260-2
inadequate in LAL activity, values in the range of 0.03-0.15 (nmol / punch / hour) were defined as LAL activity at the border. The values between 0.15-0.37 (nmol / punch / hour) with highly reduced LAL activity, 0.37-0.50 (nmol / punch / hour) values are considered as LAL activity in the transition zone [7,8]. In the treatment, cholestyramine and statins can be given. Although hematopoietic stem cell transplantation is potentially curative in patients with LAL deficiency, it is often not a good option because it carries high risks, including fatal complications. The main treatment consists of the enzyme replacement sebelipase alfa, which was approved in 2015. Sebelipase alpha is a recombinant human lysosomal acid lipase that replaces incomplete LAL enzyme activity and thereby reduces hepatic fat content and elevated transaminases [9]. Conclusion Lysosomal acid lipase deficiency; in patients with high LDL and / or low HDL levels, hepatomegaly and / or high transaminase levels without obesity or metabolic syndrome should be considered. In our study, the use of lipid electrophoresis in the diagnosis of primary hyperlipidemia is one of the weaknesses of our study. In our study, we could not find any relationship between these two diseases. As a result of our study, LAL deficiency was not detected in patients with primary hyperlipidemia. However, because the incidence of LAL deficiency is very low, large-volume clinical studies are needed to evaluate the frequency of patients with primary hyperlipidemia. Competing interests The authors declare that they have no competing interest. Financial Disclosure All authors declare no financial support. Ethical approval Ethics committee approval was obtained. Bahri Evren ORCID: 0000-0001-7490-2937 Yılmaz Bilgic ORCID: 0000-0002-2169-5548 Feyza Firat Atay ORCID 0000-0002-2841-2985 Ayse Nuransoy Cengiz ORCID: 0000-0001-9133-8602 Yasir Furkan Cagin ORCID: 0000-0002-2538-857X
References 1.
Zeynep Büşra Aksoy, Ege soydemir. Lizozomal aktivite. Güncel Gastroenteroloji. 2016;4:345-52.
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Futerman AH, Van Meer G. The cell biology of lysosomal storage disorders. Nat Rev Mol Cell Biol. 2004;5:554-65.
3.
Bernstein DL, Hulkova H, Bialer MG, et al. Cholesteryl ester storage disease: review of the findings in 135 reported patients with an underdiagnosed disease. J Hepatol. 2013;58:1230-43.
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Botero V, Garcia VH, Gomez-Duarte C, et al. Lysosomal acid lipase deficiency, a rare pathology: The first pediatric patient reported in colombia. Am J Case Rep. 2018;19:669-72.
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Andria, g. & parini, Lysosomal storage diseases early diagnosıs and new treatments edited by: rossella parini, generoso andriat. lysosomal storage d apa (american psychological assoc.). 2010.
6.
Lipiński P, Ługowska A, Zakharova EY, et al. Diagnostic algorithm for cholesteryl ester storage disease: Clinical presentation in 19 Polish Patients. J Pediatr Gastroenterol Nutr. 2018;67:452-47.
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8.
Wierzbicka-Rucińska A, Jańczyk W, Ługowska A, et al. Diagnostic and therapeutic management of children with lysosomal acid lipase deficiency (LAL-D). Review of the literature and own experience. Dev Period Med. 2016;20:212-5. Hamilton J, Jones I, Srivastava R, et al. A new method for the measurement of lysosomal acid lipase in dried blood spots using the inhibitor Lalistat 2. Clin
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Chim Acta. 2012;413:1207-10. 9.
Canbay A, Müller MN, Philippou S, et al. Cholesteryl ester storage disease: fatal outcome without causal therapy in a female patient with the preventable sequelae of progressive liver disease after many years of mild symptoms. Am J Case Rep. 2018;19:577-81.
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Available online at www.medicinescience.org
ORIGINAL RESEARCH
Medicine Science International Medical Journal
Medicine Science 2019;8(2):263-7
Can nutritional status of patients in intensive care unit predict mortality and length of hospital stay? A single center retrospective case control study Deniz Avci1, Ali Cetinkaya1, Yekta Gulunay2, Sadik Oluk1, Abdullah Eyvaz2 1 Health Sciences University, Kayseri Training and Research Hospital, Department of Internal Medicine, Kayseri, Turkey Health Sciences University, Kayseri Education and Research Hospital, Department of Infectious Diseases, Kayseri, Turkey
2
Received 23 March 2018; Accepted 01 Octaber 2018 Available online 24.12.2018 with doi:10.5455/medscience.2018.07.8941 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract To compare the hospitalization duration and mortality with the first day nutritional status of the patients who were hospitalized in intensive care unit of internal medicine department. The files of patients admitted to the ICU between 01-January-2017 and 30-June-2017 were retrospectively reviewed. Those who were not eligible for study in the selected files were later handed off. The remaining patients (169 patients) were evaluated for age, sex, stay in intensive care unit, APACHE2 and Glasgow scores, outcomes (exitus or discharge), NRS-2002 values in day of hospitalization, glucose, creatinine, albumin, White Blood Cell, hematocrit, thrombocyte, C-reactive protein and thyroid stimulating hormone (TSH) values were recorded. In addition, patients need for mechanical ventilation and underlying diseases (Chronic renal failure, cancer, sepsis, etc.) were recorded. The mean NRS-2002 score of the whole group was 4.28±0.90. The mean NRS-2002 score of discharged patients was 3.98±0.80 while the mean NRS-2002 score was 4.71±0.86 (p<0.001). There were positive correlations between NRS-2002 scores and age (r=0.537, p <0.001), APACHE2 score (r=0.250, p=0.001), blood creatinine level (r=0.255, p=0.001). There were statistically significant correlations between NRS-2002 scores and serum albumin levels (r=-0.250, p<0.001) and Glasgow coma scores (r=-0.310, p=<0.001) in the negative direction. There was a negative correlation between hospitalization and NRS-2002 scores in cancer patients (r=-0.495, p=0.019). The mean NRS-2002 score was 5.0±0.89 in patients with sepsis who were discharged, while it was 4.36±0.91 in patients with sepsis who died (p=0.014). The mean NRS-2002 score was 4.22±0.74 in patients with chronic renal disease who were discharged, whereas this value was 4.90±0.70 in exitus group (p=0.003). In this study, we demonstrated nutritional status of serious patients in ICU related with certain outcomes including mortality and hospitalization length. Keywords: NRS-2002, Mortality, intensive care unit, nutrition
Introduction Predicting mortality in intensive care unit patients has been a topic of study for many years. As a result of these studies commonly used scoring systems such as Acute Physiology and Chronic Health Evaluation 2 (APACHE2) and Glasgow coma scale have been developed and they provided to predict the possibility of mortality on the time of admission to hospital [1,2]. Various scoring systems have been developed to determine the nutritional risk. For example, Subjective Global Assessment) [3] revealed in 1987, MNA (Mini-Nutritional Assessment) [4] in 1999, MUST (Malnutrition Universal Screening Tool) [5] recommended by European guidelines to determine nutritional risk in 2002 and NRS-2002 ( Nutritional Risk Screening 2002)was published in 2003 [6]. *Coresponding Author: Deniz Avci, Health Sciences University, Kayseri Training and Research Hospital, Department of Internal Medicine, Kayseri, Turkey E-mail: denav38@gmail.com
The NRS-2002, which is still the most valid nutritional assessment test in especially hospitalized patients, was created by evaluating 128 randomized controlled trials. It is a scoring system that takes into account the deterioration of the nutritional condition of the patient, the severity of the illness and the age of the patient [6]. For today, NRS-2002 database is available in Turkey Clinical Enteral Parenteral Nutrition Society (KEPAN) website [6]. Malnutrition is a common problem in intensive care units. The degree of malnutrition is positively correlated with the hospitalization length of patient [7]. Malnutrition increases the risk of infection and multi organ dysfunction [8]; it is also an important factor that affects immunity [9]. It has been demonstrated that immune system is impaired [10] and infectious diseases are badly affected in the deficiency of micronutrients [11]. Relation between the prognoses of nutrition in intensive care patients was studied in many types of intensive care and various diseases [12,13]. In this study, we investigated the relationship of NRS-2002, APACHE2, Glasgow coma score calculated in the day 263
doi: 10.5455/medscience.2018.07.8941
of intensive care admission with mortality and hospitalization time in patients who were taken to Internal Medicine intensive care unit (IMICU) with the diagnosis of cancer, chronic kidney disease and sepsis. Material and Methods Files of patients that were hospitalized between 01-January-2017 and 30-June 2017 in Training and Education Hospital were reviewed retrospectively. The Kayseri Training and Research Hospital Ethics Committee approved this study. Drug intoxications, patients hospitalized in intensive care unit less than 24 hours and patients younger than 18 years were not included in the study. 225 ICU patients’ records were reviewed
Med Science 2019;8(2):263-7
Chicago, IL, USA). The suitability of the normal distribution of the data was performed with Shapiro–Wilk test and histograms. Continuous variables were presented as mean ± standard deviation or median (minimum-maximum), depending on whether their distribution is normal or not. Mean values between groups were compared using Student’s T test, and median values were compared using Mann-Whitney-U test. Chi-square test was used to compare categorical data. Pearson correlation analysis was used for correlation calculations between continuous variables. The receiver operating characteristic (ROC) curves were used to evaluate the performance of NRS-2002 to indicate the presence of mortality in patients. A p-value <0.05 was considered significant. Results The mean age of whole group was 69.2±17.1 years. The median age of discharged patient’s was 67.3±18.8 years and was 72.0±14.0 years for patients with mortality and the difference was not statistically significant (p=0.057).
27 patients were excluded due to short hospitalization (<24 28 patients with drug intoxication were excluded 169 ICU patients’ records were remained
The remaining 169 patient’s ages, sex, duration of stay in intensive care unit, APACHE 2 and Glasgow coma scores, outcomes (discharge or exitus), NRS-2002 values at admission day; glucose, creatinine, albumin, white blood cell, hematocrit, platelet, C-reactive protein (CRP), Thyroid stimulating hormone (TSH) levels were recorded. Besides these, need of patients to mechanical ventilation and underlying diseases (chronic kidney disease, sepsis, cancer etc) were also recorded. The NRS-2002 evaluation of patients was routinely performed by relevant dieticians in the day of intensive care unit admission. APACHE 2 scores and Glasgow scores of patients were recorded by the physicians in the intensive care unit. Patients’ laboratory tests were the routinely taken values in intensive care unit admission. Statistical analysis Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS) software version 21.0 (SPSS Inc.,
Both groups were similar in terms of gender. The male/female ratio (M/F) of the whole patient group was 58.6% (n = 99)/41.4% (n = 70). There was no statistically significant difference between the sex-distributions of discharged patient’s M/F: %56. (n=39)/%43.5 (n=30) and mortal patients’ M/F: %60 (n=60)/%40 (n=40) (p=0.652). NRS-2002 scores were 4.28±0.90 in the whole group evaluation. The mean NRS-2002 score was 3.98±0.80 in the discharged patients. In mortal cases, the mean NRS-2002 score was 4.71±0.86. The difference between these two mean values were a statistically significant difference (p<0.001). While 68.8% (n=47) of the cancer cases ended with death in intensive care unit, this rate was 34.4% (n=22) in the non-cancer patients (p <0.001). 51.8% (n=26) of patients with sepsis resulted in death in intensive care unit while the mortality rate in patients without sepsis was 36.4% (n=43) (p=0.078). This difference was tending to be statistically significant. Group comparisons are summarized in Table 1.
Table.1 Comparison of variables according to outcomes of patients in intensive care unit Continuous variables
Total
Outcome Exitus
Discharge
p
Age(year)
69.2±17.1
72.0±14.0
67.3±18.8
0.057
APACHE 2 score
23 (3-48)
25 (10-48)
19 (3-44)
0.002
Glasgow coma score
11 (3-15)
10 (3-14)
12 (3-15)
0.001
Hospitalization duration (day)
5 (2-32)
7 (2-37)
5 (2-21)
0.018
4.28±0.90
4.71±0.86
3.98±0.80
<0.001
Glucose (mg/dL)
126.5 (54-818)
129 (54-412)
124 (69-818)
0.772
Creatinine (mg/dL)
1.4 (0,2-14,6)
1.9 (0.3-14.6)
1.3 (0.2-13.2)
0.035
2.73±0.71
2.6±0.6
2.8±0.8
0.111
WBC(1/uL)
10500 (600-40000)
11150 (3300-38000)
10200 (600-40000)
0.388
Hematocrit
34.4±9.0
35.1±9.8
34.0±8.5
0.448
182000 (4000-488000)
173000 (27000-478000)
195000 (4000-488000)
0.638
0.9 (0.01-99)
0.9 (0.01-99)
0.9 (0.2-10)
0.479
58.6(n=99)/41.4 (n=70)
56.5(n=39)/43.5 (n=30)
60 (n=60)/40 (n=40)
0.652
99 (3-212)
121 (9-212)
64 (3-199)
0.010
NRS-2002
Albumin (g/L )
Platelet (1/uL) TSH (mU/L) Categoric variables Gender M/F (%) CRP (mg/dL)
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There were statistically significant correlations in the positive way between NRS-2002 scores and age (r=0.537, p<0.001), APACHE2 score (r=0.250, p=0.001), blood creatinine levels (r=0.255, p=0.001) and CRP levels (r=0.356, p<0.001). When the whole group is considered: there was no correlation between NRS-2002 scores and hospitalization duration (r=0.117, p=0.129). In order to estimate the power of NRS-2002, APACHE2, Glasgow coma scoring and CRP as predictors of intensive care unit mortality area under curve (AUC) was used for ROC analyses. (Figure 1) (Table 2).
Med Science 2019;8(2):263-7
Patients with sepsis 26 of 51 septic patients were died while 25 of them discharged from intensive care unit. The mean NRS-2002 score in survivals was 5.0±0.89, while it was 4.36±0.91 in non-survival septic patients. The difference between these two values was statistically significant (p=0.014). In patients with sepsis there was a moderate, statistically significant correlation on positive way between the age of the patients and the NRS-2002 scores (r=0.504, p<0.001). In patients with sepsis there was not statistically significant correlation between the length of hospital stay and the NRS-2002 scores (r=-0.037, p=0.798). In patients with sepsis there was a mild, statistically significant correlation on positive direction between blood glucose level and NRS-2002 scores (r=0.288, p=0.049). Patients with chronic kidney disease Forty-four patients were diagnosed as chronic kidney disease (CKD). Twenty-one of them were died and 23 of patients discharged. The mean NRS-2002 score was 4.22±0.74 in discharged patients while the value was 4.90±0.70 in non-survivals with CFD. The difference between these two means was statistically significant (p=0.003). In patients with CKD there was a strong, statistically significant correlation on positive direction between the ages of the patients and the NRS-2002 scores (r=0.701, p<0.001). In patients with CKD there was a moderate, statistically significant correlation on positive way between serum CRP levels and the NRS-2002 scores (r=0.484, p<0.049).
Figure 1. In order to estimate the power of NRS-2002, APACHE2, GCS and serum CRP as predictors of intensive care unit mortality area under curves (AUC) were used for ROC analyses Table 2. Area under curves for NRS-2002, APACHE2 scores, Glasgow Coma Scores and Serum CRP for predicting mortality in patients admitted to internal medicine intensive care unit Variables
AUC
p
NRS-2002
0.728
APACHE2 score Glasgow Coma score CRP
95% Confidence Interval Lover
Upper
<0.001
0.640
0.815
0.630
0.011
0.537
0.723
0.359
0.006
0.267
0.451
0.628
0.012
0.535
0.720
Patients with cancer There were 32 patients with cancer. Twenty-two of these patients were died in intensive care unit, while 10 of them could be discharged. The mean NRS-2002 score in survivors was 4.8±0.78 while it was 4.5±0.80 in non-survivals. The difference between these two means was not statistically significant (p=0.332). In cancer patients there was a moderate, statistically significant correlation on the negative direction between the length of hospital stay and the NRS-2002 scores (r=-0.495, p=0.019). In cancer patients there was a moderate, statistically significant correlation on positive direction between the age of the patients and the NRS2002 scores (r=0.426, p=0.048).
Patients with mechanical ventilation necessity There were 54 patients who needed mechanical ventilation. 35 of these patients had mortality while 19 of them discharged from intensive care unit. The mean NRS-2002 score was 4.58±0.77 in discharged patients while the value was 4.74±0.89 in nonsurvival patients. The difference between these two values was not statistically significant (p=0.500). In patients with mechanically ventilated there was a moderate, statistically significant correlation on positive way between the ages of the patients and the NRS2002 scores (r=0.672, p<0.001). In patients with mechanically ventilated there was a mild, statistically significant correlation on negative direction between serum albumin levels and the NRS2002 scores (r=-0.336, p=0.033). Discussion Malnutrition affects a significant proportion of hospitalized patients and is associated with increased hospital mortality and morbidity [14]. The efforts of the discovery of new laboratory/ clinical parameters that may predict mortality in the intensive care unit are still maintain their importance. A series of scoring systems have been proposed for predicting mortality. Glasgow coma scale and APACHE2 models are the best known of these systems. In addition, many parameters have been studied in some special patient groups in intensive care units [15-17]. The aim of the present study was to compare the certain outcomes such as mortality and hospital stay of intensive care patients with NRS-2002. The mean NRS-2002 score of whole group was 4.28±0.90. The mean NRS-2002 score was 3.98±0.80 in discharged patients, while it was 4.71±0.86 in patients with mortality. When all patients were taken into account, the NRS-2002 scores on the day of admission were significantly higher in patients resulted with mortality compared to those discharged. The NRS-2002 scores 265
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were generally associated with hospital mortality and morbidity when the literature was reviewed [14,18].
of malnutrition. For this reason, the statistical significance to be obtained can be interpreted as valuable.
Patients were also examined in terms of specific disease groups. In this context, the mortality status of cancer patients did not seem to be related to the NRS-2002 scores. The mean NRS-2002 score in surviving patients was 4.80±0.79, whereas in cancer patients resulted with death it was 4.50±0.80. However, there was a significant correlation between the NRS-2002 scores of cancer patients and the age (positive direction) and hospitalization duration (negative direction). In the accumulated literature, the NRS-2002 score was reported to be associated with increased mortality and morbidity in hospitalized cancer patients (in ICU or not) [19,20].
Limitations 1-The fact that the diseases are not homogenously distributed among the groups and additionally disease stages are not standardized could affect the results.
Similarly, patients with chronic kidney disease were examined. The difference between groups was statistically significant in terms of mortality. Forty-four patients had chronic kidney disease. 21 of these patients had mortality while 23 of them discharged. The mean NRS-2002 score was 4.22±0.74 in discharged patients while the mean NRS-2002 score was 4.90±0.70 in mortal chronic kidney disease patients. Also in chronic kidney disease patients there were statistically significant correlations between NRS-2002 scores and age of patients and serum CRP levels. Rather than randomized controlled trials working the mortality relation of NRS-2002 scores of patients with chronic kidney disease in intensive care unit, studies in nephrology services were more intense and in these studies NRS-2002 scores were associated with mortality and morbidity [21,22]. The number of sepsis patients in the group was 51. 26 of these patients were mortal while 25 of patients discharged from intensive care unit. The mean NRS-2002 score in discharged patients was 5.0±0.89, whereas in septic patients with mortality this value was 4.36±0.91.The difference between this two values was statistically significant. There was no correlation between NRS-2002 scores and hospitalization length. However, NRS-2002 scores showed a statistically significant correlation with both the blood glucose level and the mean age of the patients. In previous studies, there were associations between NRS-2002 and sepsis mortality or hospitalization [13]. It is known that the nutritional support of the patient after admission is related to the outcome of the patients in the intensive care unit and hospitalization time [23]. In our study this was confirmed by another method. Patient entry values were taken and disease states were examined separately. There should be no escape from the fact that the diseases are not distributed homogeneously among the groups. For example, a 10 day hospitalized stomach perforation and a septic patient who died within 2 days affected the homogeneity of hospitalization time. Patients with a gastric perforation and a low NRS-2002 score may stay longer for the treatment of the primary pathology, but in severe cases this may be different and the duration of hospitalization may be shorter. Another factor was the length of hospitalizations was relatively short. Patients’ progress in non-ICU clinics may be more predictable. Associating malnutrition scores with length of stay in these patients may be associated with more predictable outcomes [21]. It would not be wrong to think that patients in intensive care units are more likely to be close to death. In other words, it is not uncommon for patients to die from other causes without experiencing the consequences
2-Retrospective design may have affected the standard feature of NRS-2002 evaluations. Conclusion Malnutrition is a factor that negatively affects the mortality, morbidity and hospitalization length of patients in intensive care units. It was once again shown that the NRS-2002 scores calculated for patients in Internal medicine-ICU admission is an important predictor of mortality and hospitalization time, in terms of total and disease groups. There was a significant correlation between the NRS-2002 scores of cancer patients and the age (positive direction) and hospitalization duration (negative direction). The mean NRS-2002 score in septic patients with mortality was significantly higher than discharged septic patients’. Also in chronic kidney disease patients there were statistically significant correlations between NRS-2002 scores and age of patients and serum CRP levels. Competing interests The authors declare that they have no competing interest Financial Disclosure The authors declared that this study has received no financial support Ethical approval Before the study, permissions were obtained from local ethical committee Deniz Avci ORCID: 0000-0001-9220-194X Ali Cetinkaya ORCID: 0000-0001-8485-0982 Yekta Gulunay ORCID: 0000-0002-9341-4776 Sadik Oluk ORCID: 0000-0001-5837-7706 Abdullah Eyvaz ORCID: 000-0001-6911-299X
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16. Cetinkaya A, Erden A, Avci D, et al. Is hypertriglyceridemia a prognostic factor in sepsis? Ther Clin Risk Manag. 2014;10:147-50. 17. Fuhrmann V, Kneidinger N, Herkner H. et al. Impact of hypoxic hepatitis on mortality in the intensive care unit. Intensive Care Med. 2011;37:1302-10. 18. Masopust J, Kratochvíl J, Martínková V, et al. The relation between nutritional risk category identified by the modified Nutritional Screening 2002 and mortality in metabolic intensive care unit. Vnitr Lek. 2008;54:817-20. 19. Planas M, Álvarez-Hernández J, León-Sanz M, Celaya-Pérez S, et al. Prevalence of hospital malnutrition in cancer patients: a sub-analysis of the PREDyCES® study. Support Care Cancer. 2016;24:429-35. 20. Schwegler I, von Holzen A, Gutzwiller JP, et al. Nutritional risk is a clinical predictor of postoperative mortality and morbidity in surgery for colorectal cancer. Br J Surg. 2010;97:92-7.
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ORIGINAL RESEARCH
Medicine Science International Medical Journal
Medicine Science 2019;8(2):268-73
Is childhood trauma a predictive factor for increased preoperative anxiety levels? Ayse Vahapoglu1, Suna Medin Nacar2, Yagmur Suadiye Dalgic3 Hande Gungor1 SBÜ Gaziosmanpaşa Taksim Research and Training Hospital Clinic of Anesthesia and Reanimasyon, Istanbul, Turkey 2 Istanbul Occupational Diseases Hospital Clinic of Psychiatry, Istanbul, Turkey 3 SBÜ Gaziosmanpaşa Taksim Research and Training Hospital Clinic of Psychiatry, Istanbul, Turkey
1
Received 15 September 2018; Accepted 03 October 2018 Available online 13.11.2018 with doi:10.5455/medscience.2018.07.8928 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract Childhood trauma is a well-known source of lifelong anxiety and various personality disorders. Also preoperative anxiety is related with perioperative physical and physicological responses. The aim of this study was to investigate possible relationship –which has not been studied yet- between having a childhood trauma history and preoperative anxiety levels. A total of 190 patients (aged between 18-65) with a history of childhood trauma presenting for different types of surgery were investigated prospectively using the Childhood Trauma Questionnaire (CTQ). A childhood trauma questionnaire total score of ≥35 points was accepted as an indicator of significant childhood trauma history. Preoperative and postoperative anxiety levels of patients were assessed using State Trait Anxiety Inventory (STAI). Also relationship between childhood trauma types (physical, emotional neglect/abuse, sexual abuse) and pre-postoperative State Trait Anxiety Inventory levels were evaluated. Correlations between several factors that might effect preoperative anxiety levels including such as; gender, type of surgery, type of anesthesia, educational and maritial levels of patients with or without a childhood trauma history were investigated. We found significant correlations between higher Childhood Trauma Questionnaire scores and increased preoperative State Trait Anxiety Inventory trait and state scores (p<0.05). Female gender, lower educational level, major surgery, general anesthesia were significantly associated with higher preoperative anxiety levels in patients with childhood trauma history. Having a childhood trauma history is closely related with increased preoperative anxiety levels in patients undergoing surgical procedures. Keywords: Preoperative anxiety, childhood trauma, childhood trauma questionnaire, state trait anxiety inventory
Introduction Anxiety can be described as a feeling which is unpleasant, uncomfortable and difficult to deal with that emerges from various types of stress [1]. Independent from the source of anxiety, sympathetic, parasympathetic and endocrine system activation results in several hemodynamical responses such as hypertension, tachycardia, sweating and tachypnea [1]. It is well known that many patients scheduled for surgery manifest different degrees of anxiety during preoperative period [2,3]. Several factors may affect the degree of preoperative anxiety levels. Age and gender of patient, type of surgery, education level of patient, surgical history of patient and patient’s personal susceptibility to anxious conditions are important factors that determine level of preoperative anxiety [4,5]. Different studies conducted in various surgical patients reported different preoperative anxiety with incidence ranging *Coresponding Author: Ayse Vahapoglurkey, SBÜ Gaziosmanpaşa Taksim Research and Training Hospital Clinic of Anesthesia and Reanimasyon, Istanbul, Turkey E-mail: aysevahapoglu@yahoo.com
between 60%-92% [6,7]. Female gender, lower education level, bein a non-smoker or divorced were found in relation with higher preoperative anxiety levels [8,9]. Undergoing elective surgery, possibility of surgery being postponed, harmful mistakes done by doctor or other caregivers, fear of being unable to awakening from general anesthesia, awareness during surgery and high levels of postoperative pain were reported as important reasons for preoperative anxiety [10,11]. Uncontrolled preoperative anxiety often results in delayed muscle relaxation, coughing during anesthesia induction, increased doses of anesthetics and analgesics include narcotics, rapidly changing hemodynamical responses to anesthetics and surgical stimuli, postoperative increased pain, nausea vomiting and delayed recovery [12,13]. Childhood trauma is a wide description of different types of trauma exposure including emotional and physicial neglect, emotional and physicial abuse and sexual abuse. Previous studies revealed close relationship between childhood trauma and impaired emotion regulation, behavioral instability and developmental lack of healthy personality [14,15]. Also childhood traumatic events commonly 268
doi: 10.5455/medscience.2018.07.8928
lead to psychiatric disorders, increased suicide risk, depressive disorders, obsessions, decreased quality of life, engagement in high risk behaviors and anxious personality [14,16-19]. Data regarding child sexual abuse is a good example for ongoing effects of childhood trauma in adulthood which was shown that 26%32% of adult onset disorders (depressive disorders, high levels of anxiety, drug addiction) were closely related with childhood sexual abusement [20,21] .
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the person independent from the situation and environment that surround the person. Turkish version of STAI is validated and accepted as a reliable tool for patients as its true for original version of instrument [25,26].
We hypothesized that childhood trauma – a triggering factor for anxious personality/ high levels of anxiety- might lead to higher preoperative anxiety levels measured by STAI-state and STAItrait scores. So we aimed to investigate possible relationship between childhood trauma and preoperative anxiety levels in patients undergoing different types of surgery. Also we measured effects of several factors include age, gender, educational level, working status, type of anesthesia and surgery on preoperative and postoperative anxiety levels in conjunction with having a history of childhood trauma.
Statistical Analysis The statistical package SPSS 22.0 for Windows (SPSS, Chicago, IL) was used for statistical analyses. Descriptive statistics of numerical variables were expressed as mean ±standard deviation where categorical variables were expressed as numbers and percentage. Correlations between categorical variables were evaluated using Pearson X2 test or Fisher-Freeman-Halton Exact test. Pearson correlation analyses was used in order to evaluate continuous variables. Independent Sample t-test and One Way ANOVA were used in order to compare intergroup mean values of numerical variables. Two-Way Repeated Measures ANOVA test was used to compare preoperative and postoperative STAI values. For all statistical analysis, a p value <0.05 was accepted as significant.
Material and Methods
Results
The study was conducted in Gaziosmanpaşa Taksim Education and Research Hospital Anesthesiology and Reanimation Clinic in a period of three month after obtaining ethical commitee approval of the hospital, using Childhood Trauma Questionnaire and Spielbergs Situation-Trait Anxiety Inventory tools were filled on the day before operation by 190 patients who filled out the written informed consent before being a participant of study. At postoperative 8th hour, all patients filled STAI forms again. A blinded psychiathrist to patients’ personal features and other variables that investigated during study, evaluated CTQ and STAT scores. Inclusion criteria were patients with age18-65, ASA I-II, having sufficient mental and educational level for adequately filling the questionnaries who underwent surgical interventions under general or regional anesthesia. Exclusion criteria were patients younger than 18 or older than 65 years, unable to speak Turkish language, with known psychiatric diseases or any advanced neurological problem that might limit properly filling of questionnaries, patients underwent emergency surgery, being pregnant, blind and/or deaf patients.
A total of 190 patients were enrolled in the study whose mean age was 39,8 ±13.02 years (ranged between 18 to 65). 76 female (40%) and 114 male (60%) patients data was investigated. 141 patients (74.21%) were classified as ASA I where 49 patients (25.79%) patients were classified as ASA II. Majority of patients (63.68%) were primary school graduates while the proportion of university graduates was 13.68%. 58 patients (30.52%) were housewifes, 57 patients (30%) were self-employed. Majority of patients (73.68%) were married.
The Childhood Trauma Questionnaire The 28-item Childhood Trauma Questionnaire (CTQ) is a selffilled questionnaire that asseses abuse and neglect maltreatments quantitatively using 28 different questions. There are five subscores derived from either sexual, physical, emotional abuse, emotional and physical neglect in addition to total score which is the sum of subscores. Validity and reliability of CTQ have been documented [22,23] also Turkish version of the questionnaire was accepted as valid and reliable with a cutoff value ≥35 for total CTQ scores which indicates significant history of childhood trauma [24]. State-Trait Anxiety Inventory Spielberg’s State Trait Anxiety Inventory is a commonly used and validated self report instrument that measures anxiety depending on personal features (trait anxiety inventory) and anxiety depending on changing environmental events (state anxiety inventory). State anxiety inventory is used to determine feelings –anxiety- of a person in a special situation and environment. On the other hand trait anxiety inventory is used to determine feelings –anxiety- of
Preoperative and postoperative mean STAI scores, CTQ subscores and total CTQ scores were demonstrated in Table 1. Table 1. Preoperative and postoperative mean STAI scores, CTQ subscores and total CTQ scores of all patients. Mean ± SS
Min - Max
Preoperative STAI-State
38.38 ± 10.18
20 - 66
Preoperative STAI-Trait
42.18 ± 7.61
22 - 64
Postoperative STAI-State
38.00 ± 11.21
20 - 72
Postoperative STAI-Trait
40.83 ± 7.47
21 - 59
Physical neglect
10.14 ± 2.10
6 - 19
Emotional neglect
10.04 ± 4.27
5 - 25
Physical abuse
5.85 ± 2.49
5 - 24
Emotional Abuse
6.52 ± 2.74
5 - 23
Sexual Abuse
5.27 ± 1.20
5 - 17
Total CTQ Score
37.82 ± 9.54
29 - 102
Trauma subscores and total CTQ scores for evaluated patients were shown in Table 2. 269
doi: 10.5455/medscience.2018.07.8928
n (%) 186 (97.9)
Emotional neglect>12
43 (22.6)
Physical abuse >5
36 (18.9)
Emotional abuse>7
44 (23.2)
Sexual abuse>5
17 (8.9)
Total CTQ Score>35
91 (47.9)
We accepted a CTQ cutoff value of ≥35 according to study conducted by Sar et al. [24] The CTQ cut off values were physical neglect ≥7, emotional neglect ≥12, physical abuse ≥5, emotional abuse ≥7 and sexual abuse ≥5 (Cutoff score for Total score ≥35). We found positive correlation between higher CTQ total score and preoperative STAI-State and STAI-Trait scores and postoperative STAI-Trait scores (Table 3). Also positive correlations were found between CTQ subscores and STAI scores (Table 4). Table 3. Correlations between CTQ scores and STAI scores Preop. STAI-State
Preop. STAI-Trait
Postop STAI-State
Postop STAI-Trait
Physical neglect
R
0.061
0.106
-0.065
0.031
P
0.405
0.145
0.374
0.669
Emotional neglect
R
0.121
0.196
0.044
0.151
P
0.096
0.007
0.550
0.038
Physical Abuse
R
0.134
0.167
0.017
0.094
P
0.065
0.021
0.819
0.199
Emotional Abuse
R
0.173
0.220
0.007
0.182
P
0.017
0.002
0.927
0.012
R
0.111
0.154
0.006
0.106
P
0.126
0.034
0.936
0.146
R
0.166
0.237
0.007
0.164
p
0.022
0.001
0.924
0.024
Sexual Abuse CTQ Total Score
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Physically abused female patients had higher preoperative and postoperative STAI-Trait scores. Emotionally abused female patients had higher preoperative and postoperative STAI-Trait scores where higher preoperative STAI-State scores were found in emotionally abused male patients (p<0.05). Sexually abused male patients had higher preoperative STAI-State and Trait scores (p=0.030 and 0.006 respectively). Also postoperative STAI-Trait scores were higher in this group (p=0.050). Female patients with a total CTQ score ≥35 stated higher preop and postoperative STAI-Trait scores where preoperative STAI-State scores were higher in male patients (p<0.05).
Table 2. Trauma subscores and total CTQ scores of patients
Physical neglect >7
We found that both of preoperative STAI-trait scores in CTQ<35 and CTQ≥35 groups were significantly higher than postoperative STAI-trait scores (p=0.002). On the other hand, preoperative and postoperative STAI-trait scores found in CTQ≥35 group were significantly higher than those found in CTQ<35 group (p<0.05). Table 4. Pre and postoperative STAI scores in groups created using CTQ cutoff value of ≥35 CTQ<35 (n=99)
CTQ ≥35 (n=91)
p
Preop. STAI-state
37.03±9.81
39.85±10.43
>0.05
Postop. STAI-state
37.60±10.36
38.44±12.10
>0.05
Preop. STAI-trait
40.42±7.63
44.10±7.14
<0.05
Postop. STAI-trait
39.62±7.40
42.15±7.35
<0.05
We analysed correlations between gender and CTQ subscores and total CTQ scores. We found significantly higher preoperative STAI-Trait scores in physically neglected female patients (p=0.026). Preoperative STAI-Trait scores were significantly higher in emotionally neglected male patients (p=0.014).
Correlations were investigated between type of anesthesia (general versus regional anesthesia) and CTQ scores. We found that emotionally neglected or physically abused patients who were operated under general anesthesia had significantly higher preoperative STAI-Trait scores (p=0.036 and 0.038 respectively). Emotionally abused patients who were operated under general anesthesia had higher preoperative and postoperative STAIState scores (p=0.012 and 0.038 respectively). In terms of CTQ total scores, general anesthesia was found to have a positive correlation with increased preoperative and p ostoperative STAITrait scores. We examined possible correlations between type of surgery (major or minor) and trauma subscores and total CTQ scores. We found that major surgery was strongly correlated with increased STAI scores in patients with a history of physical neglect, emotional neglect, physical abuse and emotional abuse (p=0.016, 0.001, 0.012 and 0.009 respectively). Minor surgery was correlated higher preoperative and postoperative STAI-Trait scores in patients with a history of sexual abuse (p=0.001 and 0.006 respectively). Also major surgery was found in correlation with increased preoperative STAI-state and postoperaitve STAItrait scores (p=0.017 and 0.010 respectively). We evaluated the correlations between CTQ subscores STAI scores and educational level of patients. We found significantly lower preoperative and postoperative STAI-Trait scores in university graduated patients (p=0.005 and 0.002 respectively). Also trauma scores including physical and emotional neglect, physical and emotional abuse and total CTQ scores of university graduates were significantly lower than those measured in other patiens (p<0.05). In another analysis, correlation between CTQ and STAI scores and occupational status of patients were investigated. We found that housewifes reported higher scores in all STAI scores (p<0.05). On the other hand there was no significant differences of CTQ scores in all occupation types (p>0.05). We compared marital status of patients in terms of CTQ subscores, STAI scores. We couldn’t find any significant difference between single patients and married patients in terms of CTQ and STAI scores (p>0.05). Also there was no significant difference between ASA I and ASA II patients in terms of CTQ subscores, STAI scores (p>0.05). Finally, we compared STAI scores of patients with or without 270
doi: 10.5455/medscience.2018.07.8928
any relatives during perioperative period and found lower preoperative and postoperative STAI-State scores in patients without any relatives during perioperative period (p=0.026 and 0.002 respectively). Discussion In this study we found significant correlation between higher CTQ scores and preoperative STAI scores –both Trait and State- which indicates close relationship between having a history of childhood trauma and increased prepoperative anxiety. STAI is a very commonly used, validated with high reliability inventory that measures levels of anxiety. It has two categories -trait and state anxiety which trait anxiety is closely related with feature of personality (an anxious personality) where state anxiety indicates the level of the anxiety at the time of assessment [4]. We used this inventory because of advantage of two way measurement regarding trait and state anxiety levels which are good indicators of showing anxious personality and preoperative anxiety [27,28]. There are many environmental and personal factors that influence and trigger preoperative anxiety. Fear of death, being in an unfamiliar condition, feeling vulnerable, feeling of loss of control, extent of surgery (major surgeries like coronary artery bypass surgery etc), fear of awareness during operation, postoperative pain, female gender, low educational level are prominent factors that influence prepoperative anxiety [4,11,28]. Also without a previous history of surgery, younger or middle ages, non-smokers, being divorced are other factors might have effects on preoperative anxiety [9,29]. There are large number of studies investigating preoperative anxiety provoking factors however –to the best of our knowledge- there is no study investigating possible correlation between childhood traumas and preoperative anxiety. Childhood trauma is closely associated with inception, severity and course of anxiety disorders [30-32]. Physical, emotional neglect, abuse, sexual abuse are important types of childhood trauma which can result in adulthood anxiety, depression, personality disorders and other psychopathologic diseases [33,34]. Although exact pathways that provoke anxiety are not clear, cognitive-behavioral approach suggests threat and danger in childhood as triggering factor for anxiety [35]. Impaired hypothalamo pituitary axis (HPA) and corticotropin releasing factor (CRF) stress systems following biological effect of trauma have been shown [30]. As a consequence increased stress sensitivity leads to decreased threshold which provoke anxiety [30]. In this context our findings those indicating positive correlation between an anxious personality with higher STAI scores and having childhood trauma history indicated by higher CTQ scores become more important. Beyond total CTQ score, we evaluated correlation between each of childhood trauma questionnaire subscores and STAI scores. Preoperative STAI-state scores were higher in only emotionally abused patients where preoperative STAI-trait scores were higher in all childhood trauma types except physical neglect (Table 3). As mentioned above, STAI-trait inventory investigates anxious personality and the correlation between high preoperative STAItrait scores and childhood trauma types is evidence of prolonged effect of childhood trauma in adulthood. Generally childhood physical and sexual abuse are accepted as primary causative
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factors for various psychological disorders include depression, substance dependency, dissociation, anxiety disorders however there is accumulating data indicating important role of emotional abuse on psychological disorders [36-38]. Similarly Huh et al.[30] showed effects of different types of childhood abuse and neglect on depression, state-trate anxiety and anxiety sensitivity. The authors reported significant correlations between emotional abuse, neglect and sexual abuse and interpersonal problems in adulthood [30]. They concluded that co-occurence of emotional and physical trauma –not only physical trauma- lead more to severe trait anxiety and state anxiety. In line with previous studies we showed that emotional abuse is the only trauma type that correlates with increased preoperative STAI-state scores. Many previous studies showed that females had higher preoperative STAI-trait and state scores than males [39-41]. In contrast there are several studies unable to show any correlation between gender and preoperative anxiety. In this manner we evaluated correlation between gender and preoperative anxiety in patients with history of childhood trauma. We found significantly higher preoperative STAI-trait scores in emotionally neglected female patients in addition to higher pre and postoperative STAI-trait scores in physically abused females. On the other hand emotionally neglected male patients had higher preoperative STAI-trait scores and sexually abused males had higher preoperative STAI-state scores. Also female patients with a CTQ total score of ≥35 had higher preop and postoperative STAI-trait scores where male patients with a CTQ total score of ≥35 had higher preoperative STAI-state scores. Type of anesthesia (either general or regional) is another important factor for preoperative anxiety [42,43]. Also awareness during surgery is a well documented triggering factor for anxiety [4]. In the present study we evaluated correlation between type of anesthesia, STAI scores and childhood trauma questionnaire sub- and total scores. We found significantly higher preoperative STAI-trait scores in patient having history of emotional neglect or physically abuse who underwent surgery under general anesthesia. Also pre- and postoperative STAI-state scores of patients having history of emotional abuse who underwent surgery under general anesthesia were significantly higher than those measured in other group. Finally we showed positive correlation between general anesthesia and increased pre and postoperative STAI-trait scores in patient with a CTQ score≥35. These findings indicate that general anesthesia has more powerful effect than regional anesthesia in terms of provoking preoperative anxiety in patients with history of childhood trauma. Major surgery is a well known anxiety increasing factor [39] and we investigated association between type of surgery and STAI scores in patients with history of childhood trauma. We found that major surgery (debulking surgery, hip replacement, whipple surgery etc) was strongly correlated with increased STAI scores in patients with a history of physical or emotional neglect, physical or emotional abuse. Also patients with a CTQ score≥35 had significantly increased preoperative STAI-state and postoperative STAI-trait scores. Positive correlation between lower educational level and preoperative anxiety was shown in previous studies [44-46]. Low education level is related with insufficient accurate information 271
doi: 10.5455/medscience.2018.07.8928
about possible risks of interventions, decreased consciousness level which help to cope with anxious situations [44]. In the present study we found lower pre- and postoperative STAI-trait scores in patients graduated from university. Additionally, physical or emotional neglect, physical or emotional abuse and total CTQ scores of university graduated patients were found significantly lower than others. Similarly when we evaluated correlation between occupational status and STAI scores, we found significantly higher STAI scores in patients who were housewifes. Although we did not make any additional analysis to determine the relationship between being a housewife and having a low education level, previous studies considered being a housewife as an anxiety triggering factor [44]. In line with previous studies we suggest that this finding of study is in correlation with findings that showed positive correlation between low educational level and increased STAI scores. When we compared CTQ sub- and total scores, STAI scores and marital status of patients, we couldn’t find any significant difference between these two groups. However Nigussie et al. [4] reported – independent from childhood trauma history of patients- that being divorced was significantly related with higher preoperative anxiety, also the authors considered being single as an anxiety promoting factor. Interestingly when we compared CTQ sub- and total scores, STAI scores of patients with or without any relatives during perioperative period, there was no significant difference in terms of CTQ scores however we found lower pre and postoperative STAI-state scores in patients without any relatives. This finding is in contrast with previous study results that indicate higher preoperative anxiety levels in single patients than with relatives/family/friends [44]. Several studies showed positive correlations between anesthetists’ preoperative visit and anxiety reduction [1,47,48]. Fitzgerald et al. [49] reported over 40% reduction of patients anxiety levels following anesthetists visit. An attempt to inform patients about diagnosis, treatment, surgery, anesthesia type, risks of interventions and important features of perioperative care may help reducing preoperative anxiety. Although preoperative anesthetist visit of all patients was performed on the day before surgery during our study, we did not evaluate its effect on patients and this seems a shortcoming of our study. Limitations CTQ and STAI are widely used and validated tools however using these tools can sometimes provide inaccurate information because of self-report design of them. Especially patients with a history of childhood trauma which may lead a traumatic memory might have given inaccurate or insufficient responses to questions. Conclusion In conclusion we suggest that the present study indicates important relationship between having a childhood trauma history and preoperative (also postoperative) anxiety. Findings of the study have to be supported by future larger scaled studies and after sufficient accumulation of scientific data, any type of childhood trauma may be accepted as a preoperative anxiety promoting factor that will be managed by multidisiplinary attempts.
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Competing interests The authors declare that they have no competing interest Financial Disclosure The financial support for this study was provided by the investigators themselves. Ethical approval Our study was approved by the local ethics review board. Ayse Vahapoglu ORCID:0000-0002-6105-4809 Suna Medin Nacar ORCID: 0000-0003-4426-1862 Yagmur Suadiye Dalgic ORCID: 0000-0001-9094-8513 Hande Gungor ORCID: 0000-0002-8920-1516
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McMurray A, Johnson P, Wallis M, et al. General surgical patients’ perspectives of the adequacy and appropriateness of discharge planning to facilitate health decision‐making at home. J Clin Nurs. 2007;16:1602-9.
10. Ebirim L, Tobin M. Factors responsible for pre-operative anxiety ın elective surgical patients at a university teaching hospital: A pilot study. Internet J Anesthesiol. 2010;29:2. 11. Masood Z, Haider J, Jawaid M, et al. Preoperative anxiety in female patients: the issue needs to be addressed. Khyber Med Univ J. 2009;1:38-41. 12. Pokharel K, Bhattarai B, Tripathi M, et al. Nepalese patients anxiety and concerns before surgery. J Clin Anesth. 2011;23:372-8. 13. Fauza A K, Shazia N. Assessment of pre operative anxiety in patients for elective surgery. J Anaesthesiol Clin Pharmacol. 2007;23:259-62. 14. Evren C. Cinar O. Evren B, et al. The mediator roles of trat anxiety, hostility, and impulsivity in the association between childhood trauma and dissociation in male substance-dependent inpatients. Compr Psychiatry. 2013;54:158-66. 15. Shipman K, Edwards A, Brown A, et al. Managing motion in a maltreating context: a pilot study examining child neglect. Child Abuse Negl. 2005;29:1015-29. 16. Hovens JG, Giltay EJ, Wiersma JE, et al. Impact of childhood life events and trauma on the course of depressive and anxiety disorders. Acta Psychiatr Scand, 2012. 17. Briere J. The long-term clinical correlates of childhood sexual victimization. Ann N Y Acad Sci. 1988;528:327-34. 18. Beitchman JH, Zucker KJ, Hood JE, et al. A review of the longterm effects of child sexual abuse. Child Abuse Negl. 1992;16:101-18. 19. Widom CS, Kuhns JB. Childhood victimization and subsequent risk for promiscuity, prostitution, and teenage pregnancy: a prospective study. Am J Public Health. 1996;86:1607-12.
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2013;74:991-8. 36. Schaefer I, Reininghaus U, Langeland W, et al. Dissociative symptoms in alcohol dependent patients: associations with childhood trauma and substance abuse characteristics. Compr Psychiatry. 2007;48:539-45. 37. Schäfer I, Langeland W, Hissbach J, et al. TRAUMAB-Study group. Childhood trauma and dissociation in patients with alcohol dependence, drug dependence, or both—a multi-center study. Drug Alcohol Depend. 2010;109:84-9. 38. Evren C, Ustunsoy S, Cakmak D. Dissociative symptoms among alcohol and substance dependents and its relationship with childhood trauma history, depression, anxiety, and alcohol/substance use. Anatol J Psychiatry. 2003;4:30-7. 39. Ramesh B, Nayak S, Pai VB, et al. Pre-operative anxiety in patiens undergoing coronary artery bypass graft surgery-A cross sectional study. Int J Africa Nursing Sci. 2017;7:31-6. 40. Gallagher R, McKinley S. Anxiety, depression and perceived control in patients having coronary artery bypass grafts. J Adv Nurs. 2009;65:238696. 41. Tung HH, Hunter A, Wei J, et al. Gender differences in coping and anxiety in patients after coronary artery bypass graft surgery in Taiwan. Heart Lung. 2009;38:469-79. 42. Maheshwari D, Ismail S. Preoperative anxiety in patients selecting either general or regional anesthesia for elective cesarean section. J Anaesthesiol Clin Pharmacol. 2015;31:196-200. 43. Papanikolaou MN, Voulgari A, Lykouras L, et al. Psychological factors influencing the surgical patients’ consent to regional anaesthesia Acta Anaesthesiol Scand. 1994;38:607-11. 44. Ay AA, Ulucanlar H, Ay A, et al. Risk factors for perioperative anxiety in laparoscopic surgery. JSLS. 2014;18:e2014.00159. 45. Moerman N, van Dam FS, Muller MJ, et al. The amsterdam preoperative anxiety and information scale (APAIS). Anaesth Analg. 1996;82:445-51. 46. Carr E, Brockbank K, Allen S, et al. Patterns and frequency of anxiety in women undergoing gynaecological surgery. J Clin Nurs. 2006;15:341-52.
33. Gamble SA, Talbot NL, Duberstein PR, et al. Childhood sexual abuse and depressive symptom severity: the role of neuroticism. J Nerv Ment Dis. 2006;194:382-5.
47. Hepner LD, Bader MA, Hurwitz S, et al. Patient satisfaction with preoperative assessment in a preoperative assessment testing clinic. Anesth Analg. 2004;98:1099-105.
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48. Kouki P, Matsota P, Christodoulaki K, et al. Greek surgical patients’ satisfaction related to perioperative anesthetic services in an academic institute. Patient Prefer Adherence. 2012;6:569-78.
35. Etain B, Aas M, Andreassen OA, et al. Childhood trauma is associated with severe clinical characteristics of bipolar disorders. J Clin Psychiatry.
49. Fitzgerald BM, Elder J. Will a 1-page informational handout decrease patients’ most common fears of anesthesia and surgery? J Surg Educ. 2008;65:359-63.
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ORIGINAL RESEARCH
Medicine Science International Medical Journal
Medicine Science 2019;8(2):274-6
Our experience and results of clinical incidental gallbladder carcinomas Oguz Catal, Bahri Ozer, Mustafa Sit Bolu Abant Izzet Baysal Univercity Medical Faculty, Depertmant of General Surgery, Bolu, Turkey Received 03 October 2018; Accepted 21 October 2018 Available online 2018 with doi:10.5455/medscience.2018.07.8952 Copyright Š 2019 by authors and Medicine Science Publishing Inc. Abstract This study aimed to eveluate our experience in incidental gallbladder carcinomas the effect of resection on life time .We suggest that liver resection may contribute to the disease free survival of the patients with incidental gallbladder carcinomas. Between January 2012 and December 2017, 3691 patients who underwent cholecystectomy in the Department of General Surgery of Abant Izzet Baysal University Medical Faculty and who did not consider biliary stricture in their preoperative evaluation were evaluated retrospectively.Patients were grouped according to age, sex, stone size, bile duct wall thickness and histopathological results. The preoperative diagnosis of all patients undergoing cholecystectomy was cholelithiasis. Of the 3691 patients, gallbladder cancer was detected in the evaluation of the pathology specimens of 16 patients (0.50%) of the patients who were diagnosed with gallbladder carcinomas, 12 had female gender and 4 had male gender. All of the patients were found to have adenocarcinoma when the pathology specimens were examined. In the pathology specimens, 2 patients had carcinoma insitu, 2 patients had T1, 5 patients had T2, 7 patients had T3. In this study we share our experience in incidental gallbladder carcinomas and suggest that liver resection may contribute to the disease free survival of the patients with incidental gallbladder carcinomas. Keywords: Incidental gallbladder carcinomas,gallbladder stones,liver resection,disase free survival,cholecyctectomy
Introduction Gallbladder carcinomas are rare tumors with poor prognosis. Biliary tree tumors are one of the most common cancers, and the 5th most common cancers of the gastrointestinal tract. Biliary cancer is 2-3 times more frequent in males than females, and most commonly seen in 7th decade. It is seen 0.4% in autopsy series and approximately 1% of patients who underwent cholecystectomy because of bile stone. Geographically, biliary incident cancers are more common in the USA, Mexico, Chile, Israel, Poland, India and Japan. The greatest risk factor for the development of gallbladder cancer is gallbladder stones and gallbladder stones and have been found in 95% of patients with gallbladder cancer [1]. The risk of developing cancer within 20 years in patients with biliary stones is less than 0.5% for the entire population, while it is 1.5% for the high-risk group. Although the pathogenesis is unknown, it is associated with chronic inflammation. It is associated with a 10fold increased risk of cancer in large stones > 3cm [2]. Other risk factors for gallbladder carcinoma include: female sex, obesity, *Coresponding Author: Oguz Catal, Bolu Abant Izzet Baysal Univercity Medical Faculty, Depertmant of General Surgery, Bolu, Turkey E-mail: otuzogur@hotmail.com
advanced age, porcelain gall bladder, typhus carriage, monosilent (> 10 mm) polyps, scleroderma colonitis and exposure to carcinogens. The use of laparoscopic cholecystectomy for benign biliary diseases today has dramatically increased the incidence of incidental gallbladder cancer. This also increased the rate of gallbladder cancer, which had a good prognosis when detected in early stage. After simple cholecystectomy for benign conditions, the rate of malignancy detected in the pathology specimen varies from 0.3% to 2% and often provides complementary surgical radical treatment. We aim to evaluate our clinical experience incidental gallbladder carcinomas and we evaluate the patients disase free survival after which we apply resection procedure. Material and Methods Between January 2012 and December 2017, 3691 patients who underwent cholecystectomy in the Department of General Surgery of Abant Izzet Baysal University Medical Faculty and who did not consider gallbladder cancer in their preoperative evaluation were 274
doi: 10.5455/medscience.2018.07.8952
evaluated retrospectively. Patients were grouped according to age, sex, stone size, bile duct wall thickness and histopathological results. The preoperative diagnosis of all patients undergoing cholecystectomy was cholelithiasis. Preoperative hemogram, cholestasis enzymes, ultrasonography results and pathology results of the patients were evaluated. All of the emergency and elective patients were included in the study. Ultrasonography results were classified as> 3 cm stone, 1-2 cm stone and <1 cm stone size according to stone dimensions. Again, the biliary tree was classified as having wall thickness> 3 mm and wall thickness <3 mm according to wall thickness. Examination of the specimens used according to TNM staging of AJCC in cancer stage. The contribution of T wall invasion to survival and life time of liver resection was evaluated in cases with gallbladder cancer. Results Of the 3691 patients with cholecystectomy who were evaluated retrospectively, 1022 were men gender and 2669 were women. The mean age of the patients was 54.86 (range 19-92)Of the 3691 patients, gallbladder cancer was detected in the evaluation of the pathology specimens of 16 patients (0.50%). The mean age of this group was 61.5 (50-86), which was significantly higher than the mean age of the remaining group (table 1). Of the patients who were diagnosed with gallbladder carcinomas, 12 had female gender and 4 had male gender (table 1). All of the patients were found to have adenocarcinoma when the pathology specimens were examined. In the pathology specimens, 2 patients had carcinoma insitu, 2 patients had T1, 5 patients had T2, 7 patients had T3 (table 1). Eleven patients were electively treated (Table 1), while 5 of the 16 patients who were incidentally diagnosed with gallbladder stone pathology specimens were treated with acute cholecystitis. Of these 16 patients, 2 were operated on before ERCP and stent was inserted. Patients who underwent cholecystectomy due to the presence of stone at the gallbladder when two of 16 patients were opposed to colon cancer and concomitant gallbladder carcinomas. When the degrees of differentiation in the pathology specimens of patients with incidental gallbladder stones cancer were examined, it was found that 6 had good differentiation, 4 had moderate differentiation, and 6 had worse differentiation (table 1). In our study, the thickness of the gallbladder wall was found to be 3 mm or less in 4 patients, whereas it was seen that the thickness of the wall was 4 mm or more in 12 patients. The size of stones were larger than 30mm in 10 patients and 30mm or smaller in 6 patients (table 1). A lymph node dissection was performed with resection of liver tumor segment 4B and 5 with T2 tumor. The number of patients with T3 is 7. Four patients did not accept resection after cholecystectomy. We performed liver resection 7 of 12 patients with t2 and t3 cancer. One patient was unable to be performed liver resection due to cardiac and pulmoner problems who underwent cholecystectomy performed during advanced colon cancer surgery Two patients underwent segment 4,5,8 resection and lymph node dissection.
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One patient who underwent resection in T2 was treated for 5 years, 1 patient for 4 years, 1 patient for 2 years and 1 patients for disease free survival for one year. 1 patient who underwent resection of T3 complained of peritoneal carcinomatosis and liver metastases after completing 3 year disease-free survival period and deceased at 4th year of follow up. The other two patients with T3 disease were completed their 1.5 and 1 year disease-free survival. Table 1. Demographic and pathological distributions of incidental gallbladder cancer Age â&#x2030;Ľ60 years
13
81.25%
<60 years
3
18.75%
Women (n)
12
75.00%
Men (n)
4
25.00%
â&#x2030;¤3
5
31.25%
>3
11
68.75%
<3
6
37.50%
>3
10
62.50%
Elective
11
68.75%
Emergent
5
31.25%
worse
6
37.50%
moderate
4
25.00%
good
6
37.50%
Tis
2
12.50%
T1
2
12.50%
T2
5
31.25%
T3
7
43.75%
Yes
7
58.33%
No
5
41.67%
Gender
Wall thickness (mm)
Stone size (cm)
Elective /Emergent Surgery
Differentiation
T Stage
Resection
Discussion Most of the gallbladder carcinomas are unresectable at the time of diagnosis. Due to their aggressive attitudes, the 5 year life span is below 5% and the median life span is about 6 months [3]. Clinical signs and symptoms in gallbladder carcinomas are similar to those of cholelithiasis and cholecystitis. More than half of gallbladder cancer can not be diagnosed preoperatively. Diagnosis is made by examination of the specimens of patients who have benign diseases, for example gallbladder stones, polyps, etc., by the most common diagnostic pathologists [4,5]. The high rate of use of ultrasonography and the worldwide progress of laparoscopic cholecystectomy as a widespread surgical procedure are expected to increase the number of incidentally found gallbladder cancer over time [6,7]. The main goal of treatment in gallbladder carcinomas is surgical resection of the intended R0 without leaving the residual tissue behind. Patients undergoing resection in gallbladder carcinomas have also shown that the 5-year survey rate 275
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ranges from 0-100%. This change is strongly related to the stage of the patient. Simple colecystectomy is sufficient for carcinoma in situ and T1a cases [5,8,9]. Resection (radical cholecystectomy with regional lymph node dissection) should be performed in the patient group of T1b and over in order to perform resection of R0 [8,10]. Our patient found incidence of incidental gallbladder carcinomas 0.5%, which was 0.19% -2.8% in literature [11,12]. In our study, the mean age of the benign patient group who were operated on for gallbladder stones was 54.86 (range 19-92), whereas the mean age of the patients with incidental gallbladder cancer was 61.50 (range 50-86) it is seen that there is a further age group. The gender distribution of gallbladder cancer is three times higher in females than in males [13]. In our study, it was observed that 12 of the 16 patients were female and 4 were male, and the ratio was 3: 1. Concerning the stone size and number of incidentally detected gallbladder cancers, it was found to be a risk factor for gallbladder cancer, which is a multiple stone in stone and gallstones over 3 cm in previous studies [13,14]. In our study, 16 preliminary ultrasonographic findings of incidentally detected gallbladder cancer patients were found to have a stone size of> 3 cm in 10 gallbladder stones and multiple gallbladder stones in all patients except one. Patients with pathologic end-stage carcinoma in situ in patients with gallbladder cancer and those with T1 results do not require additional treatment for cholecystectomy and 5-year survival is 90-100% in this patient group. Similar results were obtained in our patient series. More than simple cholecystectomy is needed in T2 cancers. Segment 4B and segment 5 resection is the appropriate treatment approach, as the resection of the liver bed adjacent to the biliary tree at a depth of 2 cm is acceptable. In addition, regional lymphadenectomy is needed. When T2 cancer cases are treated with radical cholecystectomy, the 5-year survival rate is 80-90%. Our patient underwent lymphadenectomy with segment 4B and 5 resection in our series and we obtained a similar survival result. In patients without resection, the survey is between 6 and 8 months. In the last decade in patients with T3 cancer, most centers have reported that aggressive surgery provides 25-50% longer survival in locally advanced disease. In our study, 1 patient who underwent resection of T3 complained of peritoneal carcinomatosis and liver metastases after completing 3 year disease-free survival period and deceased at 4th year of follow up. The other two patients with T3 disease were completed their 1.5 and 1 year disease-free survival. When the pathologies of patients after resection were evaluated, lymph node metastasis was reported in 1 patient of 7 resected patients, while the lymph node pathologies of other patients were reactive. Conclusion In conclusion, we suggest that liver resection may contribute to
Med Science 2019;8(2):274-6
the disease free survival of the patients with incidental gallbladder carcinomas. Competing interests The authors declare that they have no competing interest Financial Disclosure The financial support for this study was provided by the investigators themselves. Ethical approval Bolu Abant Izzet Baysal Education and Reserch Ethics commite accept our study in 05.01.2018 and 00060010850 serial number Oguz Catal ORCID: 0000-0002-4067-251X Bahri Ozer ORCID: 0000-0002-4326-2101 Mustafa Sit ORCID: 0000-0002-7475-7298
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Serra I, Calvo A, Baez S, et al. Risk factors for gallbladder cancer. An international collaborative case control study. Cancer Cancer. 1996;78:15157.
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Lowenfels AB, Walker AM, Althaus DP, et al. Gallstone growth, size and risk of gallbladder cancer: An interracial study. Int J Epidemiol. 1998;18:50-4.
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Noshiro H, Chijiiwa K, Yamaguchi K, et al. Factors affecting surgical outcome for gallbladder carcinoma. Hepatogastroenterology. 2003;50:939-44.
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Shih SP, Schulick RD, Cameron JL, et al. Gallbladder cancer: the role of laparoscopy and radical resection, Ann Surg. 2007;245:893-901.
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Fuks D, Regimbeau JM, Le Treut YP, et al. Incidental gallbladder cancer by the AFC-GBC-2009 Study Group, World J Surg. 2011;35:1887-97.
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Jensen EH, Abraham A, Habermann EB, et al. A critical analysis of the surgical management of earlystage gallbladder cancer in the United States, J Gastrointest Surg. 2009;13:722-7.
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de Aretxabala XA, Roa IS, Mora JP, et al. Wanebo, Laparoscopic cholecystectomy: its effect on the prognosis of patients with gallbladder cancer. World J Surg. 2004;28:544-7.
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Pawlik TM, Gleisner AL, Vigano L, et al. Capussotti, Incidence of finding residual disease for incidental gallbladder carcinoma: implications for reresection, J Gastrointest Surg. 2007;11:1478-86.
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Shimizu H, Kimura F, Yoshidome H, et al. Aggressive surgical approach for stage IV gallbladder carcinoma based on Japanese Society of Biliary Surgery classification. J Hepatobiliary Pancreat Surg. 2007;14:358-65.
10. Yagi H, Shimazu M, Kawachi S, et al. Retrospective analysis of outcome in 63 gallbladder carcinoma patients after radical resection. J Hepatobiliary Pancreat Surg. 2006;13:530-6. 11. Misra S, Chaturvedi A, Misra NC, et al. Carcinoma of the gallbladder. Lancet Oncol. 2003;4:167-76. 12. Tian YH, Ji X, Liu B, et al. Surgical treatment of incidental gallbladder cancer discovered during or following laparoscopic cholecystectomy. World J Surg. 2015;39:746â&#x20AC;&#x201C;52. 13. Hamdani NH, Qadri SK, Aggarwalla R, et al. Clinicopathological study of gall bladder carcinoma with special reference to gallstones: our 8- year experience from eastern India. Asian Pac J Cancer Prev. 2012;13:5613-7 14. Vitetta L, Sali A, Little P, et al. Gallstones and gall bladder carcinoma. J Surg. 2000;70:667-73.
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ORIGINAL RESEARCH
Medicine Science International Medical Journal
Medicine Science 2019;8(2):277-81
Assessment of readability level of informed consent forms used in intensive care units Munise Yildiz, Betul Kozanhan, Mahmut Sami Tutar University of Health Sciences, Konya Education and Research Hospital, Clinic of Anesthesiology and Reanimation, Konya, Turkey Received 08 October 2018; Accepted 23 October 2018 Available online 04.11.2018 with doi:10.5455/medscience.2018.07.8933 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract Informed consent forms are printed forms prepared to assist patients in the treatment process by explaining the indications, benefits and possible risks of medical practices. Readability describes understanding difficulty and is calculated by mathematical formulas. The study aimed to assess the readability level of “Informed Consent Forms” used in intensive care units. The informed consent forms from 45 hospitals in our country have been gathered. In each average form number of words, the average number of syllables and the average number of words with 4 or more syllables were manually calculated using the “Microsoft Office Excel 2016®” program. Their readability levels have been assessed with Atesman and Bezirci-Yılmaz readability formulas. The readability level of forms was “difficult” according to the Atesman readability formula and at “undergraduate level” according to the Bezirci-Yilmaz readability formula. The readability level of forms used in private hospitals was found to be significantly lower than that used in state and university hospitals (p=0.019, p=0.012). The average number of words and the average number of words with 4 or more syllables in forms were found to be significantly higher in private hospitals compared to state and university hospitals (p=0.004, p=0.01). It has been determined that the readability level of informed consent forms was at academic literacy level. To protect patient rights and to regulate patient-physician relationships by taking into account individuals rights, informed consent forms should be reviewed and that their readability levels should be adjusted to cover the overall educational level of individuals in the general population. Keywords: Intensive care, informed consent form, readability
Introduction Informed consent forms are printed forms containing the diagnosis of disease, the proposed treatment method and the risks of this method for the patient’s health, the use and possible side effects of medical treatments and the outcomes of disease if the proposed treatment is refused [1]. The informational obligation is a debt for the physician and a right for the patient regarding the physicianpatient relationship. Although the patient’s right to be informed is mentioned in the “Patients Rights Regulation” which has been put into force in Turkey in 1998, it is specified that the mentioned information should be clear and understandable enough and then must answer all possible questions. Before obtaining a patient’s informed consent for any medical intervention, the patient should be informed about the type, prognosis and possible side effects of the medical intervention, the outcomes of disease in case of *Coresponding Author: Munise Yildiz, University of Health Sciences, Konya Education and Research Hospital, Clinic of Anesthesiology and Reanimation, Konya, Turkey E-mail: drmunise@hotmail.com
treatment refusal [2]. However, the reliability and update of, as well as their “readability” and “understandability,” are somewhat important because the value of information is limited by the ability of individuals to comprehend. Although readability has been popular in recent years, it was based on past studies. It is a concept that provides some numerical data about texts and gives information about whether the text is easy to be understood by the reader at a certain level using characteristic features of syllables, words, and sentences of the language. Although this concept has been used mostly in inter-institutional correspondence, military organizations and healthcare companies in the past, today, it has become a concept which is used by linguistic scientists as well as other scientists and on which studies are performed frequently [3]. Besides the average number of words, the average number of syllables and the average number of words with 4 or more syllables, various criteria such as number synonym words must be placed in mathematical formulas to determine the readability level of a written text. To perform readability analysis, different formulas have been developed in Turkish as well as many foreign languages such as English and Spanish 277
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[4-7]. The Atesman and Bezirci-Yilmaz readability formulas, which have been described for determining the readability level of Turkish texts [5,6] and the Gunning-Fog and Flesch–Kincaid readability formulas, which measure the overall readability, [7,8] are commonly used readability formulas. There is a limited number of studies on informed consent forms used in intensive care units in our country. The study aimed to assess the readability level of “Informed Consent Forms” that are mandatory to be obtained regarding both legal and ethical issues before any medical intervention performed in intensive care units. Materials and Methods The study has been approved by the Education Planning Board of University of Health Sciences Konya Training and Research Hospital (Decision No: 1 March 2018/13-17). There are informed consent forms that are created according to certain standards and are routinely used in intensive care units of hospitals in our country. For the study, informed consent forms that were regularly used in intensive care units of 45 hospitals including university hospitals and training and research hospitals (n=15), state hospitals (n=15), and private hospitals (n=15) have been gathered. Each informed consent form was transferred to the “Microsoft Word 2016®” in the electronic environment. The institutional knowledge sections have been deleted to keep objectiveness of readability results. The average number of words, the average number of syllables and the average number of words with 4 or more syllables in these forms have been manually calculated using the “ Microsoft Office Excel 2016®” program. For the calculation of the readability levels of each informed consent form, using Atesman and Bezirci-Yilmaz formulas data have been transferred to a computer software program [5,6]. The rate of medical terms within these 100 words has been determined as a percentage (%). Atesman Readability Formula: It has been adapted into Turkish from Flesch’s Reading Ease Formula by Atesman (1997). It is a formula based on word and sentence length [5]. The Atesman readability formula gives a score on a scale ranging from 0–100; a higher score indicates that the text is easier to read while a lower number suggests that the text is more difficult to understand (Table 1). Atesman readability formula: Readability Score = 198.825 – 40.175 x (total number of syllables/ total number of words) – 2.610 x (total number of words/total number of sentences) Bezirci-Yilmaz Readability Formula: This formula was developed in 2010 based on the length of sentences in a text, the number of syllables in a word, and the statistical properties of Turkish language [6]. When the readability level is calculated, the number of syllables in each word is multiplied by its number. The readability level is formulated as follows: √(ANW×((H3×0,84) + (H4×1,5) + (H5×3,5) + (H6× 26,25)) ANW: average number of words H3: average number of 3-syllable words H4: average number of 4-syllable words H5: average number of 5-syllable words H6: average number of words with 6 or more syllables
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According to this formula, the readability level becomes more difficult as the length of sentences increases in texts. Moreover, an increase in the number of syllables in words makes it difficult to read words and indirectly sentences. This formula explains which class level a text represents according to the education system in our country: 1-8= primary school; 9-12= secondary school (high school); 12-16 = undergraduate level, and ˃16 = higher education. Statistical Analysis: The SPSS® 21 (IBM Inc, USA) software was used to analyze the data. Categorical data were expressed as frequency and percentage. Numerical data were expressed as a mean ± standard deviation. The One Way ANOVA and Kruskal-Wallis tests were used to compare numerical data between independent groups. All statistical analyzes have been performed bidirectionally at the 5% significance level and the 95% confidence interval. Results Informed consent forms which were used in intensive care units of 45 medical institutions in our country have been included in the study. The mean readability value of these forms according to the Atesman and Bezirci-Yilmaz readability formulas as well as the average number of words, the average number of syllables and the average number of words with 4 or more syllables in these forms are shown Table 2. The mean readability value of these forms according to the Atesman readability formula was calculated as 41.8 for university hospitals and training and research hospitals, 43.0 for state hospitals and 35.7 for private hospitals, respectively. The readability level of informed consent forms was “difficult” according to the Atesman readability formula. The readability level of informed consent forms used in private hospitals was found to be significantly lower than those of informed consent forms used in state and university hospitals (p=0.019). The mean readability value of these forms according to the Bezirci-Yilmaz readability formula was calculated as 14.9 for university hospitals and training and research hospitals, 14.4 for state hospitals and 17.7 for private hospitals, respectively. The readability level of informed consent forms was at “undergraduate level” according to the Bezirci-Yilmaz readability formula. According to the BezirciYilmaz readability formula, there was a significant difference between the mean readability values of informed consent forms used in intensive care units of university hospitals and training and research hospitals, state hospitals and private hospitals (p=0.012). The average number of words and the average number of words with 4 or more syllables in informed consent forms were found to be significantly higher in private hospitals compared to state and university hospitals (p=0.004, p=0.01). There was no significant difference between these institutions regarding the average number of syllables (p=0.361). There was no significant difference between these institutions regarding the rate of medical terms in the 100-word text. Table 1. Atesman Turkish Readability Formula Level
Readability range
Very easy
90-100
Easy
70-89
Moderate
50-69
Difficult
30-49
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Table 2. Readability Values of Informed Consent Forms Private Hospital (n=15) Mean ± SD
State Hospital (n=15) Mean ± SD
University, Training and Research Hospital (n=15) Mean ± SD
p
Atesman readability formula*
35.79 ± 6.23
43.06 ± 9.10
41.84 ± 5.21
0.016
Bezirci-Yilmaz readability formula**
17.70 ± 2.92
14.40 ± 3.77
14.99 ± 2.25
0.012
Average number of words **
16.36 ± 2.44
13.52 ± 3.24
13.76 ± 1.91
0.004
Average number of syllables*
2.99 ± 0.03
2.99 ± 0.47
3.01 ± 0.04
0.361
Average number of words with 4 or more syllables*
5.59 ± 0.77
4.59 ± 1.17
4.79 ± 0.65
0.010
*One Way Anova **Kruskal-Wallis test
Discussion This study is the first study to analyze the readability level of written informed consent forms routinely used in intensive care units in our country. According to Atesman classification, it was found that the readability level of informed consent forms prepared for intensive care units was “difficult.” According to Bezirci classification, the readability level of written informed consent forms routinely used in intensive care units in our country, it was found “undergraduate level.” Intensive care units are one of the hospital departments where many emergency interventions are performed in the presence of life-threatening and critical illnesses, where physicians and other healthcare professionals often have to make urgent decisions. It is complicated to get consent before medical interventions due to the nature of the job and generally there is not enough time. However, as in other hospital departments in intensive care units, it is necessary to inform the patient about the possible complications that can occur during medical practice and request approval for this procedure. Ethically, the patient’s understanding of the proposed medical treatment is essential for the patient to make a conscious decision. In Patient Rights Regulation, it is stated that the patient himself/herself is the direct interlocutor of being informed and exceptional cases are addressed for children, saying that “if the patient is small and has a limited or absent power of judgment, his/ her parent or guardian may request” [1]. It is clearly stated that if the patient does not have the capacity to make a decision about the medical intervention to be performed due to a disease or a similar reason, this intervention can be performed with consent obtained from his/her representative or the competent authority, person, or institution determined by a law [9]. Since most of the patients in intensive care units are unconscious and do not have the capacity to make a decision, it is not possible to get informed consent directly from the patient himself/herself. Therefore, indirect approval is mentioned if the patient is unable to give permission. Informed consent, permission granted in full knowledge of the possible consequences, typically given by a doctor for treatment with knowledge of the potential risks and benefits. However, insufficiently understanding of this informed consent and thereby the medical intervention may lead to significant legal and ethical consequences. Although this is the first study that analyzed the readability level of written informed consent forms routinely used in intensive care units in our country, the readability level of informed consent forms used in various hospital departments
had been previously reported. Hancı et al. analyzed the readability level of anesthesia informed consent forms and reported that the readability levels of anesthesia consent forms used in university hospitals were “very low” according to the Atesman readability formula [4]. They also showed that the readability level of anesthesia consent forms used in training and research hospitals and state hospital were “low” according to the Atesman readability formula [4]. In another study evaluating informed consent forms which are routinely used for open, endoscopic, and laparoscopic urological surgery, it was reported that the readability level of all consent forms was “moderately difficult” according to the Atesman readability formula[10]. The same forms were at ‘’high school level’’ according to the Bezirci-Yilmaz readability formula [10]. In a study assessing the readability index of informed consent forms used for contrast materials, it was found to be at ‘’educational level above undergraduate’’ according to the SMOG readability formula [11]. Similar to these studies, we found that the readability level of informed consent forms prepared for intensive care units was “difficult” according to the Atesman readability formula and at “undergraduate level” according to the Bezirci-Yilmaz readability formula. Today, many different formulas have been described to calculate readability level. However, each language has its unique word and sentence structures. Since Turkish is an agglutinative language, the number of letters and syllables in words can be high. Therefore, a meaning which is described with a word in Turkish can sometimes be explained with a sentence in another language [12]. Hence, the use of formulas which are used for texts in a foreign language but are not defined for our language may lead to unhealthy and improper outcomes [13]. For these reasons, instead of formulas such as FLESCH and SMOG, which are frequently used in readability analyzes in the literature, the readability formulas developed for the Turkish language were preferred in our study. Determination of the educational level by analyzing the readability level of a written text may give an idea about the understandability of that text. Klare has described readability as that all linguistic features in the text are more or less acceptable to the reader and has specified that readability is a factor that affects the performance of the reader [14]. According to Atesman, there are some differences between readability and understandability. While the content of the text is significant in understandability readability based on the fact that the written text is easy or difficult to read for individuals [6]. According to the results of this study, we found that the readability level of informed consent forms used in intensive care units in our country was “difficult.” However, we did not assess 279
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the understandability level of these forms by healthcare recipients. In a study, that was conducted to determine the attitudes of patients in informed consent practices and to identify the problems experienced in this process in 2014, it has been found that only 34% of the participants read the entire consent form and, 55.7% of participants have not understood the forms. [15]. It can be assumed that the level of understandability of informed consent forms may be low when it is taken into account that the levels of readability according to our findings require training at “undergraduate level” according to the education system in our country. If individuals receiving health care have a lower educational level than the readability level of informed consent forms, a “readability gap” can be mentioned. This means that patients or their legal representatives cannot fully understand medical procedures [16]. Studies have found that there is a relationship between the overall educational level and comprehension level. ‘’Health literacy’’ is defined as the ability to obtain, read, understand, and use healthcare information to make appropriate health decisions and follow instructions for treatment. It has been found that the average duration of education in the US is 12.6 years and that approximately 40% of the population have inadequate health literacy. For this reason, written health materials recommended to be arranged according to the sixth grade level of education or below to maximize the understandability level of the content of medical consent forms [17]. According to the data from the Turkish Statistical Institute (TUIK, 2016), 5% of individuals aged 25 years and over in Turkey are illiterate, but 16% were university graduates [18]. In a study conducted in 2014, it was determined that the general health literacy index of Turkey was 30.4 and that 64.6% of the adult population of Turkey was in insufficient health literacy categories [19]. Problematic health literacy leads to the fact that individuals have less information about their illnesses and treatments, are more exposed to medical malpractice and have difficulties in reaching healthcare services. Informed consent forms should be reviewed to protect patient rights and to regulate patient-physician relationships by taking into account patient rights. Their readability levels should be adjusted to cover the overall educational level of individuals in the general population (six years of education or below). Patients with the lowest educational level are included in this way. Several suggestions for an adequate understanding of the informed consent forms by the readers are; limiting medical words, choosing words with three or fewer syllables if possible, using short and simple sentences and dividing the paragraphs if necessary. In this study, informed consent forms which were routinely used in intensive care units of 45 hospitals (including university hospitals and training and research hospitals, state hospitals, and private hospitals) in Turkey were assessed. Therefore, the results of our study are difficult to reflect the general status of our country directly. It will be more appropriate to give information about the general situation in our country with further extensive studies.
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units in our country. According to Atesman classification, it was found that the readability level of informed consent forms prepared for intensive care units was “difficult.” According to Bezirci classification, the readability level of written informed consent forms routinely used in intensive care units in our country, it was found “undergraduate level.” As a result, it has been found that the readability level of informed consent forms used in intensive care units is “difficult,” which is an important step in the protection of patient rights and the prevention of legal problems in the practice of health. The readability level of “Informed Consent Forms” that are mandatory to be obtained regarding both legal and ethical issues before medical interventions should be restructured with the cooperation of active associations and institutions in accordance with the proposed strategies. Competing interests The authors declare that they have no competing interest Financial Disclosure The financial support for this study was provided by the investigators themselves. Ethical approval The study was approved by the Education Planning Board of University of Health Sciences Konya Training and Research Hospital (Decision No: 1 March 2018/1317). Munise Yildiz ORCID: 0000-0003-2644-7540 Betul Kozanhan ORCID: 0000-0002-5097-9291 Mahmut Sami Tutar ORCID: 0000-0002-5709-6504
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11. Ören E, Eren CS, Yeşildere FB, et al. Informed consent of contrast media applications in radiology: assesment of comprehensibility and the anxiety of the patients. TERH. 2010;20:122-30.
This study is the first study to analyze the readability level of written informed consent forms routinely used in intensive care
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ORIGINAL RESEARCH
Medicine Science International Medical Journal
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The contribution of implantable cardioverter defibrillators to systemic inflammation in heart failure patients Ozcan Orscelik, Bugra Ozkan, Mert Koray Ozcan Mersin University Medical Faculty, Department of Cardiology, Mersin, Turkey Received 03 October 2018; Accepted 03 October 2018 Available online 28.12.2018 with doi:10.5455/medscience.2018.07.8951 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract Heart failure (HF) is associated with an increased ‘inflammatory burden’, which is manifested by the elevation of serum levels of some inflammatory mediators such C-reactive protein (CRP), cytokines. In addition, high levels of inflammatory markers in patients with HF have been associated with poor outcomes. Lethal ventricular arrhythmias such as asystole and ventricular fibrillation-tachycardia are common in patients with HF and implantable cardioverter defibrillators (ICDs) are effective in preventing these situations. But like every foreign object in the body, ICDs also cause fibrosis and inflammation. This study aimed to show additional contribution of ICDs to systemic inflammation in patients with HF. This is a single centrer retrospective study included 140 HF patients with and without ICD (group 1 and 2) and 53 healty control subjects (group 3). Three groups were compared with regard to Hs-CRP and Neutrophil / Lymphocyte ratio (NL ratio). In order that acute inflammation did not affect the results, the earliest 6th month laboratory measures after ICD implantation were recorded. There are not significant difference between all groups in terms of age and gender, and among group 1 and 2 in terms of disease history, ejection fraction, heart rate and creatinine. When compared to the three groups according to Hs-CRP and NL ratio, there was a significant difference between the groups (both p<0.001). Hs-CRP levels and NL ratio was high in the group 1(ICD group) than group 2 but it was not significantly. Hs-CRP levels and NL ratio were significantly negative correlated with ejection fraction. CRP and NL that are inflammatory markers were higher in patients with HF. Likewise as every foreign object in the body, ICDs also cause fibrosis and inflammation but in our study, we showed that this additional inflammation was not statistically significant. Keywords: Systemic inflammation, implantable cardioverter defibrillators, heart failure
Introduction Heart failure (HF) affected over 23 million people in the world is a major health problem. HF is a clinical syndrome accompanied by typical signs and symptoms that develop as a result of structural and/or functional defects [1]. It is expected that the result of aging the world population, the prevalence of heart failure will increase. Heart failure is associated with an increased ‘inflammatory burden’, which is manifested by the elevation of serum levels of some inflammatory mediators such C-reactive protein (CRP), cytokines [2]. Previous studies have shown that the neutrophil/ lymphocyte (NL) ratio is as a marker of systemic inflammation. Additionally, there was seen that High NL ratio has associated with cardiovascular mortality [3]. Because of ventricular arrhythmias, bradycardia and asystole, sudden and unexpected deaths are common in patients with heart *Coresponding Author: Ozcan Orscelik Mersin University Medical Faculty, Department of Cardiology, Mersin, Turkey E-mail: ozcanorscelik@yahoo.com
failure, especially with mild symptoms. Current medical treatments for HF improve or delay the progression of cardiovascular disease, and reduce the annual rate of sudden death. Nevertheless, the effects on lifetime risk of sudden death are more limited and in case occur ventricular arrhythmia, these drugs will not treat it. Implanted cardioverter defibrillators (ICDs) are very effective to correction of the lethal ventricular arrhythmias and ICD implantation is recommended by current guidelines in secondary prevention of ventricular arrhythmias and primary prevention in heart failure patients with reduced ejection fraction (HFrEF) [4]. But like every foreign object in the body, ICDs also cause fibrosis and inflammation [5]. ICD and pace maker leads extend from the vena cava superior to the right ventricular apex. After the implantation process, an inflammatory reaction that will last for years takes place around the entire lead and generator, and these foreign bodies are surrounded with a fibrous capsule [5]. In a previous study, it was found that there was a significant increase in the number of leukocytes after the implantation of ICD or pace maker [6]. 282
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There is no study showing that the contribution of ICDs to systemic inflammation in heart failure patients. This study aimed to show additional contribution of ICDs to systemic inflammation in patients with HF. Material and Methods In this study, the patients who admitted to our cardiology clinic between from 2015 to 2017 were retrospectively screened. Patients with left ventricular ejection fraction (LVEF) <50% on transthoracic echocardiography (TTE) and healthy subjects without any disease were included in the study. Patients that younger than 18 years and older than 90 years and have history of active infection, surgery for any reason, chronic obstructive lung disease, rheumatic disease, severe hepatic dysfunction, stage 4-5 chronic kidney disease were excluded from the study. Similarly, patients with myocardial infarction (MI), percutaneous coronary angioplasty and coronary artery grafting until 6 months before admitted date of clinic were not included. Subjects were divided into 3 groups as heart failure patients with (group 1) and without (group 2) ICD and control group (group 3). All patients had VVI or DDD ICD and in all of them, the procedure had been performed in right or left pectoral area with local anesthesia. Haemogram, biochemistry and CRP values were recorded from the hospital digital registry system. In order that acute inflammation did not affect the results, the earliest 6th month laboratory measures after ICD implantation were recorded (group 1). Haemogram and biochemical analyses had been done with the Sysmex XN-1000 (Sysmex America, Inc. Lincolnshire, IL, USA) and Roche Cobas C501 (Roche Diagnostics GmbH, Penzberg, Germany) devices. Neutrophil to lymphocyte ratio (NLR) was
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calculated by formula the neutrophil/the lymphocyte count. C reactive protein was measured on routine autoanalysis (Cobas c501, Roche, Manheim, Germany) with high sensitive kit. In this study, we investigated that whether there is difference in terms of inflammatory parameters between three groups. Our study was approved by the clinical research ethics committee (11.01.2018 and 2018/05). Statistical analyses were performed using a 64-bit Windows version of SPSS (version 21.0, Statistical Package for Windows, Chicago, Illinois). Continuous variables were analysed for normal distribution by the Kolmogorov-Smirnov test. We reported continuous data as mean and standard deviation. Categorical variables were summarized as percentages, frequencies and compared with the X2 test. We compared parametric variables using the Student’s t test, non-parametric variables using MannWhitney U. One-way ANOVA and Dunnett’s test were used to compare group means. For determine to association between variables, Pearson correlation analysis were used. Analysis results were evaluated within a 95% confidence interval and p<0.05 was interpreted as a statistically significant difference. Results Demographic, echocardiographic and laboratory characteristics of the patient groups and the control group are shown in table 1. There were no differences between the groups in age, gender, triglyceride, or AST (p>0.05). Similarly, between heart failure patients with and without ICD (group 1 vs 2), there were no significant differences in terms of ejection fraction, diabetes mellitus, coronary artery disease, or hypertension (p>0.005) (Table 1).
Table 1. Demographic, echocardiographic and laboratory characteristics of patients and control subjects Group 1 (ICD+HF patients) n=70
Group 2 (HF patients) n=70
Control Group n= 53
p
64.4 ± 11.1
65.4 ± 11.2
61.1 ± 7.1
0.057
57/13
49/21
37/16
0.214β
Diabetes mellitus
30, % 42.9
31, % 44.3
-
0.865β
Hypertension
45, % 64.3
47, % 67.1
-
0.722β
Coronary artery disease
50, % 71.4
52, % 74.3
-
0.704β
Ejection fraction, %
32 ± 8.7
34.1 ± 9.0
-
Heart rate, beat/min
79.8 ± 15.6
82.1 ± 10.5
73.2 ± 13.2
Fasting LDL cholesterol, mg/dL
99.9 ± 36.2
Fasting triglyceride, mg/dL
Age, year Gender, M/F Disease history:
0.16 ¥,π
0.002
113.5 ± 41.2
¥
127.2 ± 34.8
0.001
161.6 ± 89.4
146.7 ± 59.5
142.7 ± 61.9
0.296
Creatinine, mg/dL
1.20 ± 0.8
1.25 ± 0.8
0.81 ± 0.13
AST, U/L
24.5 ± 16.1
21.9 ± 8.4
24.4 ± 7.2
Hemoglobin, g/dL
12.7 ± 1.9
12.6 ±1.9
14.7 ± 1.
Hs-CRP, mg/L
8.5 ± 6.9
6.8 ± 4.4
2.2 ± 0.7
<0.001*
Neutrophil / Lymphocyte ratio
4.46 ± 3.5
3.5 ± 2.8
2.1 ± 0.8
<0.001*
¥, π
3¥, π ¥,π ¥,π
<0.001* 0.343 <0.001
* Analyzed with Kruskal-Wallis Analyzed with chi-square ¥ p < 0.05 Group 1 vs control subjects πp< 0.05 Group 2 vs control subjects β
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When heart rate and LDL cholesterol values were examined, it was seen that there was a significant difference between the three groups (p=0.002; 0.001 respectively). In subgroup analyses, heart rate was lower in healthy subjects than other two groups. Additionally, in terms of heart rate, group 1 and 2 were similar. When sub-analysis was performed in terms of LDL values, it was determined that the significance was caused by the difference between groups 1 and 3 (Table 1).
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and 2 (Table 1). Similarly, in terms of inflammatory parameters which we investigated Hs-CRP and NLR in this study, Levels of the parameters were significantly different between three groups (p<0.001) and we found that this condition emerging from difference of group 3 and other groups (Table 1). Correlation analyzes of inflammatory markers with important variables for heart failure are given in table 2. We demonstrated a negative and significate correlation between Hs-CRP and ejection fraction (r= -0.329, p<0.001). Likewise, there were seen that NLR correlated with ejection fraction and creatinine (r= 0.324, p<0.001, r=-0.245 p= 0.003 respectively) (Table 2, Figure 1).
It was found that there was a significant difference between the groups respect to creatinine and heamoglobin (p <0.001 for both). In subgroup analysis, for both parameters, group 3 was significantly different from both group 1 and group 2. But not between group 1 Table 2. Correlation analysis between inflammatory markers and major parameters. Age, year
Creatinine, mg/dL
Ejection fraction, %
Hemoglobin, g/dL
r
p
r
p
r
p
r
p
Hs-CRP
-0.142
0.094
0.073
0.394
-0.329
<0.001
-0.120
0.158
NL ratio
0.081
0.343
0.324
<0.001
-0.245
0.003
-0.147
0.084
Analyzed with Spearman correlation test
Figure 1. The correlation curves between ejection fraction and Hs-CRP and NL ratio
Discussion The results of our study showed a significant increase in inflammatory parameters in HF patients as compared to controls. Additionally, these parameters in the patients with ICD was a little higher than in patients without ICD, although the difference was not significant. HF is a clinical syndrome associated with typical signs and symptoms resulting from structural and/or functional cardiac diseases [1]. HF with reduced EF, HF with preserved EF and HF with mid-range EF was considered as EF <40%, ≥50% and 4049% respectively according to 2016 ESC Heart Failure Guidelines [4]. Although hypertension, cardiac valvular diseases, and cardiomyopathy may cause to HF, ischemic heart disease is the underlying etiology in most cases. While HF is already associated
with an increased risk of morbidity and mortality, nearly 60% of the patients with ischemic heart failure die from arrhythmias such as ventricular tachycardia, bradycardia, or asystole [7]. Although some antiarrhytmic drugs may decrease deaths associated with tachy-arrhytmia in these patients, a reduction in all-cause mortality could not be shown. In these patients, ICDs may be implanted for primary and secondary prevention of sudden cardiac death. ICD implantation for reduce to risk of sudden cardiac death and all-cause mortality has been recommended in subjects with recovered from a ventricular arrhythmia [4]. Similarly, An ICD is recommended in patients with symptomatic HF, and an LVEF ≤35% despite ≥3 months of optimal medical treatment (OMT), provided they are expected to survive substantially longer than one year with good functional status [4]. Even if the above criteria are met, it is not recommended since the absence of a proven benefit of ICD implantation within 40 days after acute MI [8]. 284
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The neutrophil/lymphocyte (NL) ratio has been utilized as an inflammatory marker for several cardiac and non-cardiac diseases, and has been used for prognostic estimations in a number of diseases including acute myocardial infarction (MI), stroke, or heart failure [9,10]. Also, poor prognosis in heart failure was shown to be associated with elevated levels of Hs-CRP, which is another inflammatory marker [11]. Furthermore, statin treatment has been found to suppress the increased cardiovascular risk associated with inflammation (Hs-CRP) [12]. Patients with congestive HF has been known to have elevated levels of inflammatory mediators. CRP is an acute phase reactant and a non-specific inflammation marker primarily produced by hepatoyctes [13]. Previous studies have clearly established that HF patients have elevated levels of CRP as compared to controls [14]. In our study, in accordance with previous data, HF patients with or without ICD had higher Hs-CRP than controls. Once again, neutrophil/lymphocyte ratio, which is considered a marker of systemic inflammation, was higher in both groups as compared to healthy controls. However, although HF patients with ICD had higher Hs-CRP and NL than those without ICD, the difference was statistically insignificant. Despite the underlying mechanisms responsible for the elevated CRP in HF patients is not completely understood, it is thought that it may be due to hepatocellular injury as a result of hepatic congestion [15]. Also, CRP levels have been shown to be more markedly elevated during periods of decompensation, with return to baseline levels after failure is compensated [16]. On the other hand, the elevation in inflammatory markers due to HF is associated with poor prognosis per se. Although this was explained on the basis increased myocardial stiffness, neurohormonal activation, and immune response etc., the exact mechanisms remain unclear [2]. ICDs consists of batteries that are able to deliver shocks to the myocardium, which may lead to right ventricular injury and development of local fibrotic areas. Furthermore, the foreign body reaction due to ICD leads may also result in injury of the right ventricular apex together with areas of fibrosis [17]. Although subtle in most patients with ICDs, these may also be partially responsible for the increased inflammatory response. Even if not significant in patients with ICD, these may be responsible for the increased inflammatory response. In a study by Stumpf et al., a negative and significant correlation between CRP and LVEF was found among MI patients [18]. Again, Wojciechowska et al. found a similar correlation between LVEF and CRP. In our study, there was also a correlation between LVEF and both CRP and NL ratio, suggesting that lower ejection fraction is associated with an increased inflammatory burden [14]. Anemia is a common comorbidity in HF patients that has been shown to be associated with poor functional capacity as well as increased morbidity and mortality [19]. Anemia has been reported in up to 70% of the patients with heart failure [19]. In our study, HF patients had lower hemoglobin levels than controls, while the difference between HF patients with or without ICD was not significant. HF patients frequently have sinus tachycardia, both as a result of increased sympathetic activity and as an attempt to compensate for the reduced ventricular function. Also, tachycardia in patients with HF negatively affects the prognosis of the diseases. Patients with lower baseline heart rate or pharmaceutically reduced
Med Science 2019;8(2):282-6
hear rate are known to have better clinical outcomes [20]. In our study, while resting heart rate was similar between patients with or without ICD, both groups had significantly elevated pulse rate as compared to healthy controls. Conclusion HF patients have increased levels Hs-CRP and NL ratio, which are inflammatory markers. Furthermore, statically a significant correlation exists between these inflammatory markers and LVEF. As with every foreign body, ICDs are also caused fibrosis and inflammation, although in our study their effect on inflammatory markers was statistically insignificant. Limitations of our study Major limitations of our study include the relatively smaller sample size and its retrospective design. Also, the history of device shocks in patients with ICD was not inquired. More comprehensive studies on the subject should be planned. Competing interests The authors declare that they have no competing interest Financial Disclosure The financial support for this study was provided by the investigators themselves. Ethical approval Our study was approved by the clinical research ethics committee (11.01.2018 and 2018/05) Ozcan Orscelik ORCID:0000-0003-4349-9852 Bugra Ozkan ORCID:0000-0002-0603-4370 Mert Koray Ozcan ORCID:0000-0001-6075-753X
References 1.
Orscelik O, Ozkan B, Arslan A, et al. Relationship between intrarenal reninangiotensin activity and re-hospitalization in patients with heart failure with reduced ejection fraction. Anatol J Cardiol. 2018;19:205-12.
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Lappegard KT, Bjornstad H, Mollnes TE, et al. Effect of Cardiac resynchronization therapy on inflammation in congestive heart failure: A review. Scand J Immunol. 2015;82:191-8.
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Kocyigit I, Eroglu E, Unal A, et al. Role of neutrophil/lymphocyte ratio in prediction of disease progression in patients with stage-4 chronic kidney disease. J Nephrol. 2013;26:358-65.
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Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The task force for the diagnosis and treatment of acute and chronic heart failure of the european society of cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37:2129-200.
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Candinas R, Duru F, Schneider J, et al. Postmortem analysis of encapsulation around long-term ventricular endocardial pacing leads. Mayo Clin Proc. 1999;74:120-5.
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Tompkins C, Cheng A, Brinker JA, et al. Significance of leukocytosis after cardiac device implantation. Am J Cardiol. 2013;111:1608-12.
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Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American college of cardiology foundation/American heart association task force on practice guidelines. J Am Coll Cardiol. 2013;62:147-239.
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Hohnloser SH, Kuck KH, Dorian P, et al. Prophylactic use of an implantable cardioverter-defibrillator after acute myocardial infarction. N Engl J Med. 2004;351:2481-8.
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Brancati FL, Whittle JC, Whelton PK, et al. The excess incidence of diabetic end-stage renal disease among blacks. A population-based study of potential
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doi: 10.5455/medscience.2018.07.8951 explanatory factors. JAMA. 1992;268:3079-84. 10. Rudiger A, Burckhardt OA, Harpes P, et al. The relative lymphocyte count on hospital admission is a risk factor for long-term mortality in patients with acute heart failure. Am J Emerg Med. 2006;24:451-4. 11. Ridker PM, Paynter NP, Rifai N, et al. C-reactive protein and parental history improve global cardiovascular risk prediction: the Reynolds Risk Score for men. Circulation. 2008;118(22):2243-51, 4p following 51. 12. Verma A, Lavie CJ, Milani RV. C-Reactive Protein: How Has JUPITER Impacted Clinical Practice? Ochsner J. 2009;9:204-10. 13. Norata GD, Marchesi P, Pulakazhi Venu VK, et al. Deficiency of the long pentraxin PTX3 promotes vascular inflammation and atherosclerosis. Circulation. 2009;120:699-708. 14. Wojciechowska C, Romuk E, Tomasik A, et al. Oxidative stress markers and C-reactive protein are related to severity of heart failure in patients with dilated cardiomyopathy. Mediators Inflamm. 2014;2014:147040.
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15. Pye M, Rae AP, Cobbe SM. Study of serum C-reactive protein concentration in cardiac failure. Br Heart J. 1990;63:228-30. 16. Sato Y, Takatsu Y, Kataoka K, et al. Serial circulating concentrations of C-reactive protein, interleukin (IL)-4, and IL-6 in patients with acute left heart decompensation. Clin Cardiol. 1999;22:811-3. 17. Cevik C, Perez-Verdia A, Nugent K. Implantable cardioverter defibrillators and their role in heart failure progression. Europace. 2009;11:710-5. 18. Stumpf C, Sheriff A, Zimmermann S, et al. C-reactive protein levels predict systolic heart failure and outcome in patients with first ST-elevation myocardial infarction treated with coronary angioplasty. Arch Med Sci. 2017;13:1086-93. 19. Anand IS. Anemia and chronic heart failure implications and treatment options. J Am Coll Cardiol. 2008;52:501-11. 20. Vazir A, Claggett B, Jhund P, et al. Prognostic importance of temporal changes in resting heart rate in heart failure patients: an analysis of the CHARM program. Eur Heart J. 2015;36:669-75.
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ORIGINAL RESEARCH
Medicine Science International Medical Journal
Medicine Science 2019;8(2):287-90
An investigation of speech sounds of patients applied to orthodontics clinic Guzin Bilgin Buyuknacar1, Aysegul Gulec2 1 Private Practice, 56006 no’lu Sk. No:4/4, Gaziantep, Turkey Gaziantep University, Dentistry Faculty, Department of Orthodontics, Gaziantep, Turkey
2
Received 18 July 2018; Accepted 23 October 2018 Available online 19.12.2018 with doi:10.5455/medscience.2018.07.8938 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract The aim of this study is to determine the sound characteristics of speech sounds of patients applied to orthodontics clinic to understand how speech will be affected after orthodontic treatment. The study included 60 patients (35 females, 25 males; 13.60±2.35 years) Fricatives (/f/, /s/, /ş/) were selected for spectral center of gravity analysis. Sounds were examined under four groups: syllable-initial, syllable-final, /a/ context and /i/ context. The Shapiro Wilk test and Mann-Whitney U-test, were used for statistical evaluations. There was a statistically significant difference between syllable-initial and syllable-final measurements of /f/ sound (p=0.008). There was a significant effect of gender in all groups of /s/ sound and syllable-initial group of /ş/ sound (p<0.05). In conclusion, vowel environments and different positions within a word can affect the center of gravity of fricatives. Keywords: Speech sounds, speech acoustics, orthodontics
Introduction Speech, consists of sounds coming into play through the interaction of articulator and phonetic systems, is the most commonly used form of communication [1]. Speech sounds are formed at the speech articulation stage generated through breathing, phonation, resonance and articulation and dynamic movement of the tongue, lips, and teeth, resulting in partial or complete closure of the airway. Among the causes of speech disorders are articulation disorders, which accounts for 50%- 60% of cases [2]. Speech sounds are divided into two categories, vowels and consonants. There are about 200 different vowels and more than 600 consonant voices in languages used by the communities [3]. While the consonants are produced, the airstream is interrupted, either partially or completely in the vocal tract. In contrast, while the vowels are produced, the airstream is unobstructed in any way [4]. Spoken language, structural characteristics of language, characteristics of sounds in the language, speech characteristics of person, structural status of the vocal tract and sound quality can change the acoustic characteristics of voices. Thus, it is possible
*Coresponding Author: Guzin Bilgin Buyuknacar, Private Practice, 56006 no’lu Sk. No:4/4, Gaziantep, Turkey, E-mail: guzinbilgin@hotmail.com
to determine the acoustical properties of the sound system [5]. In many acoustic studies, spectral moment measurements were used for analyzing fricatives [6-9]. Also, it is stated that the spectral center of gravity values, one of the spectral moments, has a descriptive attribute [6,7]. It is quite important to determine and know the sound characteristics of spoken language. If the language features are unknown, it will not be possible to predict which differences may lead to language and speech problems. Nowadays computer-aided sound analysis programs are more preferred in sound analysis studies because they are objective, convenient, and repeatable. In this study, computer-aided sound analysis programs were used to determine the acoustic properties of Turkish fricatives (/f/, /s/, /ş/) and investigated whether the spectral center of gravity values differed according to vowel environment and syllable position. Material and Methods G*Power software version 3.1.2 (Franz Faul, Kiel University, Kiel, Germany) was used to determine the number of individuals to be included in the study. We determined that a total of 60 patients would be sufficient for a study with a significance level of 0.05, the statistical power of 0.80 and an impact size of 0.83. Our study included 60 patients (35 female, 25 male, 13.60 ± 2.35 years) who applied to the Orthodontics Department of Gaziantep 287
doi: 10.5455/medscience.2018.07.8938
University Dentistry Faculty. Included patients were native Turkish speakers, and they had no speech or hearing problems. Exclusion criteria were having hearing loss or ear pathology, having a respiratory or neurologic disease and having congenital anomalies such as cleft lip and palate or those linked to the stomatognathic system. Approval was received from Gaziantep University Clinical Trials Ethics Committee for our study with decision no. 2016/322 dated 28/12/2016. Informed consent was obtained in writing from each patient and their guardians.
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The compliance of the data with normal distribution was tested with the Shapiro Wilk test, and the Mann Whitney U test was used in the comparison of the characteristics without normal distribution in 2 independent groups. The consistency between measurements taken at different intervals was tested with the intraclass correlation coefficient. SPSS for Windows version 22.0 software package was used for statistical analyses and p< 0.05 was considered statistically significant. Twenty sound recordings were randomly selected and reassessed by the same investigator (GBB) to rule out any measurement error. The consistency between measurements was tested with the intraclass correlation coefficient. The coefficients of reliability varied from 0.86 to 0.99. The results showed that the repeated measurements were reproducible and reliable.
The sound recording procedure was performed in a soundproof dedicated sound recording room with acoustic insulation and a noise level of less than 30 dB. For this purpose, a desktop computer with an external sound card and a condenser microphone positioned 10 cm away from the patient were used. Using the Audacity program (version 2.0.5, http://audacity.sourceforge.net/) for audio recording, the sounds were recorded at a sampling rate of 44100 Hz and at a 16-bit quantization level, in mono, and in “. wav” format. Fricatives (/f/, /s/, /ş/) were selected for investigation. Sounds were examined under four groups: syllable-initial, syllablefinal, /a/ context and /i/ context. The sounds were placed within a carrier sentence such as ‘Mehmet …… said’. Table 1 shows the words used in our study. In the study, 720 sound data (3 fricatives x 2 positions x 2 vowels x 60 samples) were examined. Acoustic analysis was performed using the PRAAT program (version 5.3.57 Paul Boersma; David Weenink www.praat.org). The onset and offset of the fricative segmentation were conducted based on a visual inspection of the waveform and spectrogram. The point at which high-frequency energy first appeared and/or rapid increase in zero-crossings characterized the fricative onset. The fricative offset was defined prior to the onset of the vowel periodicity and/ or absence of high-frequency energy. After segmentation, the spectral center of gravity (cog) was examined at the midpoint of the segment.
Results There was a statistically significant difference between syllableinitial and syllable-final measurements of /f/ sound (p=0.008). There were no statistically significant differences between syllableinitial and syllable-final measurements of /s/ and /ş/ sounds and different vowel environments values of all sounds (p>0.05) (Table 2). There was a significant effect of gender in all groups of /s/ sound and syllable-initial group of /ş/ sound (p<0.05) (Table 3). Table 1. List of words used in the study Fricatives /f/
/s/
/ş/
fal
saf
şak
saf
yas
kaş
fil
sim
şirk
lif
mis
diş
Table 2. Comparison of the groups in different vowel environments and different positions Syllable-initial Mean ±SD
Syllable- final Mean ±SD
p
/a/ context Mean ±SD
/i/ context Mean ±SD
p
f
5764±2855
4784±2790
0.008
5080±2954
5468±2760
0.316
s
9152±1447
8820±1551
0.117
8906±1464
9065±1550
0.362
ş
5383±909
5400±971
0.732
5391±946
5392±936
0.835
Fricatives
*Mann-Whitney U Test; p<0.05; SD: Standard deviation Table 3. Comparison of the groups between the genders Fricatives
f
s
ş
Groups
Female Mean ±SD
male Mean ±SD
p
Syllable-initial
6108±2625
5518±3003
0.338
Syllable- final
5060±2917
4585±2699
0.431
/a/ context
5498±2859
4781±3006
0.217
/i/ context
5670±2787
5323±2750
0.523
Syllable-initial
9789±1221
8259±1263
0.001
Syllable- final
9378±1396
8038±1423
0.001
/a/ context
9479±1307
8103±1292
0.001
/i/ context
9688±1340
8193±1405
0.001
Syllable-initial
5583±976
5085±717
0.004
Syllable- final
5534±1097
5211±732
0.088
/a/ context
5606±1013
5090±753
0.115
/i/ context
5510±1061
5209±694
0.082
*Mann-Whitney U Test; p<0.05; SD: Standard deviation
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doi: 10.5455/medscience.2018.07.8938
Discussion One method of determining the properties of the fricatives is to examine the spectral center of gravity. The average energy distribution from any point (beginning, middle, and end) of the fricative sound shows the spectral center of gravity value [10]. The fricative spectrum is dependent on the size of the oral cavity, and if a difference occurs in the narrowing area, a change occurs in the average distribution in the spectrum of the fricative [11]. In this study, the spectral center of gravity value of /s/ is higher than /ş/ (Table 2). There are also many studies indicated that the spectral center of gravity values of /s/ sound is higher than /ş/ sound [1214]. Sounds’ place of articulation can explain this situation. /ş/ is produced with a more posterior place of articulation than /s/ and consequently the front oral cavity is longer. For this reason, /ş/ has lower resonant frequencies. In our groups, each fricative occurred in different vowel environments and different positions within a word [15]. Therefore, this changes the speaking effort. The spectral center of gravity varies not only with front oral cavity size but also changes in speaking effort. When our groups are evaluated, the cog values in /s/ sound were found to be higher than in /ş/ and /f/ sounds. Similarly, Jongman et al. found that spectral center of gravity was highest for alveolar sounds (for our study /s/) and lowest for postalveolar sounds (/ş/). Additionally, labiodental sounds (/f/) were between them [8]. Ertan reported that /s/ sound has the highest spectral center of gravity values, followed by /ş/ sound, and /f/ sound has the lowest values [9]. The vowel environment is evaluated, and the values of the center of gravity are compared in our study. Tabain stated that any changes in articulation, due to vowel environment, are generally reflected in the spectrum [11]. Oral cavity size is dependent on the vowels. For example, if /s/ sound were produced with rounded vowels, the oral cavity size would increase, and the spectral center of gravity would lower relative to produce with unrounded vowels [16]. Nittrouer reported that the spectral center of gravity values of the front vowel /i/ is higher than the back vowel /a/ [17]. Although our study findings were not statistically significant, /i/ context values of the center of gravity were higher (Table 2). Nirgianaki evaluated acoustic properties of fricatives and reported that the spectral center of gravity values could be affected by positions of sounds [18]. Ertan investigated the effect of syllables number and position within a word on the center of gravity. She concluded that the center of gravity value was higher in single syllable and syllable-initial position. In addition, the number of syllables did not affect the spectral center of gravity [9]. In our findings, syllable position values of /f/ sound were statistically significant, and syllable-initial values were found higher. There was a main effect of gender on the spectral center of gravity values. Females have significantly higher values than males. Many researchers also indicated that the center of gravity values of females have higher values [8,12,15]. Higher frequencies in females could originate from smaller vocal tract sizes [15]. In many languages, the speech sounds were examined acoustically [8,9,14,18]. The determined features will form the basis of studies on language and speech disorders. As 80% of specific speech
Med Science 2019;8(2):287-90
movements occur at the front of the mouth, whether or not speech problems will improve after orthodontic treatment in individuals with speech impairment is an issue of curiosity for both the orthodontist and the patient [19]. It is thought that speech will be positively affected by the correction of the malocclusion. It is important to know the language features to understand how speech will be affected after orthodontic treatment. Conclusion In conclusion, the center of gravity of /f/, /s/ and /ş/ sounds can be affected by vowel environments and different positions within a word. It is important to determine the sound characteristics of spoken language to understand how speech will be affected after orthodontic treatment. Acknowledgments This study was produced from the thesis of Güzin Bilgin Büyüknacar Competing interests The authors declare that they have no competing interest Financial Disclosure The authors declared that this study has received no financial support Ethical approval Approval was received from Gaziantep University Clinical Trials Ethics Committee for our study with decision no. 2016/322 Guzin Bilgin Buyuknacar ORCID: 0000-0002-8845-1193 Aysegul Gulec ORCID: 0000-0001-8838-1546
References 1.
Jesus LMT, Araújo A, Costa IM. Speech production in two occlusal classes. Onomázein. 2014;29:129-51.
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Johnson NC, Sandy JR, Tooth position and speech—is there a relationship?. Angle Orthod. 1999;69:306-10.
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Ladefoged P. Vowels and consonants: An introduction to the sounds of languages. 1st edition. Blackwell Publishers, Oxford, 2001.
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Yavuz H, Balcı A. Turkish Phonology and Morphology (Türkçe Ses ve Biçim Bilgisi). Anadolu Üniversitesi Yayınları, Eskişehir, 2011;15-33.
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Fry DB. The physics of speech. Cambridge University Press, Cambridge, 1979.
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Forrest K, Weismer G, Milenkovic P, et al. Statistical analysis of word-initial voiceless obstruents: preliminary data. J Acoust Soc Am. 1988;84:115-23.
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Gordon M, Barthmaier P, Sands K. A cross-linguistic acoustic study of voiceless fricatives. J Int Phon Assoc. 2002;32:141-74.
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Jongman A, Wayland R, Wong S. Acoustic characteristics of English fricatives. J Acoust Soc Am. 2000;108:1252-63.
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Ertan E. Türkçe’deki Sürtünmeli Seslerin Akustik Özelliklerinin Belirlenmesi. Ph.D. thesis, Anadolu University, Eskişehir, 2011.
10. Ladefoged, P. Phonetic data analysis: An introduction to fieldwork and instrumental techniques. Blackwell Publishing, Oxford, 2003;138-69. 11. Tabain M. Variability in fricative production and spectra: Implications for the hyper-and hypo-and quantal theories of speech production. Lang Speech. 2001;44:57-94. 12. Nittrouer S, Studdert-Kennedy M, McGowan RS, The emergence of phonetic segments: Evidence from the spectral structure of fricative-vowel syllables spoken by children and adults. J Speech Hear Res. 1989;32:120-32.
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doi: 10.5455/medscience.2018.07.8938 13. McFarland DH, Baum SR, Chabot C. Speech compensation to structural modifications of the oral cavity. J Acoust Soc Am. 1996;100:1093-104. 14. Hughes GW, Halle M. Spectral Properties of Fricative Consonants. J Acoust Soc Am. 1956;28:303-10. 15. Koenig LL, Shadle CH, Preston JL, et al. Toward improved spectral measures of /s/: results from adolescents. J Speech Lang Hear Res. 2013;56:1175-89. 16. Munson B. A method for studying variability in fricatives using dynamic
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measures of spectral mean. J Acoust Soc Am. 2001;110:1203-6. 17. Nittrouer S. Children learn separate aspects of speech production at different rates: Evidence from spectral moments. J Acoust Soc Am. 1995;97:520-30. 18. Nirgianaki E. Acoustic characteristics of Greek fricatives. J Acoust Soc Am. 2014;135:2964-76. 19. Lubit EC. The relationship of malocclusion and faulty speech articulation. J Oral Med. 1967;22:47-55.
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ORIGINAL RESEARCH
Medicine Science International Medical Journal
Medicine Science 2019;8(2):291-5
Prevalence of dysmenorrhea in young women and their coping methods Aynur Kizilirmak1, Bahtisen Kartal2, Pelin Calpbinici1 1
Nevsehir Haci Bektas Veli University, Semra and Vefa Kucuk Health College, Department of Gynecology and Obstetrics Nursing, Nevsehir, Turkey 2 Gaziosman Pasa University, Health Science Faculty, Department of Gynecology and Obstetrics Nursing, Tokat, Turkey Received 26 September 2018; Accepted 25 October 2018 Available online 16.12.2018 with doi:10.5455/medscience.2018.07.8937 Copyright © 2019 by authors and Medicine Science Publishing Inc.
Abstract The study was conducted to determine the frequency of dysmenorrhea in young women and their coping methods. The study was conducted at 2014-2015 education year, spring semester of a university as descriptive. Total 3526 girl students consisted of the universe. Sample size table was used for sample choosing and sample size was determined as 600 participants with 0.03 sample error and p = 0.08. A questionnaire form that improved by the researcher and Visual Analogue Scale (VAS) were used. It is determined that average age of the students was 20.58±1.73, 65.0% lived at hall of residence, 8.7% smoked and 3.5% used alcohol. Of them; average age of menarche was 13.45±1.17, 68% had 3-6 days for menstrual period, 48.5% had 28-33 days for menstrual cycle, 15.3% lived menstrual irregularity. Also, 93.3% lived dysmenorrhea, mean of severity of dysmenorrheal pain was 6.33±2.69 and 24.5% of them who lived pain applied to health institute. It is found that of the girls; 63.2% used analgesic, 67.8% had rest in bed, 63.7% applied hot for foot, 56.3% applied hot for abdomen, 26.0% applied massage to abdomen for coping with dysmenorrhea. Also, 66.4% of them stated that these methods make them relax.In the study, it is found that dysmenorrheal prevalence was high in young women and they used both pharmacologic and nonpharmacologic methods for coping with it. It is suggested that informative education programs about complementary and holistic treatment approaches for young women. Keywords: Dysmenorrhea, coping methods, menstruation
Introduction Women live some problems related to menstruation and menstrual period. There are premenstrual syndrome, abnormal uterus bleedings and dysmenorrhea among these problems [1]. Dysmenorrhea that is one the gynecologic problems [2,3] in women in fertility period is defined as painful menstruating periodic [4]. There are two types as primer and secondary [5]. Primer dysmenorrhea generally appears under 20 years old women, after ovulation cycle starts without any pelvic pathologic disease. However, there is pathology in secondary dysmenorrhea and it is more common in women over than 20 years [6,7]. Prevalence of dysmenorrhea in young women shows change from country to country and changes between 45% and 86.9% [5,8-14]. Dysmenorrhea is characterized by a severe pain especially in subabdominal region, and similar to labour pain. Pain could spread out suprapubic or sub-abdominal region as lumbar region and upper leg [1,15] Also, nauseous, vomiting, diarrhea, headache, irritability and anorexia could go with dysmenorrheal [1-3]. *Coresponding Author: Aynur Kizilirmak, Nevsehir Haci Bektas Veli University, Semra and Vefa Kucuk Health College, Department of Gynecology and Obstetrics Nursing, Nevsehir,Turkey E-mail: aynur268@gmail.com
In the studies, it is stated that age, age at first menstruation, regular menstrual cycle, frequency of menstrual cycle, presence of dysmenorrhea in family history and use of oral contraceptive pills are risk factors of dysmenorrhea in young women [16,17]. It is suggested that dysmenorrhea decreased quality of life [10] and concentration, changed normal physical activity [8], and cause to school absenteeism, insomnia and skipping meal [18]. Treatment of dysmenorrhea changes according to its type, in secondary dysmenorrhea, treatment is planned direct to eliminate pathology under pain. However, in primer dysmenorrhea, some methods are used as hot application, balanced nutrition, regular exercise, regular and enough sleep, massage besides medicine treatment [19]. Again, Acupuncture, Acupressure, Spinal Manipulation Therapy, Yoga, Vitamin and mineral support, vegetative therapies are among holistic therapies [15]. There are many integrated treatment methods in coping with dysmenorrhea. It is important for nursing approaches to know whether young women use these methods. Therefore, this study was conducted to determine the prevalence of dysmenorrhea in young women and their coping methods. 291
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Material and Methods The study was conducted to determine prevalence of dysmenorrhea and coping methods in young women attending to a university between 2014-2015 education years spring semester, as descriptive. Total 3526 girl students constituted of the universe of the study. Sample size table was used for choosing sample and sample size was calculated as 600 with 0.03 sample error and p = 0.08. The study was conducted with 600 participants who accepted to participate and filled the forms, completely. A questionnaire form that improved by the researchers was used. The form consisted of 34 questions related to socio-demographic characteristics (age, gender, living place, body mass index, using cigarette or alcohol etc.), menstrual characteristics, dysmenorrhea and coping strategies of the students. Also, Visual Analogue Scale (VAS) was used for determining severity of pain. VAS is a scale that is used to determine the pain commonly and it has got scores between 0-10. According to this, “0” means no pain, 1-4 means mild pain, 5-6 means middle pain and 7-10 means severe pain [20]. Ethical dimension of the study Ethical Committee consent from a university (ethical number: 84902927) and institute consent were obtained. Also, aim and subject of the study were told to the students and their verbal consents were obtained with voluntary principle. Statistical analysis Data was analyzed with SPSS/Windows/15.0 (Statistical Package for the Social Sciences) package program. Data was evaluated by using descriptive statistics (mean, standard deviation, percentage). Results It is found that of the students; average age was 20.58±1.73, mean of length was 163.36±5.72 cm, mean of weight was 56.62±8.06 kg, and mean of Body Mass Index (BMI) was 21.22±2.83. It is determined that 65.0% of the girls lived hall of residence, 8.7% smoked and 3.5% of them used alcohol. When their gynecologic characteristics were investigated; their mean menarche age was found as 13.45±1.17. Of them; 68% had menstrual duration as 3-6 days, 48.5% had menstrual cycle as 28-33 days and 15.3% had irregular menstrual cycle. Also it is determined that of the young women; 91% took information related to menstruation, 51.7% took this information from health professional, 33.3% took from their mothers and 64.8% took the information before menarche (Table 1). While 47.5% of the young women lived dysmenorrhea at every menstrual cycle, 45.8% had dysmenorrhea sometimes and totally, 93.3% had dysmenorrhea, mean pain score of VAS was 6.33±2.69. It is determined that 46.8 of the young women had dysmenorrhea at the first 2-3 days, 41.7% had at the first day and 24.5% of them who had dysmenorrhea applied to hospital because of this problem. Also, there were dysmenorrhea history in their mothers and sisters (30.3%, 29.3% respectively) (Table 2). When the dysmenorrhea status of some young women is examined; a statistically significant relationship was found between age and dysmenorrhea (p<0.005)(Table 3). When their coping strategies were investigated; it is found that of the young women; 63.2% used analgesic, 46.3% used same analgesic regularly, and the most common used analgesic was non-
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inflammatory (64.2%). They used analgesic because of their pain is getting increased, when their pain started and with doctor advice (48.3%, 41.2%, 38.7%, respectively). Again, 65.0% of the young women used other methods except analgesic. It is determined that of them; 67.8% had rest in bed, 63.7% applied hot application for their feet, 56.3% performed hot application for their abdomen and 26.0% massaged for abdomen in order to cope with dysmenorrhea. Also, 66.4% of them stated that these methods made them relax (Table 4). Table 1. Some Socio-Demographic and Gynecologic Characteristics of Young Women CHARACTERISTICS X±SS Age 20.57±1.73 BMI 21.22±2.83 Menarche Age 13.45±1.17 Living place n % With family at home 62 10.3 With friends at home 92 15.3 At residence 190 65.0 Other 56 9.3 Smoking Yes 52 8.7 No 548 91.3 Using alcohol Yes 20 3.5 No 579 96.5 Mean of menstrual duration < 3 days 19 3.2 3-6 days 408 68.0 7-10 days 173 28.8 Menstrual Period/Day 20-27 days 201 33.5 28-33 days 291 48.5 40-45 days 16 2.7 Irregular 92 15.3 Taking information relation to menstruation Yes 546 91.0 No 54 9.0 Information Source * Relatives 202 33.8 Friends 30 5.3 Health Professional 310 51.7 Teacher 55 9.2 Other (Conference, Religious Books) 9 1.5 Time of taking information Before menarche 389 64.8 After menarche 157 26.2 *More than one answer was given. Table 2. Some characteristics about dysmenorrhea in young women CHARACTERISTICS Living Dysmenorrhea At every menstruation Some menstruation No Dysmenrrhea duration (n=560) First day First 2-3 days Until the end of menstruation Other Applying to Health Institute because of Dysmenorrhea (n=560) Applied VAS mean (n=560) Mild Middle Severe X±SS Dysmenorrhea History in Family* No In mother In sister In Aunt Other
n
%
285 275 40
47.5 45.8 6.7
250 281 20 9
41.7 46.8 3.3 1.5
147 413
24.5 68.8
69 263 228
11.5 47 40.8
158 178 171 43 38
6.33±2.69
26.3 30.3 29.3 7.2 6.3
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Table 3. According to Some Characteristics of Young Women Living Dysmenorrhea* Characteristics Living Dysmenorrhea No ( n=40 ) Some menstruation ( n= 275) At every menstruation ( n= 285 ) n % n % n % Age ≤19 age 13 6.9 102 54.3 73 38.8 ≥20 age 27 6.6 173 42.0 212 51.5 Menarche Age <12 2 11.8 5 29.5 10 58.8 ≥12 38 6.5 270 46.3 275 47.2 Mean of menstrual duration < 3 days 2 10.5 10 52.6 7 36.8 3-6 days 26 6.4 195 47.8 187 45.8 7-10 days 12 6.9 70 40.5 91 52.6 Body mass index Underweight <18.5 8 8.3 47 49.0 41 42.7 Normal 18.5 <24.9 30 6.8 197 44.9 212 48.3 Overweight/obese >25 2 3,1 31 47.7 32 49.2 Living place With family at home 9 14.5 28 45.2 25 40.3 With friends at home 6 6.5 45 48.9 41 44.6 At residence 23 5.9 175 44.9 192 49.2 Other 2 3.6 27 48.2 27 48.2 Smoking Yes 4 7.7 19 36.5 29 55.8 No 36 6.6 256 46.7 256 46.7 Using alcohol Yes 3 15.0 6 30.0 11 55.0 No 37 6.4 268 46.3 274 96.1 *Percentage of rows received Table 4. Using Analgesic for Dysmenorrhea Treatment in Young Women and Their Coping Strategies except Analgesics CHARACTERISTICS n % Using analgesics (n=560) Not used 206 36.8 Used 197 35.2 Sometimes used 157 28.0 Using Same Analgesic Regularly Yes 164 46.3 No 190 53.7 Analgesic Type (n=299)** Paracetamol 124 41.4 Noninflamatory 192 64.2 Relaxant 6 2.01 Antispasmodic 17 5.6 Time of taking Analgesic When pain starts 146 41.2 When menstruation starts 37 10.4 With increased pain 171 48.3 People who advice analgesic* Friend 49 13.8 Doctor 137 38.7 Midwife/Nurse 11 3.1 Family members 79 22.3 Own self from pharmacy 78 22.0 Other (women blogs on the internet) 7 1.9 Using another method except analgesic Used 364 65.0 Not used 196 35.0 Coping Methods that used except analgesic** Having rest in bed 247 67.8 Hot application to feet 232 63.7 Hot application to abdomen 205 56.3 Massage for abdomen 95 26.0 Having hot shower by standing 84 23.0 Walking 70 19.2 Distracting 41 11.2 Consider for nutrition 26 7.1 Exercise 24 6.5 Having hot shower by sitting 17 4.6 Relaxation techniques 17 4.6 Other (Hot drinks) 14 3.8 Relaxing Statutes of These Coping Methods Except Analgesics Yes 241 66.4 Sometimes 114 31.4 No 8 2.2 *More than answer was given. **It is calculated on the basis of people gave answer and more than one answer was given.
p .014 .336
.439
.630
.216
. 391 .173
Discussion It is found that prevalence of dysmenorrhea was high in young women. Again, in other studies, it is found as 84.1% in Italy by Grandi et al.[12]; 76.1% in Egypt by Mohamed [21]; 78% in Nigeria by Adegbite et al. [22]; 78% in Pakistan by Gulzar et al. [23]; 89.1% in Iran by Habibi et al. [24]; 80% in Australia by Hillen et al. [25]; 72.8% in Japan by Kazama et al. [26]; and 74.5% in Malesia by Wong and Khoo [27]. It is seen that between 72.7% and 85.7% in studies conducted in Turkey [5,16,17,28]. The studies show that although there are geographic differences, dysmenorrhea is a common gynecologic problem among young women. In the study, almost half of women had got middle degree pain. Similar results of some studies support this finding [5,16,22,30,31,39]. Also, almost one quarter of women who had dysmenorrhea applied a health institute because of this problem. Most of studies that were conducted support this result [21,28,32]. It could be stated that dysmenorrhea was accepted as a normal state by the most of the women and they preferred individual treatment methods. Otherwise, it is thought that although rate of applying was low, high rate of using analgesic could be because of its accessibility and its use as unconsciously. Cheng and Lin [33] suggested that using medicine unconsciously for coping with dysmenorrhea could increase adverse effects and priority should be given for women education about safe use of drug for coping with dysmenorrhea. In the study, a significant difference was found between age and dysmenorrhea. Women who were older than 20 years had more dysmenorrhea. In another study, it was determined that women under twenty years had more dysmenorrhea but no statistically significant difference was found [31]. Pharmacologic treatment that used in dysmenorrhea and evidence as high level is non-inflammatory (NSAID) drugs [21,34]. NSAID 293
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decrease uterine prostaglandin level, contractility of uterine and so minimize the pain [34]. The most used drug among young women was non-inflammatory drugs (NSAID). However, when literature is screened, it is seen that there are different analgesics [22,23,35].
Education programs for raising awareness of women, about using analgesic and evidence based complementary and holistic treatment should be organized and the outcomes of these programs should be followed.
Young women use very different methods for coping with dysmenorrheal pain except using analgesic and they believe that these methods reduce the pain density [31]. In the study, it is found that two of three of the young women used complementary treatment except analgesics and the most used methods were as following; having rest in bed, hot application to feet and abdomen. As similar to our results, according to literature also, Gün et al. [36] found that hot application to abdomen was used mostly; in the study of Mohamed [21], this method was having rest in bed; Potur et al. [16] found resting and hot application were common; Karabulutlu [37] found resting in bed, having shower as standing were common; Erdoğan and Özsoy [38] determined that sleeping and hot application were used mostly.
This study was announced in Complementary and Supportive Care Practices Congress, 27-29th of May 2015 Kayseri Turkey, as poster announcement.
In the study, relaxation techniques, watching the nutrition and exercise were the methods that were used as the coping strategies by the young women, at least. However, in literature, healthy nutrition is seen as an effective method in management of dysmenorrhea [15]. In a study of Kazama et al. [26], it is determined that level of dysmenorrheal symptom was higher in women who didn’t have breakfast. It is thought that lack of taking some nutrients could be reason for this finding. It is determined that lack of taking polyunsaturated fatty acids had got anti-inflammatory effect and this effect could cause the pain [39,40]. Again, in literature, exercise had got positive effects on dysmenorrhea. Such that, Daley [41] suggested that exercise did not only decrease the dysmenorrhea, but also got under control the menstrual cramps and other related symptoms, decreased the need of medicine treatment. Kiatmalaa [42], also, suggested that the nurses who give gynecologic care should have information about exercise in order to help to reduce dysmenorrheal pain. There are a lot of complementary treatment methods that evidenced in coping with dysmenorrheal as acupuncture, TENS, aromatherapy, acupressure and yoga, in literature [43-46]. Besides, difference in affectivity of these methods are also discussed as differences of methods. Aziato et al. [47] suggested that as well as some methods aren’t effective on dysmenorrhea pain, some of them could increase dysmenorrhea symptoms. In the study, the young women applied to complementary and holistic treatment but they used limited methods. As seen in literature; there are various methods in coping with dysmenorrhea. Thus, it is very important that nurses should have information about complementary and holistic treatment and raise awareness of women about this subject. It is determined that prevalence of dysmenorrhea was high in young women; they used both pharmacologic and non-pharmacologic methods in coping with dysmenorrhea. Also, while the rate of applying any health institute of them was low, their using analgesic was very high. It is found that they preferred resting and hot application among non-pharmacologic methods for coping with dysmenorrhea, mostly. Conclusion As basing on this, it is needed that the nurses should take more active roles regarding treatment of dysmenorrhea and consultancy.
Acknowledgments We would like to thank our students, Kubra Ergün, Hatice Merve Biber and Muhammed Tokcan, for their support during the data collection phase of our work. Competing interests The authors declare that they have no competing interest Financial Disclosure The authors declared that this study has received no financial support. Ethical approval Ethics committee approval was received for this study from the ethics committee of Nevsehir Haci Bektas Veli University. Aynur Kizilirmak ORCID: 0000-0002-5032-7234 Bahtisen Kartal ORCID: 0000-0002-2168-6844 Pelin Calpbinici ORCID: 0000-0001-8242-2773
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ORIGINAL RESEARCH
Medicine Science International Medical Journal
Medicine Science 2019;8(2):296-300
Effect of benidipine on experimental gastric ulcers in rats Bahadir Suleyman1, Renad Mammadov1, Adalet Ozcicek2, Fatih Ozcicek2, Mehmet Kuzucu3, Durdu Altuner1, Zeynep Suleyman4 1 Erzincan Binali Yildirim University, Faculty of Medicine, Department of Pharmacology, Erzincan, Turkey Erzincan Binali Yildirim University, Faculty of Medicine, Department of Internal Medicine, Erzincan, Turkey 3 Erzincan Binali Yildirim University, Faculty of Arts and Sciences, Department of Biology, Turkey 4 Erzincan Binali Yildirim University, Faculty of Health Sciences, Department of Nursing, Erzincan
2
Received 15 Octaber 2018; Accepted 26 Octaber 2018 Available online 28.10.2018 with doi:10.5455/medscience.2018.07.8921 Copyright Š 2019 by authors and Medicine Science Publishing Inc. Abstract Peptic ulcer has been reported to increase acid secretion and lead to oxidative stress. Benidipine is an antihypertensive drug with antioxidant properties. This study aims to investigate the effects of benidipine on indomethacin-induced gastric ulcers in rats. Four groups were designed in this study. Gastric ulcer was occurred with indomethacin in the first three groups. These groups were treated with famotidine, benidipine and distilled water respectively 5 minutes before indomethacin administration. The fourth group rats didnâ&#x20AC;&#x2122;t have gastric ulcer and they received only distilled water. Six hours after drug administration gastric tissue was extracted and macroscopic and biochemical examinations were performed. Damaged areas in the stomach of benidipine and famotidine receiving animal groups were smaller than the indomethacin received animals. Indomethacin elevated the levels of malondialdehyde and myeloperoxidase in the stomach tissue (p<0.0001), and also decreased glutathione, glutathione related enzymes and superoxide dismutase (p<0.0001). Benidipine may be useful in preventing the toxic effect of indomethacin on the stomach. Keywords: Benidipine, oxidant, antioxidant, gastric ulcers, rats
Introduction As is known, peptic ulcer is a common name used for stomach and duodenum ulcers. Incidence of peptic ulcer is 11-14% in male and 8-11% in female. However, stomach ulcers are seen equally in male and female [1]. Research has shown that 89-95% of peptic ulcers are associated with Helicobacter pylori and nonsteroidal anti-inflammatory drugs (NSAIDs) usage [2]. Serious gastrointestinal complications have been clinically reported in 1-4% of patients taking NSAIDs [3]. The factors leading to peptic ulcer cause disruption of the permeability of stomach mucosa and the intracellular calcium accumulation [4]. Studies show that calcium stimulates gastric mucosal oxyntic cells and gastric acid secretion in in-vivo conditions [5]. It also known that intracellular calcium dysregulation is related with reactive oxygen species [6]. The increase of intracellular calcium was directly proportional to membrane lipid peroxidation increase and glutathione (GSH) *Coresponding Author: Bahadir Suleyman, Erzincan Binali Yildirim University, Faculty of Medicine, Department of Pharmacology, Erzincan, Turkey E-mail: bahadir.suleyman@yandex.com
decrease [7]. Although the aggressive factors that make up the ulcer are different, the free oxygen radicals are one of the responsible mechanism of all ulcer types [8]. This information supports the fact that reactive oxygen species are closely related to ulcer pathogenesis [9]. It has reported that the amounts of malondialdehyde (MDA) and myeloperoxidase (MPO) increased, and the levels of glutathione and its enzymes, superoxide dismutase (SOD), catalase (CAT) decreased in damaged stomach tissue [10]. Indomethacin indole derivative is a NSAID that we utilized to create an experimental ulcer model in the present study. Indomethacin is the most preferred drug to create an experimental ulcer model because its ulcer making potential is more than other NSAIDs [11, 12]. It is argued that indomethacin causes damage to the stomach tissue by inhibiting the secretion of cytoprotective prostaglandin, mucus and bicarbonate, increasing the stomach acid secretion [12]. Cyclooxygenase-2 (COX-2) enzyme regarded as leading to the anti-inflammatory impact of indomethacin and Cyclooxygenase-1 (COX-1) enzyme inhibition for the gastrointestinal toxic effects [13]. Indomethacin have been reported to change the oxidantantioxidant balance in stomach tissue including MDA, MPO, tGSH, GST, SOD, CAT and GPO in favor of oxidants [14,15, 296
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16]. All this information suggests that calcium channel blockage and antioxidant administration are treatments for gastric ulcer pathogenesis. Benidipine is an L-type calcium channel blocker drug used in hypertension [17]. Benidipine prevents the increase of oxidant parameters in tissues and decrease of antioxidants, and suppresses oxidative stress [18,19]. Calcium channel blockade and antioxidant properties of benidipine suggest that it may provide a treatment for the pathogenesis of gastric ulcer. Therefore, the study aims to investigate the effect of benidipine on indomethacininduced gastric ulcers in rats.
rpm at +4 °C for 15 minutes. The supernatant was used as an analysis sample.
Material and Methods
Total glutathione analysis The amount of tGSH in the stomach tissue was performed according to the method defined by Sedlak and Lindsay [24]. The tGSH levels in the gastric tissue are expressed as nmol/g protein.
Experimental animals In total, 24 male albino Wistar rats, each weighed 270–287g, were used in these experimental research. The rats were provided from Medical Experimental Research and Application Center of Ataturk University. The animals were housed and fed for a week (7 days) in the normal laboratory environment (22ºC) in groups before the experiment. This experiment was confirmed by the local animal experimentation committee of ethics (Ataturk University animal experiments local ethics committee, Date: 30.03.2017, Meeting no: 3, Decision: 33). Chemical substances Thiopental sodium was obtained from IE Ulagay (Turkey) and its commercial form benidipin from Deva (Turkey). Experimental groups The animals used in the experiment were grouped as Indomethacin (IND), Indomethacin + Benidipine (IBN), Indomethacin + Famotidine (IFN) and healthy (HG) groups. Indomethacin ulcer test Benidipine was given orally at 2 mg/kg dose for the IBN (n-6) group and famotidine 20 mg/kg for the IFN (n-6) group to 24 h fasted rats. IND (n-6) and HG (n-6) groups were applied distilled water of an equal volume of (0.5 ml) as a solvent [20,21]. Five minutes after the application of the drugs, all rats were administered orally 25 mg/kg of indomethacin (excluding HG) [21]. Six hours after the administration of indomethacin, the animals were sacrificed by administration of high dose of anesthetic (thiopental sodium 50 mg/kg). The stomach of the killed animals was removed, and the ulcers on the stomach surface were macroscopically evaluated. The ulcer area on the stomach surface was measured on the paper rulers with the scale of mm2. Then, MDA, MPO, total glutathione (tGSH), glutathione peroxidase (GPO), glutathione S transferase (GST), GSHRd and SOD levels were measured in all stomach tissues. Biochemical processes Preparation of samples The phosphate buffer containing 0.5% HDTMAB (0.5% hexadecyltrimethyl ammonium bromide) pH=6 for the determination of MPO, the potassium chloride solution of 1.15% for the determination of MDA were used, and for the other measurements, it was adjusted to 2 mL in phosphate buffer (pH 7.5) and homogenized on ice. Then, it was centrifuged at 10000
Malondialdehyde analysis The barbituric acid test was used by assessment MDA to define the amount of lipid peroxidation in gastric tissue [22]. MDA levels are expressed as μmol/g protein. Myeloperoxidase analysis MPO activity was measured according to the method of Bradley et al. [23]. MPO activity are expressed as U/g protein.
Glutathione peroxidase analysis GPO activity was measured according to the method of Lawrence and Burk [25]. Results were expressed as U/g protein. Glutathione reductase analysis GSHRd activity was determined spectrophotometrically by measuring the rate of NADPH oxidation at 340 nm according to Carlberg and Mannervik method [26]. Results were expressed as U/g protein. Glutathione s-transferases analysis GST activity was measured by using 1-chloro-2, 4-dinitrobenzene (CDNB) and GSH as described in Habig et al. [27]. Results were expressed as U/g protein. Superoxide dismutase analysis SOD activity was measured according to Sun et al. [28]. Estimates were based on the generation of superoxide radicals produced by xanthine and xanthine oxidase, which react with nitroblue tetrazolium (NBT) to form formazan dye. SOD activity is expressed as U/g protein. Statistical analysis The results were shown as “mean±standart error of the mean” (x±SEM). The differences between the groups were defined using one-way ANOVA and followed it Fisher’s post-hoc LSD test. “SPSS for Windows 18.0” software used for data analysis, and p<0.05 was considered statistically significant. Results Indomethacin ulcer test Macroscopic examination results Macroscopically black-colored damage was observed in the stomach tissue of indomethacin, benidipine and famotidine treated groups. The damage foci on various shapes and sizes scattered across the entire stomach surface. The damage foci were round, oval and irregular mucosal defects at different diameter and depth. The boundaries of the damages were clear. The number and area of damage foci in the stomachs of benidipine and famotidine receiving animal groups were less than the control group. Severe hyperemia was observed in the control group receiving only indomethacin (Figure 1).
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Antiulcer activity of benidipine and famotidine As shown in Table 1, the average of ulcer area in the stomach of rats in the control group of indomethacin was 44.5±1.6, and the average of the ulcer area in rats receiving benidipine at the 2 mg/kg doses and famotidine in 20 mg/kg doses were 0.5±0.2 and 0.3±0.2 mm2. In the indomethacin group, the ulcer area was significantly greater than the group of benidipine and famotidine. However, there was no statistically significant difference for the mean ulcer area between benidipine and famotidine groups. Biochemical findings Oxidant parameters As our ,results show, indomethacin increased MDA and MPO levels in stomach tissue of indomethacin group rats significantly compared to the HG group (p<0.0001). MDA and MPO levels decreased in benidipine and famotidine groups compared to the IND group (p<0.0001). The difference of the MDA and MPO levels between IBN and IFN group was found to be statistically insignificant (p>0.05) (Figure 2). Antioxidant parameters Indomethacin decreased the levels of tGSH, GPO, GST, GSHRd, and SOD in stomach tissue of indomethacin group rats significantly compared to the HG group (p<0.0001). The levels tGSH, GPO, GST, GSHRd, and SOD increased in the IBN and IFN groups (p<0.0001). The difference of tGSH, GPO, GST, GSHRd and SOD levels was found to be insignificant between IBN and IFN groups (p>0.05) (Figure 3).
Figure 1. Ulcer areas (Arrow) of stomach tissue in the HG (1a), IND (1b), IBN (1c) and IFN (1d) groups.
Figure 2. MDA and MPO levels in the stomach tissue of study groups. *=p˂0.0001 according to HG group. **=p˂0.0001 according to IND group.
Figure 3. tGSH, GPO, GST, GSHRd and SOD levels in the stomach tissue of study groups. *=p˂0.0001 according to HG group. **=p˂0.0001 according to IND group. Table 1. Ulcer areas of stomach tissue in the Healty (HG), Indomethacin (IND), Indomethacin + Benidipine (IBN) and Indomethacin + Famotidine (IFN) groups. Groups
HG
IND
IBN
IFN
Ulcer area (mm2)
0
44.5±1.6
0.5±0.2
0.3±0.2
p
-
<0.0001
>0.05
>0.05
Discussion In this study, effects of benidipine on indomethacin-induced gastric ulcers in rats was investigated and compared with famotidine. This study was carried out based on the effect mechanism of benidipine and the literature information on the pathogenesis of gastric ulcer. Our results showed that indomethacin damaged the stomach tissue of animals and that benidipine protected the stomach tissue from indomethacin damage. The stomach tissue of the animals that indomethacin was applied alone developed affected areas with different diameter and depth in various shapes and sizes macroscopically in black color. These macroscopic symptoms are considered to be gastric ulcers in literature [16]. In many previous studies, antiulcer activity was evaluated with the area width of the damage to stomach tissue [29,30]. The area of ulcer foci in the indomethacin group was found to be larger than the group of benidipine and famotidine. This suggests that benidipine and famotidine have an antiulcer effect. Oxidant and antioxidant parameters are used to evaluate the biochemical effect of indomethacin on the stomach [15,31]. As we can see from our experimental results, oxidant parameter levels such as MDA and MPO in the indomethacin group with larger ulceration area showed a significant increase compared to the healthy, benidipine and famotidine group. It has reported that the MDA level increases in the damaged stomach tissue due to indomethacin [32]. Polat et al. [33] reported increased MPO activity in the stomach tissue of the indomethacin group, where MDA also increased. There were no studies showing the effects of benidipine on MDA and MPO induced by indomethacin in stomach tissue, but it was reported that benidipine inhibited MDA increase in damage tissue induced by over ischemia-reperfusion [20]. Also, the findings about benidipine reduced MPO activity in heart tissue was reported [34].
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The levels of tGSH, GPO, GST, GSHRd and SOD in the stomach tissue of indomethacin group were significantly decreased compared to the healthy, benidipine and famotidine groups. These results show that indomethacin changes oxidant-antioxidant balance in stomach tissue in favor of oxidants. There are many studies reporting that antioxidant parameters decreases in the experimental damaged stomach tissue, and oxidized parameters increases. Especially MPO and MDA levels increased in damaged stomach tissue and GSH, GST, SOD and GPO levels decreased [35]. This literature information demonstrates the importance of maintaining oxidant-antioxidant balance with the superiority of antioxidants so that drugs can have an anti-inflammatory effect. It also reveals that the relationship between antioxidant activity and anti-ulcer effect is important. Famotidine has been reported to inhibit the decrease of antioxidant levels in stomach tissue and oxidants to increase in the dose of anti-inflammatory effect [15, 33, 36]. Benidipine has also been shown experimentally to prevent the increase of MDA and the decrease of tGSH in damaged tissue [20]. These results suggest that the protective effect of benidipine on the stomach is due to antioxidant activity, same as famotidine. In literature, we can see whether tissue damage occurs is evaluated with oxidant/antioxidant balance [37]. There was no study in literature about the effects of benidipine on gastric ulcers. However, a L-type calcium channel blockers belonging to the same group have been documented to suppress the formation of indomethacin ulcers; also, lacidipine has been determined to decrease the oxidant parameters and increase the antioxidant parameters, same as benidipine [21]. As a result, indomethacin caused significant damage to the stomach tissues. Oxidantantioxidant balance in the stomach tissue of the animal groups receiving indomethacin changed in favor of oxidants. Benidipine and famotidine significantly reduced the gastric damage induced by indomethacin. Oxidant-antioxidant balance in stomach tissues of benidipine and famotidine group resulted in the superiority of antioxidants.
3.
Sokic MA, Krstic M, Popovic D, et al. Role of Helicobacter pylori infection and use of NSAIDs in the etiopathogenesis of upper gastrointestinal bleeding. Acta Chir Iugosl. 2007;54:51-62.
4.
Szabo S, Trier J, Brown A, et al. Early vascular injury and increased vascular permeability in gastric mucosal injury caused by ethanol in the rat. Gastroenterology. 1985;88:228-36.
5.
Aadland E, Berstad A. Effect of verapamil on gastric secretion in man. Scand J Gastroenterol. 1983;18:969-71.
6.
Kato T. Role of mitochondrial DNA in calcium signaling abnormality in bipolar disorder. Cell Calcium. 2008;44:92-102.
7.
Zavodnik IB, Dremza IK, Cheshchevik VT, et al. Oxidative damage of rat liver mitochondria during exposure to t-butyl hydroperoxide. Role of Ca2+ ions in oxidative processes. Life Sci. 2013;92:1110-7.
8.
Itoh M, Guth PH. Role of oxygen-derived free radicals in hemorrhagic shockinduced gastric lesions in the rat. Gastroenterology. 1985;88:1162-7.
9.
Salim A. Scavenging free radicals to prevent stress-induced gastric mucosal injury. Lancet. 1989;334:1390.
Conclusion
16. Polat B, Suleyman H, Alp HH. Adaptation of rat gastric tissue against indomethacin toxicity. Chem Biol Interact. 2010;186:82-9.
Our results show that benidipine has as much anti-inflammatory efficacy as famotidine. Therefore, benidipine may be used in place of famotidine to eliminate the gastrotoxic effect of indomethacin. Competing interests The authors declare that they have no competing interest Financial Disclosure The financial support for this study was provided by the investigators themselves. Ethical approval Before the study, permissions were obtained from local ethical committee. Bahadir Suleyman ORCID:0000-0001-5795-3177 Renad Mammadov ORCID:0000-0002-5785-1960 Adalet Ozcicek ORCID:0000-0003-3029-4524 Fatih Ozcicek ORCID:0000-0001-5088-4893 Mehmet Kuzucu ORCID:0000-0002-7786-7687 Durdu Altuner ORCID:0000-0002-5756-3459 Zeynep Suleyman ORCID:0000-0003-0128-7990
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ORIGINAL RESEARCH
Medicine Science International Medical Journal
Medicine Science 2019;8(2):301-5
Malaria prevalence and risk analysis among pregnant women in Bungoma county, Kenya Wekesa Antony Wanyonyi1, Chrispinus Siteti Mulambalah2, David H. Mulama1, Elizabeth Omukunda1 1
Masinde Muliro University of Science and Technology, Department of Biological Sciences, Kakamega, Kenya. 2 Moi University, School of Medicine, Department of Medical Microbiology & Parasitology, Eldoret, Kenya Received 07 August 2018; Accepted 26 Octaber 2018 Available online 11.01.2019 with doi:10.5455/medscience.2018.07.8947 Copyright Š 2019 by authors and Medicine Science Publishing Inc.
Abstract Malaria during pregnancy has adverse consequences on the mother and fetus. Information describing the prevalence, Plasmodium species types and the influence of socio-economic risk factors of malaria in pregnancy is scarce. In order to determine the distribution of malaria parasite species and risk factors among pregnant women in Bungoma County, a cross sectional hospital based study was carried out between March 2016 and January 2017 among 750 consented expectant mothers seeking antenatal services at the Bungoma County hospital. Malaria positivity and species identification were determined microscopically using Giemsa stain technique. Socio economic risk factors were collected using a structured pre-tested questionnaire. Data was analysed using STATA version 12. Descriptive analysis was used to determine malaria prevalence. Chi-square (X2) and regression analyses were used to determine the association between malaria and risk factors with P-<0.05 and 95 % CI. A total of 162/750 (21.6%) of expectant mothers had malaria parasites. Plasmodium falciparum being the most prevalent species 83.3%, Plasmodium malariae, 10.5%, Plasmodium ovale, 1.2%, and mixed infection of Plasmodium falciparum and plasmodium malariae 4.9%. Risk factors were unemployment OR 2.134 (1.228-3.371) P-value 0.006; lack of malaria treatment OR 3.615(1.285-10.167) P-value 0.015; lack of mosquito net use 3.220 (2.019-5.138) P-value 0.0001. Participants in first and second trimesters of pregnancy were at higher risk of infection by malaria OR 2.126 (1.238-6.651), P-value 0.006. Routine screening of pregnant women for malaria parasites and treatment is essential during all trimesters. Provision of treated mosquito nets and continuous health education are important in preventing malaria in pregnancy. Keywords: Prevalence, malaria, pregnant women, socio economic risk factors
Introduction Malaria is still a major global health burden in tropical and subtropical countries, despite the intensive control measures that are carried out worldwide. Annually, approximately 350 to 500 million cases of malaria are reported globally [1]. The disease kills more than one million people worldwide with most deaths occurring in Sub-Saharan Africa. It is the leading cause of deaths in children under five years, pregnant women and those in low socioeconomic status [2]. Human malaria is caused by five known parasite species in the genus Plasmodium: Plasmodium falciparum, P.vivax, P.ovale. P.malariae and P.knowlesi. Most infections are caused by P. falciparum [1]. Malaria in pregnancy is a major cause of maternal and fetal morbidity and mortality. Compared to other malaria parasites, Plasmodium falciparum is known to be a major contributor to
*Coresponding Author: Chrispinus Siteti Mulambalah, Moi University, School of Medicine, Department of Medical Microbiology & Parasitology, Eldoret, Kenya E-mail: csmulambalah@gmail.com
pregnancy anemia especially in nulliparous women [3]. The species has been consistently and widely associated with pathologies including maternal anemia, low birth weight (LBW) infants, intrauterine growth retardation, premature deliveries and infant mortality during gestation [4]. However, the impact of the other malaria parasites (P.vivax, P. malariae and P.ovale) particularly in pregnancy is not clear although it is estimated that up to 200,000 infants die annually worldwide as a result of maternal malaria infection during pregnancy [5,6]. Therefore, there is an urgent need to understand the prevalence and risk factors that predispose to malaria in pregnancy. Previously it has been reported that malaria prevalence in the general population is influenced by a number of factors such as maternal age parity, use of prophylaxis, nutritional status, host genetics, parasite genetics and transmission rate [7]. It remains however unclear which factors are significantly associated with malaria in pregnancy. Pregnant women are particularly vulnerable to infections due to suppression of their immune system during pregnancy [8]. A clear understanding of the epidemiology and risk factors of malaria parasites in human population is inadequate specifically in respect to expectant mothers [9]. 301
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Malaria transmission in Kenya can be described as stable, unstable depending on location and altitude with children and expectant mothers being the most vulnerable [10]. In western Kenya, malaria is prevalent and a persistent public health problem. A recent study by Jekins and colleagues in the Lake Victoria region reported Plasmodium falciparum malaria prevalence of 28% in adult females with concomitant anemia [10]. The high prevalence of malaria associated anemia in pregnancy compared with low anemia in non-pregnant women in western Kenya has been a major concern to health personnel [11]. Although efforts aimed at preventing malaria in pregnancy have been ongoing, the disease is still prevalent in counties in Western Kenya more so in Bungoma County. No study has looked at the distribution of malaria parasite species among pregnant women in Bungoma County. Thus, this study sought to determine the distribution and risk factors of malaria parasites among pregnant women in Bungoma County. The findings from this study provide useful information for designing strategies for effective control and management of malaria in expectant mothers. Material and Methods Study Design A cross sectional hospital based study was adopted. Consecutive sampling was used to recruit participants who met inclusion criteria from March 2016 to January 2017. Study Setting The study was conducted at Bungoma Country referral hospital. The hospital is located in Kanduyi Sub County; Bungoma County in Western Kenya. The study area lies between latitude 0° 34′0”N and Longitude 34° 34′ 0”E. Bungoma County has an area of 3,032.2sq km with an estimated human population of 1,375,063 according to Kenya 2009 national census [12]. It has 9 sub counties, Kanduyi, Bumula, Sirisia, Kabuchai, Kimilili, Webuye East, Webuye West, Tongaren and Mount Elgon. It has a tropical climate characterized by hot and humid conditions with two rainy seasons, long rains season (April and August) and the short rains (October to December). Dry season is experienced from January to March of every year. The predominant ethnic groups are Luhyas (Bukusu),Teso and Sabaot, who practise subsistence farming. Sampling Frame and Inclusion Criteria A total of 750 pregnant women were recruited in the study as they sought antenatal services at the Bungoma County referral hospital. The recruited expectant mothers were grouped into three age groups 18-27 years, 28-37 years and 38-49 years. Inclusion criteria were based on age range 18 -49 years, being residents of Bungoma County for at least six months and willing to participate in the study. Collection of Demographic Data Pre-tested, semi-structured questionnaire was developed and administered to participants’ prior to blood sample collection. The questionnaire was used to collect data on age, use of malaria preventive measures, housing conditions, residence, stage (trimester) of pregnancy, marital status, level of education and employment. Quality control was performed by daily review of each questionnaire. Blood Sample Collection and Processing Blood samples were aseptically collected from all the 750
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participants. A finger was cleaned with cotton swap moistened in 70% alcohol. The swabbed area was dried using a piece of dry cotton wool. A prick was done using a sterile disposable blood lancet. The first drop of blood was wiped off. Thick and thin films were made on the same slide. A drop of blood was put at one end of the glass slide, using a clean spreader blood was spread to make a circle. Another drop of blood was put at the middle of the same slide, using a clean spreader; blood was spread at an angle of 35-45 degrees to make a thin film covering approximately ¾ of the slide. Slides were air-dried in a horizontal position. Thin blood films were fixed by dipping in a jar of 70% methanol for 30 seconds then air-dried. Both thin and thick films were stained using 10% Giemsa for 10 minutes. Thick and thin blood films were preferred because thick blood film concentrates malaria parasites for easier viewing while thin blood film facilitates Plasmodium species identification by their morphological features. Detection and Quantification of Malaria Parasites The slides were examined microscopically using 100 magnification by a qualified medical laboratory technologist. All asexual forms of malaria parasites (trophozoites and schizonts) in each preparation were identified by their morphological features and recorded. Malaria parasites density per microliter of blood was calculated by counting the number of malaria parasites against 200 white blood cells (WBCs) and multiplying by 8,000 to obtain malaria parasites/µl of blood. At least 100 high-power fields were examined before a film was declared negative [13]. For quality control 10% buffered (pH 7.2) Giemsa stain was prepared for use after every 6 hours. Further, known malaria positive controls with low parasitemia were stained and examined daily to check the quality of the stain. At least 10% of the read blood smears were re-examined by the second qualified laboratory technologist for quality control. Relevant procedures for waste segregation and disposal were followed. Data Analysis Data was analysed using STATA version 12 (STATA Corporation college station TX USA). Both descriptive and inferential statistical tools were used to analyse data. Prevalence of malaria and parasite quantification per microliter of blood was calculated based on blood sample results. Chi-squire (X2) was used to determine the relationship between malaria and risk factors. Multivariate logistic regressions were employed for those variables that had significant association at bivariate analysis to determine the main socio economic risk factors of infection. P-value ≤ 0.05 was considered significant. Odds ratios (OR) with a 95% confidence interval were computed to compare the strength of association between explanatory variables. Ethical Considerations The study was approved by Masinde Muliro University of Science and Technology Institutional Review Board (approval number MMU/COR403OO9 (57). Further approval was obtained from Bungoma County Referral Hospital. Oral and written informed consent was obtained from all study participants in either English, Kiswahili. Pregnant women were given explanations pertaining to the study objectives and procedures before signing written individual consent forms. Study participants were given the option to withdraw from the study at any time they wished. Data obtained was coded and kept strictly confidential. The results were shared 302
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with individual study participants and those confirmed positive for malaria were treated in accordance with clinical guidelines of WHO and Ministry of Health, Kenya.
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Results
participants who lived in semi-permanent houses (houses build of mud walls, earthen floors and iron -roofed) were more infected with malaria 110 (67.9%), χ28.174 p=0.002 compared to those residing in permanent houses (houses build of cement walls, cement floors and iron sheet roofs) 52(32.1%), χ20.871 p=0.201.
Malaria Prevalence and Density The overall malaria prevalence was 21.6% (n=162) with Plasmodium falciparum being the most prevalent species 83.3% (n=135), Plasmodium malariae 10.5 % ( n=17), Plasmodium ovale 1.2 % ( n=2), and mixed infection of Plamodium falciparum and Plasmodium malariae 4.9 % (n=8). The mean malaria parasite density in pregnant women was as follows Plasmodium falciparum 528, CI (405-751), Plasmodium malariae 312, CI (254-370) and Plasmodium ovale 132, CI (48-74) parasites per micro litter of blood (Parasites/µl) (Table1).
Expectant mothers with primary level of education were more likely to be infected with malaria 79 (48.8%), χ222.786 p=0.001 compared to those who had attained tertiary and higher education 22 (13.6%), χ24.366 p=0.359. Unemployed study participants were more likely to be infected with malaria 87 (53.7%), χ2 11.999 p=0.007 compared to those employed 23 (14.2%), χ28.738 p= 0.033. Expectant mothers in their 2nd trimester were more likely to be infected with malaria 107(66.1%), χ2 3.478 p=0.176 than those in 1st trimester 31(19.1%), χ2 8.327 p= 0.16 and 3rd trimester 24 (14.8%), χ2 4.309 p=0.116.
Social Economic Risk Factors Expectant mothers of age group 18-27 years were more likely to be infected with malaria parasites 79% (n=128), χ22.151 p=0.341 compared to higher age groups for instance 28-37years 19.8% (n=32) χ25.086 p=0.079, 38-49 years 1.2% (n=2), χ20.341 p=0.184.
Multivariate Analysis of Risk Factors for Malaria in Pregnancy The risk factors for malaria infection among expectant mothers considered in the study included unemployment P=0.002 OR 9.588 (2.281-40.304), lack of malaria treatment P=0.015 OR 3.615(1.285-10.167), not sleeping under treated mosquito net P=0.001 OR 3.220 (2.019-8.138) and 2nd trimester of pregnancy P=0.006 OR 2.126 (1.238-3.651). The analyzed variables are presented in Table 2.
Malaria prevalence was higher in expectant mothers residing in rural areas 129 (79.6%), χ22.709 p=0.001 compared to those in urban areas 33 (20.4%), χ2 0.330 p=0.467. Similarly, study
Table 1. Prevalence and density of malaria parasites No. +ve for malaria parasites
P. falciparum
P. malariae
P. ovale
P. falciparum and P. malariae
21.6% (n=162)
83.3% (n=135)
10.5%(n=17)
1.2%(n=2)
4.9%(n=8)
Mean malaria parasites/µl of blood P.f 528 CI (405-751)
P.m 312 CI (254-570)
P.o 132 CI (48-74)
Key: P.f- Plasmodium falciparum, P.m- Plasmodium malariae, P.o- Plasmodium ovale, CI-95% confidence interval
Table 2. Risk factors for malaria in pregnancy Variable
Malaria p-value
OR
95% CI
No treatment
0.015
3.615
1.285-10.167
More than 6 months
0.078
0.520
.251-1.075
Does not use
0.001
3.220
2.019-5.138
Not always
0.001
0.035
0.004-0.276
Unemployed
0.006
2.034
1.228-3.371
Employed
0.149
1.333
0.92-1.970
1st
0.040
0.708
0.509-0.984
2nd
0.006
2.126
1.238-3.651
3rd
0.013
2.235
1.186-4.211
Malaria Treatment
Mosquito net use
Employment
Trimester
Key: 95% CI=Confidence interval, OR= Odds ratio, P<0.05 was considered significant
303
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Discussion Malaria is one of the most serious public health problems in Kenya. The disease epidemiology varies depending and locality and may be influenced by several factors relating to parasite species, host and environmental. Our study has shown that socioeconomic factors, age, stage of pregnancy and parity status of the mother are important determining factors in malaria infection in pregnancy. In this study, malaria prevalence was 21.6% with Plasmodium falciparum being the most prevalent species. Plasmodium malariae and Plasmodium ovale were recorded as common. These results are comparable to a study in Ghana where the prevalence was 25.7% which lie in the same tropical region as Kenya [3]. The two countries lie within tropical belt of Africa with comparable climatic conditions. Locally, these observation suggest high transmission of malaria in Bungoma county. This could be attributed to favorable tropical environmental conditions suitable for the development of Anopheles mosquitoes and consequently to the development and propagation of Plasmodium parasite. Our study reported a prevalence rate that was lower than what was obtained in similar studies elsewhere due to differences in ecosystems. For instance a similar study in Cameroon where the prevalence rate of 77.2 % was reported [14] while another similar study along the coastal region of Kenya a prevalence rate of 32% was reported [15]. However, malaria prevalence rate in this study was higher than11.6% reported in Ethiopia [16] and 16.5% in Ghana [11]. The observed differences could be linked to dissimilarities in the geo-ecological and climatic conditions that influence the number and distribution of malaria vector breeding in different study sites. Further, population and demographic dynamics in the study sites are not identical and this can impact on the disease epidemiology. Malaria parasite intensity in this study was quantified as moderate and varied considerably depending on malaria parasite species. These findings could be attributed to the infection rate which may vary depending on the Plasmodium species in study sites and the preventive measures operational in the study sites for instance chemoprophylaxis. These and other factors such as host immunity are known to influence malaria infection intensity [17]. Malaria intensity was classified as described by Trape [18] and our study findings were comparable with a study by Yatich and others in Ghana [3] which showed that mean intensity of malaria species specific infections vary considerably in individuals. The study was undertaken during the long rains season characterized by flooding and with several stagnant pools of water favorable for Anopheles mosquito vector breeding. Therefore, relatively high malaria prevalence and intensity was anticipated but this was not the case. This unexpected observation could be due to widespread use of insecticide treated mosquito nets, a policy that has been enforced by the Kenyan government for expectant mothers and which protect them from mosquito bites and consequently reduction in malaria transmission. Mothers in second trimester of pregnancy had the highest malaria parasite prevalence rate (66.1%). This could be explained by the observation that expectant mothers miss out on first trimester antenatal care and later seek antenatal services during the second trimester of pregnancy when the malaria diagnosis was done.
Med Science 2019;8(2):301-5
Malaria risk factors were unemployment, lack of mosquito net use, staying in rural area and age group 18-25 year. Unemployment leads to poverty which results in low standard of living. Majority of malaria positive expectant mothers were from rural set ups and lived in semi-permanent structures a reflection of poor and deprived communities. Similar findings were also observed in a recent study in Nigeria [19]. Explanation for these findings could be attributed to poor sanitation in rural communities living in environmental conditions favoring breeding of vector mosquitoes and thus increased risk of being bitten and acquiring malaria. These findings support the idea that it is essential to scale up malaria prevention efforts in more isolated and deprived communities as highlighted in a meta-analysis of data from 25 African countries [20]. Although one of the first line prevention of malaria in Kenya among pregnant women relies on nationwide distribution of treated mosquito nets at antenatal clinic visits, we found out that close to half of expectant mothers do not sleep under mosquito nets. These findings demonstrate the need for public health awareness campaigns. It is important for expectant mothers to know how to use bet nets when provided, otherwise they will not have desired impact. Therefore integrated effort for controlling malaria transmission especially in rural areas, particularly in deprived communities is essential. Conclusion A multipronged strategy should be employed in the control of malaria in expectant women. The strategy should incorporate aspects relating to the age of the mothers, parity, socio-economic status as well as stage in pregnancy. Apart from Plasmodium falciparum being prevalent, the study findings revealed that Plasmodium malariae and Plasmodium ovale were also common in the study area. Principal risk factors were primary education, unemployment, lack of malaria treatment, lack of mosquito nets and second trimester pregnancy. Exposure to malaria in pregnancy was associated mainly with the failure to use treated mosquito nets and unemployment. These findings are useful in designing control and management strategies for malaria among pregnant women in Bungoma County The study recommends routine diagnosis and prompt treatment of malaria; provision of treated mosquito nets together with health awareness to expectant mothers during their visit to antenatal clinics. Acknowledgement We thank Dr Isaac Omeri, medical superintendent, Bungoma County referral hospital who granted us permission to carry out the study in the hospital. We also thank hospital staff for their assistance. Special thanks go to pregnant women who participated in the study. Competing interests The authors declare that they have no competing interest. Financial Disclosure The authors declared that this study has received no financial support. Ethical approval The study protocol was approved by the University ethics committee with reference numbers MMU/COR403009(57).
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doi: 10.5455/medscience.2018.07.8947 Wekesa Antony Wanyonyi ORCID: 0000-0002-3800-4184 Chrispinus Siteti Mulambalah ORCID: 0000-0002-5760-3000 David H. Mulama ORCID: 0000-0003-2198-2798 Elizabeth Omukunda ORCID: 0000-0001-7516-7962
References 1.
World Malaria Report. http://www.who.int/malaria/publications/worldmalaria -report 2015 access date 5.5.2018
2.
World Malaria Report. http://www.who.int/malaria/publications/world_ malaria_report_2013 access date 5.5.2018
Med Science 2019;8(2):301-5
11. Samuel C, Kofi T, Emmanuel A, et al. Parasitic infections and maternal anaemia among expectant mothers in the Dangme East District of Ghana. BMC Research Notes. 2017;10:1. 12. Government of Kenya National Bureau of Statistics. The 2009 population and housing census: Ministry of State for Planning, National Development and Vision 2030, counting our people for implementation of Vision 2030 Vol 1. Government printer, 2010. 13. Cheesbrough M. District Laboratory Practice in Tropical Countries. Part I. Cambridge University Press. 1998:242-53. 14. Francis Z, Viviane H, Matong T, et al. Co-infections of Malaria and Geohelminthiasis in two rural Communities of Nkassomo and Vian in the Mfou District, Cameroon, PLoS Negl Trop Dis. 2014 Oct 16;8:e3236.
3.
Yatich NJ, Pauline EJ, Ellen F, et al. The Effect of Malaria and Intestinal Helminth Coinfection on Birth Outcomes in Kumasi, Ghana. Am J Trop Med Hyg. 2010;82:28-34.
4.
Yatich NJ, Yi J, Agbenyega T, et al. Malaria and intestinal co-infection among pregnant women in Ghana: prevalence and risk factors. Am J Trop Med Hyg. 2009;80:896-901.
5.
Steketee RM, Nahlen BL, Praise ME, et al. The burden of malaria in pregnancy in malaria endemic areas, Am J Trop Med Hyg. 2001;64:28-35.
6.
Bhattacharyya PC. Malaria in pregnancy. Medicine Update. 2011:477.
7.
Tako EA, Zhou A, Lohoue J, et al. Risk factors for placenta malaria and its effect on pregnancy outcome in Yaounde, Cameroon. Am J Trop Med Hyg. 2005;72:236-42.
8.
Meeusen EN, Bishof RJ, Lee CS. Comparative T-cell response during pregnancy in large animals and humans Am J Repro Immunol. 2001;46:16979.
9.
Telfer S, Lambin X, Birtles R. Species interactions in a parasite community drive infection risk in a wildlife population. Science. 2010;330:243-6.
19. Fredrick OA, Taiwo AO, Christopher EO, et al. Co-infection of malaria and intestinal parasites among pregnant women in Edo state, Nigeria. J Med Trop. 2017;1:43-8.
10. Rachel J, Raymond O, Michael O, et al. Prevalence of malaria parasites in adults and its determinants in malaria endemic area of Kisumu County, Kenya. Malaria Journal. 2015;14:263.
20. Eisele TP, Larsen DA, Anglewicz PA, et al. Malaria prevention in pregnancy, birth weight, and neonatal mortality: a meta-analysis of 32 national crosssectional datasets in Africa. Lancet Infect Dis. 2012;12:942-9.
15. Fairley JK, Bisanzio D, King CH. Birth weight in offspring of mothers with high prevalence of helminth and malaria infection in coastal Kenya. J Trop Med Hyg. 2013;88:48-53. 16. Getachew M, Tafess K, Zeynudin A, et al. Prevalence soil transmitted helminthiasis and malaria co-infection among pregnant women and risk factors in Gilgel Gibe Dam area, southwest Ethiopia. BMC Res Notes. 2013;6:263. 17. Bigoga JD, Nanfack MF, Awono-Ambene HP, et al. Seasonal prevalence of malaria vectors and entomological inoculation rates in the rubber cultivate area of Niete, South Region of Cameroon. Parasites Vectors. 2012;5:197. 18. Trape FJ. Rapid evaluation of malaria parasite density and standardization of thick smear examination for epidemiological investigations. Trans R Soc Trop Med Hyg. 1985;78:181-4.
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Available online at www.medicinescience.org
ORIGINAL RESEARCH
Medicine Science International Medical Journal
Medicine Science 2019;8(2):306-10
The evaluation of the effects of occupational arsenic exposure on man reproductive hormones Meside Gunduzoz1, Lutfiye Tutkun2, Servet Birgin Iritas3, Aybike Dip4, Serdar Deniz5 Occupational Diseases Hospital, Department of Family Medicine, Ankara, Turkey 2 Bozok University, Department of Medical Biochemistry, Yozgat, Turkey 3 Ministry of Justice, The Council of Forensic Medicine, Ankara, Turkey 4 Ministry of Justice, The Council of Forensic Medicine, Adana, Turkey 5 Provincial Health Directorate, Malatya, Turkey
1
Received 17 September 2018; Accepted 10 November 2018 Available online 10.01.2019 with doi:10.5455/medscience.2018.07.8957 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract The aim of this study is to determine the relationship between arsenic levels and reproductive hormones of workers with occupational arsenic exposure. Forty arsenic exposed workers, who applied to Ankara Occupational Disease Hospital, Occupational Health Outpatient Clinic between 2013-2017 with no complaints about infertility and erectile dysfunction (ED), were included in this study. Arsenic exposed individuals in the study group were working in the recycling and pest control companies. A healthy group, who consists of 57 office workers with no heavy metal exposure at workplace, was selected as the control group. Workers who have chronic disease, prescripted or herbal medicines were not included in this study. Whole group was composed of 97 male subjects, with 40 arsenic exposed workers and 57 control subjects. In the study group, urine arsenic levels (UAL) was significantly higher than the control group (57.98±26, 70 μg/L and 12.84±6.82 μg/L respectively) (p=0.000). Serum follicle stimulated hormone (FSH) and luteinizing hormone (LH) levels were found to be higher in the study group (FSH: 4.52±2.08/3.58±2.10, LH: 4.66±1.92/ 4.20±1.92). Total testosterone (TT), free testosterone (FT), and prolactin levels were significantly lower than in the control group (TT: 5.63±2.01/6.80±2.43, FT: 10.31±2.87/16,74±4,32, Prolactin: 12.61±7.03/15.55±6.93). Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), thyroid stimulating hormone (TSH), uric acid (UA), creatinine, triiodothyronine (T3) and thyroxine (T4) levels were similar in both groups. In the complete blood count (CBC) parameters, the HGB and HTC values were found lower in the study group. This is a pilot study that shows the toxic effects of arsenic exposure on male reproductive hormones. Keywords: Testosterone, arsenic, occupational exposure, Prolactin, follicle stimulated hormone (FSH), luteinizing hormone (LH)
Introduction Arsenic (As) compounds are widely used in the production of paint, glass, ceramics, semiconductors and agrochemicals. It is a toxic metalloid which is a natural part of earth crust [1-3]. Most prevalent arsenic is inorganic types found mainly is waters. Organic form of it are found in natural gas and petroleum source. As changes its chemical forms and oxidation level easily by the effect of microbiologic activity, redox potential, water pH and the presence of ions [4]. Leading routes of As exposure are production of ceramics, mining process, herbicides and insecticides [5]. Arsenic enters the human body via ingestion or inhalation or absorption by skin. Ingested
*Coresponding Author: Servet Birgin Iritas, Ministry of Justice, The Council of Forensic Medicine, Ankara, Turkey, E-mail: sbiritas@gmail.com
arsenic is easily absorbed through gastrointestinal tract. Inhaled arsenic is also well absorbed by lungs and enters bloodstream. First target of arsenic compounds is erythrocyte in body after systemic absorption [6]. Chronic arsenic exposure leads to metabolic and structural changes in hepatocyte and mitochondria in the liver as well as apoptosis, oxidative damage and lipid peroxidation [7-9]. It has been proven that As is clinically relevant bladder, lung, liver and skin cancers and it is defined as Group 1 carcinogen by the IARC (The International Agency for Research on Cancer) [10]. Adverse effects of As on circulation, respiration, digestion, hematology, musculoskeletal system, neurological and reproductive system have been proven by many scientific researches [7,11-13]. Effects of As exposure on reproductive system is mostly studied by animal models. Mehranjani and Hemadi [14] reported a statistically significant reduction in FSH and LH concentrations in rats treated with sodium arsenide at 8 mg kg BW-1 daily dose for eight weeks. Ali et al. found that FSH and LH levels increase and testosterone levels decrease in As exposed mices [15]. In another study with 306
doi: 10.5455/medscience.2018.07.8957
wistar rats, the plasma levels of FSH, LH and testosterone were found to be decreased with intraperitonally injected sodium arsenite [16]. However, Chiou et al. observed no FSH level change in arsenic trioxide injected mice although testosterone and LH levels decrease [17]. In the same study epididymal sperm number, motility and viability were found significantly decreased. In several animal studies, it has been found that arsenic causes a significant decrease in testicular weight, epithelial degeneration in seminiferous tubules, and loss of both Leydig and epithelial epididymal cells [1,18,19]. However, there is a limited number of studies about the effects of As exposure, both occupational or environmental, on the male reproductive system in humans [2,2022]. In this study total testosterone (TT), free testosterone (FT), follicle-stimulated hormone (FSH), luteinizing hormone (LH) and prolactin were measured and compared with urine arsenic levels of As exposed workers in order to show effect of As on male reproductive system. This is a case-control study that investigates the effects of occupational arsenic exposure on male reproductive system.
Med Science 2019;8(2):306-10
workers in control group. The mean UAL of exposed group was significantly higher than of control group, (57.98±26.70 μg/L and 12.84±6.82 μg/L respectively) (p=0.000). FSH and LH levels were found to be higher (FSH: 4.52 ± 2.08 / 3.58 ± 2.10, LH: 4.66 ± 1.92 / 4.20 ± 1.92); TT, FT and prolactin levels were lower (TT: 5.63 ± 2.01 / 6.80 ± 2.43, FT: ± 2.87 / 16.74 ± 4.32, Prolactin: 12.61 ± 7.03 / 15.55 ± 6.93) in the study group. When both groups are examined; there were no significant differences in ALT, AST, TSH, uric acid, creatinine, T3 and T4 levels. In our study, it was found that the levels of Hgb and Htc decreased in the exposed group that is similar to the results of some other researches [3,23,24]. Table 1. Laboratory findings of the groups
Parameters
Arsenic exposed group (n=40)
Control group (n=57)
p value*
57.98±26,70
12.84±5.79
0.000
Material and Methods
Urinary arsenic (μg/L)
Study Group Forty arsenic exposed volunteer workers with a mean age of 39.57, who applied to the Ankara Occupational Disease Hospital, were selected as study group, 31 people were recycling workers and nine were pest control workers. Healthy office workers, with a mean age of 33.07 with no exposure to arsenic or any toxic material, were chosen as control group. Both groups consist of non-smoker male subjects with over 18 years old. This study was approved by Ankara Keçiören Training and Research Hospital Research Ethics Committee of Health Sciences University (Decision No: 2012KAEK-15/1619).
Total testosterone (ng/dl)
5.63±2.01
6.80±2.43
0,014
Free testosterone (pg/ml)
10.31±2.87
16,74±4,32
0.000
FSH (mIU/ml)
4.52±2.08
3.58±2.10
0.033
LH (mIU/ml)
4.66±1.92
4.20±1.92
0.250
Prolactin(U/L)
12.61±7.03
15.55±6.93
0.044
TSH (µIU/ml)
1.43±0.75
1.38±0.69
0.767
T3(pg/ml)
3.08±0.44
3.11±0.39
0.723
T4(ng/dl)
1.06±0.15
1.03±0.11
0.301
ALT (U/L)
21.97±10.65
20.80±12.59
0.634
AST (U/L)
19.22±4.48
18±4.89
0.212
Uric asit (mg/dl)
5.47±1.12
5.16±1.08
0.180
Creatinine (mg/dl)
0.82±0.15
0.81±0.10
0.851
HGB (g/dl)
15.40±1.07
15.92±1.22
0..034
HCT %
45.73±2.97
47.29±3.40
0.021
WBC(kµ/L)
7.27±2.10
7.63±1.70
0.350
Age (years)
39.57±5.79
33.07±8.13
0.000
Measurements All blood samples were taken to Ethylenediamine Tetra Acetic Acid (EDTA) tubes. Haematological analyses were carried by Cell-Dyn Emerald Hematological Analyzer. Arsenic levels were measured by Inductively Coupled Plasma-Mass Spectrometer (ICP-MS) Agilent 7700 instrument. The levels of FSH, LH, PRL and testosterone were determined by Abbott Architect i2000 Immunoassay instrument. Serum AST, ALT were analyzed by spectrophotometric methods on Roche E170 Modular System (Roche Diagnostics, Mannheim, Germany). Statistical Analysis The data were statistically analyzed by SPSS 22.0 software. The normal distribution convenience of the data was determined by the Kolmogorov-Smirnow test. In the study, the statistical significance level was accepted as 0.05. The difference between the averages of the two independent variables and the correlation between two variables were evaluated by the t-test and Pearson Correlation analysis, respectively. Results The laboratory findings of the participants were presented in Table 1. There were 40 As exposed workers in study group and 57
*; p<0.05 is statistically significant, values are presented as “mean ± SD”
The Pearson Correlation coefficients (r) of continuous variables are presented in Table 2. There was a negative correlation between UAL and free testosterone (r = -0.263, p <0.01). Regression analysis, in which FT is dependent variable, age and UAL is independent variable, showed that UAL and age are responsible 32.4% of the change in FT. The results of the regression analysis and obtained formula are presented in Table 3. 307
doi: 10.5455/medscience.2018.07.8957
Med Science 2019;8(2):306-10
Table 2. Pearson correlation of continuous variables
Age
R
UAL
R
FT
R
TT
R
ALT
R
AST
R
TSH
R
Cre
R
T3
R
T4
R
UA
R
HGB
R
HCT
R
FSH
R
LH
R
PRL
R
Age
UAL
FT
TT
ALT
AST
TSH
Cre
T3
T4
UA
HGB
HCT
FSH
LH
PRL
1
.245*
-.416**
-.036
.005
.069
.111
.063
-.189
.012
-.063
-.137
-.165
.289**
.239*
-.220*
1
-.263**
-.023
.004
-.014
.178
-.071
-.084
-.052
-.083
-.003
-.008
.101
.051
-.075
1
.383**
-.050
-.140
.023
-.058
.116
-.001
-.139
.105
.126
-.161
-.162
.278**
1
-.112
-.130
.087
-.091
-.070
-.011
-.230*
.090
.115
-.143
.074
.035
1
.783**
-.049
.059
.255*
-.018
.150
.118
.163
.013
-.068
-.199
1
-.054
.127
.202*
-.008
.139
.039
.099
.013
-.017
-.141
1
.217*
.115
.105
-.128
-.052
-.048
.258*
.159
-.037
1
.133
.259*
.228*
.031
.091
.269**
.187
.005
1
.223*
.110
.314**
.369**
-.073
-.084
-.120
1
.008
-.075
-.074
.220*
.083
-.181
1
.004
-.067
-.015
-.038
.026
1
.896**
-.100
-.044
-.034
1
-.175
-.128
-.086
1
.516**
-.074
1
.096 1
shown that if blood As levels higher than 5.8Îźg/L resulted in decrease in sperm motility [34].
Table 3. Regression analysis results Dependent Variable FT
Independent Variable
F
Beta
t
R2
Age
22.499*
-0.287
-3.219*
0.324
-0.409
-4.581*
UAL Formula
FT= 22.729-0.179.age-0.071.UAL
*p<0.001
Discussion Toxic effects of As on human tissues and body systems are well documented by both human and animal studies. However, studies about its effects on reproductive system are very limited. Manna et al. found degeneration of seminiferous tubules and defoliation of spermatocytes in orally sodium arsenite given mouse [25]. Decrease in sperm count and increase in abnormal sperm in the epididymis were found after gallium arsenite intratracheal installation in rats [26]. Sperm abnormalities, decrease in serum testosterone and prostate cancer were reported in occupationally arsenic exposed men [27,28]. Ali et al. observed significant reduction in sperm count and motility and also declined level of testosterone and LH in As given mice [16]. Sarkar et al. reported reduction in LH, FSH and testosterone level and deterioration in germ cells of testicular tissue due to arsenic toxicity [29]. Depletion of testes weight, LH, FSH, testosterone and semen parameters also observed in As treated rabbit bucks [30]. Momeni and Eskandari found reduced sperm number, motility, viability and morphology in sodium arsenite treated rats [31]. Reduced testes, epididymis, prostate and seminal vesicle were found in sodium arsenite given swiss albino rats [32]. FSH, LH and testosterone levels were found decreased in the same study. In another study although no significant change in testis weight was observed, reduction in total motility of sperm, rapid moving spermatozoa, moderately moving spermatozoa and slow moving spermatozoa was present in arsenic treated animals [33]. It was
In our study, in the presence of high As levels, testosterone levels decrease with an increase in FSH (p <0.05) and LH (p=0.250) levels. These findings suggest that As causes testicular damage with direct toxic effect and reduces testosterone synthesis, and this status results in compensatory increase in FSH and LH concentrations. Our results also support the animal studies showing formation of sertoli cell damage due to arsenic exposure [1,2,19,20]. In a study conducted by Meeker et al. [35], the LH level was found to be lower when arsenic level was increased in blood. Hsieh et al. found that the increase in arsenic exposure caused decrease in testosterone levels in 177 men. They found significant ED in individuals with FT level <0.23 nmol / L. The mean testosterone and free testosterone levels were found to be lower in patients living in As endemic areas and having arsenic exposure greater than 50 ppb concentration [21]. There were no clinical complaints in our study group, but according to the obtained results, it can be considered that these individuals are vulnerable for the development of clinical outcomes such as ED due to testosterone release damage. The toxic effect mechanism of As exposure on the endocrine system is not clear. However, the oxidative stress during metal exposures is thought to be one of the important causes of this toxic mechanism [36,37]. Anterior pituitary gland plays an important role in the reproductive system. In animal studies, As has been shown to affect gonadotropin levels by showing hypothalamic pituitary axis or anterior pituitary toxic effects on the hypothalamus. Meeker et al. [38] showed that there was a significant decrease in prolactin levels by arsenic exposure in 219 male volunteers. Similarly, in the study by Jahan et al. prolactin levels were found to be significantly reduced in arsenic exposed mice [39]. Sonia et al. [40] showed that arsenic induced cellular apoptosis by the effect of oxidative stress in 308
doi: 10.5455/medscience.2018.07.8957
the anterior pituitary gland. In their study on mice, they found significant decrease in prolactin levels with increased arsenic level. Parallel to the results of these studies, we found statistically lower prolactin level in the arsenic exposed group. Our results also support toxic effect of arsenic on the hypothalamic pituitary axis. In addition to reproductive system effects, It is known that chronic arsenic exposure also causes hepatocyte damage in the liver [8,9]. In our study, although they were not statistically significant, AST and ALT levels were high in arsenic-exposed group, which may be consistent with possible hepatocyte damage of As exposure.
Med Science 2019;8(2):306-10
arsenic-induced liver damage. Ulus Cerrahi Derg. 2016;32:233-7. 10. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Some drinking-water disinfectants and contaminants, including arsenic. Monographs on chloramine, chloral and chloral hydrate, dichloroacetic acid, trichloroacetic acid and 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)furanone. IARC Monogr Eval Carcinog Risks Hum. 2004;84:269-477. 11. Liu J, Zheng B, Aposhian HV, et al. Chronic arsenic poisoning from burning high-arsenic-containig coal in Guizhou, China. Environ Health Perspect 2002;110:119-22. 12. Morales KH, Ryan L, Kuo TL, et al. Risk of internal cancers from arsenic in drinking water. Environ Health Perspect. 2000;108:655-61.
Conclusion
13. Greenberg SA. Acute demyelinating polyneuropathy with arsenic ingestion. Muscle Nerve. 1996;19:1611-3.
Our results showed that chronic As exposure creates the toxic effects on the male reproductive system by reducing testosterone release. FSH and LH seem to show a compensatory elevation reflecting decreased testosterone release.
14. Mehranjani MS, Hemadi M. The effects of sodium arsenite on the testis structure and sex hormones vasectomised rats. Iran J Reprod Med. 2007;5:127-33.
Although there is no clinical findings in study group, there could be a certain degree of damage and its effects may become clinically apparent in more severe and prolonged As exposures. Competing interests The authors declare that they have no competing interest. Financial Disclosure This study received no specific grant from any funding agency, commercial or notfor-profit sectors Ethical approval This study was approved by Ankara Keรงiรถren Training and Research Hospital Research Ethics Committee of Health Sciences University.
15. Ali M, Khan SA, Dubey P, et al. Impact of Arsenic on testosterone synthesis pathway and sperm production in mice. Innov J Med Health Sci. 2013;3:185-9. 16. Sarkar M, Chaudhuri GR, Chattopadhyay A, et al. Effect of sodium arsenite on spermatogenesis, plasma gonadotrophins and testosterone in rats. Asian J Androl. 2003;5:27-31. 17. Chiou TJ, Chu ST, Tzeng WF, et al. Arsenic trioxide impairs spermatogenesis via reducing gene expression levels in testosterone synthesis pathway. Chem Res Toxicol. 2008;21:1562-9. 18. da Silva RF, Borges CDS, de Almeida Lamas C, et al. Arsenic trioxide exposure impairs testicular morphology in adult male mice and consequent fetus viability. J Toxicol Environ Health A. 2017;80:1166-79. 19. Sanghamitra S, Hazra J, Upadhyay SN, et al. Arsenic induced toxicity on testicular tissue of mice. Indian J Physiol Pharmacol. 2008;52:84-90.
Meside Gunduzoz ORCID:0000-0001-6140-8331 Lutfiye Tutkun ORCID:0000-0002-8333-7404 Servet Birgin Iritas ORCID:0000-0001-5283-9973 Aybike Dip ORCID:0000-0001-8686-2637 Serdar Deniz ORCID:0000-0002-6941-4813
20. Hsieh F, Hwang TS, Hsieh YC, et al. Risk of erectile dysfunction induced by arsenic exposure through well water consumption in taiwan. Environ Health Perspect. 2008;116:532-6.
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Baltaci BB, Uygur R, Caglar V, et al. Protective effects of quercetin against arsenic-induced testicular damage in rats. Andrologia. 2016;48:1202-13.
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21. Mathur N, Pandey G, Jain GC. Male reproductive toxicity of some selected metals: A review. J Biol Sci. 2010;10:396-404.
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Saha JC, Dikshit AK, Bandyopadhyay M, et al. A review of arsenic poisoning and its effects on human health. Crit Rev Environ Sci Technol. 1999;29:281313.
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Bashir S, Sharma Y, Irshad M, et al. Arsenic induced apoptosis in rat liver following repeated 60 days exposure. Toxicology. 2006;217:63-70.
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Bali I, Bilir B, Emir S, et al. The effects of melatonin on liver functions in
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26. Omura M, Tanaka A, Hirata M, et al. Testicular toxicity of gallium arsenide, indium arsenide and arsenic oxide in rats by repetitive intratracheal instillation. Fundam Appl Toxicol. 1996;32:72-8. 27. Golub MS. Reproductive toxicology of water contaminants detected by routine water quality testing. Epidemiology. 1992;3:125-9. 28. Benbrahim-Tallaa L. and Waalkes MP. Inorganic arsenic and human prostate cancer. Environ Health Perspect. 2008;116:158-64. 29. Sarkar S, Hazra J, Upadhyay SN, et al. Arsenic induced toxicity on testicular tissue of mice. Indian J Physiol Pharmacol. 2008;52;84-90.
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36. Jain M, Kalsi AK, Srivastava A, et al. High serum estradiol and heavy metals responsible for human spermiation defect-a pilot study. J Clin Diagn Res. 2016;10:09-13. 37. Pahune PP, Choudhari AR, Muley PA. The total antioxidant power of semen and its correlation with the fertility potential of human male subjects. J Clin Diagn Res. 2013;7:991-5. 38. Meeker JD, Rossano MG, Protas B, et al. Multiple metals predict prolactin and thyrotropin (TSH) levels in men. Environ Res. 2009;109:869-73. 39. Sarwat Jahan, Shakeel Ahmed, Samina Razzaq and Hussain Ahmed. Adverse effects of arsenic exposure on the mammary glands of adult female rats. Pakistan J Zool. 2012;44:691-7. 40. Ronchetti SA, Bianchi MS, Duvilanski BH, et al. In vivo and in vitro arsenic exposition induces oxidative stress in anterior pituitary gland. Int J Toxicol. 2016;35:463-75.
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ORIGINAL ARTICLE
Medicine Science International Medical Journal
Medicine Science 2019;8(2):311-5
Static and dynamic balance between older individuals with and without chronic low back pain at the University College Hospital, Ibadan Ayodeji Ayodele Fabunmi, Oluwafikemi Adedolapo Badmus University of Ibadan, College of Medicine, Department of Physiotherapy, Oyo State, Nigeria Received 31 August2018; Accepted 10 November 2018 Available online 10.01.2019 with doi:10.5455/medscience.2018.07.8955 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract Balance is an essential component of an individual’s gait and it has been found to decline with age. Chronic low back pain is a common musculoskeletal disorder among aging population. This study compared dynamic and static balance performance between older individuals with and without chronic low back pain. This study was a cross sectional survey design. Willing elderly individuals with and without low back pain were recruited at three different clinics to participate in this study. Information on age, gender, occupation, marital status and duration of onset of low back pain was obtained from all participants. Sharpened Romberg test was used to measure static balance, while functional reach test and time up and go test were used to measure dynamic balance. Data were analyzed using descriptive statistics of mean, range, percentages and Inferential statistics of independent ‘t’ test. Alpha level was set at 0.05. Ninety- two participants (46 with chronic low back pain and 46 participants without chronic low back pain) with mean age of 67.02 years participated in this study. The participants comprised of 49 females (53%) and 43 males (47%). Elderly participants with chronic low back pain had significantly lower measure of functional reach test and significantly higher measure of time up and go test. Sharpened Romberg (eyes opened and eyes closed) test measure was significantly higher in participants without chronic low back pain than participants with chronic low back pain. Balance (static and dynamic) performance among elderly with chronic low back pain was significantly affected negatively. Routine evaluation and training of balance is advocated in management of elderly patients with chronic low back pain. Keywords: Static balance, dynamic balance, chronic low back pain, elderly
Introduction Low Back Pain (LBP) is pain appearing between 12th rib and hip with or without leg pain [1] and is one of the leading musculoskeletal disorders, with a lifetime prevalence of up to 84% [2]. The cause of LBP could be mechanical (including nonspecific musculoskeletal strains, herniated discs, compressed nerve roots, degenerative discs or joints disease and broken vertebra), non-mechanical (tumors, inflammatory conditions such as infections and spondylo-arthritis), or referred from internal organs (gallbladder disease, kidney stones, kidney infections and aortic aneurysm among others) [3]. Mechanical low back pain is the general term that refers to any type of back pain caused by placing strain on the muscles of the
*Coresponding Author: Ayodeji Ayodele Fabunmi, University of Ibadan, College of Medicine, Department of Physiotherapy, Oyo State. Nigeria E-mail: aafabunmi@yahoo.com
back [4]. Typically, mechanical pain results from bad habits, such as poor posture, poorly designed sitting, and incorrect bending and lifting motions. Non mechanical low back pain refers to any low back pain that is not caused by external physical force to the spine. Low back pain maybe classified by duration as acute (pain lasting less than 6 weeks), subacute (6 to 12 weeks) or chronic (more than 12 weeks) [5]. Chronic low back pain (CLBP) is established by the persistence of pain beyond 3 months of symptoms [6] and very often, the pain is non-specific, meaning that it is related to a mechanical origin [6]. Balance is an essential element in an individual’s gait and daily life activities involving sight, hearing, vestibular apparatus, proprioceptive sense, position sense, muscular force, and cognition [7]. Postural control is defined as the act of maintaining, achieving or restoring a state of balance during any posture or activity [8]. It can be described as either dynamic or static. Static postural control is attempting to maintain a base of support while minimizing movement of body segments and the center of mass, while dynamic postural control involves the completion of a functional task with 311
doi: 10.5455/medscience.2018.07.8955
purposeful movements without compromising an established base of support [9]. Factors that influence balance include sensory information obtained from the somatosensory system, the visual system, vestibular system and motor responses from the motor system which affects coordination, joint range of motion and muscle strength [10]. Proprioception is sensed from mechanoreceptors of muscles, ligaments, and joints and retains stability and bearings of the body during its static and dynamic movements [11,12]. Postural control is achieved by the integration of the information regarding body movement sensed through the somatosensory system in the central nervous system and the appropriate reaction of the musculoskeletal system [13]. Decrease of mobility and stability of the waist occurs in patients with chronic low back pain, and these bring about a decline of muscle strength and coordination capability and a change in proprioception [14,15]. The disabilities of the musculoskeletal system affect balance performing ability and limit use of a proper exercise strategy in perturbation [16]. In particular, patients with low back pain have a decreased balance ability compared with normal individuals [17]. When the human body is exposed to an unexpected load, muscles have to respond quickly to maintain the body’s balance and posture against the load. It is said that patients with low back pain will have problems with balance and maintaining posture caused by a delayed response time [18,19]. This study therefore compared balance performance between elderly individuals with and without chronic low back pain at the University College Hospital, Ibadan. Nigeria Material and Methods This study was a cross-sectional survey. Ethical approval was sought and obtained from the University of Ibadan/University College Hospital (UI/UCH) Research Ethics Committee before the commencement of the study. Verbal consent was obtained from the head of the three units in the hospital and from each participant in this study. Participants All consenting elderly patients with and without chronic low back pain above the age of 60 years were allowed to participate in this study. Elderly patients with chronic low back pain were diagnosed to have low back pain of more than 12 weeks duration from time of onset. Patients were recruited from 3 clinics (Physiotherapy out-patient clinic, Chief Anthony Anenih Geriatric Clinic, General out-patient clinic) in University College Hospital (UCH), Ibadan. Measurements were taken in the respective clinics where they were recruited in a treatment room. Procedure of measurement: The following instruments and forms were used for collection of data: 1. Socio-demographic and clinical data form: This was used to obtain socio-demographic information (age, sex, occupation, marital status). 2. Balance tests: Static and dynamic balance test were used to asses balance performance among the participants (elderly individuals with and
Med Science 2019;8(2):311-5
without chronic low back pain) Static balance test Sharpened Romberg test eyes opened and eyes closed: this test was performed as described by Briggs et al [20]. A leveled floor was used and the participant assumed a heel-to-toe standing position with the dominant leg placed at the back of the non-dominant leg. This test was done with the shoes off and with the eyes opened or closed while standing on a white plain sheet of paper. The timing started after the participants assumed the proper test position and indicated their readiness and values were recorded in seconds. The time was stopped when any of the following occurred: (a.) when the participant moves the foot/feet from the proper starting position or swayed. (b.) when the participant opened his or her eyes in the eyes closed trial. (c.) when the participant reached the maximum balance time of 60 seconds. Dynamic balance test a. Functional reach test (FRT): measured the distance between the length of the arm and a maximal forward reach in the standing position, while maintaining a fixed base of support. It was developed as a dynamic measure of balance with no attempt to control for the movement strategy [21]. To perform the test, the patient stood comfortably parallel to a wall, make a fist, and raise their arms to 90 degrees of flexion. A meter rule was placed parallel to the patient’s raised arm. The test was stopped when touched the wall or required any assistance from the examiner while trying to reach forward. The values obtained were recorded in centimeter. b. Time ‘up and go’: the participant rose from a chair, walked three meters, turned, walked back and sat down. During the test, the patients wore their routine foot wear. No form of assistive device was allowed during the test. No physical assistance was also allowed during the test. A stopwatch was used to time each test and the time was recorded in seconds. The patients received no score when they were unable to complete the test or required assistance to refrain from losing their balance or falling during the test. Data Analysis Descriptive statistics of frequency, percentages, mean, range and standard deviation were used to summarise participants’ age, sex, marital status, occupation, duration of onset of low back pain, static and dynamic balance performance. Inferential statistics of Independent ‘t’ test was used to compare the mean of functional reach test, time up and go test and Sharpened Romberg test (eyes opened and eyes closed) between elderly individuals with and without chronic low back pain. Alpha level was set at 0.05. Results A total number of 92 participants (46 participants with chronic low back pain and 46 participants without chronic low back pain) were involved in this study conducted at the University College Hospital, Ibadan. Nigeria. The participants comprised of 49 females (53%) and 43 males (47%) as shown in (table 1) with an overall mean age of 67.02 years. Out of the 92 participants, 69 312
doi: 10.5455/medscience.2018.07.8955
(75.0%) were married and 49 participants (53.0%) were retired from their occupations. Out of the 46 participants with chronic low back pain, 25 participants had chronic low back pain below 5 years, 15 participants had chronic low back pain between 5-10 years and 6 participants had chronic low back pain. Table 1. Socio-demographic Characteristics of participants Variables
Frequency
Percentage (%)
Male
43
47
Female
49
53
60-64
29
32
65-69
32
35
70-74
26
28
75-79
5
5
Retirees
49
53
Trader
12
13
Civil servants
11
12
Clergy
3
3
Teacher
2
2
Married
69
75
Widowed
18
20
Divorced
3
3
Separated
2
2
Sex
Age
Marital Status
Independent ‘t’ test was used to compare mean balance performance between individuals with and without chronic low back pain. There was a significant difference in the balance scores obtained between the two groups. The time up and go test measure in individuals with chronic low back pain ranged 6.47-28.68sec with a mean of 16.34±3.42sec while individuals without chronic low back pain ranged 5.97-25.26sec with a mean of 12.34±4.24sec as shown in (Table 2). Table 2. Comparison of the mean scores of the static and dynamic balance tests between elderly individuals with chronic low back pain and without chronic low back pain using Independent ‘t’ test
Variables
Mean±
S.D Range
without chronic low back pain Mean±S.D
n = 46
p
Range
n = 46
Dynamic balance test TUG
16.64±3.42
6.47-28.68
12.32±4.24
5.97-25.26
<0.001
FRT
16.12±6.00
3.15-30.00
32.64±10.10
5.51-50.00
<0.001
Static balance test SR (EO)
45.91±9.22
25.00-58.00
56.88±3.97
43.00-60.00
<0.001
SR (EC)
33.42±10.30
8.00-53.00
47.19±12.30
13.00-60.00
<0.001
Key TUG: Time up and go test (sec) FRT: Functional reach test (centimeters) SR (EO): Sharpened Romberg test eyes opened (sec) SR (EC): Sharpened Romberg test eyes closed (sec)
Med Science 2019;8(2):311-5
The functional reach test measure in individuals with chronic low back pain ranged 3.15-30.00cm with a mean of 16.12±6.00cm while individuals without chronic low back pain ranged 5.5150.00cm a mean of 32.64±10.10 cm. The Sharpened Romberg test measure with eyes opened, individuals with chronic low back pain ranged 25-58sec with a mean of 45.91±9.22sec while for individuals without chronic low back pain ranged 43-60 secs with a mean of 56.88±3.97sec. The Sharpened Romberg test measure with eyes closed, individuals with chronic low back ranged 8-53sec with a mean of 33.42±10.30sec while individuals without chronic low back pain ranged 13-60sec with a mean of 47.19±12.30 sec. Discussion
Occupation
Chronic low back pain
A total number of 92 participants (46 participants with chronic low back pain and 46 participants without chronic low back pain) were recruited to participate in this study. The outcome of this study showed that elderly patients without low back pain performed significantly better in dynamic and static balance test compared with elderly patient with chronic low back pain. Out of all the 92 participants, 43 (47%) were males while 49 (53%) were females, this is consistent with the findings from a study by Leveille et al [22] which reported that prevalence of chronic low back pain is higher in females than males. It was observed that 49 participants (53%) were retirees and were often at home. This is consistent with findings from a study which reported that sedentary lifestyle is implicated in incidence of low back pain [23] and this may explain why retirees in this study who are living a sedentary lifestyle are more prone to having low back pain. The mean scores for the static balance test (Sharpened Romberg Test) was significantly greater with the eyes opened than with the eyes closed for both patients with chronic low back pain and without chronic low back pain. This implies that participants had better balance with their eyes opened compared to when the eyes were closed. Emphasis has also been placed on the importance of optical input in good balance control [24]. Unfortunately as individual increase in age the visual ability tends to decline having a negative effect of balance. Result from the sharpened Romberg test (eyes opened and eyes closed) in this study showed that the mean values obtained for participants without chronic low back pain was significantly greater than the mean values obtained for participants with chronic low back pain. This implies that participants without chronic low back had better balance than the participants with chronic low back pain. This is consistent with the findings from the study by Da Silva et al [25] which reported that people with chronic low back pain had poorer balance than people without chronic low back pain. Results from the functional reach test showed that the mean value obtained by participants with chronic low back pain was significantly lower than the mean value obtained by participants without chronic low back pain. The reason for this is explained in that participants with chronic low back pain had poor muscle strength and hence ability of muscles to contract in functional reach to maintain body posture is limited. Limitation in functional 313
doi: 10.5455/medscience.2018.07.8955
reach could also be attributed to the pain experienced at the low back while the participants were trying to reach forward during the test. In addition pain can impair attention and concentration in older adult with chronic low back pain while performing the test [26] and attention is a required component of sensory integration needed for postural balance in the elderly [27]. In the selection of participants for this study, participants were not marched on the basis of gender, though there were just 6 more female participants than males in this study. This gender imbalance may have some influence on the outcome of the study, but this will not be significant. Results from the time up and go test showed that the mean value obtained by participants with chronic low back pain was significantly greater than the mean value obtained by participants without chronic low back pain. This implies that participants with chronic low back pain took a longer time to stand up from their seated position and walk. This could be due to the pain experienced by the participants while trying to stand from their seated position and walk. This is in contrast to the study conducted by Ishak et al [28] who found out that despite the presence of chronic low back pain, the participants were still walking around at the clinic. The older individuals in the study by Ishak et al [28] were still able to walk around because the pain intensity is mild and hence they can still cope, hence their ability to walk and get involved in physical activities. It is believed that chronic pain limits both strength and endurance in muscle activity which could explain why participants with chronic low back pain took longer time to perform the timed up and go test. The greater the intensity of pain the greater the reduction in muscle strength and endurance observed in the patients with chronic low back pain Conclusion There is significant decline in balance (static and dynamic) among individuals with chronic low back pain compared with elderly individuals without chronic low back pain.
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10. Palmieri RM, Ingersoll CD, Cordova ML, et al. The effect of a simulated knee joint effusion on postural control in healthy subjects. Arch Phys Med Rehabil. 2003;84:1076-9. 11. Newcomer KL, Laskowski ER, Yu B, et al. Differences in repositioning error among patients with low back pain compared with control subjects. Spine J. 2000;25:2488-93. 12. Laskowski ER, Newcomer-Aney K, Smith J. Proprioception. Am J Phys Med Rehabil. 2000;11:323-40. 13. Nashner LM. Sensory, neuromuscular, and biomechanical contributions to human balance in:PM Duncan (Ed.) Balance: proceedings of the American Physical Therapy Association forum. APTA, Alexandria (VA); 1990:5–12.
Recommendations Physiotherapists should see the need to include balance training in the treatment regime of elderly individuals with chronic low back pain. Older individuals who are retired from their occupation should be encouraged to participate in physical activities instead of having a sedentary lifestyle that could predispose them to having low back pain.
14. Koumantakis GA, Watson PJ, Oldham JA. Trunk muscle stabilization training plus general exercise versus general exercise only: randomized controlled trial of patients with recurrent low back pain. Phys Therapy. 2005;85:209-25.
Acknowledgements The authors gratefully acknowledge all the elderly participants in this study for their cooperation and assistance in willingness to participate.
17. Alexander KM, LaPier TL. Differences in static balance and weight distribution between normal subjects and subjects with chronic unilateral low back pain. J Orthop Sports Phys Ther. 1998;28:378-83.
Competing interests The authors declare that they have no competing interest Financial Disclosure The financial support for this study was provided by the investigators themselves.
15. Chang WD, Lin HY, Lai PT. Core strength training for patients with chronic low back pain. J Phys Ther Sci. 2015;27:619-22. 16. Walker BF. The prevalence of low back pain: a systematic review of the literature from 1966 to 1998. J Spinal Disorder. 2003;13:205-17.
18. Xia T, Ankrum JA, Spratt KF, et al. Seated human response to simple and complex impacts: paraspinal muscle activity. International J. of Ergon. 2008;38:767-74.
Ethical approval Ethical approval was sought from University of Ibadan/University College Hospital Ethics Committee.
19. Huang Q, Li D, Zhang Y, et al. The intervention effects of different treatments for chronic low back pain as assessed by the thickness of the musculus transversus abdominis. J Phys Ther Sci. 2014;26:1383-5.
Ayodeji Ayodele Fabunmi ORCID: 0000-0003-2840-7665 Oluwafikemi Adedolapo Badmus ORCID: 0000-0003-3439-9390
20. Briggs RC, Gossman MR, Berch R, et al. Balance performance among noninstitution-alized elderly women. Phys Ther. 1989;69:748-56.
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25. Da Silva RA, Vieira ER, Fernandes BP, et al. People with chronic low back pain have poorer balance than controls in challenging tasks. Disabil Rehabil. 2017;40:1294-300. 26. Weiner DK, Rudy TE, Morrow L, et al. The relationship between pain, neuropschological performance, and physical function in communitydwelling older adults with chronic low back pain. Pain Med. 2006;7:60-70.
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24. Bugnariu N, Fung J. Aging and selective sensorimotor strategies in the regulation of upright balance. J Neuroeng Rehabil. 2007;4:19
28. Ishak NA, Zahari Z, Justine M. Muscle Function and Functional Performance among Older Persons with and without Low Back Pain. http://dx.doi. org/10.1155/8583963 access date 17.1.2018
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ORIGINAL RESEARCH
Medicine Science International Medical Journal
Medicine Science 2019;8(2):316-9
Evaluation of strabismus surgery effects on anterior segment measurements using pentacam Mehmet Murat, Nilay Celebi, Cetin Akpolat Siverek State Hospital, Department of Ophthalmology, SanlĹurfa, Turkey Received 21 October 2018; Accepted 11 November 2018 Available online 20.01.2019 with doi:10.5455/medscience.2018.07.8964 Copyright Š 2019 by authors and Medicine Science Publishing Inc. Abstract To evaluate and compare preoperative and postoperative anterior segment parameters in patients who underwent unilateral or bilateral medial rectus muscle surgery. Fifty-one eyes of 30 patients were enrolled in the retrospectively designed study. Anterior segment parameters were measured via Pentacam prior to surgery and after the surgery. Besides anterior segment evaluation detailed routine ophthalmic examination was also performed for each participant. All patients had successful surgery correction. No complication was observed during follow-up period. No changes were noted in visual acuity and intraocular pressure. Statistical changes were observed in corneal astigmatism (P=0.009/0.005), corneal volume (P=0.012), and anterior chamber volume (P=0.024). Strabismus surgery might cause anterior segment parametric changes in short-term follow up, which might be reversible through the compensation process. Scheimpflug imaging is an anterior segment imaging system and these changes can be measured by Pentacam. Keywords: Strabismus, anterior eye segment, corneal topography
Introduction The basic goal of strabismus surgery is to align the eyes to their primary position. Previous studies have reported several factors related to surgical outcomes in horizontal strabismus: preoperative angle deviation, near and distance angle deviation difference and age of the patient at the time of surgery [1-3]. It has been identified that several temporary anterior segment changes have been occurred following strabismus surgery [46]. These changes are thought to be due to the alteration of extraocular muscle tension on corneal topography, which may cause by transmission via the sclera to the cornea, edema of the orbit and eyelid changes in ciliary body circulation or changes in the crystalline lens [7-9].
*Coresponding Author: Cetin Akpolat , Siverek State Hospital, Department of Ophthalmology, Sanliurfa, Turkey E-mail:akpolatcetin@yahoo.com
The effects of ocular surgery on the anterior segment have been better understood with the use of imaging systems [10]. Scheimpflug imaging (Pentacam) is one of the anterior segment imaging systems in clinical use today to evaluate these changes. In this study, we aimed to investigate the effects of strabismus surgery on visual acuity, intraocular pressure and anterior segment parameters. Material and Methods Patients and Study Design The retrospectively designed study was conducted at an eye center. The study protocol conformed to the tenets of the Declaration of Helsinki and informed consent was obtained from all participants or their parents. Fifty-one eyes of 30 patients with esotropia were recruited in the study. Patients who were not compatible to maintain fixation for Pentacam (Oculus, Inc., Berlin, Germany) analysis were excluded. The patients were assessed before surgery and at month 1 and 3 after surgery for the statistical evaluation. Best-corrected visual acuity (BCVA), biomicroscopic anterior 316
doi: 10.5455/medscience.2018.07.8964
and fundus examination and intraocular pressure (IOP) were the parameters studied beside anterior segment parameters measured with Pentacam. Measurements The Pentacam (Oculus Inc, Berlin, Germany) measurements were performed by a single experienced and masked observer. The patient was asked to put his/her chin on the chin rest and the forehead against the head rest and open both eyes and look at the fixation target. The examiner aligned the joystick until the rotating Scheimpflug camera automatically captured 25 single images within 2 seconds for each eye. The measurements were checked under the quality specification window; only correct measurements were accepted (comment box reading ‘’OK’’). If the comment box was marked yellow or red, the examination was repeated. Maps with poor centration were repeated in order to provide a best-fit toric/ ellipsoid reference surface. From the Pentacam examination: We measured flat (K1) / steep (K2) and maximum simulated (Km) keratometric readings, astigmatism, axis, posterior elevation (PE), corneal thickness of the center (CCT), anterior chamber depth (ACD; center, 3 mm nasal and temporal points from the center), corneal volume (CV) and anterior chamber volume (ACV) were recorded into an excel worksheet. Surgery All strabismus surgical procedures were performed by the same experienced surgeon under general anesthesia. The surgical technique was applied by conjunctival incisions on muscle insertion and conventional recession without recession of the opposing muscle. Muscle was sutured directly to the sclera with the use of a 6.0 double armed polyglactin 910 suture.
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Statistics The data of the study was analyzed by using Statistical Package for the Social Sciences (SPSS) version 19.0. Statistical analysis was performed with the paired t test and analysis of variance (ANOVA) for multiple comparisons using Tukey’s post-hoc test. P values of less than 0.05 were considered statistically significant for all statistical analyses. Results The mean age of 30 patients was 16.40±9.26 years (range, 3-40 years). 54 % of the patients were female and the left were male. The baseline BCVA was 0.222 logMAR. BCVA was 0.252 logMAR at month 1 and was 0.207 at month 3. There was no statistical alteration in the mean of BCVA during follow-up period (P=0.254). We also observed no statistical changes in the mean of IOP measurements during follow-up. (13.04±4.42 mmHg prior to surgery, 14.52±3.88 mmHg at postoperative month 1 and 13.46±5.08 mmHg at postoperative month 3; P=0.192). All patients had esotropia with a mean preoperative deviation measured using a prism of 20.56 prism diopters (range: 15 to 25 prism diopters). All of 51 eyes underwent horizontal isolated medial rectus muscle recession only. Bilateral medial rectus muscle recession was performed in 21 patients and unilateral medial rectus muscle recession was applied in 9 patients. The mean amount of medial rectus muscle recession was 5.40±1.02 mm (range, 5.0-8.0 mm). We observed statistical changes only in corneal astigmatism in both postoperative 1st and 3rd month when compared to baseline values (Table 1). While CV was statistically changed at month 3 after surgery, ACV alteration was in the significant level at month 1 (Table 1).
Table 1. Represents the alteration and P values of the Pentacam measurements at baseline, postoperative month 1 and postoperative month 3 Preoperative
Postoperative
P Value*
1st Month
Postoperative
P Value*
3rd Month
K1(D)
43.03±1.15
43.19±1.10
0.296
43.05±1.03
0.364
K2(D)
44.11±1.89
44.24±1.95
0.177
44.14±1.78
0.357
Km(D)
43.64±1.52
43.87±1.42
0.190
43.66±1.33
0.338
C.Astg.(D)
1.09±1.11
3.23±2.79
0.005†
2.73±2.09
0.009†
Axis(Deg.)
120.12±71.83
147.87±46.08
0.054
132.34±50.23
0.290
8.20±6.38
7.09±7.91
0.155
7.11±6.09
0.062
CCT(μm)
546.94±48.29
543.34±42.39
0.311
541.46±41.79
0.118
ACD(mm)
2.98±0.31
2.99±0.26
0.896
2.97±0.28
0.647
CV(mm3)
60.61±4.51
60.17±4.02
0.333
59.63±3.93
0.012†
175.14±27.46
168.74±25.60
0.024†
172.66±27.29
0.418
PE
ACV(mm3)
Data were expressed as mean ± SD. K=keratometry; Km=maximum keratometry; C.Astg.=corneal astigmatism; CCT=central corneal thickness; PE=posterior elevation; ACD=anterior chamber depth; CV=corneal volume; ACV=anterior chamber volume; ACD=anterior chamber depth. *Statistically analyzed with repeated variance analysis test. †Statistically significant.
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Discussion Strabismus surgery may cause some refractive and anterior segment changes. Although some studies in the literature have reported that postoperative alterations may last for as long as 1 year following surgery [11], these changes are mostly thought to be transient [12]. The influence of extraocular muscle tension on corneal topography is considered as an important contributing mechanism [13]. The Pentacam is a corneal topography system that operates according to the Scheimpflug principle to create an image of the illuminated plane that appears completely sharp from the anterior surface of the cornea to the posterior surface of the crystalline lens [14]. The camera provides an overall view of the anterior segment of the eye that can be used to generate data on corneal power, elevation, curvature, pachymetry, and depth of the anterior eye chamber [15]. The purpose of this study was to investigate the effect of isolated medial rectus muscle recession surgery on the refractive error, corneal measurements, and anterior chamber depth and corneal volume measured by corneal topography. Kwito S et al [16] documented muscle recession may lead flattening in the adjacent quadrant. However, Hainsworth DP et al [9] reported muscle tension alteration, which resulted in a global change over the corneal surface rather than a change in the adjacent quadrant, so reciprocal compensation could be the reason for the refractive errors and this might be the cornerstone for alterations in the anterior chamber parameters. Emre S et al [4] used the Pentacam to study the effects of strabismus surgery on the anterior chamber and found that 6 patients who underwent recession-resection surgery were prone to change in the anterior chamber volume. Jung JH et al [17] designed a prospective study including 28 patients who underwent either horizontal muscle recession or recession plus resection of both horizontal muscles. They concluded that patients with strabismus had an ACD change during the early postoperative period. However, the ACD returned to its preoperative state by 3 months after surgery. These results showed that extraocular muscle surgery might induce reversible changes for the anterior segment parameters. In contrast to this study we did not note any statistical changes in ACD. Moreover, we observed statistical changes in CV and ACV. Noh JH et al [18] have reported that lateral rectus muscle recession resulted in short-term changes in refractive error in their cohort study. They think that all the changes might be due to postoperative tissue edema and trauma, which resolves over time. They observed a decrease in change after 1 month, which could be due to the effects of compensation by other quadrants of the eye or resolution of the surgical induced tissue damage. Parallel to this study we also observed statistical changes in astigmatism both at 1st and 3rd month following surgery and these alterations showed a decrease pattern in change compared to baseline. We observed an increase in K1, K2 and Km at both month 1 and 3 compared to baseline with a less increase at 3rd month, but all these alterations were statistically insignificant. Parallel to K1, K2
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and Km changes, we observed an increase in corneal astigmatism at both month 1 and 3 compared to baseline with a less increase at 3rd month but in contrast to K1, K2 and Km changes, alterations in corneal astigmatism were statistically significant. Conclusion In conclusion, our study demonstrates that altered muscle tension caused by horizontal muscle recession has some significant effects on anterior chamber parameters, which can be measured with Pentacam Scheimpflug camera. We observed statistical changes in astigmatism at both 1st and 3rd month after surgery. We also noted statistical changes in ACV and CV at 1st and 3rd month of followup period, respectively. We observed a decrease in increase which may show some reversible changes probably due to the effects of compensation. Sample size, follow-up period are the limitations for our study, so new studies with larger sample size and longer follow-up are warranted to clarify the clinical results. Competing interests The authors declare that they have no competing interest. Financial Disclosure All authors declare no financial support. Ethical approval Consent of ethics was approved by the local ethics committee. Mehmet Murat ORCID: 0000-0002-0919-5153 Nilay Celebi ORCID: 0000-0002-1223-3595 Cetin Akpolat ORCID: 0000-0002-7443-6902
References 1.
Kim MH, Chung H, Kim WJ, et al. Effects of Surgical Assistant’s Level of Resident Training on Surgical Treatment of Intermittent Exotropia: Operation Time and Surgical Outcomes. Korean J Ophthalmol. 2018;32:59-64.
2.
Lim SH, Hwang BS, Kim MM. Prognostic factors for recurrence after bilateral rectus recession procedure in patients with intermittent exotropia. Eye (Lond) 2012;26:846-52.
3.
Gezer A, Sezen F, Nasri N, et al. Factors influencing the outcome of strabismus surgery in patients with exotropia. J AAPOS. 2004;8:56–60.
4.
Emre S, Cankaya C, Demirel S, et al. Comparison of preoperative and postoperative anterior segment measurements with Pentacam in horizontal muscle surgery. Eur J Ophthalmol. 2008;18:7-12.
5.
Bagheri A, Farahi A, Guyton DL. Astigmatism induced by simultaneous recession of both horizontal rectus muscles. J AAPOS. 2003;7:42-6.
6.
Betts C, Olitsky S. Corneal astigmatic effects of conventional recession vs suspension recession (“hang-back”) strabismus surgery: a pilot study. Binocul Vis Strabismus Q. 2006;21:211-3.
7.
Killer HE, Bahler A. Signifi cant immediate and long-term reduction of astigmatism after lateral rectus recession in divergent Duane’s syndrome. Ophthalmologica. 1999;213:209-10.
8.
Preslan MW, Cioffi G, Min YI. Refractive error changes following strabismus surgery. J Pediatr Ophthalmol Strabismus. 1992;29:300-4.
9.
Hainsworth DP, Bierly JR, Schmeisser ET, Baker RS. Corneal topographic changes after extraocular muscle surgery. J AAPOS. 1999;3:80-6.
10. Shankar H, Taranath D, Santhirathelagan CT, et al. Anterior segment biometry with the Pentacam: Comprehensive assessment of repeatability of automated measurements. J Cataract Refract Surg. 2008;34:103-13. 11. Fix A, Baker JD. Refractive changes following strabismus surgery. Am Orthop J 1985;35:59-62.
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doi: 10.5455/medscience.2018.07.8964 12. Hutcheson KA. Large, visually significant, and transient change in refractive error after uncomplicated strabismus surgery. J AAPOS 2003;7:295-7. 13. Kwitko S, Feldon S, McDonnell PJ. Corneal topographic changes following strabismus surgery in Graves’ disease. Cornea 1992;11:36-40. 14. Cerviño A, Gonzalez-Meijome JM, Ferrer-Blasco T, et al. Determination of corneal volume from anterior topography and topographic pachymetry: application to healthy and keratoconic eyes. Ophthalmic Physiol Opt. 2009;29:652-60. 15. Mannion LS, Tromans C, O’Donnell C. Reduction in corneal volume with
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severity of keratoconus. Curr Eye Res. 2011;36:522-7. 16. Kwito S, Sawusch MR, McDonnell PJ, et al. Effect of extraocular muscle surgery on corneal topography. Arch Ophthalmol 1991; 109:873-8. 17. Jung JH, Choi HY. Comparison of preoperative and postoperative anterior segment measurements with Pentacam® in strabismus surgery. J Pediatr Ophthalmol Strabismus. 2012;49:290-4. 18. Noh JH, Park KH, Lee JY, et al. Changes in refractive error and anterior segment parameters after isolated lateral rectus muscle recession. J AAPOS. 2013;17:291-5..
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Available online at www.medicinescience.org
ORIGINAL RESEARCH
Medicine Science International Medical Journal
Medicine Science 2019;8(2):320-4
Aortic cross clamp duration in cardiopulmonary bypass oxidative stress relationship Zinet Asuman Arslan Onuk Antalya Training and Research Hospital, University of Health Science, Department of Anesthesiology, Antalya, Turkey Received 19 Febuary 2019; Accepted 18 March 2019 Available online 21.03.2019 with doi:10.5455/medscience.2019.08.9021 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract The aim of this study was to determine whether there is a direct correlation between the aortic cross-clamp (ACC) duration and oxidative stress marker levels in systemic blood of patients undergoing CPB (cardiopulmonary bypass). We have evaluated the changes in oxidant-antioxidant balance and its relation to ACC time by measuring PON1, ARE, TOS and TAS. The ACC duration mean of 70 patients (43 males, 27 females) to whom CPB was made was 37 minutes. We divided the patients into two groups since their ACC duration was below and above 37 minutes. The HDL (high-density lipoprotein) and levels of TAS, TOS, PON1 and ARE; the oxidative stress markers, were analyzed by taking blood from the patients in the first hour before the pump and after the pump. The levels of oxidative stress markers, PON1, ARE, TOS and TAS were MEASURED within 1 hour before the pump and after the pump. While the serum TOS levels were 4.59±5.32 as preoperative and 4.01±4.34 as postoperative in Group I (ACC over 37 minutes), they were found 4.28±5.54 as preoperative and 2.02±2.57 as postoperative in Group II and determined as a statistically significant decrease (p<0.05, p=0.034). A significant difference was statistically found in the preoperative and postoperative TAS and TOS values’ comparison. A postoperative significant reduction was observed for the TOS values in both Group I and Group II (p=0.034). It is thought that the factors will be able to affect the oxidative stress differently from the ACC duration in the CPB based upon our study’s results. Further controlled studies are needed on this topic. Keywords: Cardiopulmonary bypass, oxidative stress, aortic cross-clamp
Introduction The myocardial tissue significantly increases subjected to the oxidative stress in the operations, in which the cardiopulmonary bypass (CPB) was used. The primary resources of oxidative stress occurred in these operations are thought to be ischemia and perfusion of the extracorporeal circulation and myocardial tissue. Oxidative stress is an oxidant-antioxidant imbalance status, due to oxidants which exceed the antioxidant capacity. CPB is a part of cardiac surgery that has been associated with harmful effects in several organs [1,2]. Numerous studies describing the nature of oxidant and antioxidant status and the time course of their formation during CPB were published [3,4]. During cardiac surgery aorta cross-clumping and cardioplegic cardiac arrest induce global ischaemia, so cardiac surgery can be considered as human model of controlled ischeamia similar to this occurring in myocardial infarction [5,6]. Aortic cross-clamp
*Coresponding Author: Zinet Asuman Arslan Onuk, University of Health Science, Antalya Training and Research Hospital, Department of Anesthesiology, Antalya,Turkey E-mail: asumanonuk@hotmail.com
(ACC) manipulation is the most attributive resource of oxidative stress secondary to ischemia-reperfusion damage [7]. Increased levels of oxidative stress are associated with inflammatory changes, such as lipid peroxidation, modification of proteins, activation of complement cascades, excessive reactive oxygen radicals, and expression of adhesion molecules [8]. Serum Paraoxonase (PON) E.C.3.1.8.1.is an arylesterase synthesized in the liver and is a HDL associated enzyme which is responsible for the antioxidant properties of HDL [9]. Human serum paraoxonase (PON1) and arylesterase (ARE) are lipophilic antioxidant enzymes. Serum PON1 binds to highdensity lipoprotein (HDL) and contributes to the elimination of organophosphorus compounds and free radicals and can reduce oxidative stres [10]. Contribution of the various mechanisms on the oxidant-antioxidant balance during on-pump coronary artery bypass grafting has not been fully evaluated yet [11,12]. The aim of this study was to determine whether there is a direct correlation between the aortic cross clamp duration and oxidative stres marker levels in systemic blood of patients undergoing CPB. We have evaluated the changes in oxidant-antioxidant balance and 320
doi: 10.5455/medscience.2019.08.9021
its relation to ACC time by measuring PON1, ARE, TOS and TAS. The HDL (high-density lipoprotein) and levels of TAS, TOS, PON1 and ARE; the oxidative stress markers, were measured by taking blood from the patients in the first hour before the pump and after the pump. We compared the serum TAS (total antioxidative stress), TOS (total oxidative stress), PON1 and ARE levels and researched their changes on the oxidative stress for the groups separated in accordance with aortic cross-clamp durations of the patients, who underwent open-heart surgery by using the cardiopulmonary bypass. Material and Methods This study was performed in University of Health Science, Antalya Training and Research Hospital, Department of Anesthesiology. The ACC duration mean of 70 patients (43 males, 27 females) to whom CPB was made in our hospital was 37 minutes. We divided the patients into two groups since their ACC duration was below and above 37 minutes. The HDL (high-density lipoprotein) and levels of TAS, TOS, PON1 and ARE; the oxidative stress markers, were analyzed by taking blood from the patients in the first hour before the pump and after the pump. Those having chronic kidney failure, neoplastic disease, autoimmune disease, liver disease, and antioxidant use were not included in the study. The premedication was made by 0.1 mg/kg midazolam to each group before the anesthesia induction. The radial artery cannulation was made for the hemodynamic follow-up. All cases were had breathed by 100% O2 during the anesthesia induction and intubated by 5-7 mg/kg thiopental, 5 mcg/kg fentanyl and 0.6 mg/kg rocuronium bromide. In the maintenance, 5-6% desflurane, 50% O2 + 50% dry air, and rocuronium bromide and fentanyl were used. The rectal body temperature and urination were followed up during the surgery by applying 3-lumen central catheter from the right internal jugular vein. After systemic administration of heparin (300 UI/kg body weight), CPB was initiated in a standard manner with cannulas placed in the ascending aorta and right atrium. Moderate hypothermia was used (32–33°C), and local hypothermia for myocardial protection was achieved by anterograde infusion of a cool cardioplegic solution (Cardi-Braun), administered intermittently (every 25– 30 minutes average) during clamping. After removing the cross clamp, protamine was given for heparin reversal. The ACC duration was above 37 minutes in 30 patients in Group I and 11 of the patients were coronary artery patients (3 grafts to 8 patients, 4 grafts to 3 patients), 15 of them were valve patients (mitral valve to 8 patients, aorta valve to 7 patients) and 4 of them were valve+coronary artery patients. The ACC duration was below 37 minutes in Group II and there were 40 patients. 27 of the patients in this group were coronary artery patients (4 grafts to 3 patients, 3 grafts to 18 patients and 2 grafts to 6 patients) and 13 of them were patients to whom valve replacement was made (10 mitral valves; 3 aortic valves) (Table 1).
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The patients’ body mass index (BMI), left ventricular ejection fraction (LVEF), pump duration, surgery, and anesthesia durations were recorded. The patients’ smoking habits and associated diseases were also recorded. The blood samples were taken just before and after the cardiopulmonary by-pass. Samples were separated from the cells for 10 minutes by a centrifuge running at 3000 rounds per minute (rpm), then kept at -80 °C and used to analyze the TOS, TAS, PON1 and ARE. The statistical analysis was performed at the statistics department of Akdeniz University, Wilcoxon paired test was used to compare mean values at each stage of the experiment. The Mann Whitney test was used to compare the differences of TAS, TOS, PON1 and ARE activity between groups according to the clinical features. P values less than 0.05 were considered significant. Results In our study, we researched the cross-clamp duration length’s influence on the oxidative stress for the patients underwent openheart surgery and analyzed the oxidative stress indicators’ levels including serum TAS, TOS, PON1 and ARE. The male/female ratio of 30 patients included in the study in Group I was 16/14 (53% of them were female, 46% of them male), male/female ratio of 40 patients included in the study in Group II was 27/13 (67% of them were female, 32% of them male) and age means of the patients found in Group I and Group II were found as 59.10±14.25 and 59.10±14.2, respectively (p=0.42). The diabetes mellitus, one of the associated diseases, was found in 7 patients in Group I (n=30) and in 12 patients in Group II (n=40) and hypertension was found in 21 patients in Group I and in 27 patients in Group II. While there was a smoking history in 10 of 30 patients in Group I, there was in 14 of 40 patients in Group II. While the LVEF values were 57.27±9.12 in Group I, it was 58.60±8.07 in Group II. There was not statistically any significant difference between the intergroup LVEFs (p=0.52). There was a statistically significant difference when both groups’ pump durations were compared (p=0.001). The pump durations were found as 74.83±15.51 in Group I and as 54.45±16.60 in Group II, respectively (Table 1). When the preoperative serum PON1 levels (128.70±60.19 in Group I and 114.30±85.24 in Group II) in each group were compared by the postoperative serum PON1 levels (118.55±44.33 in Group I and 109.65±61.48 in Group II) they were not statistically significant (p>0.05, p=0.18, p=0.50, Table2. When the preoperative serum ARE levels (229.25±71.69 in Group I and 218.07±66.87 in Group II) in the groups were compared by the postoperative serum ARE levels (222.80±44.05 in Group I and 207.71±49.1 in Group II) they were not statistically significant (p>0.05, p= 0.42, p=020, Table 2). While the serum TAS levels decreased to 2.01±0.27 preoperatively and 1.97±0.22 postoperatively in Group I (ACC over 37 minutes) and were at the value of 2.01±0.25 preoperatively in Group II, they were postoperatively found as 2.12±0.35 and statistically 321
doi: 10.5455/medscience.2019.08.9021
evaluated as significant (p<0.05, p=0.042, Table 2, Figure 2). While the serum TOS levels decreased to 4.59±5.32 preoperatively and 4.01±4.34 postoperatively in Group I (ACC over 37 minutes)
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and were at the value of 4.28±5.54 preoperatively in Group II, they were postoperatively found as 2.02±2.57 and statistically evaluated as significant (p<0.05, p=0.034, Table 2, Figure 1).
Table 1. Demographic data and perioperative variables of groups Characteristics Age (years) Sex (M/F) BMI (kg/m2) Diabetes mellitus (n) Hypertension (n) Cigarette smoking (n) LVEF(%) Pump duration Anesthesia time Surgery time Aortic valve replacement (n) Mitral valve replacement (n) Valve replacement with coronary graft CABG (n) Number of grafts per patients 2 greft 3 greft 4 greft
Group I(n=30) (ACC over 37 minutes)
Group II(n=40) (ACC under 37 minutes)
59.10±14.25 16/14 26.87±4.15 7 21 10 57.27±9.12 74.83±15.51 201.00±41.18 174.17±37.49 7 8 4 11
59.58±11.96 27/13 27.75±4.99 12 27 14 58.60±8.07 54.45±16.60 194.25±41.15 164.50±34.93 3 10 27
8 3
6 18 3
p 0.42 0.44
0.52 0.001* 0.49 0.36
ACC: Aortic Crossclamp, BMI: Body Mass Index, LVEF: Left ventricular ejection fraction , CABG: Coronary Artery Bypass Greft *P<0,05 significantly Table 2. PON1, HDL, ARE, TAS and TOS values of groups.
PON1 HDL ARE TAS TOS
GROUP I
GROUP 2
p
preoperative
128.70±60.19
114.30±85.24
0.18
postoperative preoperative postoperative preoperative postoperative preoperative postoperative preoperative postoperative
118.55±44.33 35.77±10.61 34.20±8.91 229.25±71.69 222.80±44.05 2.01±0.27 1.97±0.22 4.59±5.32 4.01±4.34
109.65±61.48 35.56±11.35 36.46±10.08 218.07±66.87 207.71±49.1 2.01±0.25 2.12±0.35 4.28±5.54 2.02±2.57
0.50 0.93 0.32 0.42 0.20 0.51 0,042* 0.46 0.034*
Values expressed as mean±SD. PON1: Paraoxonase 1, HDL: High density lipoprotein, ARE: Arylesterase TAS: Total Antioxidative Stress, TOS: Total Oxidative Stress *P<0.05 significantly Figure 2. Postoperative TAS levels in in group I (n=30 )and group II (n=40) *p<0.05, p=0.042
Discussion The free radicals are controlled by antioxidants levels and excessive free radical formation and insufficient removal by antioxidants leads to oxidative stress on heart [13].
Figure 1. Postoperative TOS levels in in group I (n=30 )and group II (n=40) *p<0.05, p=0.034
Ischemic period associated with oxidative stres in open heart surgery patients. Authors (Garcis-de-la-Asuncion et al.) reported that ACC time was positive correlated with total peroxide, 8-isoprostane and nitrites/nitrates levels in patients undergoing open heart surgery patients [14,15]. As a reference, they took the median value of the aortic cross-clamp duration (50 minutes) from all patients (n = 30). However, they could not find an intergroup difference in 30 patients who were separated into two groups (coronary surgery and valve surgery). 322
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The groups were classified as those being shorter and being longer than 37 minutes since the ACC duration was meanly observed as 37 minutes in our study (Group I, n=30; Group II, n=40). We could not find a positive correlation between the ACC durations and TOS, TAS, PON1 and ARE levels in the patients who underwent cardiopulmonary bypass surgery. Some studies have measured other oxidative stress markers, such as TBARS, malondialdehyde, oxidized glutathione, protein carbonyls [16,17]. We measured the oxidative stress markers such as PON1, ARE, TAS and TOS in the blood before and after the pump within this study. Ferrari et al. reported a significant and sustained increase in OS in 10 patients undergoing ONCABG with a mean ACC duration of 55.2 minutes, while a mild and temporary increase in oxidative stress in 10 patients undergoing ONCABG (on-pump coronary artery bypass graft) with a mean ACC duration of 25.2 minutes [18]. Nowicki et al. also reported the absence of a significant oxidative damage in the myocardial biopsy specimens of 8 patients undergoing ONCABG with a mean ACC duration of 29.5 minutes [19]. In our study, while the ACC duration was 27.48±5.96 in 30 patients to whom CPB was made in Group I, it was found as 50.20±13.31 in 40 patients in Group II. The Diabetes Mellitus, hypertension and smoking history also affect oxidative stress. There was diabetes mellitus, one of the associated diseases, in 7 patients in Group I (n=30) and in 12 patients in Group II (n=40) for the patients that we included in our study. The hypertension was found in 21 patients in Group I and in 27 patients in Group II. While there was smoking history in 10 of 30 patients in Group I, there were 14 of 40 patients in Group II. There was not statistically any significance between the groups. Previous studies in patients have demonstrated that cardiac surgery with CPB is associated with ischemia-reperfusion consecutive to cross-clamping [22-25]. In our study, our patients were the patients, whose on-pump CPB was applied due to the CABG, valve (mitral and aortic) and valve replacement with coronary greft operations. The pump times were found as 74.83±15.51 (Group I) and 54.45±16.60 (Group II), respectively. This difference was statistically found significant (p: 0.001, Table 1) We think that the differences seen in TAS and TOS values do have a relationship with the pump. These patients may suffer systemic oxidative stress with an increase of multiple oxidative stress markers and a decrease in antioxidant reserves that can result in increased postoperative morbidity and prolonged hospital stay [26,27]. The TAS, TOS, PON1 and ARE levels were also evaluated in our study in order to determine the cardiopulmonary bypass application’s relationship with the oxidative stress. A significant difference was statistically found in the preoperative and postoperative TAS and TOS values’ comparison. A postoperative significant reduction was observed in the TOS values in both
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Group I and Group II (p=0.034, Table 2, Figure 1). A postoperative reduction also revealed similarly in the PON1 and ARE, however, the difference is not significant. On the other hand, not any significant difference was statistically found in the intergroup oxidative stress markers. Conclusion In conclusion, we believe that the results of this study contribute to a better understanding of the pathophysiology of reperfusion of the human heart. This study suggests that considerable oxidative stress occurs early during conventional cardiac surgery with CPB. The degree of oxidative stress in the myocardium and in other tissues depends on the duration of the ischemic period. It is thought that the factors will be able to affect the oxidative stress differently from the ACC duration in the CPB based upon our study’s results. Further studies, in which the different parameters are evaluated, are needed on this topic. New strategies need to be proven to reduce the systemic oxidative stress and to improve patient outcomes after CPB, which will require large-multicenter studies Financial Disclosure All authors declare no financial support. Ethical approval The study was approved by Ethics Committee of Antalya Education and Research Hospital. Zinet Asuman Arslan Onuk ORCID: 0000-0002-9189-2926
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van Himbergen TM, van der Schouw YT, Voorbij HAM, et al. Paraoxonase1 (PON1) and the risk for coronary heart disease and myocardial infarction in a general population of Dutch women. Atherosclerosis. 2008;198:408-14.
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Ayub A, Mackness MI, Arrol S, et al. Serum paraoxonase after myocardial infarction. Arterioscler Thromb Vasc Biol. 1999;19:330–5.
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Biglioli P, Cannata A, Alamanni F, et al. Biological effects of off-pump vs. on-pump coronary artery surgery: focus on inflammation, hemostasis and oxidative stress. Eur J Cardiothorac Surg. 2003;24:260-9.
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Med Science
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Medicine Science International Medical Journal
Medicine Science 2019;8(2):325-9
Effect of alveolar recruitment maneuver on ischemia-modified albumin and oxidative stress in laparoscopic cholecystectomy Zubeyir Cebeci1, Betul Kozanhan2, Huseyin Kurku3, Sadik Ozmen4 1 Ordu University Faculty of Medicine Department of Anesthesia and Reanimation, Ordu, Turkey Konya Education and Research Hospital, University of Health Science Department of Anesthesia and Reanimation, Konya, Turkey 3 Konya Education and Research Hospital, University of Health Science Department of Biochemistery, Konya, Turkey 4 Antalya Education and Research Hospital, University of Health Science Department of Anesthesia and Reanimation, Antalya, Turkey 2
Received 12 October 2018; Accepted 12 November 2018 Available online 21.01.2019 with doi:10.5455/medscience.2018.07.8960 Copyright Š 2019 by authors and Medicine Science Publishing Inc. Abstract The effect of intraoperative recruitment maneuver on ischemia-modified albumin (IMA) and oxidative stress in performed laparoscopic cholecystectomy with intraabdominal 12 mmHg pressure was investigated. Fifty patients undergoing laparoscopic cholecystectomy were included in the study by separating the two groups. Basal ventilator settings in both groups were set as tidal volume: 6-8 ml / kg, respiratory rate: 12 breaths / min, I: E = 1: 2, flow: 4 l / min. In group R, after intubation, 5 cm H2O PEEP was adjusted in addition to basal ventilator settings. Five minutes after CO2 insufflation and exsufflation, PEEP was step by step raised to 10-15-20 cm H2O, and patients were ventilated for 10 breaths. Venous blood samples were taken from the patients for three times in perioperative periods to measure IMA and oxidative stress. There was no difference between the groups in terms of demographic data, surgery and insufflation times. Significant differences in IMA,TOS,TAS and OSI levels within the group were observed but no difference was between groups. The recruitment maneuver that we used in laparoscopic cholecystectomies was found to have no effect reducing tissue ischemia and oxidative stress response in the intraoperative period. Keywords: Cholecystectomy, laparoscopic, ischemia-reperfusion injury, ischemia-modified albumin, oxidative stress, positive-pressure respiration
Introduction In laparoscopic cholecystectomy operations, the pneumoperitoneum is achieved by applying intraperitoneal carbon dioxide (CO2) via insufflation. Increased intraperitoneal pressure due to pneumoperitoneum leads to pathophysiological changes in pulmonary and hemodynamic functions [1]. These changes cause ischemia in the splanchnic area and also cause reperfusion injury after deflation. The deterioration of gas exchange between the tissues and increasing CO2 absorption due to increased intraabdominal pressure cause hypercarbia and acidosis [2,3]. The resulting ischemia, hypercarbia and acidosis cause changes in serum oxidative stress markers [4]. In the study, the effect of intraoperative recruitment maneuver application on ischemia modified albumin, total oxidant status, *Coresponding Author: Zubeyir Cebeci, Ordu University Faculty of Medicine Department of Anesthesia and Reanimation, Ordu, Turkey E-mail:zubeyircebeci@gmail.com
and complete antioxidant status is evaluated in laparoscopic cholecystectomies performed with an intra-abdominal pressure of 12 mmHg. Material and Methods This study was performed with the permission of the Necmettin Erbakan University Meram Faculty of Medicine Ethics Committee (protocol no. 2014/47). ASA l-ll 50 patients aged between 18 and 60 years who will be applied laparoscopic cholecystectomy with written and oral consent are enrolled in the study. Chronic hypertension, diabetes mellitus, chronic obstructive pulmonary disease, coronary artery disease, ischemic heart disease, decompensated heart failure, burger disease, chronic renal failure, chronic liver disease, neoplastic disease, hyperlipidemia, hypertriglyceridemia, statin use, hypoalbuminemia, smoking history and those who are allergic to the drugs used are removed from the study. After taking the patients on the operation table, the vascular access 325
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was established using 20G intravenous cannula, and the heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP), peripheral oxygen saturation (SpO2) were monetarized (Datex-Ohmeda Cardiocap/5®). Anesthesia induction is applied with intravenous lidocaine, 2 mg/kg propofol and 0.6 mg/kg rocuronium in both groups after preoxygenation. After the tracheal intubation, the basal ventilation parameters of patients were set as tidal volume of 6-8ml/kg, respiration rate of 12 min-1, I:E=1:2, and flow rate of 4 l/min. Then, the patients were connected to anesthesia device (DatexOhmeda). Anesthesia was maintained using 0.05-0.2mcg/kg/min remifentanil, 50% O2+air, and 1-2% sevoflurane. The muscle relaxant effect was antagonized with 0.04 mg/kg neostigmine and 0.02 mg/kg atropine at the end of the surgical procedure. The patients, who would be undergone laparoscopic cholecystectomy under 12 cmH2O intra-abdominal pressure, were divided into control group (Group K) and study group (Group R) by using closed envelopes containing numbers. While the patients in the Group K undergo anesthetic follow-up with baseline ventilator settings, the patients in the Group R were applied alveolar recruitment maneuver in addition to basal ventilator settings. In addition to the basal ventilator settings, PEEP was set to 5 cmH2O after the intubation for the patients in Group R, and the PEEP value was gradually increased to 10-15-20 cmH2O twice after 5 minutes from insufflation and exsufflation. In each of PEEP increase, the plateau and peak pressure limits were set below 30-50 cmH2O limits, and the recruitment maneuver was performed by implementing 10 times ventilation to the patient. Intraoperative follow-up of all patients was performed with end-tidal carbon dioxide (ETCO2) values of 35-45 mmHg and Sp02: 95-100%. Values of HR, SBP, DBP, MBP, SpO2, and ETCO2 were recorded before induction and every 5 minutes after induction. When the mean blood pressure is reduced by 25% compared to the basal value, 0,5 mg ephedrine was given; 100 mg of nitroglycerin was given in case of an increase. When the heart rate decreased below 50 beat/min, 0.02 mg/kg atropine was pushed intravenously. 5ml venous blood samples were taken from the patients into the biochemistry gel tube for ischemia-modified albumin (IMA), total antioxidant status (TAS), and total oxidant status (TOS) analyses at preoperative (T0), 20 minutes after insufflation (T1), and postoperative 6th hour (T2). The venous blood sample was allowed to clot for 30 minutes at room temperature and then centrifuged at 3000 G for 20 minutes and the serums were separated. Separated samples were stored at -80 C until the working day. Samples are centrifuged again before
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working after dissolution at working day. IMA level measurement was measured with Human Ischemia Modified Albumin (IMA) ELISA kit (Shanghai Sunred Biological Technology Co., Ltd, Shanghai, China). The results were expressed in U/ml. TOS and TAS levels were measures using Total Oxidant Status (TOS) and Total Antioxidant Status (TAS) commercial kits (Rel Assay Diagnostics, Megatıp Sanayi Ticaret Ltd. Şti., Gaziantep, Turkey) and Prestige 24i clinic chemical auto-analyzer (Tokyo Boeki Ltd., No.13.8 2-Chome Hachobori Chuo-ku, Tokyo, JAPAN). The results were expressed in Trox equivalent millimole per liter for TAS (mmol Trolox equiv/L), and H2O2 equivalent micromolar per liter for TOS (μmol H2O2 equiv/L). The TOS values were proportioned to TAS values as percentage, and the oxidative stress index (OSI) that is accepted as the indicator of oxidative stress was calculated. (While calculating the oxidative stress, TAS concentrations were converted to µmolTroloxEquiv./L and OSI = (TOS = µmol/ H2O2 Equiv/L) / (TAS = mmolTroloxEquiv./L x 1000) x 100 formula was used in calculation.) Demographic data, duration of operation and duration of insufflation were compared between groups using Student’s t-test and Chi-square test. ANOVA was used for repeated measurements and Bonferroni correction paired t-test was used as the second test of this test in-group comparisons. The difference between the groups was made by covariance analysis (ANCOVA). Results There were no differences between the groups in terms of demographical data, and surgery and insufflation durations (Table 1). The systolic blood pressure, diastolic blood pressure, mean blood pressure, heart rate and peripheral oxygen saturation values were not statistically significant difference between the groups. But there were statistically significant differences in intragroup comparison in terms of diastolic blood pressure (p=0.022) (Figure 1) and mean blood pressure (p=0.027) at 5th minute (Figure 2). There was statistically significant difference in intragroup comparison of ischemia-modified albumin (p <0.001), total oxidant status (p <0.001), total antioxidant status (p <0.001) and oxidative stress index (p <0.001). But there was no difference between the groups (Table 2) (Figure 3).
Table 1. Demographic data of patients Group K
Group R
(n=25)
(n=25)
40.96±13.145
35.04±10.338
0.083*
5/20
6/19
0.733‡
Weight (kg)
72.36±14.728
73.28±13.085
0.816*
Height (cm)
165.68±6.388
164.44±8.559
0.564*
Operation time (min)
49.24±17.826
47.56±12.162
0.699*
Insuflation time (min)
35.76±15.262
32.76±12.056
0.444*
Age (years) Sex (Male/Female)
p
* Student’s t tests, ‡ Pearson chi-square test
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Figure 1. Diastolic Blood Pressure * Bonferroni paired t test (p=0,022)
Figure 2. Mean Blood Pressure * Bonferroni paired t test (p=0,022) Table 2. IMA, TAS, TOS and OSI T0
T1
T2
P
Group K (n=25)
32.49±13.68
62.24±32.57
136.55±98.15
0.001*
Group R (n=25)
32.58±12.34
91.85±42.63
163.04±80.62
0.252‡
Group K (n=25)
1.07±0.29
1.32±0.19
1.44±0.21
0.001*
Group R (n=25)
1.15±0.28
1.31±0.18
1.45±0.17
0.173‡
Group K (n=25)
4.17±1.55
6.58±2.38
18.46±10.47
0.001*
Group R (n=25)
4.65±2.34
7.71±4.28
14.56±8.54
0.403‡
Group K (n=25)
0.40±0.14
0.49±0.16
1.18±0.18
0.001*
0.52±0.40
0.57±0.39
0.93±0.07
0.203‡
IMA
TAS
TOS
OSI
IMA: ischemia-modified albumin (U/ml) TAS: Total antioxidant status (mmol Trolox equiv/L) TOS: Total oxidant status (μmol H2O2 equiv/L) OSI: Oxidative stress index
T0: Preoperative T1: 20 minutes after insufflation T2: 6th hour postoperative
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may contribute to the tissue ischemia. At the end of laparoscopic cholecystectomy surgeries, the perfusion of tissues increases and, together with the perfusion, the oxidative reactions, in which the free radicals arise in tissues, occur. Together with the cellular damages, the free radicals cause tissue damages [4,19]. The oxidative stress increases occurring due to ischemia in laparoscopic cholecystectomies were shown using different methods [20-23]. In our study, the measurement methods based on total antioxidant status (TAS) and total oxidant status (TOS), which are easier and more affordable than separately measuring the oxidants and antioxidants, was employed [24,25].
Figure 3. IMA, TAS, TOS and OSI
Discussion The increased intra-abdominal pressure in laparoscopy abdominal surgeries leads to changes in the circulation and respiratory system. Complications related to these changes are trying to be reduced by keeping the CO2 insufflation pressure as low as possible, appropriate anesthesia management, application of ventilation strategies, proper position, cardiac monitoring and close observation [5-7]. For this purpose, the efficacy of alveolar recruitment maneuver which has been investigated in many studies applied to reduce the adverse effects of laparoscopic surgery on the respiratory system has been shown to increase partial arterial oxygen pressure and pulmonary compliance [8-12]. Ischemia-modified albumin is used in early diagnosis of ischemic heart diseases as well as it is seen to be used in the diagnosis of other diseases with ischemia to [13-15]. It has been shown that increased intra-abdominal pressure in laparoscopic cholecystectomy leads to decreased tissue perfusion in the abdominal organs and ischemia [16-18]. Koksal et al.; have been shown that the increase in intra-abdominal pressure due to pneumoperitoneum during the laparoscopic cholecystectomy has an increasing effect on IMA and the increase can be used to determine the changes in the blood flow of splanchnic area and intra-abdominal organs [14]. In our study, the difference in intra-group comparison of IMA values at preoperative (T0), 20 minutes after insufflation (T1), and postoperative 6th hour (T2) are significant (p<0.0001) and this results supports that the increased intra-abdominal pressure changes the blood flow of the abdominal organs [14]. However, although there was no difference between the groups in terms of IMA (p-0,252), the increase the IMA value is higher in the Group R than Group K, indicates that the applied recruitment maneuver
The increase in oxidative stress on the pulmonary system by the increase in intra-abdominal pressure has been demonstrated by measuring oxidant and antioxidants in bronchoalveolar lavage fluid [26,27]. In open abdominal surgeries, in which the standard ventilation is implemented, the displacement of the diaphragm due to general anesthesia and use of muscle relaxant, cause atelectasis. It was shown that the cytokines increased due to atelectasis in the taken bronchoalveolar lavage fluid sample [28,29]. In studies comparing the recruitment maneuver and standard ventilation in open abdominal surgeries found that respiratory complications such as pleural effusion and atelectasis were less and FEV and FVC capacity were higher in the recruitment maneuver group patient [29]. In our study, the statistically significant difference (p<0.001) found in the intragroup comparison of TOS, TAS, and OSI values measured at preoperative (T0), 20 minutes after insufflation (T1), and postoperative 6th hour (T2) indicated that increased intra-abdominal pressure increases the oxidative and antioxidative response [20-23,26]. But, despite that there was no difference between the groups, the rise in TOS in the sixth hour postoperatively was lower in the Group R compared to the Group K, suggests that the recruitment maneuver that was applied reduced the oxidative response. Even though there are studies reporting that vasopressor usage decreases in surgical operations, in which the alveolar recruitment maneuver is implemented, no significant hemodynamic effect originating from maneuver was observed [8,12,29]. In our study, no significant hemodynamic change was observed in any of two groups but both groupsâ&#x20AC;&#x2122; post-induction diastolic blood pressure and mean blood pressure values that were lower than the initial values suggest that it is related with the cardiac depressant effect of the anesthetic agent used in induction. Conclusion In conclusion, the recruitment maneuver that we use in laparoscopic cholecystectomies was found to have no effect reducing tissue ischemia and oxidative stress response in intraoperative period. But they might contribute to reducing the ischemia reperfusion damage in postoperative period. In order to demonstrate this effect, more comprehensive studies are needed. Competing interests The authors declare that they have no competing interest Financial Disclosure This study was supported by the konya education and research hospital. Ethical approval Ethics committee approval was received from konya necmettin erbakan university meram faculty of medicine.
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doi: 10.5455/medscience.2018.07.8960 Zubeyir Cebeci ORCID:0000-0001-7862-4268 Betul Kozanhan ORCID: 0000-0002-5097-9291 Huseyin Kurku ORCID: 0000-0002-1083-4151 Sadik Ozmen ORCID: 0000-0003-3345-6365
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Medicine Science 2019;8(2):330-4
Intensive care nurses’ perception of care concept the case of Turkey: A qualitative study Veysel Tekin1, Ulviye Gunay2 1
Gazi Yasargil Diyarbakir Training and Research Hospital, Diyarbakir,Turkey 2 Inonu University, Faculty of Nursing, Malatya, Turkey Received 11 September 2018; Accepted 19 November 2018 Available online 10.01.2019 with doi:10.5455/medscience.2018.07.8956 Copyright © 2019 by authors and Medicine Science Publishing Inc.
Abstract Care is the most important concept that constitutes the core of nursing. Nurses’ perceptions on care influences the quality of care practices greatly. It is especially important that nursing care is adequate and effective at intensive care units where care is provided for patients with complex and life-threatening problems. This study was conducted with the aim of determining the perceptions of nurses on the concept of care and their care practices. This qualitative study was conducted at an intensive care unit in the Southeastern Anatolia Region in Turkey. The study was performed with 17 intensive care nurses. Private face-to-face semi-structured interviews were conducted to collect the data. The data were analyzed using the method of content analysis. All the nurses stated that the concept of care is the basis of nursing. As a result of the analysis of the data, three main themes were determined. (a) Perception of care; physical care, psychological and physical care, (b) Care; care practice, care responsibility, contribution of care practices to perception of nursing as a profession, (c) Feelings after care; feeling happy, feeling of fulfilling your responsibility. Care perceptions and care practices of intensive care nurses should be improved further. Keywords: Concept of care, intensive care nurses, qualitative study
Introduction Care is the most important concept that distinguishes nursing from other health disciplines and constitutes the core of nursing. The concept of care may be defined as being sensitive to the needs and desires of others [1]. Many nursing theorists define the concept of care differently. According to Leininger (1988), care is a basic human need, and it is the use of vocational knowledge and skills to improve health on the basis of values such as empathy, compassion, reassurance and help [2]. Swanson (1991) defined care as the care and feeding of the needy and noted that it includes getting to know the patient and doing something for the patient [3]. Hall defined care as the combination of factors that make up the concept of motherhood, such as nurturing and providing comfort [4]. Among the definitions made in the literature, the most emphasized common view is that care is the essence and foundation of nursing. The concept of care includes elements of empathy, love, compassion, communication, caring, attention, value, ethical behavior, providing information and respect. *Coresponding Author: Ulviye Gunay, Inonu University, Faculty of Nursing, Malatya, Turkey E-mail: ulviye.gunay@inonu.edu.tr
Nursing care requires that the right decision is made for the individual for whom the nurse is responsible in accordance with the accumulated scientific knowledge of nursing. A professional nursing approach requires nurses to take the concept of care as a basis in their professional practice. Nurses’ perception of care has a significant effect on the quality of their care practices. It is especially important that nursing care is adequate and effective at intensive care units, where care is provided for patients with complex and life-threatening problems. The physical structure of the intensive care units in Turkey varies. Especially at major university hospitals in Ankara, Istanbul and Izmir, first, second and third tier intensive care services are provided with fully equipped medical equipment in line with the standards of intensive care units. In some cities, however, the physical conditions and medical equipment of intensive care units are not on a desired level. Whether intensive care units are fully equipped or not, there are various problems in intensive care services in Turkey. The main problems are intensive care patient bed capacity, the low number of physicians specializing in this area and problems in intensive care nursing [5-7]. In Turkey, intensive care nursing is performed by nurses who 330
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graduate from different levels of education (high school, undergraduate and graduate). Intensive care nurses are not adequate in number. Additionally, most of the currently working nurses did not receive special training for intensive care. Nurses work with a large number of patients at intensive care units over long hours and under difficult conditions [8,9]. These problems affect the quality of nursing care negatively. In a study conducted by Karadağ and Taşçı in Turkey, it was determined that nurses perform tasks such as giving medication to patients and monitoring vital sings, but they did not perform the practices related to care in general. In the same study, it was found that unfavorable working conditions, lack of motivation, communication problems and nurses performing tasks that are not part of their responsibilities affected their care practices negatively [10]. Care practices of intensive care nurses are also influenced by the concept of care in addition to their working conditions. There is no study in Turkey that described how nurses perceive the concept of care. This study was conducted with the aim of determining the perceptions of nurses on the concept of and the care practices of intensive care unit (ICU) nurses. Material and Methods Design This study was a qualitative one which used a content analysis approach. Qualitative content analysis is a technique that is widely used to interpret the meaning of the content of the data in texts. Qualitative studies investigate phenomena rooted in the context of social sciences. This research method may be effective in clarifying ambiguous and unknown areas, and it is the best way to describe life experiences and essential social processes in these which focuses on the “entire” perception and comprehension. Therefore, this was thought to be the most appropriate method for determining the perceptions of intensive care nurses on the concept of care and their care practices in a multi-dimensional and in-depth manner [11]. Setting and participants This study was conducted with nurses in the period of JanuaryMarch 2016, who were working at intensive care units of Diyarbakir Gazi Yasargil Research and Training Hospital located in southeast Turkey. The intensive care units at this hospital provide 1st, 2nd and 3rd tier Intensive Care services. Intensive care units are composed of internal, surgical, reanimation, coronary, neurology, cardiovascular and surgical units, with a total bed capacity of 73. At these units, the nurses work in two shifts, at hours of 8-16 and 16-08, for 48-56 hours a week. Nurses provide care to an average of four patients during their daytime and nighttime shifts. Before starting the study, all nurses working at the intensive care units of the hospital (120 nurses) were informed about the purpose and scope of the study. 17 nurses stated that they were willing to participate. The study was conducted with these 17 nurses. In qualitative research, the sample size is determined based on the ability of the sample to produce the data needed by the researcher. It is generally agreed that the sample size is sufficient when the same/ similar data are repeated in the interviews (when the data reaches a
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saturation level). In this study, data saturation was reached with 17 nurses, so the sample size was not increased furthe. Ethical considerations Prior to the study, institutional permission and ethical approval was obtained (Application no: 532/58). Intensive care nurses who were planned to be included in the scope of the study were informed about the scope and purpose of the study and that participation was voluntary. Verbal and written permission was obtained from the nurses who agreed to participate in the study. Data collection The data were collected by means of in-depth semi-structured one-on-one interviews. The semi-structured interview form was prepared by the researchers (Table 1). An appointment was made for when the nurses were available for the in-depth one-on-one interviews. Voice recordings were made during the interviews with permission from the nurses. All nurses consented to voice recording. Each interview lasted for 30 minutes on average. Oneon-one interviews were held in the meeting room of the hospital, in a quiet environment by the first researcher during the nurses’ free hours. The researcher allowed the participants to freely express their views during the interview. Judging, approving or refusing attitudes and expressions were avoided. The open-ended questions that were asked to the nurses during the interviews are listed in Table 1. Table 1. Questions asked to the nurses during one-on-one interviews
What is the concept of care for you? Can you explain? Which elements are included in the concept of care? Can you explain? For you, who should provide care? Can you explain? What kind of care practices do you provide for patients at your clinic? Can you explain? Do you notice the changes in your patients after you provide care? Can you explain? What do you feel after providing care for a patient at your clinic? Can you explain? What is the contribution or relationship of care practices to the professionalization of nursing? Can you explain?
Data analysis The data were evaluated by the content analysis method. The results were obtained by analyzing the data using an inductive approach and the constant comparison method. Content analysis is a research technique used to produce reproducible and valid results regarding the content of data [12]. The first researcher immediately transcribed the voice recordings he had obtained at the end of the interviews and created a transcript file. Then, two researchers read this transcript several times and coded and grouped similar and different expressions. At the next stage, the coded data were organized [13], and the main themes and sub-themes of the study are identified Table 2. 331
doi: 10.5455/medscience.2018.07.8956 Table 2. Themes of the study Main Themes
Sub-Themes
Concept of Care
Providing the physical needs of the patient Psychological and physical care
Care
Care Responsibility Care Practices Contribution of care in professionalization
Feelings After Care
Being Happy The Feeling of Fulfilling Your Responsibility
Results It was found that the mean age of the nurses was 28.73, eight nurses were male, 12 were university graduates, one had a master’s degree, the mean duration of their employment was 4 years, and seven nurses received intensive care training.
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Care is not just about cleaning the patient’s hand, face or foot and leaving the patient like that. Care is a physiological, psychological communication process. It treats the patient as a whole and meets their physiological and psychological needs. This includes cleaning the patient, the treatment of the patient, communication with the patient and their relatives, and everything else (Nurse 10). Care Care Practices The care practices stated by the nurses in the interviews included feeding the patient, providing wound care, providing hygiene, positioning, treatment and follow-up. We are mostly performing the cleaning of the patient. Wiping the entire body of the patient, haircut, nail cleaning, oral cleaning, positioning, etc. At the same time, we perform other procedures such as treatment and wound care (Nurse 7). We perform all the self-care of the patient. For this reason, there is no time left for more specific nursing practices such as bladder training, cuff training, etc. (Nurse 2).
Perception of Care Intensive care nurses stated that the concept of care constituted the core of nursing. Most of them said they perceived the concept of care more as providing the physical care of the patient. Some nurses also perceived it as the patient’s both physical and psychological well-being.
Care Responsibility The vast majority of the nurses stated that nurses and caregivers should perform patient care together. Several nurses stated that it could be implemented only by nurses.
Physical Care According to the nurses, the concept of care was defined as helping patients who were unable to meet their physical needs do so.
I think the physical care of the patient should be performed by their caregivers. We can only help them, because nurses have a heavy workload. I am not saying that they should do everything, for example, they cannot perform wound care, but they can perform most care practices (Nurse 14).
We usually provide physical care since we work at the intensive care unit. In general, body cleaning, perineal cleaning, positioning, oral care, cold treatment when necessary, all of these constitute the concept of care (Nurse 5). What we encounter most in intensive care is infections. For this reason, hygiene and physical care of patients are very important. For me, care is performing body bath, hair cleaning, oral care and nail care of patients (Nurse 13). I think the concept of care is to meet all the needs of the patient. For example, provision of hygiene, feeding and positioning. Try to maintain all the physical requirements of the patient (Nurse 14). Psychological and physical care Some of the intensive care nurses stated that the concept of care included elements such as communicating, touching, being compassionate and meeting the physical needs of the patient. Supporting the patient in the spiritual sense as well as the physical care of the patient, to speak or to hold if the patient can perceive it, are the most important aspects of a nurse’s care practice (Nurse 6). The fact that the patient is lying in the same position continuously under four walls causes depression. This is why when I go to the hospital and see the patient, I approach the patient with expressions such as good morning, how are you, you look better today (Nurse 2).
The statement of one nurse was very striking.
Care should not be performed only by nurses. Health is a team effort, so task sharing may be done. For example, the doctors are not responsible only for ordering the treatment of the patient. Doctors should also make the patient feel psychologically relaxed. However, they do not do it too much. Therefore, the overall care of the patient becomes our responsibility (Nurse 2). The view of one nurse was different: Since nurses know what patients want better, care is the responsibility of nurses (Nurse 1). Contribution of care practices to perception of nursing as a profession Intensive care nurses stated that patient care practices have an important place in the perception of nursing as a profession. Nurses are often seen as an assistant health workers in our society. I think patient care practices carry nursing to a higher level (Nurse 5). In our society, nurses are seen as the assistant of the doctor. It is seen as if the doctor calls for the treatment, and the nurse performs. Nurses are known as workers who perform injections, give medication or measure blood pressure. Yet, care is a nursing practice that demonstrates our independence and shows that we are a profession (Nurse 3). 332
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One nurse who stated that care practices do not contribute to the professionalization of nursing: Care is important for both the patient and the nurse. On the other hand, does it make any contribution to professionalization? I do not know that. I do not really know, because I do not know how it is perceived from the outside. However, I think care does not elevate the profession of nursing. I think it demeans nursing (Nurse 14). Nursesâ&#x20AC;&#x2122; feelings after care practice Feeling Happy The nurses stated that they observed positive changes in the patients after implementing care, and they felt happy. Patients look dirty before we perform care, sometimes they smell bad. I see that the patient is cleansed and relaxed after care. I see gratitude in the eyes of the patient, I feel happy and emotional (Nurse 9). The Feeling of Fulfilling Your Responsibility The nurses stated that they felt peaceful after providing care for their patients. When I provide care for the patient, I relieve their pain, I feel conscientiously relaxed, I think I am useful and beneficial to the patient (Nurse 1). Firstly, I feel peaceful. I believe that I am earning lawful â&#x20AC;&#x201C;halalmoney (Nurse 5). Discussion In this study, nurses stated that the concept of care constituted the basis of nursing, and it was perceived as fulfilling the patientâ&#x20AC;&#x2122;s physical needs and providing psychological support. The concept of care includes elements of empathy, caring, love, providing information and being open to communication [2,3,14]. In a qualitative study conducted with Pakistani nursing students regarding their perceptions of the concept of care, it was determined that most of the students referred to care as a maternal relationship and stated that communication, assistance, empowerment and development behaviors constituted the concept of care [15]. In another study conducted with a qualitative method that examined the attitudes and behaviors of nurses towards the concept of care, questions were asked about what care is and how care should be provided. Based on the responses of the nurses, it was determined that the most emphasized themes were caring, being thoughtful and sensitive, showing affection, approaching patients without judgement, being open to communication and empathy [16]. In the study by Mlinar (2010) conducted with 166 first- and third-year nursing students on their perceptions on care practices, it was found that the students perceived caregiving as being respectful, helping, teaching, getting to know patients and establishing relationships [17]. The students stated that nurses should consider the concept of care while applying their knowledge and skills. In the same study, it was found that the perception of the concept of care differed between the first-grade nursing students and third-grade nursing students. In this study, it was found that the intensive care nurses mostly perceived care as providing physical care to the patient and
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mentioned only some of the elements included in the concept of care, suggesting that the knowledge and perceptions of the intensive care nurses related to the concept of care should be improved. In the findings of this study, the vast majority of nurses stated that caregivers should assist nurses in the physical care of the patient. The nurses thought that the caregivers of the patients should help nurses because of their heavy workload. However, a few nurses stated that the care practices should be performed entirely by the nurses. There are various problems in the field of intensive care nursing in Turkey. These are important issues such as low number of nurses, lack of intensive care certificates in most of the currently working nurses and high number of patients per nurse and long working hours [8,9]. A study conducted with 112 intensive care nurses in Turkey revealed that 78.6% of nurses would not want to choose the profession of nursing again, 68.8% were considering quitting, 50.64% thought the working conditions were heavy and intense, and 33.76% were not satisfied with the working hours [18]. In the literature, it was reported that intensive care nurses experienced physical and mental exhaustion [19,20]. In this study, the reason why nurses request caregiver support may be the aim to reduce their workload or due to the fact that care awareness was not on a desired level. Whatever the case is, nursing care is a practice that is the sole responsibility of nurses. For this reason, development of awareness on nursing care and provision of appropriate working conditions may increase the time and quality of patient care. The nurses stated that the care practices they performed at the intensive care unit were feeding the patients, wound care, providing hygiene, positioning, treatment and monitoring. In the definition of the duties of intensive care nurses in Turkey, it is stated that nurses are responsible for diagnosing patients with complex and lifethreatening problems, monitoring the patients constantly, applying quality and advanced intensive care and treatment interventions, establishing therapeutic communication with patients and their relatives, and protective, healing and rehabilitative initiatives [21]. The statements of the intensive care nurses showed that they fulfilled a part of their care responsibilities. The intensive care nurses stated that care practices contribute to the professionalization of nursing. In order for a job to be considered as a profession, it needs to fulfill certain criteria such as involving theoretical knowledge, duration of training, providing services to the society, independence, having ethical values and commitment to the profession.22 Care practices that constitute the core of the profession of nursing require professional knowledge, skills and autonomy. Nurses provide important healthcare services to individuals and the society through care practices. For this reason, care practices have a significant contribution to the professionalization of nursing. In a study conducted in Turkey, it was found that the nursing services that were provided were insufficient, and the care practices in the profession of nursing gave a psychological satisfaction to nurses [22]. In the literature, it was emphasized that nursing and care cannot be independent from each other [4,23]. In this study, although the statements of the nurses regarding the contribution of care for the professionalization of nursing is encouraging, it is believed that the awareness of nurses on the care practices they perform independently should be developed further. 333
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The intensive care nurses stated that their patients were physically and psychologically relaxed after care. After providing care, the nurses stated that they felt happy, conscientiously relaxed and motivated since they were beneficial to their patients. Nurses feeling happy and thinking that they are putting the effort for the money they make, öay lead to job satisfaction and increased motivation.
The findings of this study suggested that the perceptions of the ICU nurses were not on a desired level, and a comprehensive training should be provided to nurses on the concepts of care and nursing care. Intensive care nurses should receive special training in their field, and their working conditions should be improved. Acknowledgement We sincerely thank to the intensive care nurses who participated in the study. Competing interests The authors declare that they have no competing interest. Financial Disclosure This paper is based on the Master’s degree dissertation of the first author, carried out under the supervision of the second author. Ethical approval Ethical Approval All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/ or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed Consent Informed consent was obtained from all individual participants included in the study. The research received IRB approval from the Scientific Research Ethics Board of Diyarbakır Gazi Yaşargil Training and Research Hospital, Turkey. Veysel Tekin ORCID:0000-0002-7228-4001 Ulviye Gunay ORCID:0000-0002-6312-6853
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Kavlu İ, Pınar R. Effects of Job Satisfaction and Burnout on Quality of Life in Nurses Who Work in Emergency Services. Turkiye Klinikleri J Med Sci 2009;29:1543-55.
Conclusion Improving the perceptions of nurses on the concept of care will improve the quality of patient care. It is important for intensive care nurses to ground their practices on the concept of care. The study examined the nurses’ care practices from various aspects. The intensive care nurses defined the concept of care as follows: providing the physical care of the patient and supporting the patient spiritually.
10. Karadağ S, Taşçı S. The factors affecting the nursing care given by the nurses working in Kayseri State Hospital. J Health Sci. 2005;14:13-21. 11. Corbin JM. Strauss A. Grounded theory research: Procedures, canons, and evaluative criteria. Qualitative Sociology. 1990;13:3-21. 12. Graneheim UH, Lundman B. Qualitative content analysis in nursing research: concepts, procedures and measures to achieve trustworthiness. Nurse Educ Today. 2004;24:105-12. 13. Lawrence J, Tar U. The use of grounded theory technique as a practical tool for qualitative data collection and analysis. Electronic J Business Res Method. 2013;11:29-40. 14. Karaöz S. Turkish nursing students’ perception of caring. Nurse Educ Today. 2005;25:31-40. 15. Begum S, Slavin H. Perceptions of “caring” in nursing education by Pakistani nursing students: An exploratory study. Nurse Educ Today. 2012;32:332-6. 16. Dyson J. Nurses’ conceptualizations of caring attitudes and behaviours. J Advanced Nurs. 1996;23:1263-9. 17. Mlinar S. First-and third-year student nurses’ perceptions of caring behaviours. Nurs Ethics. 2010;17:491-500. 18. Yıldız N, Kanan N. The factors that affect job satisfaction in nurses working in the intensive care units. Yoğun Bakım Derg. 2005;9:8-13. 19. Kaya N, Kaya H, Ayık S, et al. Burnout of nurses who work in a government hospital. Uluslararası İnsan Bilimleri Dergisi. 2010;7:401-19. 20. Altay B, Gönener D, Demirkiran C. The level of burnout and influence of family support in nurses working in a university hospital. Fırat Tıp Dergisi. 2010;15:10-6. 21. Akdeniz S, Ünlü H. Intensive care nursing. Yoğun Bakım Dergisi. 2004;4:179-85. 22. Korkmaz F. Profesionalizm and nursing in Turkey. Hacettepe Univ Fac Health Sci Nurs J. 2011;18:59-67. 23. Alligood MR. Nursing Theorists and Their Work-E-Book. Elsevier Health Sciences. https://books.google.com.tr/books? access date: 05.01.2018.
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Available online at www.medicinescience.org
ORIGINAL RESEARCH
Medicine Science International Medical Journal
Medicine Science 2019;8(2):335-42
Dermatological findings in common rheumatologic diseases in children Melike Kibar Ozturk1, Ilkin Zindanci1, Betul Sozeri2 2
1 Umraniye Training and Research Hospital, Department of Dermatology, Istanbul, Turkey Umraniye Training and Research Hospital, Department of Child Rheumatology, Istanbul, Turkey
Received 01 November 2018; Accepted 19 November 2018 Available online 21.01.2019 with doi:10.5455/medscience.2018.07.8966 Copyright Š 2019 by authors and Medicine Science Publishing Inc. Abstract The aim of this study is to outline the common dermatological findings in pediatric rheumatologic diseases. A total of 45 patients, nineteen with juvenile idiopathic arthritis (JIA), eight with Familial Mediterranean Fever (FMF), six with scleroderma (SSc), seven with systemic lupus erythematosus (SLE), and five with dermatomyositis (DM) were included. Control group for JIA consisted of randomly chosen 19 healthy subjects of the same age and gender. The age, sex, duration of disease, site and type of lesions on skin, nails and scalp and systemic drug use were recorded. Ď&#x2021;2 test was used. The most common skin findings in patients with psoriatic JIA were flexural psoriatic lesions, the most common nail findings were periungual desquamation and distal onycholysis, while the most common scalp findings were erythema and scaling. The most common skin finding in patients with oligoarthritis was photosensitivity, while the most common nail finding was periungual erythema, and the most common scalp findings were erythema and scaling. We saw urticarial rash, dermatographism, nail pitting and telogen effluvium in one patient with systemic arthritis; and photosensitivity, livedo reticularis and periungual erythema in another patient with RF-negative polyarthritis. Vascular skin lesions like Raynaudâ&#x20AC;&#x2122;s phenomenon, livedo reticularis, palmar erythema, periungual telangiectasia and nailfold abnormalities were common in SLE, DM and SSc. Patients with FMF displayed signs of atopy. Specific skin lesions can be the peculiar features of rheumatologic diseases in pediatric population. Since it is not always easy to perform biopsy in children to confirm skin involvement of a rheumatologic disease, skin findings can help both dermatologists and rheumatologists in diagnosis. Keywords: Juvenile idiopathic arthritis, familial mediterranean fever, scleroderma, systemic lupus erythematosus, dermatomyositis
Introduction Specific skin lesions can be the hallmark and initial involvement area of certain common rheumatologic diseases. Skin involvement can alert both the dermatologists and rheumatologists about systemic involvement and prognostic outcome. On the other hand, skin lesions may diminish after the initiation of systemic therapy or escalate as an adverse reaction to immune suppressants, biologics and targeted therapies for the treatment of rheumatologic diseases. Since it is not always easy to perform skin biopsy in pediatric population to confirm skin involvement of a rheumatologic disease, skin findings in such diseases can help physicians. In this regard, they may be helpful in the diagnosis, follow-up of the disease course and the adverse skin reactions to systemic drugs. On the other hand, there is scarce information in the literature on skin findings of rheumatologic diseases in children [1-8]. In this study,
*Coresponding Author: Melike Kibar Ozturk, Umraniye Training and Research Hospital, Department of Dermatology, Istanbul, Turkey, E-mail:kibarmelike@hotmail.com
the involvement of the skin, nail and scalp of 19 patients with juvenile idiopathic arthritis (JIA) (Of these 19 patients, 1 of them had systemic arthritis, 1 of them had RF-negative polyarthritis, 7 of them had psoriatic arthritis, 6 of them had oligoarthritis, 2 of them had enthesitis-related arthritis and 2 of them had undifferentiated arthritis), 8 patients with familial mediterranean fever (FMF), 7 patients with systemic lupus erythematosus (SLE), 6 patients with scleroderma (SSc) [3 patients with diffuse SSc and 3 patients with limited SSc], and 5 patients with dermatomyositis (DM) were evaluated. Material and Methods The study was approved and performed in accordance with the guidelines of the institutional review board at our hospital and all patients signed informed consent forms before enrollment in the study (IRB#B.10.1.TKH.4.34.H.GP.0.01/107). Nineteen patients with JIA, 8 patients with FMF, 7 patients with SLE, 6 patients with SSc, and 5 patients with DM were included in this study. Nineteen controls were included in this study. Control group for JIA consisted of randomly chosen healthy subjects of the same age 335
doi: 10.5455/medscience.2018.07.8966
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and gender without any skin and rheumatologic diseases. The complete medical data of patients diagnosed with these disorders in 2017 were evaluated. Patients with JIA and FMF were diagnosed by rheumatologists clinically while the diagnosis of the patients with SLE, DM and SSc were verified by skin biopsy. Skin, nail and scalp findings were evaluated by a manual dermatoscope with x10 magnification in addition to naked eye. All photographs were taken from each patient using a contact & non-contact, polarized, manual dermatoscope (Dermlite DL4 PigmentBoost Plus X10; 3 Gen, San Juan Capistrano, CA, USA) equipped with magnetically attached smartphone. The age, sex, duration of disease, site and type of lesions on skin, nails and scalp and systemic drug use of patients prior to admission were recorded. All statistical analyses were performed using SPSS version 15.0 (SPSS Inc, Chicago, IL, USA). For continuous variables, normality tests were performed with Kolmogorov-Smirnov test. Chi-Square test was used to compare (the categorical data) clinical differences with other healthy children. The level of significance for all analyses was set at p<0.05. Results A total of 45 patients were admitted to the hospital with diagnosis of a rheumatologic disease. Clinical characteristics such as the age, sex, duration of disease, prior systemic drug use and the location and type of lesions on skin, nails and scalp were summarized in Tables 1 and 2. Nine (47.4%) patients with JIA were female while 10 (52.6%) patients were male. The mean age of the patients was 11.5±3.3. The control group for JIA consisted of randomly chosen 10 (52.6%) male and 9 (47.4%) female patients. The mean age of this group was 10.5±4.6. Of the 19 patients with JIA, one of them had systemic arthritis (adolescent-onset Still’s disease), one of them had RF-negative polyarthritis, seven of them had psoriatic arthritis, six of them had oligoarthritis (persistent or extended), two of them had enthesitis-related arthritis and two of them had undifferentiated arthritis.The most common findings in JIA patients were erythema, scaling and pruritus on scalp, periungual desquamation and telogen effluvium (figure 1). Periungual desquamation was the most common nail finding of JIA in our patient group. The less frequent nail findings in the study group included distal onycholysis, pitting, leukonychia, Beau’s lines, subungual hyperkeratosis, and splinter hemorrhages over the distal third of the nail plate (figure 1). The most common skin finding in patients with psoriatic JIA was flexural psoriatic lesions and the less common findings were periorbital hyperpigmentation and dactylitis. The most common nail findings in patients with psoriatic JIA were periungual desquamation and distal onycholysis, while the less common finding was splinter hemorrhages. The most common scalp findings in patients with psoriatic JIA were erythema, scaling and pruritus, while telogen effluvium was a less common finding. The most common skin finding in patients with oligoarthritis was photosensitivity, nail finding was periungual erythema, and scalp findings were erythema, scaling and pruritus. We saw transient urticarial rash over the trunk, legs and arms, dermatographism, nail pitting and telogen effluvium in one patient with systemic arthritis; and photosensitivity, livedo reticularis, periungual erythema and telogen effluvium in another patient with RF-negative polyarthritis.
Figure 1. a&b; erythema and coarse squam on scalp, c&d; periungual desquamation in patients with JIA, e; distal splinter hemorrhages on onychodermal band and distal onycholysis, f; pitting in patients with JIA
Four patients with SLE were female and 3 patients were male. The mean age of the patients was 12.8 ±3. All but one of 7 patients showed photosensitivity, malar rash, nailfold capillary abnormalities and non-scarring alopecia clinically. Five patients had non-specific vascular lesions like Raynaud’s phenomenon, livedo reticularis and palmar erythema (figure 2).
Figure 2. a&e; acute erythematous rash with fine scaling on face and hand, b; periungual erythema, blood spots and splinter hemorrhages on nails, c; dilated and tortious capillaries in nailfold, d; elongating and tortious capillaries alternating with loss of capillaries in nailfold, f; livedo reticularis on the dorsum of hand, g; palmar erythema, h; telogen effluvium with erythematous background in patients with SLE
336
9
10
10
12
15
16
3
13
14
13
15
11
6
10
10
15
JIA-1 Psoriatic
JIA-2 Psoriatic
JIA-3 Psoriatic
JRA-4 Psoriatic
JIA-5 Psoriatic
JIA-6 Psoriatic
JIA-7 Psoriatic
JIA-1 Oligoarthritis
JIA-2 Oligoarthritis
JIA-3 Oligoarthritis
JIA-4 Oligoarthritis
JIA-5 Oligoarthritis
JIA-6 Oligoarthritis
JIA-1 Undifferentiated arthritis
JIA-2 Undifferentiated arthritis
JIA-1 Enthesitis-related F
F
M
M
F
F
M
M
F
F
F
F
M
F
M
M
Gender
1
2
1
1
1
1
1
3
1
1
3
4
1
1
3
1
Duration (years)
C/S+Mtx
Mtx
NSAİDs
Mtx+NSAİDs
Sulfasalazine+C/S
Mtx+NSAİDs
Mtx
Sulfasalazine+Mtx
NSAİDs
NSAİDs+C/S
Sulfasalazine+Mtx
Mtx+NSAİDs
NSAİDs
C/S
Mtx
Mtx
Systemic medication
Erythema, scaling and pruritus, Telogen effluvium
Periungual desquamation Distal onycholysis Splinter hemorrhages Subungual hyperkeratosis
Photosensitivity Livedo reticularis
None
Periorbital hyperpigmentation, Dennie-Morgan lines
None
Upper eyelid dermatitis
Photosensitivity Oral apthosis kserosis
Periorbital hyperpigmentation Plaque psoriasis (flexural areas)
Photosensitivity Livedo reticularis Oral apthosis Raynaud’s phenomenon
Vitiligo
Dactylitis Plaque psoriasis (flexural areas)
Sulfasalazine+Mtx
Plaque psoriasis (flexural areas and face)
Periorbital hyperpigmentation Plaque psoriasis (flexural areas)
Splinter hemorrage Periungual desquamation
Periungual desquamation Punctate leukonychia
Nail Pitting
Periungual erythema
Periungual erythema
Periungual desquamation Nail Pitting Distal onycholysis
None Punctate leukonychia
Periungual erythema Distal onycholysis
None
Periungual desquamation
Nail Pitting Distal onycholysis Splinter hemorrhages Beau’s lines
Nail Pitting Punctate leukonychia
Erythema, scaling and pruritus Telogen effluvium
Distal onycholysis Subungual Hyperkeratosis Punctate leukonychia
Plaque psoriasis (elbows and knees)
Erythema, scaling and pruritus
Periungual desquamation Splinter hemorrhages
Periorbital hyperpigmentation Kserosis Plaque psoriasis (flexural areas, dorsum of hand) Dactylitis
Telogen effluvium
Telogen effluvium
Erythema, scaling and pruritus
Erythema, scaling and pruritus
Erythema, scaling and pruritus Telogen effluvium
None
Telogen effluvium
Erythema, scaling and pruritus
None
Erythema, scaling and pruritus
Erythema, scaling and pruritus
None
Erythema, scaling and pruritus
Erythema, scaling and pruritus Telogen effluvium
Telogen effluvium
Erythema, scaling and pruritus Telogen effluvium
Distal onycholysis Periungual desquamation Nail Pitting Punctate leukonychia
Periorbital hyperpigmentation Kserosis Dactylitis
Scalp skin findings
Nail findings
Skin findings
JIA-2 13 M 2 NSAİDs None Periungual desquamation Enthesitis-related JIA Photosensitivity 15 M 1 Mtx+NSAİDs Periungual erythema Polyarticular RF negative Livedo reticularis JIA Transient urticarial rash over the trunk legs 10 M 1 NSAİDs+C/S Nail Pitting Systemic arthritis and arms dermatographism JIA: Juvenile idiopathic arthritis, M: Male, F: Female, Mtx: Methotrexate, NSAİDs: non-steroidal anti-inflammatory drugs, C/S: Corticosteroids
Age
JIA disease categories
Table 1. Clinical characteristics such as the age, sex, duration of disease, prior systemic drug use and the location and type of lesions on skin, nails and scalp in patients with JIA.
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337
8
14
14
16
12
10
12
16
14
8
11
9
16
14
13
7
SLE-2
SLE-3
SLE-4
SLE-5
SLE-6
SLE-7 DM
DM-1
DM-2
DM-3
DM-4
DM-5
Diffuse SSc-1
Diffuse SSc-2
Diffuse SSc-3
Limited SSc (CREST 1)
Limited SSc (CREST 2)
14
7
7
12 11 7 8
FMF-2
FMF-3
FMF-4
FMF-5 FMF-6 FMF-7 FMF-8
F F F M
M
F
F
M
2 1 1 2
4
1
10
4
1
1
1
4
4
2
2
1
7
2
6
2
2
5
6
2
7
2
Duration
colchicine colchicine colchicine colchicine
colchicine
colchicine
colchicine
colchicine
C/S
C/S
Mtx+C/S
Mtx+C/S
Mtx+C/S
Mtx+C/S
Mtx
Mtx
Mtx
Mtx + C/S
Mtx
C/S
C/S
C/S
C/S
C/S
C/S
C/S
Systemic medication
Scalp skin findings Non-scarring alopecia Non-scarring alopecia, Erythema, scaling and pruritus Non-scarring alopecia Non-scarring alopecia Non-scarring alopecia
Nail findings Subtle nailfold abnormalities, Periungual erythema Subtle nailfold abnormalities, Splinter hemorrhage Blood spots Subtle nailfold abnormalities Distinct nailfold abnormalities Subtle nailfold abnormalities
Photosensitivity, Malar rash Raynaud’s phenomenon, Livedo reticularis, Chillblain lupus
Photosensitivity Red poikiloderma, Malar rash Raynaud’s phenomenon, Livedo reticularis, Edematous hyperemic rash with scaling on trunk, arms and dorsal aspects of hands sparing knuckles
Violaceous erythema, scaling and pruritus Violaceous erythema, scaling and pruritus Violaceous erythema, scaling and pruritus None
Nail fold erythema, Distinct nailfold abnormalities, Cuticular dystrophy Distinct nailfold abnormalities, Nail fold erythema, Cuticular dystrophy Distinct nailfold abnormalities, Nail fold erythema, Cuticular dystrophy Nail fold erythema, Distinct nailfold abnormalities Nail fold erythema, Distinct nailfold abnormalities
Photosensitivity Violet poikiloderma, Upper eyelid eczema Heliotrope rash, Gottron’s papules Photosensitivity Violet poikiloderma, Calsinosis cutis Gottron’s papules, Gottron’s sign
Kserosis Kserosis Periorbital hyperpigmentation Kserosis Periorbital hyperpigmentation Kserosis
Kserosis, Pitriasis alba, Periorbital hyperpigmentation
Kserosis
Upper eyelid eczema
Kserosis, Periorbital hyperpigmentation
Raynaud’s phenomenon Calcinosis cutis, Sclerodactyly, Telangiectasia on face and hands
Raynaud’s phenomenon, Calcinosis cutis Sclerodactyly, Telangiectasia on face and hands
Raynaud’s phenomenon, Calcinosis cutis Sclerodactyly, Telangiectasia on face and hands
Raynaud’s phenomenon, Pitting edema of the digits Taut and shiny skin Loss of substance from finger pads Pruritus Raynaud’s phenomenon, Erythema nodosum Taut and shiny skin, Salt and pepper sign, Digital pitted scar loss of substance from finger pads, Pruritus Raynaud’s phenomenon, Taut and shiny skin, Salt and pepper sign, Telangiectasia, Loss of substance from, Finger pads Pruritus
Violet poikiloderma, Gottron’s papules Gottron’s sign
Photosensitivity Violet poikiloderma, Gottron’s papules
Erythema, scaling and ruritus elogen effluvium None None None Non-scarring alopecia None Anagen effluvium
None Anagen effluvium Anagen effluvium Telogen effluvium Telogen effluvium
Distinct nailfold abnormalities, Total leukonychia, Periungual erythema Distinct nailfold abnormalities, Leukonychia totalis, Periungual erythema Distinct nailfold abnormalities Distinct nailfold abnormalities, Distal onycholysis Distinct nailfold abnormalities Distal onycholysis, Leukonychia punctata Longidutinal white lines, Leukonychia punctata Pitting, Distal onycholysis, Leukonychia punctata Distal onycholysis,, Leukonychia punctata Pitting, Leukonychia punctata Leukonychia punctata Leukonychia punctata Pitting,
Anagen effluvium
None
Distinct nailfold abnormalities, Total leukonychia, Periungual erythema
Erythema, scaling and pruritus
Non-scarring alopecia
Distinct nailfold abnormalities
Photosensitivity, Violet poikiloderma, Gottron’s papules
None
Subtle nailfold abnormalities
Raynaud’s phenomenon Livedo reticularis, Malar rash Periungual telangiectasia Photosensitivity Malar rash, Raynaud’s phenomenon
Photosensitivity, Malar rash Raynaud’s phenomenon Livedo reticularis
Photosensitivity, Malar rash Raynaud’s phenomenon
Photosensitivity Malar rash, Palmar erythema Periungual telangiectasia
Skin findings
SLE: Systemic Lupus Erythematosus, DM: Dermatomyo¬sitis, SSc: Scleroderma, FMF: Familial Mediterranean Fever, M: Male, F: Female, Mtx: Methotrexate, C/S: Corticosteroids
8
F
F
F
F
F
F
M
M
F
F
F
M
M
F
F
F
M
F
Gender
FMF-1
Limited SSc (CREST 3) FMF
12
16
SLE-1
SSc
Age
SLE
Table 2. Clinical characteristics such as the age, sex, duration of disease, prior systemic drug use and the location and type of lesions on skin, nails and scalp in patients with SLE, DM, SSc and FMF
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338
doi: 10.5455/medscience.2018.07.8966
Three patients with DM were female and the remaining 2 were male patients. The mean age of this group was 12.2±3. All five patients displayed photosensitivity, violet poikiloderma, Gottron’s papules, distinct nailfold abnormalities and nail fold erythema (figure 3).
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telangiectasia on face and hands and distinct nailfold abnormalities while all three patients with diffuse SSc displayed Raynaud’s phenomenon, taut and shiny skin, loss of substance from finger pads, total leukonychia, periungual erythema and pruritus (figure 4) . Telangiectasias involving the face, lips and palms were more common in patients with limited SSc, but were also noticed in patients with diffuse disease. We saw capillary loss alternating with dilated loops in nailfold and arborising vessels in distal finger with the dermatoscope. Distinct nailfold changes like prominent large, tortuous capillaries and areas of marked avascularity were as well seen in patients with DM in our study (figure 4). Five patients with FMF were female while the remaining 3 were male patients. The mean age of this group was 9.25±2.7. Almost all the patients with FMF had signs of atopy; kserosis, pitriasis alba, periorbital hyperpigmentation, leukonychia punctata and pitting. Four of the patients with FMF suffered from anagen effluvium. Discussion
Figure 3 a&b; violaceous erythema and coarse squam on scalp, c&d; Gottron’s papules in patients with DM
The skin, joints and musculoskeletal system are often involved concomittantly in rheumatologic diseases [1]. Rheumatologic diseases are the second most common autoimmune diseases in childhood after diabetes mellitus [2] and there is scarce information in the literature on skin findings in this population [1-8]. In this study, we aimed to evaluate the clinical and dermatoscopic skin, nail and scalp findings of common rheumatologic diseases in the pediatric population. The biggest number of patients referred to our clinic was JIA while the smallest groups were SLE and DM. This may be due to the fact that SLE or DM are diseases with an occasional later onset in adolescence or adulthood while JIA starts in childhood [2,3]. The skin, nail and scalp findings in common pediatric rheumatologic diseases are listed into subheadings and discussed below. Juvenile Idiopathic Arthritis Juvenile idiopathic arthritis is a disease of unknown cause characterized by the presence of a chronic arthritis persisting for more than 6 weeks in children or adolescents under 16 years of age [9]. JIA is the most common rheumatologic disease encountered in the pediatric population that is almost exclusively seen in this age group, so it is important to recognize the skin findings of JIA, which are not known well, in this particular patient population [2,3]. Seven disease categories have been suggested for JIA by the Pediatric Task Force of the International League of Associations for Rheumatology. These categories are systemic arthritis (adolescent-onset Still’s disease), RF-negative polyarthritis, RFpositive polyarthritis, psoriatic arthritis, oligoarthritis (persistent or extended), enthesitis-related arthritis and undifferentiated arthritis [9].
Figure 4. a; loss of capillaries on nailfold b; arborizing vessels on nailfold, c; salt and pepper sign on scalp, d; loss of substance from finger pads, e; digital pitted scar on the 5th finger, f&g; leukonychia totalis, punctata and periungual erythema in patients with SSc.
Five patients with SSc were female and 1 patient was male. The mean age of the patients was 11.8±3.3. Three patients with limited SSc had Raynaud’s phenomenon, calcinosis cutis, sclerodactyly,
In our study, plaque psoriasis was seen in 36.8% of JIA patients. Psoriatic JIA may occur in concurrence with psoriasis. On the other hand, without the presence of any skin lesions, it is defined as the arthritis with any two of the following: psoriasis in a firstdegree relative, dactylitis, and nail pitting or onycholysis. Plaque psoriasis, the most common type of psoriasis in JIA [6], was the most frequent type in our study as well. 339
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Psoriatic lesions in JIA are often smaller, thinner and less scaling than adult psoriasis and tend to develop more often on the face and flexural areas [10] similar to the patients in this study. The scalp is also frequently involved and is often the first site of presentation in children [6] as was the case in our study group. In this study, the most common findings in JIA patients were erythema, scaling and pruritus on scalp (63.1%, p=0.0001), telogen effluvium (47.3%, p=0.003) and periungual desquamation (42.1%, p=0.007). In our opinion, the presence of periungual desquamation and telogen effluvium were associated with the adverse effects of systemic administered drugs, especially methotrexate [6]. Periungual desquamation was the most common nail finding of JIA in our patients that contrasts with the literature where distal onycholysis has been reported as the most frequent finding. The less frequent nail findings in the study group included, distal onycholysis (31.5%, p=0.03), pitting (31.5%, p=0.03), periungual erythema (21%, p=0.14), splinter hemorrhages (21%, p=0.14), and dactylitis (15.7%, p=0.2) which are consistent with the findings in the literature [11,12], [fig 1]. On the other hand, punctate leukonychia (26.3%, p=0.4) and periorbital hyperpigmentation (26.3%, p=0.2) were also common in JIA while they were not statistically significant. In our opinion, the presence of these signs was associated with concomitant atopy. Systemic Lupus Erythematosus The cutaneous lupus erythematosus (LE) is classified into two groups as specific and non-specific. Within the category of specific skin lesions, it is divided into acute, subacute and chronic subgroups [13]. Acute specific cutaneous lesions that have been associated with SLE [14] were also observed in our study group. In our study, one of the patients had edematous hyperemic rash with scaling on trunk, arms and dorsal aspects of hands sparing the knuckles. In lupus, the face is most commonly affected; but often times, lesions may be more widespread in distribution sparing the knuckles [14] as seen in one of our patients. In the current study, six of seven patients with SLE exhibited photosensitivity, malar rash, subtle nailfold capillary abnormalities and non-scarring alopecia clinically. Nonspecific vascular lesions like Raynaud’s phenomenon, livedo reticularis, palmar erythema and periungual telangiectasia are common in patients with LE, particularly in those who have SLE. Other non spesific lesions that can be seen in LE are purpurae, urticarial papules or ulcerations, livedo reticularis, thromboses, ulcerations, lesions resembling Degos’ disease, sclerodactyly, calcinosis, rheumatoid nodules, papulonodular mucinosis and anetoderma [14]. The pathogenesis of these skin changes in SLE are mostly vascular such as nail-fold abnormalities (large and tortuous capillaries together with areas of avascularity), more severe complications such as vasculitis (urticarial vasculitis, leukocytoclastic vasculitis and nodular vasculitis) and other forms of vasculopathy (livedo reticularis, atrophie blanche, Degos’ disease, ulcerations, and thromboses) [14,15]. In our study, five of the patients displayed common nonspesific vascular lesions like Raynaud’s phenomenon, livedo reticularis, palmar erythema and periungual telangiectasia [figure 2]. Dermatomyositis Common skin findings of DM like photosensitivity, violet poikiloderma, Gottron’s papules, distinct nailfold abnormalities,
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nail fold erythema and cuticular dystrophy were seen in five of six patients with DM in our study [figure 3]. In our study, poikiloderma in DM was characterized by a violet color, whereas it was red-pink in patients with SLE and it was distributed around the eyes and extensor surfaces, including the knuckles. Gottron’s papules (lichenoid lesions on knuckles) and Gottron’s sign (violaceous discoloration of the knuckles, elbows and/or knees) were located on knuckles and elbows in our patients. One of our female patients with DM had calcinosis cutis on her legs in the deep fascia and intramuscular connective tissue which was thought to be secondary to recurrent trauma to her legs and this was convenient with the fact that it occurs most often at sites of friction and trauma (15). Calcinosis cutis consists of painful, hard, irregular nodules that eventually drain chalky material to the skin surface, and it is known to be more prevalent in juvenile dermatomyositis, affecting between 25% and 70% of patients [1517]. The scalp and cutaneous lesions of DM were pruritic and had a violet background with arborizing vessels with dermatoscopy in our patients while the lesions were not pruritic in patients with SLE. According to the literature, this pruritus can significantly affect the patients’ quality of life and may help in distinguishing DM from SLE [14,18,19] . Alopecia appears to be a significant sign in the course of SLE. The involvement of the scalp is also a common finding in DM, and is often characterized by a diffuse, violaceous, scaly, non-scarring and symptomatic hair loss [7] that was observed as violaceous erythema, scaling and pruritus in our study group. Histopathologic examination of a heliotrope, violet erythema reveals an interface dermatitis. More inflammatory lesions (i.e., Gottron papules) show lichenoid infiltrate and acanthosis of the epidermis as well. This may explain the violet colour of lesions on the skin and scalp. Scleroderma SSc has two major clinical subtypes: Limited and diffuse. Limited SSc is characterized by fibrotic skin changes that are limited to the fingers, hands and face, and includes the CREST syndrome. In diffuse SSc, generalized fibrotic skin changes spread to involve the forearms, arms, trunk, face and lower extremities. CREST syndrome describes the clinical features in a subset of patients with limited SSc: calcinosis, Raynaud’s phenomenon, esophageal involvement, sclerodactyly and telangiectasia [14]. In our study we evaluated the skin findings of 3 patients with CREST syndrome and 3 patients with diffuse SSc. All patients with limited SSc displayed Raynaud’s phenomenon, calcinosis cutis, sclerodactyly, telangiectasia on face and hands, and distinct nailfold abnormalities; while all patients with diffuse SSc had Raynaud’s phenomenon, taut and shiny skin, loss of substance from finger pads and pruritus. In our study, late atrophic phase with a beaked nose and microstomia were not observed in the pediatric population. The term sclerosis describes induration as a result of excessive deposition of collagen and subsequent tissue fibrosis. When cutaneous involvement proceeds, an edematous phase of the affected sites often takes place, especially on the fingers. Similar changes may be seen on the forearms, legs, feet, face and 340
doi: 10.5455/medscience.2018.07.8966
trunk as well [15]. This edema results in taut and shiny appearance of our patients. This is followed by gradual thickening of the skin in which the initial inflammation is replaced by interstitial fibrosis caused by abnormal collagen metabolism and subsequent sclerodactyly. The impaired acral blood flow in sclerodactyly may lead to digital pits and ulcers as seen in our patients. A rare skin sign in patients with SSc is hyperpigmentation. Variants of skin discoloration in patients with SSc include “salt and pepper sign” which describes localized areas of depigmentation with sparing of the perifollicular skin. The leukoderma of scleroderma is characterized by salt and pepper sign and arborising vessels were as well seen by dermatoscope in the scalp skin of one of our patients with diffuse SSc and this was parallel to the findings reported in the literature [15,20]. Telangiectasias involving the face, lips and palms are more common in patients with limited SSc but may also be seen in patients with diffuse disease, similar to our patients. Capillary abnormalities in the proximal nail fold have been reported in more than 90% of SSc patients [14,21]. We noted capillary loss alternating with dilated loops in nailfold and arborising vessels in distal finger with the dermatoscope. Distinct nailfold changes like prominent large, tortuous capillaries and areas of marked avascularity were also seen in patients with DM in our study. Parallel to the previous reports [13], our patients with SLE had more subtle nailfold capillary abnormalities than patients with scleroderma or dermatomyo¬sitis. Familial Mediterranean Fever FMF is a disease characterized by recurrent attacks of fever accompanied by peritonitis, pleuritis and arthritis. Skin lesions of FMF are known as erysipelas, such like the erythema that occur mainly on the legs, between the ankle and the knee, or on the dorsum of the foot [22,23]. Vasculitides are rare, approximately 5% of individuals with FMF have been reported to have HenochSchonlein purpura and about 1% to have polyarteritis nodosa [24,25]. In addition to these, recurrent urticaria and atypical hyperemic recurrent skin lesions had been reported as rare manifestations of FMF [26,27]. In contrast with the reports in the literature, almost all the patients with FMF displayed signs of atopy; kserosis, pityriasis alba, periorbital hyperpigmentation, leukonychia punctata and pitting in our study. Common hair disorders in autoimmune connective tissue diseases are known to be telogen hair loss, diffuse thinning or fragility of hair and scarring alopecia. In addition to this, some drugs used to treat autoimmune connective tissue diseases may cause hair loss like methotrexate and colchicine, as observed in our study. Four of eight patients with FMF suffered from anagen effluvium that was thought to be the adverse effect of colchicine [28-31]. To sum up, when we see a child with arthralgia accompanied with pruritus on scalp with fine scales and periungual desquamation, one may consider JIA as the diagnosis; and when arthralgia is accompanied by signs of atopy like kserosis, pityriasis alba, periorbital hyperpigmentation, leukonychia punctata and pitting, FMF should be considered in the differential diagnosis. Vascular skin lesions like Raynaud’s phenomenon, livedo reticularis, palmar
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erythema, periungual telangiectasia and nailfold abnormalities viewed by dermatoscopy are common in childhood rheumatologic diseases. This study has several limitations. The study population included a relatively small sample of rheumatologic diseases. Further clinical trials with larger patient populations where comparison of pediatric findings with adult rheumatologic diseases and detailed evaluation of nail findings with dermatoscopy and comparison of these findings with capillaroscopy are carried out are needed to gather more conclusive data on the dermatological findings in pediatric rheumatological diseases. Conclusion Specific skin lesions can be the peculiar features of common rheumatologic diseases like JIA, SLE, DM, SSc and FMF in the pediatric population. Since it is not always easy to perform biopsy in children to confirm skin involvement of a rheumatologic disease, clinical and dermatoscopic skin findings can help both dermatologists and rheumatologists in diagnosis. Competing interests The authors declare that they have no competing interest. Financial Disclosure All authors declare no financial support. Ethical approval Consent of ethics was approved by the local ethics committee.
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ORIGINAL RESEARCH
Medicine Science International Medical Journal
Medicine Science 2019;8(2):343-8
Evaluation of the relationship between health belief of breast cancer screening and health anxiety; A cross-sectional study Meryem Askin1, Esra Meltem Koc1, Merve Yekta Ates2, Mehmet Arslan3, Gizem Dag1, Ali Murat Koc4, Kaan Sozmen5 Izmir Katip Celebi University, Faculty of Medicine, Department of Family Medicine, Izmir, Turkey 2 Necat Hepkon State Hospital, Izmir,Turkey 3 Karabaglar Health Directorate, Izmir,Turkey 4 Izmir Bozkaya Research and Education Hospital, Department of Radiology, Izmir, Turkey 5 Izmir Katip Celebi University, Faculty of Medicine, Department of Public Health, Izmir, Turkey
1
Received 13 November 2018; Accepted 20 November 2018 Available online 10.12.2018 with doi:10.5455/medscience.2018.07.8935 Copyright Š 2019 by authors and Medicine Science Publishing Inc. Abstract Breast cancer (BC) is the most frequent type of cancer among women. Screening and early diagnosis is crucial for reducing the disease burden. However the screening rates for BC is not at desired levels. Health belief and health anxiety are two conditions that affect participation in cancer screening. The aim of this study is to explore the relationship between health beliefs regarding breast cancer screening and health anxiety among women. This cross-sectional study included 301 women between 20 and 69 years of age who were admitted to the family medicine outpatient clinic. The study data was collected using the Health Anxiety Inventory (HAI) and Championâ&#x20AC;&#x2122;s Health Belief Model Scale (CHBMS). The questionnaires were filled with face-to-face interview technique. To explain the relationship between anxiety and the components of the health belief model a multivariate linear regression model was used. High anxiety levels were positively correlated with the seriousness and health motivation components and negatively correlated with the self-efficacy component of the health belief model related to breast cancer (p<0.001, p<0.001, p=0.001, respectively). No significant relationship was detected between anxiety and the other components of the health belief model. In this study, it was observed that people with high levels of health anxiety score high in the seriousness and health motivation components and low in the self-efficacy component of the health belief model. Health anxiety can particularly affect health behavior and its effect on the decision to engage in screening programs. Keywords: Cancer screening, health anxiety, health belief
Introduction With a gradually increasing prevalence over the years, breast cancer is one of the most prevalent cancers among women. According to International World Cancer Research Fund data, 1.7 million new breast cancer cases were identified globally in 2012 [1]. Besides this, breast cancer is the second most fatal type of cancer after lung cancer around the world [2]. In Turkey, breast cancer is the most common and mortal cancer among women. The prevalence of breast cancer has increased by more than 2 folds during last twenty years in Turkey, and its incidence was reported as 45.1 per one hundred thousand women [3].
*Coresponding Author: Meryem Askin , Izmir Katip Celebi University, Faculty of Medicine, Department of Family Medicine, Izmir, Turkey E-mail: obgndrmeryem@hotmail.com
Early diagnosis is very important for the prognosis of the disease as early detection of breast cancer by screening reduces breast cancer-related mortality [4]. By means of mammography and other screening methods, 63.7% of breast cancers can be diagnosed at early stages, and the 5-year survival rate among early diagnosed patients can reach as high as 97.9% [4]. The participation of women in breast cancer screening is not at the desired levels around the world and in Turkey [4,5]. There are many social determinants that influence the participation of women in breast cancer screening programs such as age, education level, and marital status [6]; however, it is believed that there also are factors other than socio-economic charactheristicsthat have not been identified yet. Emotions are the most effective source of motivation known, and they are the fundamental factor that defines the behavior of people regarding participation in cancer screenings [5]. Although women feel anxious about breast cancer screening due to various reasons, it is still unclear whether this anxiety they experience influences 343
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their decisions about participating in breast cancer screening methods positively or negatively [5]. The Health Belief Model (HBM) is a conceptual theoretical framework frequently used to identify people’s behavior regarding breast screening methods such as mammography and breast self-examination [6]. According to the Health Belief Model the perceptions of susceptibility, seriousness, benefits, barriers, health motivation, and confidence (self-efficacy) influence people’s health behaviors [6]. Health anxiety is an exaggerated negative interpretation of normal bodily sensations in people with no physical illnesses. Health anxiety has two fundamental components: the perception that the person has a serious illness and that this illness leads to adverse outcomes [7]. Recently conducted epidemiological studies reported the prevalence of health anxiety as 0.26-8.5% [8]. Studies conducted have also shown that the health perceptions of people with high levels of health anxiety are impaired and that these patients cause excessive health expenditures [8]. Studies conducted to date have focused on the general anxiety or cancer anxiety of people [5]. The number of studies that explore the association between health anxiety and health belief of breast cancer screening [5]. Besides this, there are not enough studies conducted about the effect of people’s anxiety on the subdimensions of the Health Belief Model. The goal of this study is to investigate the relationship between people’s health anxiety level and their health beliefs regarding breast cancer screening. Materials and Methods Participants The study have a cross-sectional design and study population involved women aged 20-69 years who applied to the outpatient clinic of Family Medicine Department of Izmir Katip Celebi University, Turkey during December 2016 and April 2017. The ethical approval for the study was obtained from the Izmir Katip Celebi University Non-Interventional Clinical Research Ethics Committee (approval number: 283, date of approval: 02.11.2016). Participants were excluded if they were diagnosed with a psychiatric disease and were on medication, under 20 or over 69 years of age, who are illiterate, have communication barriers (auditory or verbal), who were physically or mentally unable to answer the questions, women whose mental condition prohibited them from comprehending and answering the questions, or that did not accept to answer the surveys or did not fill in the forms completely were excluded from the study. Sample Size The sample size was calculated by using GPOWER 3.1 software. In order to detect a statistical difference with a medium effect size (d=0.30) between CHBMS scores stratified by HAI threshold with 80% power, 5% type 1 error, the minimum number of sample size was calculated as 278. We increased this figure by 20% in order to handle with refusal and total sample size was 334. Data Collection Tools:
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In this study, the 15-question sociodemographic data form prepared by the researchers was used to determine the sociodemographic characteristics of the patients, the Champion’s Health Belief Model Scale was used to assess health beliefs regarding breast cancer screenings, and the Health Anxiety Inventory was used to measure health anxiety level. Sociodemographic characteristics; The independent variables included sociodemographic characteristics, health Belief, and health anxiety. Participants’ age was categorized into 2 age groups (40 years ≥, 40 years ≤). Marital status was classified as married and single/widowed. Educational level was coded into 3 levels of highest educational level attained: less than primary school or primary school, Middle school and high school and university and higher education. Other sociodemographic variables were coded as yes / no. Champion’s Health Belief Model Scale: The scale developed by Champion in 1984 that assesses health beliefs regarding breast examination and mammography screenings was revised in 1993, 1997, and most recently 1999 [9]. The most recent revision of the scale was adapted into Turkish by Gozum et al9.The scale consists of 8 subdimensions, namely seriousness, health motivation, barriers and benefits regarding breast selfexamination, self-efficacy, and benefits and barriers regarding mammography and 52 items. The scale is a Likert-type scale that is scored between 1 to 5, the answer “strongly disagree” is given 1 point, “I do not agree” is given 2 points, “undecided” is given 3 points, “I agree” is given 4 points, and “I strongly agree” is given 5 points. Each dimension of the scale is assessed individually, and they are not summed up in a single total score. The Health Anxiety Inventory The Health Anxiety Inventory developed by Salkovkis et al. to assess health anxiety is a self-reported scale that contains 18 items [10]. The Turkish validity and reliability study of the scale was performed by Aydemir and colleagues [10]. Fourteen of the items in the scale contain four consecutive statements that question the mental state of the patient. In the remaining 4 questions, patients are asked to express their opinions about how their mental state would be, assuming if they had a serious illness. The score of each item in the scale ranges between 0 and 3 and a total HAI score higher than 20 means that individual have a serious health anxiety [11]. Statistical Analysis In this study, numeric data were expressed as average, mean, standard deviation, and value range and categorical data were expressed by descriptive methods such as ratio and percentage. The statistical comparison of mean values of two independent groups was performed using the Student t-test. The intergroup comparisons of categorical variables were performed using the Chi-square test. The relationships between two continuous variables were assessed using the Spearman/Pearson correlation tests. The linear regression model was created for health anxiety score. The independent variables with a statistically significant relationship of p≤0.10 according to bivariate analysis were included in the multivariate linear regression model and adjusted coefficents are presented with their 95% confidence intervals. 344
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Results In total, 334 women were invited to the study and 301 of the women (90.1%) that filled in the forms completely were included in the study. The mean age of the participants was 39 (min=20, max=69), 63.1% (n=190) were married, and 41.5% (n=125) had high education level. Of the participants, 58.1% (n=175) practiced breast selfexamination and 27.9% (n=84) screened mammography. The mean health anxiety scores of the patients were 18.02 and aproximately 40% of the patients had anxiety scores higher than 20. The mean and minimum-maximum values of the participant’s scores in the HAI (Health Anxiety Inventory) and CHBMS (Champion’s Health Belief Model Scale) subgroups are presented in Table-I. The relationship between HAI scores and sociodemographic data is presented in Table-II. While individuals with a positive family history had higher anxiety levels (p=0.024), women who received mammography or clinical breast examination before and the ones
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with higher education level presented significantly lower scores of HAI compared to their counterparts (p=0,019, 0,039, 0,030, respectively). Table 1. Descriptive findings for HAI and CHBMS Scale subdimensions
Scores obtained
Scores
Min
Max
Mean
Standard deviation
0
47
18.02
8.90
Susceptibility
3
15
7.50
2.42
Seriousness
6
30
19.09
5.11
Health motivation
5
25
20.01
4.05
BSE benefits
4
20
15.36
3.48
BSE barriers
8
39
18.30
5.51
BSE self-efficacy
10
50
32.77
8.63
Mammography benefits
5
25
17.86
4.41
Mammography barriers
11
53
26.19
7.91
Health Anxiety Inventory (HAI) Health Belief Model Scale (CHBMS)
Table 2. The relationship between HAI scores and sociodemographic data
Age
Marital Status
Mean ± SD <40 ≥40
Single/widow Married History of breast cancer in a first degree relative None Positive Status of having a mammography Yes No Presence of a benign breast disease Positive None Status of having received information about breast cancer Yes No The desire to receive information about breast cancer Yes No Breast self-examination Yes No Status of having a clinical breast examination Yes No Education level Primary School and lower (Group I) Middle school and high school (Group II) University and higher (Group III) Frequency of performing BSE Once a month (Group IV) A few times a year (Group V) Once a year (Group VI) a Group I is significantly higher than Group II and Group III b Group III is significantly higher than Group I and Group II c Group III is significantly higher than Group I d Group II is significantly higher than Group III e Group VI is significantly higher than Group IV and Group V
HAI Total Score
18.12 ± 8.01 17.93 ± 9.77 18.32 ± 9.09 17.85 ± 8.81 17.51 ± 8.73 20.62 ± 9.39 16.22 ± 7.82 18.72 ± 9.21 19.70 ± 10.05 17.74 ± 8.68 17.32 ± 8.07 18.80 ± 9.71 18.04 ± 8.62 17.98 ± 9.86 17.36 ± 8.53 18.95 ± 9.35 16.36 ± 8.58 18.70 ± 8.96 20.21 ± 10.75a 17.06 ± 7.79 17.29 ± 8.11 15.00 ± 6.56 17.90 ± 8.59 17.38 ± 11.37 *p<0.05, **p<0.01, ***p<0.001
p value 0.853
0.662
0.024*
0.019*
0.178
0.155
0.962
0.128
0.039*
0.030*
0.245
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When the Health Anxiety Inventory was assessed based on the CHBMS subdimensions the susceptibility and seriousness score was significantly higher in the group with high HAI scores, and the self-efficacy score was significantly higher in the group with low HAI scores (p<0.001, p<0.001, p=0.001, respectively) (Table 3). A
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low or non-significant level of correlation was identified between the serious HAI score and the CHBMS susceptibility, seriousness, BSE self-efficacy and mammography benefits scores (0.224, 0.249, -0.185, -0.132, respectively) (Table-III).
Table 3. Comparison of HAI scores stratified by CHBMS subdimensions Subdimensions of CHBMS
Health Anxiety Inventory <20 (n=178)
≥20 (n=123)
HAI total score correlation coefficients Statistical Analysis
Statistical Analysis
Mean ± SD
Mean ± SD
P value
r
Susceptibility
7.07 ± 2.32
8.37 ± 2.41
<0.001***
0.224a
Seriousness
18.21 ± 4.94
20.91 ± 4.98
<0.001***
0.249a
Health motivation
19.74 ± 4.08
20.59 ± 3.94
0.089
0.089
BSE benefits
15.51 ± 3.47
15.04 ± 3.49
0.266
-0.076
BSE barriers
18.15 ± 5.54
18.62 ±5.48
0.490
0.023
BSE self-efficacy
33.86 ± 8.51
30.53 ± 8.47
0.002**
-0.185a
Mammography benefits
18.11 ± 4.23
17.32 ± 4.75
0.145
-0.132a
Mammography barriers
25.25 ± 8.12
28.15 ± 7.12
0.003**
0.101 *p<0.05, **p<0.01, ***p<0.001
a
Low or non-significant correlation
According to the linear regression analysis model, those with high CHBMS seriousness and self-efficacy scores and who had a history of breast cancer in a first-degree relative had statistically significantly positive relationship with health anxiety scores (p<0.001, p=0.005, p=0.001, respectively) (Table-IV). Table 4. The linear regression analysis model for health anxiety Model Determinant factors
β
95% CI lower
upper
Age
-.018
-.099
.075
CHBMS Susceptibility score
.066
-.162
.623
CHBMS Seriousness Score
.298***
.305
.675
CHBMS BSE Self-Efficacy Score
-.240**
-.341
-.123
CHBMS Mammography Barriers Score
-.008
-.127
.110
CHBMS Health Motivation Score
.131*
.036
.505
Education level Low education level
.101
-.507
4.303
Middle education level
-.041
-2.809
1.315
.194***
1.918
6.699
Clinical breast examination
.033
-1.925
3.126
Status of having a mammography
-.120
-5.163
.709
History of breast cancer in a first degree relative
R2
48.1%
β = Regression coefficient, * p <0.05, ** p <0.01, *** p <0.001
Discussion In this study, the relationship between health anxiety and the components of the health belief model regarding breast cancer screening was evaluated. Women with low education level, presence of breast cancer history in a first-degree relative, who
haven’t undertaken clinical examination and ones who did not receive mammographies had higher levels of health anxiety. According to multivariable analysis, while seriousness and health motivation components of the health belief model regarding breast cancer was positively correlated with health anxiety, the selfefficacy component showed a negative correlation. The average HAI score of the women that participated in our study was 18.2. While the HAI scores changed between 10.5 and 11.3 in a community-based study performed in the Netherlands [12], the HAI total scores can reach high levels such as 24.7 among people with chronic diseases, in particular, neurological diseases [13]. Most recent studies state that people with HAI scores higher than 20 may experience severe health anxiety and therefore can be evaluated with respect to hypochondriasis [13]. The high HAI average scores of the participants in our study in comparison to community-based studies may be due to the study population consisted of patients from a tertiary care hospital. In our study, we identified that low education levels increase the health anxiety score. Although our finding is similar to the results from the World Mental Health Survey Initiative, there are also contradictory reports such as performed by Niedermeier et al. that show that the education level has no effect on anxiety levels [14,15]. Even, there is still no clear conclusion about this subject in the literature, the finding from our study that low education levels increase anxiety might be due to the fact that low education levels reduce a person’s income and such people have less vocational options. In our study, health anxiety was significantly higher among people with a history of breast cancer in a first-degree relative and who had not undergone clinical breast examination. There are studies in the literature that have established that people with a family history of breast cancer have higher levels of anxiety [16]. This result may be due to people with a family history of breast cancer internalizing this condition more, attributing more risk to themselves, and their 346
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development of a lower level of self-respect. The result of our study that people who undergo clinical breast examination experience less health anxiety contradicts the results of some studies in the literature. The article by Sanvido et al. discuss that clinical breast examinations might increase anxiety [17]. However, the fact that the lower levels of anxiety levels among women who have received clinical breast examination in Turkey, a developing country, might be related with gathering information of the women with a low sociocultural level from their doctors during their clinical examination which might cause an increase in their awareness levels about breast cancer [18]. In our study, we concluded that people with high levels of health anxiety were less likely to uptake mammography, but considering the studies in the literature, it is unclear whether anxiety influences the decision to engage in cancer screening programs positively or negatively5. While some studies emphasize that the will to undertake a mammography increases with higher anxiety levels [19], some state that higher anxiety leads to behaviors of avoiding mammography [19]. It is necessary to perform more studies that will particularly explain the relationship between health anxiety and the decision to receive a mammography. When we assessed the relationship between health anxiety and the components of the health belief model regarding breast cancer, we observed that individuals with high anxiety levels also had higher scores for seriousness and health motivation but lower self-efficacy scores. This result suggests that people with high levels of health anxiety undertake mammographies and breast self-examination more seriously and that they are more motivated regarding their health, but that their self-efficacy, in other words, their self-confidence is lower. There are limited number of studies in the literature that examine the effect of anxiety on the health belief model. In their study, Marmara et al. stated that anxiety has no effect on the components of the health belief model, but that the fear of being ill was positively related with the scores of all components of the health belief model [20]. Although the direction of the relationship between anxiety and behavioral motivation is discussed within different theoretical frameworks, some studies such as the study conducted by Winch et al. state that anxiety increases the motivation towards the behavioral goal [21]. Although our result that health motivation increases with health anxiety pertains to the patient’s health beliefs, it is parallel with the results of studies in the literature that evaluate the relationship between general anxiety and behavioral motivation. However, this topic deserves to be evaluated with specific consideration of the patients’ health motivation and health anxiety. Some studies in the literature have shown that self-efficacy and anxiety are inversely correlated [22]. Although the finding of our study that the self-efficacy component of the breast cancer health belief model has a negative correlation with anxiety is consistent with the previous literature, this topic should be studied specifically considering engagement in breast cancer screenings. In the study performed by Beydoun and et al. that examined the effect of anxiety on health beliefs regarding colorectal cancer screenings, they found that anxiety was associated with the perceived benefit and barrier components [23]. On the other hand, in our study, it was identified that anxiety did not significantly influence the benefit or barrier components of the health belief model regarding breast cancer screening. As emphasized in the article by Beydoun and colleagues, community-
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based studies are required to provide a better explanation of the effect of anxiety on the process of deciding to participate in breast cancer screening programs. Conclusion It was concluded that women with high levels of health anxiety have fewer mammographies and that their practice of breast selfexamination is not affected by their health anxiety levels. In this study, it was observed that people with high levels of health anxiety score high in the seriousness and health motivation components and low in the self-efficacy component of the health belief model. Health anxiety deserves to be studied further because it can particularly affect health behavior and its effect on the decision to engage in screening programs should specifically be established in larger studies. Competing interests The authors declare that they have no competing interest Financial Disclosure The financial support for this study was provided by the investigators themselves. Ethical approval The ethical approval for the study was obtained from the Izmir Katip Celebi University Non-Interventional Clinical Research Ethics Committee (Decision number: 283, date of approval: 02.11.2016). Meryem Askin ORCID: 0000-0003-1575-6946 Esra Meltem Koc ORCID: 0000-0003-3620-1261 Merve Yekta Ates ORCID: 0000-0002-5953-5822 Mehmet Arslan ORCID: 0000-0003-2791-4622 Gizem Dag ORCID: 0000-0003-0403-9044 Ali Murat Koc ORCID: 0000-0001-6824-4990 Kaan Sozmen ORCID: 0000-0001-8595-9760
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Diagn Res. 2017;11:XC01-XC05. 18. Brennan ME. The role of clinical breast examination in cancer screening for women at average risk: A mini review. Maturitas. 2016;92:61-3. 19. Shelby RA, Scipio CD, Somers TJ, et al. Prospective study of factors predicting adherence to surveillance mammography in women treated for breast cancer. J Clin Oncol. 2012;30:813-9. 20. Marmarà D, Marmarà V, Hubbard G. Health beliefs, illness perceptions and determinants of breast screening uptake in Malta: a cross-sectional survey. BMC Public Health. 2017;17:416. 21. Winch A, Moberly NJ, Dickson JM. Unique associations between anxiety, depression and motives for approach and avoidance goal pursuit. Cogn Emot. 2015;29:1295-305. 22. Can Gür G, Okanli A. The effects of cognitive-behavioral model-based ıntervention on depression, anxiety, and self-efficacy in alcohol use disorder. Clin Nurs Res. 2017:105477381772268. 23. Beydoun HA, Khanal S, Beydoun MA, et al. Are symptoms of anxiety and depression associated with colorectal screening perceptions and behaviors among older adults in primary care? 2014;4:78-89.
Available online at www.medicinescience.org
ORIGINAL RESEARCH
Medicine Science International Medical Journal
Medicine Science 2019;8(2):349-53
Is there a difference concerning red cell distribution width in patient with or without helicobacter pylori and gastric inflammation severity? Tarik Akar Bulent Ecevit University, Faculty of Medicine, Department of Gastroenterology, Zonguldak, Turkey Received 12 November 2018; Accepted 23 November 2018 Available online 30.01.2019 with doi:10.5455/medscience.2018.07.8970 Copyright Š 2019 by authors and Medicine Science Publishing Inc. Abstract Helicobacter pylori (H.Pylori) which is a widespread pathogen leading a slow chronic inflammation, may cause many clinical outcomes including gastric cancer. Red cell distribution width (RDW) is a new and promising indicator of inflammation. The primary aim of this study was to compare the red cell distribution width in patients with chronic gastric inflammation, either Helicobacter pylori positive or negative and also in gastric inflammation sub-groups. A total of 2500 patients who underwent upper gastro- intestinal system endoscopy were screened Of these 156 eligible patients, between 18 and 85 years old with no chronic disease and anemia as well as a normal of C-reactive protein and iron storage condition, were enrolled in this study. At least four gastric biopsies were taken from each patient and evaluated by the Sydney Classification. Serum RDW level and Helicobacter pylori positivity were compared as well as gastric inflammation severity. Of 156 patients, 84 (53.8%) were H.pylori positive, while 72 (46.2%) were H.pylori negative. There were no statistical differences between two groups according to mean age, gender, hemoglobin, mean corpuscular volume, ferritin, serum iron, platelet count and C-reactive protein (p>0.05). The median RDW level of H.Pylori positive and negative was not statistically different [13.4 (11.8-17.9) vs.13.4 (11.6-16), %95 confidential interval], respectively (p=0.89). Moreover, the median RDW level was not different among the groups of gastric inflammation severity according to Sydney Classification (all p-values >0.05). Our results demonstrated that there were no differences as regards to the median RDW result in patients with H.Pylori positive and negative . Also no disparity was observed between the median RDW and among the different subgroups of chronic gastric inflammation. Keywords: Red cell distribution width, helicobacter pylori, gastric inflammation
Introduction Many infective diseases with chronic inflammatory features affecting any part of the gastrointestinal tract still necessitate examining with minimally invasive endoscopic methods that are not available everywhere and suitable for every patient [1]. From another point of view, advanced immune histopathological examinations of endoscopic biopsies to identify a potential causative agent are also both expensive and time-consuming [2]. Consequently, a new diagnostic tool as a reliable and straightforward blood indicator of chronic inflammation is needed to avoid unnecessary costly and invasive processing [3]. Helicobacter pylori (H.pylori) is a common cause of infection agent causing chronic inflammation and thereby leading to various gastric diseases including gastric cancer and has an endemic feature in certain parts of the world, especially in the developing *Coresponding Author: Tarik Akar, Bulent Ecevit University, Faculty of Medicine, Department of Gastroenterology, Zonguldak, Turkey E-mail: drtarikakar@gmail.com
countries [1]. This chronic inflammation and its associated clinical condition have recently been linked with many other conditions and diseases outside of the stomach such as hematological and cardiovascular diseases [4-6]. Moreover, in recent years, the researchers regarding host immune responses occurred against the chronic H.pylori infection have begun to attract much more scientists attention before now [7]. Consequently, the identification of potential patients, who need further endoscopic investigation and need for H.pylori eradication, with simple, reliable and cheap blood markers, has become the increasingly significant subject of research studies. It is a well-known entity that there is a relationship between subgroup parameters of complete blood count (CBC) and lowgrade chronic inflammation [8]. Notably, some of these parameters are significantly elevated as correlated with the severity and duration of inflammation [9]. Red cell distribution width (RDW), which display the degree of variability of red blood cells, is one of the fundamental components of CBC and commonly used to differentiate anemia types from each other [6]. In addition to this essential function, in recent years, it is also used as a predictor 349
doi: 10.5455/medscience.2018.07.8970
and prognostic marker for various types of chronic diseases such as from diabetes mellitus, hypertension and heart failure to liver fibrosis and hepatocellular carcinoma [10-12]. New studies have clearly demonstrated this relationship [13,14]. Although there are many studies related to RDW in the gastrointestinal system, the critical role, and importance of RDW in H.pylori related chronic gastric inflammation have not been studied before. Hence, the primary aim of this study is to compare serum RDW between H.pylori positive and negative patients as well as in various degree of chronic gastric inflammation according to Sydney classification. Material and Methods This retrospective study was conducted at the department of gastroenterology in Zonguldak Bülent Ecevit University Farabi Hospital between from January 2015 and June 2017. A total of 2500 upper GIS endoscopic reports and their laboratory data were checked according to eligibility for this study. Patients between the ages of 18-85 who underwent upper endoscopy and received at least four gastric biopsies obtained from a different part of the stomach during this procedure were primarily included. The pathological report was accepted if the investigation is made according to Sydney Classification. H.pylori infection and other parameters were recorded as the degree of intensification and severity such as none, mild (+), moderate (++) and severe (+++) in this way. The measurements of CBC was accepted if done on the same day as the endoscopy procedure. It was clearly stated that if any patient had certain anemia or low and high mean corpuscular volume as well as low ferritin level, they were excluded. Since any part of anemia and anisocytosis were tightly linked and this could have caused a change in RDW values. Patients with confounding factors known to be possibly associated with anisocytosis were excluded. Besides, patients with a high level of C-reactive protein, white blood, and platelet count occurred any reason, or with any acute or chronic inflammatory disease and cancer were also excluded. Patients with gastric polyps and early gastric lesion or dysplasia during upper endoscopy were not included. A local ethics committee decision was made for this study and, consequently, this study was done according to the declaration of Helsinki, with the obtaining of approval of informant consent of each patient. For statistical analysis, Windows compatible SPSS 18 version was used. The data distribution of all groups was checked with at least three tests including the Kolmogorov Smirnov test. Parametric and non-parametric values were expressed as a mean ± standard deviation and as median with minimum and maximum levels, respectively. For mean±standard deviation type values, Student’s t-test was applied to compare the two groups, but if there were more than two groups, the individual comparisons were made with one-way ANOVA test. For median values (means as nonparametric), The Mann Whitney U test was used to compare two groups, but if there were more than two groups, the Kruskal Wallis test was used to compare among the groups. P-value <0.05 was accepted as significant. Results A total of 156 patients were enrolled in this study after the initial assessment as mentioned above. The most important demographic
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data were summarized in Table I. The study population was first analyzed as H. Pylori positive and H.pylori negative groups. Of these, 84 patients (53.8%) were H.Pylori positive, whereas 72 patients (46.2%) were H.pylori negative. There were no differences between the two groups according to the mean age, gender, hemoglobin level, endoscopic findings, mean corpuscular volume, platelet count, ferritin, serum iron and C-reactive levels (all p-values >0.05). As to the result of Sydney Classification; 1- Helicobacter Pylori; as expected the H. pylori positivity was detected only in H. pylori positive group (p<0.001), 2Inflammation; the number of patients with mild and moderate inflammation was not different in both groups, but patients with severe inflammation were significantly higher in H. pylori group (p<0.001), 3- Activation; none (0) type activation was higher in H.pylori negative group than those with H.pylori positive (p<0.05), but mild and moderate activation was higher in H.pylori positive patients than those H.pylori negative (p<0.005), 4- Metaplasia and Atrophia; there was no difference between the two groups according to metaplasia and atrpohia. The median RDW levels of H.pylori positive and negative were not statistically different in two groups, [13.4 (11.80-17.9) vs.13.4 (11.6-16), %95 Confidential Interval], respectively (p=0.89). In groups structured according to Sidney classification, there was no difference in median RDW among the five groups (all p values>0.05) (Table-II). Also, when analyzed by stratification in pairs or triple group formats, no statistical difference was found in median RDW among the groups (all p values>0.05) (Table-II). Discussion In that presenting study, the first time in literature, we investigated the comparison of the RDW levels in chronic gastric inflammation, whether H.pylori positive or negative, and clearly demonstrated that there were no differences the median RDW between H.pylori-positive and H.pylori-negative patients and also found no differences the median RDW in different subgroups of chronic gastric inflammation according to Sydney Classification. Consequently, we say that the RDW measurement does not work for demonstrating the gastric inflation severity and the presence of Helicobacter pylori. Also, it is not possible to make a decision with RDW in the inflammation of the stomach. Helicobacter pylori is a prevalent problem for all over the world, especially developing countries. Because it could lead to many gastrointestinal issues including gastric cancer, consequently, it should be eradicated in patients with high-risk features [1]. For H .pylori eradication in many countries, two weeks of dual antibiotics are recommended [1,15]. Also, the empirical H.pylori eradication therapy is not suggested without clearly H.plori detection mainly in low endemic countries, because the recommended dual drugs can cause many side effects including liver toxicity. The standard gold method for the detection of this pathogen is still upper endoscopy with histological examination [15]. Although these procedures are minimally invasive, they are expensive in some country, and timeconsuming as well as are not available, suitable for every patient and everywhere [1,2]. A reliable and straightforward indicator of inflammation is needed to avoid unnecessary invasive and expensive processing attempts [3].
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Table 1. The essential critical demographic data of the study H.PLORI (+) n,%
H.PLORI (-) n,%
P
Mean ± standard deviation Patients
84 (53.8%)
72 (46.2%)
0.337
Age
53.6 ±13.3
54.4 ±15.4
0.724
Male
45
40
0.804
Female
39
32
Hemoglobin (mg/dL) (NR:12-18)
14.1 ±1.14
14.2 ±1.1
0.304
MCV (fL) (NR:80-99)
87.4 ±3.5
88.1 ±3.9
0.274
Serum Iron υg/dl (NR:60-180)
72.2 ±12.8
67.8 ±9.7
0.689
Platelet x106 µ/mL (NR:140-400)
232 ±69
220 ±57
0.724
CRP mg/dl (NR:0-8)
2.2 ±1.5
3.06 ±1.1
0.854
Gender
Median (minimum-maximum) RDW (%) (NR:11.5-15.5)
13.45 (11.6-16)
13.4 (11.8-17.9)
0.890
Ferritin mg/dl (NR:11-308.6)
48.2 (9.5-253)
44.65 (11-323)
0.986
30
24
2-LES dysfunction +ESG
48
45
3-ESG+ Ulcer or erosion of duodenum
6
3
0
0
Endoscopic findings 1-Erythematous superficial gastritis(ESG)
NS
Histological Examination 1-H.Pylori None Mild (+)
50 (59.5%)
Moderate (++)
22 (26.1%)
Severe (+++)
12 (14.2%)
<0.001
2-Inflammation None
0
2 (2.7%)
NS
Mild (+)
15 (17.8%)
27 (37.5%)
NS
Moderate (++)
34 (40.4%)
39 (54.1%)
NS
Severe (+++)
35 (41.6%)
4 (5.5%)
<0.001
None
34 (40.4%)
64 (88.8%)
<0.05
Mild (+)
25 (29.7%)
6 (8.3%)
<0.05
Moderate (++)
24 (28.5%)
2 (2.7%)
<0.05
1 (1.1%)
0 (0%)
NS
63 (75%)
52 (72.2%)
17 (20.2%)
15 (20.8%)
4 (4.7%)
2 (2.7%)
0 (0%)
0 (0%)
None
69
66
Exist
15
6
3-Activation
Severe (+++) 4-Metaplasia None Mild (+) Moderate (++) Severe (+++)
NS
5-Atrophia NS
NR: Normal Range, NS: Not significant, CRP:C reactive protein, MCV: Mean corpuscular volume, RDW: Red cell distribution width, LES: Lower esophageal sphincter
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doi: 10.5455/medscience.2018.07.8970 Table 2. There were no differences between the median RDW and among the chronic gastric inflammation sub-groups according to Sydney Classification (all p-values >0.05). (RDW: red cell distribution width) Sydney Classification (n)
Red Cell Distribution Width Median (minimum-maximum)
1-Helicobacter pylori (n)
0.954
None (-) (72)
13.4 (11.6-16)
Mild (+) (50)
13.4 (12.7-15.3)
Moderate (++) (22)
13.5 (11.8-17.9)
Severe (+++) (12)
13.3 (12.8-14.6)
2-Inflammation (n)
0.995
None (-) (2)
13.4 (13.2-13.7)
Mild (+) (40)
13.3 (12.5-16)
Moderate (++) (69) Severe (+++) (38)
13.5 (11.6-15) 13.5 (11.8-17.9)
3-Activation (n)
0.280
None (-) (98)
13.5 (11.6-16)
Mild (+) (31)
13.4 (12.7-17.9)
Moderate (++) (26)
13.2 (11.8-15.3)
Severe (+++) (1)
13.1
4-Metaplasia (n)
0.756
None (-) (115)
13.4 (11.6-17.9)
Mild (+) (32)
13.5 (12.5-15.4)
Moderate (++) (9)
13.6 (12.8-14.2)
Severe (+++) (0)
p
0
5-Atrophia (n)
0.944
None (-) (135)
13.4 (11.6-16)
Exist (+) (21)
13.4 (12.8-17.9)
RDW is a part of routine CBC and used commonly to differentiate iron deficiency anemia and various part anemia [6]. Recently, RDW has been very popular and promising marker for predicting chronic diseases such as cardiovascular, hematological and metabolic diseases [5,16]. RDW has so far been studied in many different diseases and slow inflammation as an indicator of prognosis or as a marker of subclinical inflammation, but, no current study is available related RDW and H.pylori [14]. To best of knowledge, our study is first to paper evaluating the relationship between RDW and H.pylori and the severity of slow gastric inflammation that primarly related with H.pylori . RDW is mainly affected by age and iron storage [6]. Therefore, when evaluating the RDW, the iron storage condition should be investigated in the right way. In this study, we carefully selected our patients and, in our population, no patient was anemia and also even iron deficiency [6]. Unlike the previous studies, for evaluation of iron storage, we used the serum ferritin level and serum iron concentration as well [11]. Even in the same patients with hemoglobin and MCV levels, the serum RDW can become high if ferritin is low. In literature, because a few numbers of the studies evaluated the RDW with ferritin and serum iron, therefore, conflicting results could also be obtained. Unlike the many previous RDW related studies, we found no relationship between RDW and gastric inflammation severity, whether H.pylori positive or negative. There may be a few reasons for this. First, the RDW is mainly affected by changes in the
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stock of iron storage. When looked at the literature much more closely, the iron storage condition with ferritin has not taken into count in many RDW related studies [14,16-18]. To us and current literature, RDW should be evaluated with serum ferritin level. In our work, we checked this matter correctly and did not include any patient who had no evident anemia with low ferritin level and serum iron. It can be clearly seen that only a small number of study take care of this situation [11,19]. Second, some conditions and agents cause a more serious systemic inflammatory response than H. Pylori. Thus, RDW may be more affected by these situations. For example, YÄąlmaz et al. concluded that RDW could an easy and inexpensive marker for intrahepatic cholestasis of pregnancy, and Xanthopoulos et al. claimed that RDW levels might be a prognostic marker in patients with heart failure and diabetes mellitus [9,11,14]. In these exemplified studies, CRP, the indicator of systemic inflammatory response, was not considered as a reason to influence the results [20,21]. For this, in our study, we studied CRP level and found a similar result in groups both H. H.pylori positive and negative. Consequently, our result may be more reliable. Third, previous studies have clearly demonstrated that H. pylori-associated chronic gastric inflammation does not produce systemic cytokines such as in serum levels of tumor necrosis factor-alpha, interleukin-6 and interleukin-8 [22]. In this article, the authors concluded that since the H.pylori pylori lives only in the stomach mucosa and causes a unique form of local inflammation, thus, this inflammation cannot produce a systemic response. Conflicting results have already been reported in RDW related studies performed in local inflammatory diseases [23,24]. To us, the reason why the RDW does not differ in gastric inflammation severity and presence of H.pylori is only limited inflammation. The limitations of our study as follows; retrospective design and relatively small case number. We also believed that if we added the mean platelet volume in this study, the results could be more meaningful. Conclusion Our results demonstrated that there were no differences in the median RDW in H.pylori positive and negative patients and no association between the median RDW and among the different subgroups of chronic gastric inflammation. Consequently, RDW is not a suitable marker to differentiate H.pylori positive and negative patients and severity of gastric inflammation. Competing interests The authors declare that they have no competing interest Financial Disclosure This study was supported by the konya education and research hospital. Ethical approval The ethics committee approval (date: 29.6.2017 and clinical trial number; 201779- 29/06 ) was obtained by local department. Tarik Akar ORCID:0000-0001-8209-1513
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Shetty V, Ballal M, Balaraju G, et al. Helicobacter pylori in dyspepsia: phenotypic and genotypic methods of diagnosis. J Glob Infect Dis. 2017;9:131-4.
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Dolak W, Bilgilier C, Stadlmann A, et al. A multicenter prospective study on
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doi: 10.5455/medscience.2018.07.8970 the diagnostic performance of a new liquid rapid urease test for the diagnosis of helicobacter pylori infection. Gut Pathog. 2017;9:78. 3.
Goyal H, Lippi G, Gjymishka A, et al. Prognostic significance of red blood cell distribution width in gastrointestinal disorders. World J Gastroenterol. 2017;23:4879-91.
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14. Vural Yilmaz Z, Gencosmanoglu Turkmen G, Daglar K, et al. Elevated red blood cell distribution width is associated with intrahepatic cholestasis of pregnancy. Ginekol Pol. 2017;88:75-80. 15. Moayyedi PM, Lacy BE, Andrews CN, et al. ACG and CAG clinical guideline: management of dyspepsia. Am J Gastroenterol. 2017;112:988-1013.
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Rahmani Y, Mohammadi S, Babanejad M, et al. Association of helicobacter pylori with presence of myocardial infarction in iran: a systematic review and meta-analysis. Ethiop J Health Sci. 2017;27:433-40.
16. Siegler JE, Marcaccio C, Nawalinski K, et al. Elevated red cell distribution width is associated with cerebral infarction in aneurysmal subarachnoid hemorrhage. Neurocrit Care. 2017;26:26-33.
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Bilal A, Farooq JH, Kiani I, et al. Importance of mean red cell distribution width in hypertensive patients. Cureus. 2016;8:e902.
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Zhu A, Kaneshiro M, Kaunitz JD. Evaluation and treatment of iron deficiency anemia: a gastroenterological perspective. Dig Dis Sci. 2010;55:548-59.
17. Xiong XF, Yang Y, Chen X, et al. Red cell distribution width as a significant indicator of medication and prognosis in type 2 diabetic patients. Sci Rep. 2017;7:2709.
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Guclu M, Faruq Agan A. Association of severity of helicobacter pylori infection with peripheral blood neutrophil to lymphocyte ratio and mean platelet volume. Euroasian J Hepatogastroenterol. 2017;7:11-6. Beyazit F, Öztürk FH, Pek E, et al. Evaluation of the hematologic system as a marker of subclinical inflammation in hyperemesis gravidarum: a case control study. Ginekol Pol. 2017;88:315-9.
18. Yayla Abide Ç, Vural F, Kılıççı Ç, et al. Can we predict severity of intrahepatic cholestasis of pregnancy using inflammatory markers? Turk J Obstet Gynecol. 2017;14:160-5. 19. Nada AM. Red cell distribution width in type 2 diabetic patients. Diabetes Metab Syndr Obes. 2015;8:525-33. 20. Magri CJ, Fava S. Red blood cell distribution width and diabetes-associated complications. Diabetes Metab Syndr. 2014;8:13-7.
Kurtul BE, Kabatas EU, Boybeyi SD, et al. Increased red cell distribution width levels in children with seasonal allergic conjunctivitis. Int Ophthalmol. 2018;38:1079-84.
21. Kucukdurmaz Z, Karavelioglu Y, Karapinar H, et al. Red cell distribution width and hypertensive response to exercise in patients with type 2 diabetes mellitus. Clin Exp Hypertens. 2014;36:32-5.
10. Goyal H, Hu ZD. Prognostic value of red blood cell distribution width in hepatocellular carcinoma. Ann Transl Med. 2017;5:271.
22. Bayraktaroğlu T, Aras AS, Aydemir S, et al. Serum levels of tumor necrosis factor-alpha, interleukin-6 and interleukin-8 are not increased in dyspeptic patients with Helicobacter pylori-associated gastritis. Mediators Inflamm. 2004;13:25-8.
11. Xanthopoulos A, Giamouzis G, Melidonis A, et al. Red blood cell distribution width as a prognostic marker in patients with heart failure and diabetes mellitus. Cardiovasc Diabetol. 2017;16:81. 12. Farah R, Hamza H, Khamisy-Farah R. A link between platelet to lymphocyte ratio and Helicobacter pylori infection. J Clin Lab Anal. 2018;32. 13. Farah R, Khamisy-Farah R. Association of neutrophil to lymphocyte ratio with presence and severity of gastritis due to helicobacter pylori infection. J Clin Lab Anal. 2014;28:219-23.
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Available online at www.medicinescience.org
ORIGINAL RESEARCH
Medicine Science International Medical Journal
Medicine Science 2019;8(2):354-9
Expression of MMP-14 and CD44 associated with proliferation of retinoblastoma cells Hendrian D. Soebagjo1, Evelyn Komaratih1, Susy Fatmariyanti1, Nurwasis Nurwasis1, Aulanniam Aulanniam2 1
Faculty of Medicine University of Airlangga, Dr. Soetomo Hospital, Department of Ophthalmology, Surabaya, Indonesia 2 Science Faculty of Brawijaya University, Biochemistry Laboratory, Department of Chemistry, Malang, Indonesia Received 22 September 2018; Accepted 26 November 2018 Available online 10.01.2019 with doi:10.5455/medscience.2018.07.8958 Copyright © 2019 by authors and Medicine Science Publishing Inc.
Abstract Retinoblastoma is a the most common primary intraocular malignant tumor in childhood. The eexpressions of CD44 and MMP-14 and Their role in proliferation and migration cells appear crucial for retinoblastoma invasion. Thirty-five paraffin blocks from retinoblastoma patients with tumor material were compared with eight paraffin blocks of normal retina. Retinoblastoma patients were selected from patients diagnosed with retinoblastoma at Dr. Soetomo General Hospital, Surabaya. Immunohistochemical method was used to evaluate the expression of CD44, MMP-14, and cell proliferation (Ki-67). The expression of CD44, MMP-14, and Ki-67 protein was positive in all retinoblastoma samples. In retinoblastoma samples, 54.3% (19/35) of CD44 showed high expression (score 3). The majority (40%) of MMP-14 expression was low (score 1) in retinoblastoma samples. The majority (60%) of Ki-67 (21/35) showed high expression (score 2) in retinoblastoma samples. In normal retina, 100% CD44 was moderately expressed (score 1), Ki-67 and MMP-14 were not expressed. Their expression in retinoblastoma was significant when compared with normal retina. In retinoblastoma sample, positive staining of CD44 showed high expression in the cytoplasm of the cell. This suggests that hyaluronic acid, as a ligand to CD44 in cell’s cytoplasm, has low molecular weight, expresses angiogenesis properties, and promotes tumor cell proliferation. MMP-14 in this study was reported to be expressed mostly on low level group. The expression of CD44 and MMP-14 is thought to play a role in inducing cell proliferation and invasion of retinoblastoma cells. Keywords: CD44, MMP-14, proliferation, retinoblastoma
Introduction Retinoblastoma is a the most common primary intraocular malignant tumor in childhood. It occurs in younger children and it is both hereditary and non-hereditary. Unilateral (non-hereditary) retinoblastoma comprises 60% cases and the median age at diagnosis is two years. Bilateral (hereditary) form comprises about 40% of the cases with median age at diagnosis is one year old. Retinoblastoma is reported to occur 1 in every 15,000–20,000 live birth in the world [1-5]. Retinoblastoma is a tumor in which the initial genetic mutation is known. Knudson hypothesis was able to establish a correlation between a mutation in the first identified tumor-suppressor gene
*Coresponding Author: Hendrian D. Soebagjo, Faculty of Medicine University of Airlangga, Dr. Soetomo Hospital, Department of Ophthalmology, Surabaya, Indonesia E-mail: hendriands@yahoo.com
(RB1, chromosome 13q14) and the development of the tumor. Mutation in the RB1 gene is inherited via the germline and the second mutation occurs in somatic cells [6]. Tumors grow because the homeostatic control mechanisms that maintain the appropriate number of cells in normal tissues are defective, leading to an imbalance between cell proliferation and cell death as there is a disturbance in the immune system and some cancer cells have the ability to destroy host’s immune system[7,8]. Cells are surrounded either by other cells or by extracellular matrix (ECM that interact tightly and specifically with each other. This interaction is mediated by cell adhesion molecules (CAMs), which enable the cells to adhere tightly and specifically with cells of the same or similar type. CAMs are transmembrane receptor proteins that can be divided into four major families: immunoglobulin superfamily, integrins, cadherins, and selectins[9-10]. Extracelullar matrix (ECM) has a crucial role during the invasion of tumor cells. The invasion and migration of tumor cells involves coordinated adhesion as well as proteolytic interaction with the ECM substrate, 354
doi: 10.5455/medscience.2018.07.8958
resulting in the degradation and remodeling of interstitial tissue barriers [11]. Tumor cells produce a variety of lytic enzymes and cytokines that degrade and modify the ECM. The degradation and modification of the ECM allow the invasion of the tumor through tissue barriers, blood vessel and lymph channel walls, with the possible further metastatic development [12-14].
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primary Rabbit Monoclonal Antibody Anti-CD44/HCAM/PGP1, Primary Polyclonal Antibody (bs-0521R) Bioss Inc. (1:150), Anti MMP-14 Polyclonal Antibody (NB100-91872) Novus Biological (1:300), and Ki-67 (CRM325 AK,BK)-monoclonal antibody Biocare Medical (1:75). All samples were stained by using Labelled Streptavidin Biotin II (LSAB II) method, then incubated with biotin-labeled secondary antibody (Trekkie Universal Link) and peroxidase-conjugated streptavidin (Trekavidin-HRP Label) overnight. DAB was used as the chromogen and counterstained with Mayer`s hematoxylin.
CD44 is a ubiquitous multistructural and multifunctional cell surface adhesion molecule from the family of transmembrane glycoproteins, which is the principal cell surface receptor for hyaluronan, a component of extracellular matrix (ECM) [15,16]. It was first identified as having cell adhesion and cell homing functions, but it has already been shown to have multiplefunctions [17]. Matrix metalloproteinases (MMPs), also called matrixins, function in the extracellular environment of cells and degrade both matrix and non-matrix proteins. Membrane-type 1 matrix metalloproteinase (MT1-MMP) or called MMP-14 is a zincdependent type-I transmembrane metalloproteinase involved in pericellular proteolysis, migration and invasion. Numerous substrates and binding partners have been identified for MT1MMP, and its role in collagenolysis appears crucial for tumor invasion [18,19]. Therefore, we evaluated the expression of CD44 and MMP-14 and its role in cell proliferation and migration that appeared crucial for retinoblastoma invasion.
The numerical value for percent stained is determined by a geometric rather than linear division. Result of CD44 staining was scored on the percentage proportion of positive and negative staining with categories: 0= negative (no stained), 1= low (<35% cells stained), 2= moderate (35-75% cells stained), and 3= high (≥75% cells stained) [20]. The MMP-14 staining wasdefined as: 0= negative (no stained), 1= low (1-20% cells stained), 2= moderate (21-40% cells stained), and 3= high (>40% cells stained) [21]. Ki67 expressions were categorized as 0= negative (no cells stained), 1= low (≤40% cells stained), and 3= high (≥40% cells stained) on nuclear cell [22]. Positive control tissues were used to compare with positive expression of the samples, including tonsil cancer (CD44), ovarian cancer (MMP-14), and prostate cancer (Ki-67).
Materials and Methods Subjects
Statistical analysis was conducted by using Chi Square Test to assess the differences between retinoblastoma and normal retina. Spearmann correlation test was used to analyze correlation of the expression variables score. A p-value of < 0.05 was considered statistically significant.
A total of 35 (thirty five) paraffin blocks from retinoblastoma patients with tumor material were compared with 8 (eight) paraffin blocks of normal retina from patients with eye cancer whose retina had not been invaded with cancer. Retinoblastoma patients were selected from patients diagnosed with retinoblastoma at Dr. Soetomo General Hospital, Surabaya, between 2010 – 2013. Immunohistochemical method was used to evaluate the expression of CD44, MMP-14, and proliferation cells (Ki-67).
Results The immunohistochemical expression of CD44, MMP-14, and Ki-67 was assessed in 35 retinoblastoma samples and 8 normal retina samples. Positive CD44, MMP-14, and Ki-67 protein expression was obtained in all retinoblastoma samples (35/35). In retinoblastoma samples, 54,3% (19/35) of CD44 showed high expression (score 3). The majority (40%) of MMP-14 expression was low (score 1) in retinoblastoma samples. The majority (60%) of Ki-67 (21/35) showed high expression (score 2) in retinoblastoma samples. In normal retina, 100% CD44 was moderately expressed (score 1), Ki-67 and MMP-14 were not expressed (Table 1).
Immunohistochemical Staining Paraffin-embedded tissues of all sample sections were retrieved for sectioning and immunohistochemical staining. Deparaffinized sections were immersed in methanol containing 3% diluted hydrogen peroxide. For blocking non-specific binding, Dakocytomation (peroxidase blocking reagent S200/30-2) was applied to the sections and then they were incubated at room temperature, with Table 1. Result of Immunohistochemical Expression of Variables Variable Score
CD44 Cell
MMP-14 %
Cell
KI-67 %
Cell
%
28.57
-
-
Retinoblastoma Sample (35 cells) 3
19
54.29
10
2
10
28.57
11
31.43
21
60.00
1
6
17.14
14
40.00
11
31.43
0
-
-
-
-
3
8.57
-
-
-
100.00
8
Normal Sample (8 cells) 1
8
0
p: 0.000*
100,00
-
-
8 p: 0.007*
100.00 p: 0.000*
* statistically significant (p: < 0.05)
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CD44 expression was shown by positive staining expressed in the cytoplasm and cell membrane. From the retinoblastoma sample, positive staining showed expression in the cytoplasm of the cell, but in normal retinal samples the expression was seen on the cell membrane. MMP-14 was expressed both in the cytoplasm and in the cell membrane. Ki-67 expressed positive staining in the cell nucleus (Figures 1 and 2).
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also associated with the expression of Ki-67(B=0.545, p=0.004).
Figure 3. A schematic representation of CD44 and MMP-14 signaling in the regulation of proliferation retinoblastoma cell. Figure 1. Immunohistochemical staining pattern of CD44 in retinoblastoma and normal retina sample. (A) Expression of CD44 at cytoplasm in retinoblastoma sample. Original magnification x400; (B) CD44 expressed at cell membrane in normal retina. Original magnification x200.
Discussion Retinoblastoma is the most common form of ocular cancer in children. Retinoblastoma is a malignant tumor in retina originating from the neuroectodermal primitive tissue. This tumor is caused by mutation on 13q14 chromosome. Several malignant properties retinoblastoma possess include tumor cell proliferation and progressive metastatic process. MMP-14 is important in the cancer differentiation process, tumor invasion, and metastasis process. MMP-14 is also expressed in gliablastoma and medulloblastoma brain tumor, pleural mesothelioma, and breast cancer [18,21,23-25 ].
Figure 2. Immunohistochemical staining pattern of MMP-14 and Ki-67 in retinoblastoma and normal retina sample. (A) Expression of MMP-14 at cytoplasm and membrane cells in retinoblastoma sample and (B) negative in normal retina. (C) Retinoblastoma cells overexpressing Ki-67 with nuclear staining. (D) Normal retina cells do not express Ki-67. Original magnification x400
The expression of CD44, MMP-14, and proliferation (Ki-67) in retinoblastoma was significant when compared with normal retina(Chi Square Test, (CD44=p:40,140c;α: 0,000);(MMP14=p:29,930b;α:0.007); (Ki-67=p:40,930d;α:0.000)) (Table 1). A significant correlation was found between the expression of CD44, MMP-14, and Ki-67. Spearmann correlation test analysis showed significant correlation between CD44 with MMP-14 (r=0.383, p=0.011) and CD44 with Ki-67 (r=0.561, p=0.000). However, the association between CD44 with MMP-14 (B=0.220, p=0.100) in terms of cell proliferations was not significant. Significant correlation was found between the expression of MMP-14 with Ki-67 (r=0.567, p=0.000). Then, the correlation of these expression was tested with pathway analysis to identify the association and role of CD44 and MMP-14 expression in proliferative cells. The expression of CD44 was associated with the expression of Ki-67 (B=0.442, p=0.007) and MMP-14 was
Samples taken from retinoblastoma group displayed MMP-14 expression with the percentage of 40%, 31,43%, and 28,57% for group Score 1, 2, and 3, respectively. Normal retina specimen showed no MMP-14 expression. This finding is comparable to a study on mestohelioma cancer conducted by Crispi et al. (2009) which reported a low rate (score 1) MMP-14 expression as the most frequent expression group. They also described the group with a high rate of MMP-14 expression had a short survival time [21]. The expression of MMP-14 in retinoblastoma group was found significant compared to normal retina (Chi Square Test, (MMP14=p:29,930b;α:0.007). MMP plays a role in the process of cancer cell invasion and metastasis. MMP-14 plays a role in the migration and metastasis of tumor cells by diffusing into the basement membrane and in cell invasion through interstitial collagen type-I tissue. MMP-14 accumulates in invadopodia ECM, which specifically degrades invasive cell membrane protrusions. MMP-14 degrades some type I, II, III collagen, laminin-1 and -5, fibronectin, vitronectin, fibrin, and aggrecan which are the constituent components of ECM. In the metastatic provess of cancer cells, these collagen components are the most important substrate. Collagen is the most ECM component found in the body and forms a tissue frame structure. Therefore, collagen is a component that needs to be degraded so that cancer cells can mirate. During metastasis, cancer cells break down the extracellular matrix to clear the path for movement, and then enter the blood vessels or the lymphatics. Those results indicate the presence of MMP-14 expression in retinoblastoma, whereas it was absent on normal retina. [18,24,26-28]. 356
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In retinoblastoma samples, 54,3% of CD44 showed high expression (score 3). As much as 28,57% expressed score 2 CD44, and the remainder expressed score 1 CD44. Normal retina expressed score 1 CD44, too. From these study results, authors concluded that retinoblastoma expressed CD44. CD44 is a hyaluronic acid principal receptor. CD44 is a transmembrane glycoprotein. CD44 is encoded by chromosome 11p13 and pre-mRNA CD44 is encoded by 20 exons. This CD44 extracellular domain is connected and binds the ligand, the hyaluronic acid [17,29,30]. In retinoblastoma sample, positive staining showed expression in the cytoplasm of the cell. Hyaluronic acid in cell’s cytoplasm is observed to have particular properties such as low molecular weight, 2-25 pM polymer length, oligosaccharide fragmented shape, possessing angiogenesis capabilities, suppressing cellular apoptotic process, inducing CD44 proliferation and FasL regulation, adhesion, migration by activating several signals pathway such as kinase adhesion, mitogen activated protein (MAP) kinase and tirosin kinase cascade, and also stimulating inflammation cytokine production, suspending anchorage-independent to affect several tumor cells types growth [31-35]. Retina in normal condition expressed score 1 CD44. The expression of CD44 in retinoblastoma was significant when compared to normal retina (Chi Square Test, (CD44=p:40,140C;α: 0,000). CD44 expression was shown by positive staining expressed in the cell membrane normal retina. In this study, CD44 expression is associated with hyaluronic acid’s role in normal retina. Expression in cell membrane as receptor, hyaluronic acid has a heavy molecular weight with its common properties including progressive tumor inhibitor, antiangiogenesis, resisting endothelial cellular growth, antiinflammatory and immnosuppresive properties, decreasing monocyte and macrophage, phagocytosis process, suppressing hyaluronic acid synthesis and keeping intercellular balance. Hyaluronic acid with its 2 x 106 Da to 2 x 107 Da or 250025.000 disaccharide molecular weight on cell membrane holds physiologic, biologic, and physicochemical characteristics [30,3132,36-37]. On retinoblastoma cells, majority of Ki-67 expression as much as 60% was found in Score 2 category, with the remainder made up Score 1 and 0 group. However, examination on normal retina confirmed there was no Ki-67 expression. Normal half time of Ki67 was believed to be one to one and a half hour. Cell expressed Ki-67 during G1, S, G2, and M phase but did not during its resting (G0) phase. In cancerous cell, proliferation increases as more cells enter S phase causing neoplastic transformation. The increasing number of cells entering S phase leads to Ki-67 rising up to its highest level during mitotic phase. This phenomena, however, does not occur on normal mature retina as it is a differentiated neuronal cell and stays on G0 phase. [38,39]. The expression of Ki-67 proliferation in retinoblastoma was found significant when compared with normal retina(Chi Square Test, Ki-67=p:40,930d;α:0.000). Ki-67 expression was reported to increase when retinoblastoma’s differentiation got worse. The increase of Ki-67 expression was also found in breast cancer, colorectal carcinoma, prostate cancer, oral squamous carcinoma, and gastric cancer. The growing level of Ki-67 as one of cell proliferation markers indicates an aggresiveness of a tumor shown as an increasing mitotic cell numbers [38,40-44].
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Pathway analysis demonstrated that The expression of CD44 was associated with theexpression of Ki-67 (B=0.442, p=0.007). The binding of hyaluronic acid to CD44 on plasma extracellular cell membranes triggers the signaling process of tyrosine kinase receptors (ErbB2 and EGFR), other signal receptors (TGFßR1), and non-receptor kinases (Src families) that control the pathway of oncogenes, such as MAP kinase and proliferation pathways of PI3 kinase/Akt cells. A variety of adapter proteins such as Vav2, Grb2, and Gab-1 mediate interaction between CD44 and effectors, such as RhoA, Rac1, and Ras. On the other hand, CD44 also interacts with another carbohydrate, the heparin sulfate, to regulate and activate other tyrosine kinase receptors, the c-Met receptor. The interaction of hyaluronic acid-CD44 also induces changes in cell motility and cell invasion. The actin filaments are bound to the CD44 cytoplasmic tail by the ERM family (ezrin-radixin-moesin) or ankyrin for the process of cancer cell motility. In the interaction process of hyaluronic acid-CD44 which increases motility invasion and tumor growth, CD44 binds hyaluronic acid which has a low molecular weight. In addition, the hyaluronic acid-CD44 complex is able to induce interleukin-6 to suppress the function of p27 (kip1) CDK2-inhibitor and hyperphosphorylation of Rb protein which have a role in the proliferation process in myeloma cells. CD44 has a role to induce the E-CDK2 cyclin complex in cancer through its inhibitor, p27 (kip1), in myeloid leukemia. CD44 also induces CDK2 p21 inhibitors. These factors induce the process of tumor cell proliferation, especially in retinoblastoma. [45-47]. MMP-14 was also associated with theexpression of Ki67(B=0.545, p=0.004).MMP-14 has a role of increasing the expression of K-Ras and EGFR and inhibiting Ink4a/Arf which is a CDK4 inhibitor. The inhibited p14Arf protein activates Mdm2 to suppress the apoptotic pathway and suppressed p16Ink4a activates the D1-CDK-4 cyclin complex. MMP-14 also degrades ECM and induces cells for migration and invasion, activates proMMP2 and proMMP13, induces syndecan, activates ERK, and induces laminin-5 cleavage for the invasion of tumor cells [27,48,49]. In retinoblastoma cells, the association between CD44 and MMP14 was found not significant 14 (B=0.220, p=0.100). Ali et al (2013) reported an increase in MMP-14 expression on prostate cancer. This increasing expression was thought to correlate with the increase of EGFR and K-Ras expression which was affected by m-RNA and resulting in Ink4a/Arf expression being suppressed. Downregulated Ink4a/Arf would activate cell proliferation pathway through CDK4. Suppressed p14Arf protein would trigger Mdm2 to halt p53 and cell apoptoticpathway while downregulated p16Ink4a would activate D1-CDK4 cyclic complex which in turn would suppress Rb protein so that E2F activates proliferation pathway. MMP-14 degrades ECM and induces cell to migrate and invade, activates proMMP2 and proMMP13, induces syndecan, activates ERK, induces laminin-5 replication during tumor cell invasion process. This study described that MMP-14 induced proliferation process without CD44, while on the contrary, Itoh (2006) reported that MMP-14 was able to cut off CD44 cleavage in cell metastasis. [27,48,49]. Conclusion Retinoblastoma is the most common primary intraocular malignant tumor in childhood.This study reported expression of MMP14, CD44, and Ki-67 in retinoblastoma samples group. Their 357
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expression in retinoblastoma was found to be significant when compared to normal retina. In retinoblastoma samples, positive staining of CD44 showed high expression in cell cytoplasm. This suggests that hyaluronic acid, as a ligand to CD44 in cell’s cytoplasm, has low molecular weight, expresses angiogenesis properties, and promotes tumor cell proliferation. MMP-14 in this study was reported to be expressed mostly on low level group. The expression of CD44 and MMP-14 is thought to play a role in inducing cell proliferation and invasion of retinoblastoma cells. Competing interests The authors declare that they have no competing interest. Financial Disclosure This study received no specific grant from any funding agency, commercial or notfor-profit sectors Ethical approval This study was ethical cleareance certified at July 9th, 2013 in RSUD Dr. Soetomo, Surabaya.
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ORIGINAL RESEARCH
Medicine Science International Medical Journal
Medicine Science 2019;8(2):360-4
Evaluation of efficacy of oral honey use in adult tonsillectomy patients Muge Ozcelik Korkmaz1, Mehmet Guven1, Unal Erkorkmaz2
1
1
Sakarya University Medical Faculty, Department of Otolaryngology, Sakarya, Turkey 2 Sakarya University Medical Faculty, Department of Bioistatstic, Sakarya, Turkey Received 07 Octaber 2018; Accepted 26 November 2018 Available online 27.02.2019 with doi:10.5455/medscience.2018.07.8980 Copyright © 2019 by authors and Medicine Science Publishing Inc.
Abstract Post-tonsillectomy throat pain is one of the most common complication, which leading to delayed recovery and later hospital discharge. This study aims to evaluate the effectiveness of oral honey use on eating, condition and reducing pain with patients have applied tonsillectomy. The study included 72 patients (37 males, 35 females; mean age 26±4.16 years; range 18 to 36 years) who were applied tonsillectomy. Patients were randomized into two groups. The treatment group received postoperatively followed by oral consumption of honey three times daily for five days Patients’ pain, eating and condition situation was assessed with visual analog scale(VAS), and analgesic intake was recorded during five follow-up periods. There was no statistically different between two groups about postoperative pain at first three days. But the postoperative pain was statically significant less at honey group than the control group. There was also a significant decrease in the number of analgesics taken over the last three control periods in terms of the honey group. The eating situation was statically significant better in the honey group than the control group at all days. The patients’ condition was also better in the honey group at all days. The result of study, the early postoperative pain was relieved slightly faster in the honey + antibiotic group, which may be attributed to the soothing effect of honey. This situation improves the oral intake of the patients and shortens the recovery process in the postoperative period. Keywords: Tonsillectomy, pain, honey, condition
Introduction Tonsillectomy is one of the most frequently performed surgical operations in the world and is frequently performed due to recurrent infection and upper respiratory tract obstruction indications. Although it is a simple surgical procedure, there is a high incidence of complications during the perioperative and postoperative period. Bleeding, pain, infection, delayed wound healing, velopharyngeal insufficiency, nasal regurgitation and otalgia are the most common complications, especially in the postoperative period [1]. Posttonsillectomy throat pain is more prevalent, especially in the adult age group, and problems such as poor oral intake, general health disorders and delayed recovery time may be expected due to severe pain [2] .Various methods have been proposed for use during and after surgery to reduce pain post-tonsillectomy [3,4]. The most preferred medical treatment option after surgery is acetaminophen or nonsteroidal anti-inflammatory drugs [5]. However, the cause
*Coresponding Author: Muge Ozcelik Korkmaz, Sakarya University Medical Faculty, Department of Otolaryngology, Sakarya, Turkey E-mail: ozcelikmuge@gmail.com
of nonsteroidal anti-inflammatory drugs increase the likelihood of bleeding and the post-operative use thereof remains controversial. The biological properties and therapeutic efficacy of honey are a known fact, thus honey has been used as a therapeutic method in many diseases since ancient times .In clinical and experimental studies conducted to explain the therapeutic effects of honey, honey was shown to prevent wound infections, reduce inflammation, and accelerate wound healing [6,7]. Considering the positive effects of honey on wound healing and epithelization, it has been suggested that the use of oral honey may reduce postoperative pain after undergoing a tonsillectomy. Most of the studies conducted for this purpose were carried out on the pediatric age group, and some researchers concluded that honey does not make a significant contribution to reducing pain [8,9]. However, the re-epithelialization process in the adult age group may take longer than in the pediatric age group. This can lead to prolonged pain, difficulty in oral intake, and a decline in quality of life through general health disorders. Therefore, the use of oral honey post-tonsillectomy may accelerate the re-epithelialization process, thus reducing pain in adult patients. However, there is no study to evaluate the positive aspects of honey use only in adult 360
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tonsillectomy patients The aim of our study is to assess the effects of the use of oral honey on pain relief, oral intake, and daily quality of life in adult patients after undergoing a tonsillectomy Material and Methods A total of 72 patients over 18 years of age who underwent a tonsillectomy with a diagnosis of recurrent/chronic tonsillitis or obstructive sleep apnea were included in our study. The patients were randomized into two groups (such that each group had 36 patients). For the study, approval was obtained from the ethics committee of our medical faculty. All patients were given informed consent. Those with allergies to honey and honey products, allergies to antibiotics of the penicillin group, and those with a known history of chronic disease were not included in the study. A standard general anesthesia protocol was applied to each patient. The tonsillectomy surgery was performed with the cold dissection method. During the operation, no analgesics were used except for standard paracetamol. Patients in the first group were accepted as the control group and were treated with antibiotics (amoxicillin—clavulanic acid 1000 mg tablets 2x1) and analgesic (paracetamol 500 mg tablets, maximum 5 times/day) after surgery. Additionally, the patients in the study group were recommended to use a teaspoon of honey (produced by Altıparmak Food Industries Group, which is commercially available from Balparmak) 5 times a day for 14 days after the operation. Patients in both groups were told to use the 500 mg paracetamol tablet after discharge only if they felt they needed it, and that they should use it up to 5 times a day. The number of analgesics recorded during the patients stay at the hospital. Patients were asked to keep a record of the number of analgesics they used after the discharge period. All medicines and honey were started after oral intake. Patients were subjectively evaluated in terms of pain severity, analgesic intake quantity, eating and daily condition using the visual analog scale (VAS). Orofarengeal examination was also performed at each control period of the patients.The patients were asked to value the pain they felt from 0 (none) to 10 (very severe). Patients were asked to accept pre-operative daily eating and living habits as normal for the assessment of oral intake and daily condition. Accordingly, they were asked to score 0 to 10 on oral intake and daily condition after surgery such that their normal eating and living habits are 10 points. On the first day, the patients were interrogated about pain, oral intake, and daily condition in 2-hour intervals during which they were awake. The averages of the obtained values were taken and recorded as the first-day score. Patients were then called for a check-up on postoperative days 2, 4, 7 and 14 and assessed by being interrogated separately for each indicated category. Additionally, the patients were asked to record the total amount of analgesic tablets they used during this period. Statistical analysis Power analyses were performed by referring to similar studies before the number of working groups was calculated[8,9]. ChiSquare test was used to compare the categorical data. Categorical data were shown as counts (n) and percentages (%). Kolmogorov Smirnov normality test was used to check the normality of the continuous data. Mann Whitney U test was used to compare the
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parametric continuous data between Honey and Control groups. Friedman test was used to compare the parametric continuous data among 5 control periods. Continuous data were presented as the mean(standard deviation). P values of <0.05 were considered statistically significant. Analyses were performed using commercial software. (IBM SPSS Statistics. Version 23.0. Armonk. NY: IBM Corp.) Results Patients Data A total of 72 patients were included in the study. Of those included in the study, 37 patients (51.3%) were male and 35 patients (48.6%) were female. The mean age of the patients was 26.24±7.81 in the honey group and 26 ±8.32 in the control group. There was no significant difference between the two groups in terms of the mean age. There was also no significant gender difference between the honey group and the control group. Twenty of the patients in the honey group were male (55.5%) and 16 (44.5%) were female. In the control group, there were 17 male patients (47.3%) and 19 (52.7%) female patients. Additionally, the weight averages of both groups were close to each other. The mean weight values were 67.43±2.83 in the honey group and 70.23 ±1.1 in control group (Table 1). Table 1. Demographic Datas Of Patients
Age
Honey Group (n=36)
Control Group (n=36)
p1
26.24 (7.81)
26 (8.32)
>0.05
20 (55.5%)
17(47.3%)
>0.05
Gender Male Female
16 (44.5%)
19(52.7%)
Weight
67.43±2.83)
70.23 ±1.1)
>0.05
Data were shown as mean ( standard deviation) and n (%). 1: Statistical comparison results between Honey and Control groups
Pain score and analgesic intake There was no statistically significant difference between the pain scores of both groups on the first day when the average pain scores of the patients in both groups were examined (p>0.05). On Days 2, 4, 7 and 14, the average pain scores were significantly lower in the patients using honey than in the control group (p< 0.05). The necessary daily amount of analgesic consumed by the patients was calculated and analyzed from Day 1 to Day 14. Paracetamol was advised to be taken only as needed for both the honey and the control group(max 5 times in a day). The amount of paracetamol use was different between groups at the last three control period. Average paracetamol consumption amount during the first two control period of study respectively were 3,76±1.49 and 3.48±1.38 in the honey group, compared with 3.82±2.12 and 3.56±1,79 in the control group, which was statistically no significant (p >0.05) . However, the pattern of administered analgesic followed a downward trend with the honey group at other control periods. The amount of analgesic used was significantly lower than the control group in the honey group(p <0 .05) (Table 2) (Figure 1). 361
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Table 2. Comporasion of the patients’s pain, analgesic intake, oral intake and daily condition in post-tonsillectomy period
Pain
Honey Group (n=36)
Control Group (n=36)
P-values1
1.
7.2(2.71)
8.16(2.23)
0.189
2.
6.24(2.11)
7.68(2.06)
0.014
3
3.76(1.56)
6.08(2.61)
0.001
4
2.56(1.58)
4.88(2.39)
<0.001
0.16(0.55)
2.32(2.14)
<0.001
<.001
<.001
1
3.76(1.49)
3.82(2.12)
0.154
2
3.48(1.38)
3.56(1.79)
0.064
3
2.82(1.54)
3.43(1.21)
0.001
4
2.12(0.64)
3.32(1.32)
0.001
5
2.09(0.59)
3.28(0.67)
0.001
<.001
<.001
1
4.24(2.11)
2.72(1.9)
0.009
2
5.52(2.1)
3.44(1.69)
0.001
3
7.76(1.2)
6.16(1.99)
0.003
4
8.72(1.28)
7.36(1.7)
0.004
5
9.6(0.82)
8.72(1.51)
0.015
<.001
<.001
1
4.88(2.32)
3.04(1.54)
0.002
2
5.92(1.78)
4.08(1.96)
0.002
3
7.76(1.45)
6.64(1.98)
0.035
4
8.64(1.38)
7.82(1.63)
0.042
9.76(0.66)
9.04(1.43)
0.024
<.001
<.001
5 P-values
Analgesic Intake
2
P-values 2
Oral Intake
P-values 2
Condition
5 P-values
2
Data were shown as mean ( standard deviation) and n (%). 1: Statistical comparison results between Honey and Control groups. 2: Statistical comparison results among 5 control periods.
Oral Intake The patient’s oral intake before surgery was considered normal. When normal oral intake was regarded as 10, the results in the honey group were statistically significantly higher than the control group in each 5 control periods (p<0.05) (Table 2) (Figure 2). This was deemed in favor of honey reducing the level of difficulty in oral intake of the patient after surgery.
Figure 1. Alteration of the pain among five control periods seperately for two groups
Daily Condition The patient’s daily activity level before surgery was considered normal. When normal activity levels were regarded as 10, the results in the honey group were statistically significantly higher than the control group in each 5 control periods (p <0.05) (Table 2)(Figure 3). This was assessed as an increase in the daily condition of patients with honey’s effect of alleviating pain and enabling oral intake.
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nonsteroidal anti-inflammatory drugs (NSAIDs). However, these drugs are likely to increase hemorrhage in the postoperative period due to their negative effects on hemostasis [10].
Figure 2. Alteration of oral intake among five control periods seperately for two groups
Figure 3. Alteration of condition among five control periods seperately for two groups
Discussion At present, tonsillectomy remains one of the most frequently performed surgical operations in the practice of otorhinolaryngology. The most common complication after tonsillectomy is the postoperative pain [1]. This may lead to severe difficulty of oral intake, limitations in daily activities, and prolongation of the discharge period [2]. The main cause of severe pain following tonsillectomy is mucosal damage, irritation of the glossopharyngeal and vagus open nerve endings. Contractions that develop in the pharyngeal and palatal muscles due to the impact of thermal and mechanical damage which develops in the surrounding tissues are another cause of pain. It is also known that microorganisms forming oral flora may increase throat ache in inflammation and infection caused by tonsillar fossa [8]. Various methods have been developed to be applied during and after surgery to reduce pain. Drugs used for this purpose include steroids, local and systemic analgesics, antibiotics and anti-nausea drugs. The most preferred medical treatment option after surgery is
In recent studies, honey has been shown to have antioxidant, antibacterial and anti-inflammatory properties and has therefore been started to be used in many fields of medicine.Honey is known to accelerate wound site epithelization, reduce inflammation, edema and exudation, increase collagen synthesis, and also increase DNA content in granulation tissues. During the healing period, the positive effects of honey on the wound site are due to its acceleration of epithelization and local antibacterial properties [11]. Tonks et al. have shown that honey activates cytokines such as TNF-a, IL-1b, and IL-6, which lead to the activation of monocytes at a cellular level in their experimental study [12,13]. These mediators also play a role in the regulation of the inflammatory process in wound site healing. TNF-alpha also has effects on enhancing angiogenesis and fibroblast proliferation [14]. It is indicated that the antibacterial effect of honey is mainly attributed to the osmotic effect produced by its high sugar content (approximately 76%). Furthermore, hydrogen peroxide, nonperoxide organic antibacterial factors and a low pH value (3.5), which are released from glucose by glucose oxidase enzyme activation, are other reasons for the antibacterial properties of honey. All these factors have an effect in inhibiting the growth of many microorganisms [15,16]. Clinical studies have also shown that honey is beneficial in healing chronic wounds, ulcers and graft donor sites, necrotizing fasciitis, treating burns, and neonatal postoperative wound infections [17,18] . It has been suggested that wound site epithelialization accelerating and antibacterial properties of honey may have a positive effect on the improvement of the tonsillar fossa after tonsillectomy. For this purpose, studies have been carried out particularly on pediatric patients to evaluate the effects of honey on pain and epithelization after tonsillectomy. In a study conducted on patients aged 3-18 years, Mat Lazim et al. suggested that the use of oral honey had positive effects on tonsillar fossa epithelization after tonsillectomy [8]. In this study, the healing of tonsillar fossa was seen earlier in patients using honey. However, they had pointed out that the lack of an objective evaluation method that could demonstrate wound site healing could lead to doubt. Letchumanan et al. have shown that the use of oral honey post-tonsillectomy in placebocontrolled trials involving adults and children reduced the rate of pain and accelerated the time to return to school and work after surgery. However, they had pointed out that it did not make a significant difference in wound site epithelialization [7]. Whereas, Ozlugedik et al. reported that the mean value of pain and the use of acetaminophen in placebo-controlled clinical trials in which they studied the effects of honey on postoperative pain relief after tonsillectomy were lower in patients using honey in the first two days of study. There was no difference between the two groups after the third day [8]. Whereas, in our study, we concluded that the use of oral honey in adult patients after tonsillectomy was effective in reducing pain, especially after the first day. In addition, the need for using analgesics in patients using honey was significantly lower than the control group after the second control period. This was seen to have positively contributed to patientsâ&#x20AC;&#x2122; oral intake and daily condition. The differences which characterized the working group was to consist only of our study compared to other studies of adult patients. 363
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Although there are studies indicating that honey has positive effects on post-tonsillectomy pain, there are also publications showing there is no difference between a group using honey plus antibiotics and another using only honey after surgery. For instance, Abdullah et al. have indicated that they did not observe honey having a positive effect in reducing pain scores after tonsillectomy outside the early period [19]. This difference in the results of studies may be due to the lack of children’s expressions of pain. Visual analog scale evaluation was used to evaluate the level of pain in children in these studies. We think that our study on the adult age group provides more clarity about the assessment of pain level. Therefore, the optimal interval and time for using honey post-tonsillectomy should still be discussed. In order to increase the positive effects of honey on tonsillar fossa epithelialization, it is argued that the amount in contact with the wound should be increased and that patients need to consume honey at more frequent intervals after surgery for this purpose. However one the limitations of our study is that may support this idea with examination findings. Conducting studies including examination may provide more enlightening data on this subject. Thus, as a result of other studies, we have concluded that the use of honey in adult tonsillectomy patients will have positive effects, although no consensus has been reached regarding the use of honey for tonsillectomy. This suggests that honey results in showing effectiveness in epithelialization on the tonsillar fossa and in accelerating healing in the postoperative period, especially in adult patients. Conclusion The use of oral honey post-tonsillectomy may be effective in reducing postoperative pain in adult patients. Thus, these patients may return to their daily activities and normal eating habits more rapidly in the postoperative period. Future placebo-controlled studies will further support these findings and provide clear information regarding the optimal use of honey. Competing interests The authors declare that they have no competing interest. Financial Disclosure All authors declare no financial support. Ethical approval Consent of ethics was approved by the local ethics committee. Muge Ozcelik Korkmaz ORCID: 0000-0003-4726-7987 Mehmet Guven ORCID: 0000-0002-6743-0203 Unal Erkorkmaz ORCID: 0000-0002-8497-4704
References 1.
Randall DA, Hoffer ME. Complications of tonsillectomy and adenoidectomy. Otolaryngol. Head Neck Surg.1998;118:61-8
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Messner AH, Barbita JA. Oral fluid intake following tonsillectomy.Int. J.
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Pediatr. Otorhinolaryngol. 1997;39:19-24. 3.
Parker NP, Walner DL. Post-operative pain following coblation or monopolar electrocautery tonsillectomy in children: a prospective, single-blinded, randomised comparison. Clin Otolaryngol. 2011;36:468-74.
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Álvarez Palacios I, González-Orús Álvarez-Morujo R, Alonso Martínez C, et al. Postoperative pain in adult tonsillectomy: is there any difference between the technique? Indian J Otolaryngol Head Neck Surg. 2017.
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Dhiwakar M, Brown P. Are adjuvant therapies for tonsillectomy evidence based? J. Laryngol Otol. 2005;119:614-9.
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P.C. Molan. The antibacterial activity of honey. The nature of the antibacterial activity, Bee World. 1992;73:5-28.
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Ozlugedik S, Genc S, Unal A, et al. Can post-tonsillectomy pain be relieved with honey?. Int J Pediatr Otorhinolaryngol. 2006;70:1929-34.
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Mat Lazim N, Abdullah B, Salim R .The effect of Tualang honey in enhancing post tonsillectomy healing process. An open labelled prospective clinical trial. Int J Pediatr Otorhinolaryngol. 2013;77:457-61.
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Letchumanan P, Rajagopalan R, Kamaruddin MY.Posttonsillectomy pain relief and epithelialization with honey. Turk J Med Sci. 2013;43:851-7.
10. Merry AF, Edwards KE, Ahmad Z, et al.Randomized comparison between the combination of acetaminophen and ibuprofen and each constituent alone for analgesia following tonsillectomy in children. Can J Anaesth 2013;60:11809. 11. Kamaruddin MY, Zainabe SA, Anwar S, et al. The efficacy of honey dressing on chronic wounds and ulcers. In: Juraj M, editor. Honey: Current Research and Clinical Uses. New York: Nova Science Publishers; 2012.p.185-96. 12. Tonks A,Cooper RA, Price AJ,et al.Stimulation of TNF-alpha release in monocytes by honey. Cytokine. 2001;14:240-2. 13. Tonks AJ, Cooper RA, Jones KP, et al. Honey stimulates inflammatory cytokine production from monocytes. Cytokine. 2003;21:242-7. 14. Petro JA, Suski MD, Stupak HD. Wound healing, in: T.R. Van De Water,editor. Otolaryngology: Basic Science and Clinical Review, New York, Thieme; 2006. p. 9-31. 15. Aljadi AM, Kamaruddin MY. Evaluation of the phenolic contents and antioxidant capacities of two Malaysian floral honeys. Food Chem. 2004;85:513-8. 16. Kassim M, Achoui M, Mustafa MR, et al. Ellagic acid, phenolic acids, and flavonoids in Malaysian honey extracts demonstrate in vitro anti-inflammatory activity. Nutr Res. 2010;30:650-9. 17. Subrahmanyam M. Topical application of honey in treatment of burns. Br J Surg. 1991;78:497-8. 18. A. Misirlioglu, S. Eroglu, N. Karacaoglan, et al. Use of honey as an adjunct in the healing of splitthickness skin graft donor site. Dermatol Surg. 2003;29:168-72. 19. Abdullah B,Mat Lazim N, Salim R. The effectiveness of Tualang honey in reducing post-tonsillectomy pain. Kulak Burun Bogaz Ihtis Derg. 2015;25:137-43.
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Available online at www.medicinescience.org
ORIGINAL RESEARCH
Medicine Science International Medical Journal
Medicine Science 2019;8(2):365-9
A rare cause of acute urinary retention: Anterior urethral stones Engin Kolukcu1, Serhat Karaman2, Mehmet Necmettin Mercimek3 1 Tokat State Hospital, Department of Urology, Tokat, Turkey Tokat Gaziosmanpasa University, Faculty of Medicine, Department of Emergency Medicine, Tokat, Turkey 3 Samsun Liv Hospital, Department of Urology, Samsun, Turkey
2
Received 16 October 2018; Accepted 28 November 2018 Available online 18.02.2019 with doi:10.5455/medscience.2018.07.8981 Copyright Š 2019 by authors and Medicine Science Publishing Inc. Abstract Anterior urethra stones are extremely rare causes of acute urinary retention. The data of 34 adult patients who presented with acute urinary retention between August 2011 and September 2017 and treated with anterior urethra were evaluated retrospectively. Their ages, sizes of stones, locations, etiological factors, physical examination findings, treatment modalities, operation period and complications were analyzed. All the patients were male and the mean age was 46.9 ¹ 17.88 years. All of the stones evaluated in the study were single and the mean stone size was 12.17 ¹ 3.23 (6-19) mm. Location of the urethral calculi was fossa navicularis in 12 (35.3%) patients, bulbar urethra in 7 (20.6%) patients and penile urethra in 15 (44.1%) patients. A total of 20 patients had urinary calculi located in the other parts of the urinary system at the time of presentation. Stone of the 7 patients with fossa navicularis localized had been treated by intraurethral instillation of 2% lidocaine gel, the other 5 patients had been treated with ventral meatotomy. Urethral stone of the 7 patients with penile and bulbar urethra located was taken by the help of direct forceps without requiring any fragmentation operation. Other stones were treated with endoscopic holmium laser lithotripsy. As a result of surgery operations, urinary tract infection in 3 patients, urethrorrhagia in 2 patients and hematuria in 5 patients were observed. We consider that it is very important to keep anterior urethral stones in mind among differential diagnosis especially in male patients admitted with acute urinary retention. Keywords: Acute urinary retention, urethral stones, penile pain
Introduction Urinary system stone disease constitutes an important part of the administrations to the emergency clinics. Although there is not enough statistical data in our region, it is known that in the USA more than one million administrations related to urolithiasis to the emergency clinics per year [1]. Findings in urinary system stone disease show changes depending on age and the general status of the patient, the location, the size and formation time of the stone. However, a large part of the cases are presented emergency units with complaints of renal colic [2-5]. Urethral stones disease is the least frequently seen urinary system stone disease. Its incidence is less than 1% and it has a quite different symptom from the upper urinary tract stone disease. Patients with urethral stone may administer with very different *Coresponding Author: Engin Kolukcu, Tokat State Hospital, Department of Urology, Tokat, Turkey E-mail: drenginkolukcu@gmail.com
findings such as acute urinary retention, hematuria, difficulty in urination, dysuria, penile or perineal pain [6]. Although urethral stones emerge in small sizes, yet they are rarely observed in stone structures reaching large dimensions resulting in very difficult treatment processes [6,7]. There are two essential factors determining the clinical status of the cases in urethral stones. These are the urethral lumen structure and the size of the stone. In a natural urethral lumen, a stone that reaches large dimensions can make acute urinary retention, and it should be kept in mind that natural structure of a small stone may deteriorate and may cause the same effect in a narrowing of the urethra. In addition to all these, researches made in past years it is known that the most frequent complaints of patients who administered to clinics with urethral stones are acute urinary retention [8,9]. Acute urinary retention is a urological emergency which is characterized by a sudden loss of urine output and a distended bladder [10]. Mostly, there is a strong pain in the lower abdomen. However, rare cases of pain may not be observed in cases accompanied by neurological disorders [11]. This case should not 365
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be confused with anuria observed in acute renal failure. While there is a pathology in the urine production in patients with renal failure, there is a problem in the urinary excretion of the bladder in acute urinary retention. Acute urinary retention may appear depending upon disorders that occur on detrusor muscle such as spinal cord injury, diabetic neuropathy, central nervous system tumors. But is often secondary to the pathologies of urinary flow. To these pathologies many clinical cases such as benign prostatic hyperplasia, urethral stenosis, pelvic organ prolapses, pelvic traumas, prostate, bladder neoplasms may be given as examples [12-15]. The main aim of the treatment is to provide drainage of the urinary tract with proper catheterization and to protect the patient from pathologies that may arise secondary to urinary retention such as upper urinary tract damage, renal failure and urinary tract infections [14,15]. When the articles in the literature of the past years are examined, it is observed that urethral stones are rare and most of the manuscripts are case reports or small series. There is no detailed information about risk factors, diagnosis, treatment and follow-up approaches compared to other patients with acute urinary retention. In this retrospective study, 34 patients who administered to our clinic with acute urinary retention and whose anterior urethral stones were treated and followed-up were discussed by our results. Material and Methods The files of 34 adult patients who presented with acute urinary retention between August 2011 and September 2017 and treated with the diagnosis of anterior urethral stone were evaluated retrospectively. Preoperative evaluation was performed with a medical history form recorded by the physician, urine analysis, routine hematological, biochemical examinations, kidney-ureterbladder (KUB) and non-contrast abdominal tomography. Age, presentation complaints, stone size, location, physical examination findings, etiologic factors, treatment modalities, duration and complications of the patients were analyzed retrospectively. Patients whose data were not complete were excluded from the study. Percutaneous suprapubic cystostomy catheter was applied to all patients after the first clinical evaluation. Urinary ultrasonography was performed to all patients before catheterization. No pathology was observed in any patient to prevent suprapubic catheterization such as bladder cancer and inadequate bladder fullness. A urine culture was taken from each patient and a broad-spectrum antibiotic was started. Performed treatment procedures were shaped according to the size and location of the stone. All procedures were performed under sterile conditions. Stones smaller than 1 cm and with smooth surfaces that could be observed by fossa navicularis localized inspection were aimed to be taken out with physical manipulations under local anesthesia applied with 2% lidocaine gel. On the other hand, ventral meatotomy was performed on the stones which did not have a smooth surface or had more than 1 cm and fossa navicularis localized. Endourologic interventions were preferred in the treatment of all penile and bulbar urethral stones. When the procedures of application of endourological interventions are examined, lidocaine 2% gel was applied into the urethra in the lithotomy position. Cystourethroscopy was performed using a 0-degree lens passed into a 19. 5 Fr or 22 Fr endoscope. In addition to the patients who had urethral stenosis during cystourethroscopy,
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urethral pathologies were treated by surgical intervention. After the urethra stones were reached, and stones with the smooth surface smaller than 1 cm were taken out with the help of forceps. Other urethra stones were planned to advance to the bladder to perform holmium laser lithotripsy. In-situ holmium laser lithotripsy was applied to the stones that could not be advanced to the bladder. Holmium: Yttrium-Aluminum-Garnet laser device (Lisa Laser Spihinx 60, Germany) was used as lithotripter. During lithotripsy, different probes 272μ and 550μ were preferred depending on the size of the stone. In all endourological interventions, sterile 0.9% NaCl solution was used for fluid irrigation. All applied meatotomy or endourologic procedures were performed under general or spinal anesthesia. Statistical Evaluation SPSS (Statistical Package for the Social Sciences in PASW Statistics, SPSS Inc., Chicago, IL, USA) version 18.0 software was used for data analysis. Continuous data of patients were expressed as the mean ± standard deviation (minimum-maximum) whereas categorical data were expressed as frequencies and percentages (%). The Pearson chi-square test or Fisher’s exact test was used to comparing proportions for detected microorganisms and location of the urethral calculi. Fisher’s exact test was used when the expected value in one or more cells was less than 5.0 in the crosstab. A p value of less than 0.05 was considered statistically significant. Results 34 patients with acute urinary retention and those who were diagnosed by anterior urethral stones were included in the study. All the patients were male and the mean age was 46.9 ± 17.88 (18-78) years. All the stones were radiopaque and as a result of the genitourinary system examination it was revealed that 15 (44.1%) of the stones were palpated in the urethra. In 34 patients whose main complaint was acute urinary retention and in addition to this complaint, high fever at 4 of these 34 patients and renal failure at 3 of them were observed. Urinary tract infection was detected in 15 (44.1%) cases. The most commonly detected microorganism was Escherichia coli (66.6%; p<0.001) (Table 1). Tablo 1. Numbers and percentages of isolated microorganism Pathogen
n
%
Escherichia coli
10
66.6
Klebsiella Pneumoniae
2
13.3
Acinetobacter Baumannii
1
6.7
Enterococcus Faecalis
1
6.7
Candida Albicans
1
6.7
P value
a
<0.001*
: Fisher exact test, *statistically significant Urine culture was positive in 15 (44.1%) patients a
All of the stones evaluated in the study were single and the mean stone size was 12.17 ± 3.23 (6-19) mm. Location of the urethral calculi was fossa navicularis in 12 (35.3%) patients, bulbar urethra in 7 (20.6%) patients and penile urethra in 15 (44.1%) patients. There was no statistically significant difference between the proportions of the location of the urethral calculi (p<0.115; Table 2). A total of 20 patients had urinary calculi located in the 366
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other parts of the urinary system at the time of presentation. Of these 20 patients; 12 had renal calculi, 5 had bladder stones, 2 had distal ureteral stones, and 1 patient had both kidney stones and bladder stone. When the anamnesis forms were evaluated in details, 2 patients had endoscopic cystolithotomy, 3 patients underwent ureterorenoscopy, 1 patient had percutaneous nephrolithotomy, 4 patients had transurethral resection of the prostate and 2 patients had the frequent urethral infection. Tablo 2. Stones in the urethra Site
n
%
Penile urethra
15
44.1
Fossa navicularis
12
35.3
Bulber urethra
7
20.6
b
P value
0.115
: Chi square test
b
Considering our treatment approaches, stones of the 8 patients without urethral meatal stenosis and whose fossa navicaria localized were smaller than 1 cm in size and the surface area was evaluated as smooth were decided to take out by physical manipulations following lidocaine gel application. While the stones of the 7 patients were successfully removed, 1 patient underwent ventral meatotomy. In addition, fossa navicularis localized stones of the 4 patients whose size was larger than 1 cm or had no smooth surface were also removed by ventral meatotomy. Cystourethroscopy was performed in all patients and urethra lumens were evaluated in detail. No pathological findings were recorded in the other parts of the urethra in these 12 patients treated without endourologic methods. On the other hand, the penile and bulbar urethra stone of 7 patients, whose size was less than 1 cm in size, and the surface area were observed properly, was taken by the help of forceps. Urethral stones of the remaining 15 patients with penile and bulbar were planned to be advanced into the urethral stone bladder for fragmentation. In a total of 9 patients the urethral stone was successfully advanced into the bladder. Using holmium laser lithotripsy, the stones in the bladder were successfully fragmented and taken out with the help of forceps or evacuator. A total of 6 patients underwent in-situ holmium laser lithotripsy since the urethral stones could not be advanced into the bladder. All stones were successfully fragmented and taken out with the help of forceps. When all procedures were evaluated, urethral stenosis was detected in 19 (55.9%) patients. During the preoperative evaluation, 2 patients were found to have ureteral stones, and these patients additionally received ureterorenoscopy. Similarly, 6 patients had bladder stones. Endoscopic cystolithotomy was performed in these patients. The fragmentation of the stones was performed by holmium laser lithotripsy. The operation time was determined by subtracting the time used for these specified endourologic procedures from the recorded time for the total surgical procedure. The mean operative time was recorded as 18.67 Âą 5.40 minutes. When the complications of the procedure were examined, urinary tract infection was detected in 3 patients, urethrorrhagia in 2 patients, and hematuria was observed in 5 patients lasting less than 24 hours and did not require blood transfusions.
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Discussion Acute urinary retention, which is defined as the inability to make a sudden urination, is much more observed in the male population and the risk of encounter increases with age. Approximately while 10% of males in the 70s report acute urinary retention at least once, this rate reaches up to 33% in 80s [16]. Acute urinary retention, mostly known as the disease of advanced elderly men, is rarely seen in children and women [15-18]. Previous studies have reported that the overall incidence of acute urinary obstruction in men with USA citizens is 4.5 to 6.8 per 1000 men [15]. The publications made in the female population are quite limited and it is estimated that it is observed in 7 out of 100,000 women annually [18]. The most common cause of acute urinary retention is a prostate disease, which is observed in an increasing prevalence in the aging population. However, etiologic factors show differences between sex and age groups. The development of acute urinary retention is mainly focused on two mechanisms. The first one is the resistance that increases the urine flow by mechanical or dynamic means, and the other is the deteriorations of the detrusor muscle [13,15]. In this context, although urethra stones were extremely seen, they may cause obstruction in the urethral lumen due to mechanical causes. Urinary stone diseases are among the oldest known diseases in human history [19]. Its incidence varies in relation to many factors such as geographical region, dietary habits, gender, genetic and socio-cultural status [20]. In our country, in the study by AkÄąncÄą et al [21]. the prevalence of urinary stone disease was reported to be 14.8% and the incidence was 2.2%. The prevalence of lifelong urinary stone disease in Tokat, the province where the study was conducted, was reported as 11.42% in previous studies [22]. In routine clinical practices, urethral stones are among the most rare group of urinary tract stone diseases. Epidemiological studies in the past years indicate that urethra stones are more common in the Middle and Far Eastern countries rather than in the Western world [6,7]. Urethral stones can be seen as primary, urinary tract stones can also be seen as secondary urethral stones by migrating stones at different localizations [23]. In relation to this study, when Koga et al [24]. examined the patients with 56 urethral stones, the incidence of stone in the upper urinary tract with urethral stone was reported to be 32%. In another study, Kiciler et al [25]. had found this rate as 47.1%. In a retrospective multicentre study done by Jung et al [26]. it was reported that upper urinary tract stones and/or hydronephrosis had increased the urethral stone risk 3-fold. In our study 58.8% of patients were found to have a stone in another localization of the urinary system along with urethral stone. In addition to this information, it has been known that in urethral stone formation, many etiological factors such as urinary tract infections, urethral strictures, urinary schistosomiasis, history of endourologic intervention, pelvic trauma, forgotten foreign bodies, urethral diverticulum and fistulas play a role [6,8,2426]. Urethral stone diseases are predominantly seen in the male population. In this context, Ameen et al. [27] 72 patients with urethral stones were evaluated and only 8.6% of the patients were reported to be women. Al Ansar et al. [28] in their study, only 3.1% of the 64 patients with lower urinary calculi reported that they were women. This is directly related to the anatomy of the urethra. 367
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Normal adult male urethra diameter is 30 Fr and it allows natural stones that are smaller than 10 mm to be expelled from the body naturally [29]. Any pathology that may occur in the urethral lumen is a predisposing factor for the formation of stones in the urethra. In a study of 41 patients with urethral stones, urethral pathology was detected in 41.5% of patients [8]. In another study by Kiciler et al [25]. it was found that 35.3% of urethral pathology was found in patients with urethral stones. In a similar study of 36 patients with urethral stones, pathology was detected in 47% of patients. In the same study, the most common disorder in patients with urethral pathology was reported as 88.2% urethral stricture [30]. In our study, urethral pathology was observed in 55.9% of patients. The first step in the treatment of urethral stones causing acute urinary retention is the placement of suprapubic cystostomy catheter [8]. It should always be kept in mind that persistence of urethral catheter application in these patients may lead to pathologies that are extremely difficult to treat in the urethra. Treatment procedures of anterior urethral stones must be evaluated according to the stone size, localization, anatomical structure of urethra, age and sex of the patient. Many different methods such as milking, ventral meatotomy, forceps extraction, extracorporeal shockwave lithotripsy, transurethral lithotripsy have been used in the treatment [22,23,30-34]. In a clinical study conducted on 18 patients with urethral stones smaller than 10 mm, and without urethral stricture, it was decided to take out urethral stones as conservatively with the help of physical manipulation with 2% lidocaine gel application into the urethra. In their study, they reported that 14 patients were completely treated of urethral stones and their success rate was 77.8% [32]. In our study, the similar procedure had been applied to 8 patients with fossa navicularis stone and the success rate had been observed as 87.5%. But it is appropriate to prefer the extremely limited case with small volume characteristics with smooth surfaces. Insistence on this method is faulty and may cause damage to the urethra. Therefore, these patients should have different surgical options on the agenda of clinicians such as urethroplasty, diverticulectomy and meatotomy [35]. Ventral meatotomy was among the preferable treatments for large size or lumen implanted fossa navicularis stones. In our study, a total of 5 patients with similar features underwent ventral meatotomy and the success rate was recorded as 100%. It is seen that similar results have been obtained in the publications in previous years [25]. The use of endoscopic treatment methods that provide direct vision in the treatment of all the stones in the other parts of the urethra is very important in terms of the least damage to the treatment procedures of the urethral mucosa [8,9]. During the transurethral lithotripsy process, very different lithotriptors can be used. However, the use of holmium laser in the endourology in parallel with technological innovations appears to be prominent. According to previous studies, Maheshwari and Shah [34] reported that they achieved 100% success in in-stu holmium laser lithothipses with dimensions ranging from 7 to 22 mm in 18 urethral stones and they did not follow major intraoperative complications. In our study, holmium laser lithotripsy was applied successfully in all patients with low complication rates in the fragmentation of urethral stones. Study Limitations There are some limitations exist with this study such as retrospective nature, limited numbers of subjects and absence of
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biochemical analysis of stones that were managed. Conclusion When the past year studies were examined, there was a limited number of publications on anterior urethral stones and no detailed information about clinical approaches was found as in other urinary stone diseases.In the patients with acute urinary retention, we think that the application of correct treatment algorithms among the differential diagnosis of urethral stones is extremely important in protecting the cases against the damage to the difficult urethra diseases. Competing interests The authors declare that they have no competing interest. Financial Disclosure All authors declare no financial support. Ethical approval Consent of ethics was approved by the local ethics committee. Engin Kolukcu ORCID:0000-0003-3387-4428 Serhat Karaman ORCID:0000-0003-4554-1364 Mehmet Necmettin Mercimek ORCID:0000-0002-0680-4451
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Kaczmarek K, Gołąb A, Soczawa M, et al. Urethral stone of unexpected size: case report and short literature review. Open Med (Wars). 2016;11:7-10.
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Kölükçü E, Mercimek MN, Erdemir F. Efficacy and safety of holmium laser lithotripsy in the treatment of posterior urethral stones. J Clin Anal Med. 2018;9:552-6.
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Kamal BA, Anikwe RM, Darawani H, et al. Urethral calculi: Presentation and management. BJU Int. 2004;93:549-52.
10. Kalejaiye O, Speakman MJ. Management of acute and chronic retention in men. Eur Urol Suppl. 2009;8:523-9. 11. Choong S, Emberton M. Acute urinary retention. BJU Int. 2000;85:186-201. 12. García-Fadrique G, Morales G, Arlandis S, et al. [Causes, characteristics and mid-term course of acute urinary retention in women referred to a urodynamics unit]. Actas Urol Esp. 2011;35:389-93. 13. Thomas K, Chow K, Kirby RS. Acute urinary retention: a review of the aetiology and management. Prostate Cancer Prostatic Dis. 2004;7:32-7.
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25. Kilciler M, Erdemir F, Bedir S, et al. The Clinical experıence with urethral stones and review of the literature. Turk J Urol. 2005;31:389-95. 26. Jung JH, Park J, Kim WT, et al. The association of benign prostatic hyperplasia with lower urinary tract stones in adult men: A retrospective multicenter study. Asian J Urol. 2018;5:118-21. 27. Ameen AA, Kegham HH, Abid AH. Evaluation and management of urethral calculi. Int Surg J. 2017;4:2392-6. 28. Al-Ansari A, Shamsodini A, Younis N, et al. Extracorporeal shock wave lithotripsy monotherapy for treatment of patients with urethral and bladder stones presenting with acute urinary retention. Urology. 2005;66:1169-71. 29. Amend G, Gandhi J, Smith NL, et al. Transrectal ultrasound-guided extraction of impacted prostatic urethral calculi: a simple alternative to endoscopy. Transl Androl Urol. 2017;6:585-9. 30. Sharfi AR. Presentation and management of urethral calculi. Br J Urol. 1991;68:271-2. 31. Vashishtha S, Sureka SK, Agarwal S, et al. Urethral stricture and stone: their coexistence and management Urol J. 2014; 3;11:1204-10. 32. El-Sherif AE, El-Hafi R. Proposed new method for nonoperative treatment of urethral stones. J Urol. 1991;146:1546-7. 33. El-Sherif AE, Prasad K. Treatment of urethral stones by retrograde manipulation and extracorporeal shock wave lithotripsy. Br J Urol. 1995;76:761-4. 34. Maheshwari PN, Shah HN. In-situ holmium laser lithotripsy for impacted urethral calculi. J Endourol. 2005;19:1009-11.
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ORIGINAL RESEARCH
Medicine Science International Medical Journal
Medicine Science 2019;8(2):370-4
Serum preptin and amylin levels in acne vulgaris patients Nese Gocer Gurok1, Ibrahim Kokcam2, Demet Cicek3, Suleyman Aydin4, Denizmen Aygun5 1 Elazig Research and Training Hospital, Department of Dermatology, Elazig, Turkey Adiyaman University Training and Research Hospital, Dermatology, Adiyaman, Turkey 3 Firat University, Faculty of Medicine, Department of Dermatology, Elazig, Turkey 4 Firat University, Faculty of Medicine, Department of Medical Biochemistry and Clinical Biochemistry, Elazig, Turkey 5 Ersoy Hospital, Department of Pediatrics, Istanbul, Turkey 2
Received 26 October 2018; Accepted 02 December 2018 Available online 30.01.2019 with doi:10.5455/medscience.2018.07.8967 Copyright Š 2019 by authors and Medicine Science Publishing Inc. Abstract Acne vulgaris is a common disease with multi-factorial etiology that occupies the pilosebaceous unit. Several recent studies demonstrated that insulin and insulin resistance can play a role in acne pathogenesis. In the present study, the roles of preptin and amylin, which are directly associated with insulin secretion and released from pancreas beta cells, in acne vulgaris pathogenesis were investigated. The study was conducted with 40 cases with acne vulgaris and the control group that included 40 healthy subjects with similar body mass index. Serum preptin and amylin levels and fasting blood glucose, triglyceride, total cholesterol, LDL, VLDL, HDL, C-peptide, insulin and HbA1c levels were examined in the study group. HOMA-IR values were calculated. Although patient group serum preptin and amylin levels were higher when compared to the control group, however the difference was not statistically significant (p> 0.05). It was determined that there was a positive correlation between severity of the disease and amylin levels. In the patient group, it was found that the glucose level was significantly higher when compared to the control group (p <0.001). Serum insulin and C-peptide levels and HOMA-IR index were higher in the patient group when compared to the control group, however the difference was not statistically significant (p> 0.05). It is considered that increased preptin and amylin levels in acne vulgaris patients may be associated with the etiopathogenesis of the disease. We also considered that decreasing the elevated levels of these two peptides to normal levels may be helpful for the treatment of the disease. Keywords: Acne vulgaris, insulin resistance, preptin, amylin
Introduction Acne vulgaris is a common, chronic, inflammatory disease with multifactorial etiology that affects the pilosebaceous unit. Often observed in adolescence and in facial, bust, dorsal and shoulder areas where sebaceous glands are concentrated. Ductal hyperkeratinization, increase in sebum production, microorganisms (such as Propionibacterium acnes (P. acnes)) and inflammation are the most important factors playing a role in etiopathogenesis [1]. Furthermore, genetic factors, hormones, nutritional habits, physical factors, emotional status and drugs are the other responsible factors [1,2]. The skin, especially the pilosebaceous unit, is considered an endocrine organ where numerous hormones and receptors are synthesized. Several recent studies demonstrated the effects of various hormones on the pilosebaceous unit [3]. A number of studies showed that insulin and insulin like growth factor-1 (IGF-1) levels and insulin resistance are effective in
the pathogenesis of acne. In the abovementioned studies, it was reported that insulin could directly affect the pilosebaceous unit, induce sebum production and sebocyte proliferation, and further suppress sex hormone binding globulin (SHBG) concentrations, increasing the free androgen levels [4,5]. Furthermore, it was also reported that hyperinsulinemia may play a role in acne pathogenesis by increasing serum IGF-1 levels and decreasing insulin like growth factor binding protein (IGFBP)-3, a potent pro-apoptotic factor for keratinocytes and thus, stimulating the proliferation of basal keratinocytes [6,7]. Again, studies demonstrated that hyperinsulinemia plays an important role in ovary disfunction in patients with polycystic ovarian syndrome (PCOS) where the risk of acne is increased. Previous studies determined that hyperinsulinemia and hyperandrogenism can ameliorate with weight loss and treatment in these patients [8]. Furthermore, certain studies reported that antidiabetic agents such as insulin sensitizers such as metformin and thiazolidinedione reduced insulin levels and consequently decrease androgen levels and improve ovarian functions [9,10].
*Coresponding Author: Nese Gocer Gurok, Elazig Research and Training Hospital, Department of Dermatology, Elazig, Turkey E-mail: dr.n_g@hotmail.com
Preptin and amylin are polypeptide hormones that are synthesized with insulin in 34 and 37 amino acid pancreatic beta cells, 370
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respectively, in response to glucose and known to have effects on insulin and glucose metabolism. Preptin physiologically increases the insulin secretion that occurs as a response to glucose, while amylin inhibits insulin secretion, and acts directly on pancreatic β-cell products to inhibit glucose-induced insulin secretion and insulin-mediated glucose uptake. Peripheral insulin resistance results in chronic stimulation of pancreatic beta cells, leading to an increase in insulin and amylin released with insulin. Abnormal accumulation of amylin and pro-amylin in pancreatic β-cells leads to β-cell loss in patients. This results in secretion of insulin and an impaired glucose metabolism. Increased amylin levels were indicated in individuals with impaired glucose tolerance and obese individuals with insulin resistance [11-17]. In the present study, we aimed to investigate the variations in preptin and amylin hormone levels in patients with acne, their role in acne pathogenesis and the relationship between preptin and amylin hormone levels and acne severity. Material and Methods Forty patients between 14 and 30 years of age who were admitted to Fırat University Hospital, Dermatological and Venereal Diseases Policlinic and who were clinically diagnosed with acne vulgaris as described in ‘Acne vulgaris: review and guidelines 2009’ and 40 healthy volunteers, who applied to the hospital for annual check-up and were similar in age and body mass index (BMI) with the patient group, were included in the patient and control groups in the present study. Ethics approval was obtained from Fırat University Human Research Ethics Committee and informed consent forms were obtained from the study participants. The study was sponsored by the Firat University Scientific Research Projects Coordination Unit (project number: TF.11.72). Patients and individuals with diabetes mellitus (DM) or known endocrinological disorders or with a family member with DM or known endocrinological disorders, tobacco and alcohol users, individuals in diet or pregnant, or with over the limit BMI, individuals who are on medicine for chronic systemic diseases or medicine that could cause acneiform rash were excluded from both patient and control groups in the study. The lipid profile, which includes triglyceride, LDL, VLDL, HDL, and total cholesterol, and HbA1c, insulin, C-peptide, fasting blood sugar, values were checked, and BMI measurements were conducted in both patient and control groups. BMI was calculated with the following formula: (kg) / (height) m² [18]. The Global Acne Grading System (GAGS) was used to assess acne severity [19]. In calculating insulin resistance, homeostasis model assessment of insulin resistance (HOMA-IR) (glucose mg / dl x insulin mU / ml) / 405 formula was used. Cased with HOMA-IR> 3.2 was diagnosed with insulin resistance cases [20]. Preptin and Amylin Hormone Measurements Since preptin and amylin are peptide structured hormones and could be disintegrated by proteases, 500 kallikrein units aprotinin per ml was added to simple biochemical tubes before blood was drawn from the participants to prevent proteolysis. 5 ml fasting blood sample was obtained from each participant and after the sample was centrifuged for 5 min at 3000 g, the obtained serum was transferred to Eppendorf tubes and stored at -80 ° C until the day of the study. Serum preptin levels were studied with the human preptin ELISA (enzyme-linked immunosorbent assays) kit (ELISA CK-E10788 kit, Hangzhou Eastbiopharm, China). Serum amylin
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levels were studied with human IAPP (Islet Amyloid Polypeptide) ELISA kit (Human IAPP ELISA B831510HU kit, Bioabb, China). Statistical Analysis Study data were analyzed with “SPSS for Windows 18.0” software. The t-test was used to analyze the difference between the numerical data for the groups, Pearson’s correlation test was used for correlation analysis. The results were presented with mean and standard deviation values. The results were analyzed with a 95% confidence interval and a significance level of p <0.05. Results The age, gender, and body mass index values for the patient and control group participants were similar and there was no statistically significant difference between these values (p> 0.05) (Table 1). Table 1. Patient and control group demographics Acne Vulgaris
Control
40
40
20/20
27/13
Mean duration of disease
3.65±1.83
-
BMI
21.72±1.80
21.62±2.83
n Sex (F/ M)
p value
p>0.05
p>0.05
The study group and control group laboratory test values were measured and compared between the groups. The laboratory test results for the patient and control groups are presented in Table 2. Table 2. Preptin and amylin values and laboratory test findings for the patient and control groups Acne
Control
P
Preptin (ng/ml)
6.36±3.43
5.37±3.13
p>0.05
Amylin(pg/ml)
148.52±109.37
131.46±80.82
p>0.05
Glucose(mg/dl)
88.12±12.21
78.77±10.67
P<0.001a
Triglycerides(mg/dl)
81.30±33.30
76.77±40.50
p>0.05
LDL (mg/dl)
87.58±23.49
91.71±44.90
p>0.05
HDL (mg/dl)
53.47±12.92
49.77±15.32
p>0.05
6.72±6.03
14.95±7.70
p>0.05
VLDL (mg/dl) Total cholesterol(mg/dl)
154.30±29.28
157.50±41.96
p>0.05
HbA1c (%)
4.72±0.34
4.60±0.39
p>0.05
Insulin (ng/ml)
6.64±6.14
6.34±2.47
p>0.05
C-peptide (ng/ml)
1.84±0.75
1.70±0.72
p>0.05
HOMA-IR*
1.43±1.26
1.29±0.56
p>0.05
*(Mean Standard Deviation) a There was a statistically significant difference between the patient and control groups (p<0.001)
Analysis of the preptin and amylin levels of the individuals in patient and control groups demonstrated that serum preptin and amylin levels were higher in the patient group when compared to the control, however the difference was not statistically significant (p> 0.05). Serum preptin levels in the patient and control groups are presented in Figure 1, and serum amylin levels are presented in Figure 2. 371
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Med Science 2019;8(2):370-4
role in etiopathogenesis [1]. The androgens, which play an important role in etiopathogenesis, directly or indirectly stimulate keratinocyte proliferation, increase in the volume of sebaceous glands and sebum secretion. Androgens also play a role in the acne pathogenesis by causing proliferation and alteration in sebocytes and infundibular keratinocytes [22]. Insulin can directly stimulate androgen-sensitive pilosebaceous units [4]. Increase in serum insulin concentration stimulates sebum production and sebocyte proliferation, additionally inhibits SHBG concentrations, leading to an increase in free androgen amounts [5]. It was emphasized that hyperinsulinemia resulting from nutrition with foods with high glycemic index that is associated with insulin levels and acne pathogenesis is effective in acne pathogenesis [5]. Several recent studies demonstrated that insulin resistance can play a role in the pathogenesis of acne [23-26].
Figure 1. Serum preptin levels in the patient and control groups are presented
Despite the fact that steroid hormones were studied in the pathogenesis of acne in previous years, current studies mostly scrutinize whether peptide and protein structured hormones play a role in acne etiopathogenesis. To date, there are only a few studies published on the significance of preptin in humans. There are no previous studies on preptin and amylin levels in acne patients. The present study is the first research that investigated the roles of two new peptide hormones, namely preptin and amylin, which play a role in glucose homeostasis, in the etiopathology of the disease. Ă&#x2021;elik et al. found that plasma preptin concentration was significantly higher in patients with PCOS with increased risk of acne and insulin resistance when compared to the healthy control group with similar age and BMI [27]. In this study, they determined that BMI, plasma preptin and insulin levels and HOMA-IR index were significantly higher in PCOS patients when compared to healthy controls.
Figure 2. Serum amylin levels
It was determined that the glucose levels were significantly higher in the patient group when compared to the control group (p <0.001). Serum insulin, C-peptide levels and HOMA-IR index were higher in the patient group when compared to the control group, but the difference was not statistically significant (p> 0.05). Similarly, there was no statistically significant difference between the patient and control groups based on the lipid parameters (p> 0.05). The severity of the patients, which was graded based on the GAGS, was analyzed to determine whether there was a correlation between disease severity and serum preptin and amylin levels, and it was determined that there was a positive correlation between disease severity and serum amylin levels (r = 0.327). There was no correlation between serum preptin and disease severity (r = 0.152). Discussion Acne is a common dermatological disease and its incidence could rise up to 85% in adolescence [21]. Ductal hyperkeratinization, increased sebum production, microorganisms (such as P.acnes) and inflammation are the most important factors that play a
In another study conducted to investigate preptin levels in PCOS patients, Bu et al. suggested that elevated serum preptin levels were associated with impaired glucose tolerance [28]. Although Ă&#x2021;elik et al. claimed that the reason for elevated serum preptin levels in PCOS patients might be due to insulin resistance, Bu et al. suggested that this might be related to glucose intolerance rather than insulin resistance. In another study conducted with Type-2 DM patients by Yang et al. it was suggested that preptin could play a role in the pathogenesis of insulin resistance. Similar to these studies, we found elevated preptin levels in acne patients, albeit insignificant [29]. In the present study, we considered that elevated preptin levels in acne patient group when compared to healthy controls could contribute to acne etiopathogenesis via insulin resistance and impaired glucose tolerance. Amylin, another hormone, stimulates basal insulin secretion, while inhibiting stimulated insulin secretion. In animal experiments, amylin was shown to inhibit insulin secretion by stimulating β-cell apoptosis and increase insulin resistance [30]. In a study conducted by Reinehr et al. on obese children, it was found that serum amylin, insulin and triglyceride levels were higher in obese children when compared to the control group, and when children who lost weight were reassessed, significant decreases were indicated in amylin, insulin and triglyceride levels [17]. James et al. found high amylin levels in a study conducted with patients with PCOS, where the prevalence of acne increases [31]. 372
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Although the amylin, insulin, and triglyceride levels in the patient group were not statistically significant, it was found that the glucose level was significantly high in the patient group. The high insulin levels in the patient group, albeit insignificant, could be an indicator of an early stage insulin resistance. Again, a positive correlation was determined between serum amylin levels and triglyceride and VLDL. In the present study, a positive correlation was also identified between amylin levels and disease severity. The said positive correlation between amylin and disease severity led us consider that the elevated amylin levels increased the hyperinsulinemia and thus, the development of acne in individuals. This relationship shows that amylin levels may be indicative of disease severity.
References
In several previous studies, the relationship between peptide-protein molecules in glucose homeostasis and acne was investigated [32, 33]. However, there is no previous study on preprint and amylin levels. Although the findings of the present study demonstrated higher preptin and amylin levels in the patient group when compared to the control, the differences were not statistically significant. It was found that glucose levels were higher in the patient group when compared to the control group. We considered that the reason for the increase in glucose was elevated insulin level and HOMA-IR values. Because, high glucose levels despite the increase in insulin levels reflect the presence of insulin resistance, which is in the etiopathology of this disease. As a result, glucose levels are measured high in the circulation. Furthermore, these two parameters, which we studied with glucose concentrations, are directly correlated and their increase or decrease directly affect the glucose levels. For example, preptin and amylin levels were higher in the patient group in parallel to the high glucose levels. However, the preptin and amylin levels were partially lower in the control group when compared to the patient group, indicating that the glucose levels changed based on the concentrations of the said two hormones. Conclusion The present study findings suggested that the increased amounts of preptin and amylin in acne patients, which is directly associated with insulin secretion, might be related to the etiopathogenesis of the disease. Furthermore, the results of the present study suggested that amylin is more significant in the etiopathology of acne, because the amylin levels were increased more as the severity of the disease increased when compared to preptin. Although links between several abovementioned hormones and acne have been established, we believe that the results of the present study would contribute to the literature, since this study is the first in the literature. Competing interests The authors declare that they have no competing interest. Financial Disclosure The study was sponsored by the Firat University Scientific Research Projects Coordination Unit (project number: TF.11.72) Ethical approval Ethics approval was obtained from Fırat University Human Research Ethics Committee. Nese Gocer Gurok ORCID:0000-0001-7069-0447 Ibrahim Kokcam ORCID:0000-0003-4743-9451 Demet Cicek ORCID: 0000-0001-8405-7730 Suleyman Aydin ORCID:0000-0001-6162-3250 Denizmen Aygun ORCID:0000-0002-6450-9282
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ORIGINAL RESEARCH
Medicine Science International Medical Journal
Medicine Science 2019;8(2):375-80
Communication difficulties in perioperative anesthesia management for immigrant and refugee patients Mehmet Akif Yazar, Yasin Tire, Betul Kozanhan Konya Training and Research Hospital, University of Health Sciences, Department of Anesthesiology and Reanimation, Konya, Turkey Received 22 November 2018; Accepted 03 December 2018 Available online 18.02.2019 with doi:10.5455/medscience.2018.07.8992 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract Healthcare providers who encounter different ethnic groups have been faced with serious communication problems with immigrant and refugee (I/R) patients. The perioperative period is very important for both anesthesiologists and patients. In this study, it was aimed to reveal anesthesiologists’ problems related to I/R patients and to propose solutions for determined problems. An online survey questionnaire about the quantity and quality of communication problems that anesthesiologists come across in the perioperative period was developed. 120 of the anesthesiologists (49.0%) were trying to communicate by using body language or dictionary. 65 (26.5%) of the anesthesiologists could not communicate with these patients at all. During the process of taking “Informed Consent Form” before the anesthesia practice, 125 of the anesthesiologists (51.2%) stated that used a form written in physician’s own language which was not understood by I/R patients. 76 anesthesiologists (31%) stated that they preferred general anesthesia instead of regional anesthesia because of language barriers. As a conclusion, the present study reveals that there are serious problems in the providing health care services regarding anesthesia to I/R patients especially due to the language barriers. Keywords: Anesthesia, immigrant and refugee, communication
Introduction In recent years, migrations have begun from many Middle Eastern countries to neighboring countries due to the conflict and war in the Middle East. Since March 2011, more than 10 million Syrian people had to leave their homes and settle in neighboring countries [1]. In Turkey, about one million immigrant were hospitalized, over 797 operations and about 184 thousand deliveries were performed between 2011-2016 [2]. The communication aspects are one of the most common problems during immigrants’ and refugees’ (I/R) perioperative period. The perioperative process, which starts with preoperative patient evaluation and continues until the detection of postoperative problems is very important for both anesthesiologists and patients. In the preoperative evaluation of patients, the history of patients is quite important for determining the type of anesthesia. On the other
*Coresponding Author: Mehmet Akif Yazar, University of Health Sciences, Konya Training and Research Hospital Department of Anesthesiology and Reanimation Konya, Turkey, E-mail: makifyazar@hotmail.com
hand, the understanding of the physician’s instructions during the examination is necessary for the maximum benefit expected from the operation. Obtaining and evaluating the information or taking necessary measures is a serious problem in these patients experiencing the communication problem which may affect the perioperative vital functions. Another important element in the preoperative period is to obtain informed consent regarding the anesthesia procedure. Article 18 of the patient rights regulation in Turkey states that “information is given to the patient as simply as possible in such a way that it can be understood in accordance with the social and cultural level of the patient” [3]. Confronting patients who face with “informed consent form” without detailed information may lead to serious legal problems. Informing the patients about the procedures to be performed before operation and premedication applications are quite important in terms of prevention of surgical and psychological stress. Nervousness in the patients who do not have well communication may lead to some problems even when the patient is brought to the operation room and surgical stress can postpone the discharge. Anesthesiologists may face the inability to make a position them or to control the anesthetic effects and 375
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patients cannot follow the anesthesiologists’ instructions during awakening and post-operative period. In this study, it was aimed to reveal anesthesiologists’ problems in I/R patients and to propose solutions for determined problems. Material and Methods The study was approved by the Necmettin Erbakan University Ethical Board. A cross-sectional nationwide survey was sent to 3070 anesthesiologists across Turkey. The mailing list was obtained from the Turkish Society of Anesthesiology and Reanimation directory available to members. The questionnaire prepared according to the studies in the literature evaluating communication problems between healthcare providers and I/R patients due to differences in language and culture in developed countries. The questionnaire consisted of 23 questions about the frequency of anesthesiologists’ the encountering with I/R patients, the quantity, and quality of communication problems, the other problems they come across in the perioperative period and suggestions for solutions to these problems. Surgical procedures are classified into four categories (class I: not exceeding 30 min minor surgical procedures or interventions such as endoscopy, imaging under MRI, circumcision, abscess drainage or lipoma excision; class II: surgical procedures that
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last between 30 min and 1 hour such as inguinal herniation, cystoscopy or tonsillectomy; class III: moderate surgeries that last between 1-4 hours such as cesarean section, knee prosthesis, hysterectomy, middle ear surgery or limb fracture surgery; class IV: major surgeries that last longer than 4 hours such as radical prostatectomy, vertebra or brain surgery). Statistical Analysis In the study, it was calculated how many percents of the sample represented the population with the sample size. Accordingly, the margin of error for the sample sizes at the 95% confidence interval (Z-table value 1,962) was found as e=0.056. This means that sample size would deviate by at most 5.6% from the main mass. Data obtained from the survey were calculated using the Statistical Package for the Social Sciences (SPSS) for Windows version 13.0 (SPSS Inc, Chicago, Illinois) package program. Descriptive statistics of participants such as number, percentage and mean were used in the evaluation. Results Total of 257 anesthesiologists responded to the survey. The anesthesiologists who participated in the study were divided into 4 groups regarding ages. The highest participation was in the age group of 36-45 (n=137, %53.3). Other characteristics of the participants are shown in Table 1.
Table 1. Characteristics of Anesthesiologists n
%
n
%
25-35
64
24.9
Public Hospital
101
39.3
36-45
137
46-55
47
53.3
UHSTRH
90
35.0
18.3
University Hospital
37
14.4
>55
9
3.5
Private Hospital
26
10.1
Foundation Hospital
3
1.2
Male
92
35.9
Professional Experience (year)
Female
164
64.1
Age
Institution
Sex
Citya
b
1-5
40
15.6
6-10
92
35.8
Istanbul
62
24.4
11-15
62
24.1
Konya
26
10.2
>15
63
24.5
Ankara
24
9.4
Title
Bursa
16
6.3
Assistant
19
7.4
Sanlıurfa
13
5.1
Specialist
191
74.3
Icel
11
4.3
Academician
47
18.3
Kayseri
8
3.1
Others
97
37.7
a. Seven cities where the most answered to the survey were indicated, b. University of Health Science, Training and Research Hospital
Results of the frequency of anesthesia for I/R patients are shown in the Figure 1A and Figure 1B indicate the frequency of the categories of surgical procedures that applied to I/R patients. The frequency of anesthesiologists’ communication levels with I/R patients was scaled from 1 to 5. The first value was “No problem at all” while the 5th value was “I encounter very often”.
Only 10 (4.1%) of the anesthesiologists stated that they did not have any communication problems, while 100 of them (40.7%) stated that they had frequent communication problems and 189 of them (77.1%) stated that sufficient or effective communication was necessary during the perioperative period. The frequency of communication problems with I/R patients and the necessity of the effective communication are shown in Figure 2. 376
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Figure 1. The frequency of anesthesia (A) and the category of surgical procedures (B) for immigrant and refugee patients
Figure 2. A-The frequency of communication problem B-The necessity of the effective communication with immigrant and refugee patient. (The Likert scale was used to evaluate the anesthesiologists’ thoughts. For figure 2A, 1: Not ever, 2: Rarely, 3: Sometimes, 4: Often, 5: Always; for figure 2B, 1:Strongly disapprove, 2:Disapprove, 3:Undecided, 4:Approve, 5:Strongly approve)
64.1% of the anesthesiologists stated that the I/R patients or their relatives understood the Turkish language (n=157, 64.1%). During the preoperative evaluation most anesthesiologists stated that they use the telephone interpreter or interpretership services of their hospital (n = 124, 50.6%). One hundred twenty (49.0%) of the anesthesiologists were trying to communicate by using body language or dictionary. However, 65 (26.5%) of the anesthesiologists could not communicate with I/R patients at all. Ninety (36.6%) of the anesthesiologists stated that the given information about the anesthesia was not enough during the preoperative examination and 65 of them (26.5%) stated that they could not ask the other features such as the medical history of the patient, fasting time or allergy. During the process of taking “Informed Consent Form” before the anesthesia practice, 125 of the anesthesiologists (51.2%) stated that used a form written in physician’s own language which was not understood by I/R patients. Approximately half of the anesthesiologists thought that there was no legal validity of this consent text (n=122, 50%). Very few anesthesiologists were
using a text written in the I/R patients language (n=15, 6.1%). Eleven anesthesiologists did not answer the questions about the informed consent. The way of receiving informed consent form and anesthesiologists’ views on the legal validity of this consent form is shown in Figure 3. Seventy-six anesthesiologists (31%) stated that they preferred general anesthesia instead of regional anesthesia, while 156 anesthesiologists (63.7%) preferred a type of anesthesia practice according to appropriate indications. The most common problem was about inability to provide the necessary and proper position during performing regional anesthesia (n=195, 82.3%). The most common problem encountered by anesthesiologists was “problems that could be overcome” (n = 180, 73.5%). Thirty-one of the anesthesiologists (12.7%) did not face with any problems, 112 of them (45.7%) could not fulfill the planned anesthesia method, 20 of them (8.2%) encountered serious morbidity and 2 of them (0.8%) resulted in mortality. One hundred ninety-nine anesthesiologists, (80.9%) were not exposed to any violence by I/R patients, but they were exposed to psychological, verbal and 377
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physical violence, respectively 34 (13.8%), 33 (13.4%) and 1 (0.4%). Seventy-five (30.6%) of them stated that these problems were more frequent than non-I/R patient. Ninety-five of the subjects stated that I/R patients had more problems in the postoperative period, especially in conditions requiring follow-up such as pain.
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Most of the anesthesiologists stated that it is necessary to provide interpreting services in hospitals to overcome language barriers (n=208, 84.9%). The proposed solutions to the problems that are met due to the communication difficulties are shown in Table 2.
Figure 3. The way of receiving informed consent form (A) and anesthesiologists’ views on the legal validity of incomprehensible consent form by the patients (B) Table 2. The proposed solutions to the problems that are met due to the communication difficulties Suggestions
n
%
This is a language problem and the Turkish language education should be extended for them
118
48.2
Interpreting services must be provided in the hospitals
208
84.9
Patient information texts and informed consent forms should be prepared in a way that patients can understand in their own language
165
67.3
This is an acculturation and quality communication will be provided in progress of time
50
20.4
A patient safety system must be standardized for these patients
1
0.4
Discussion People who migrate from their original country to another country or region in order to improve their financial or social status or increase their future expectations for themselves or their families are defined as “immigrants”; while people who are outside of their country where they are a citizen because they are worried about being persecuted, and who can not benefit from the protection of their country [4,5]. According to the data of 2017, only the number of Syrian I/R in Turkey are more than 3 million and a majority of these people admitted to the hospital to receive any medical services [6]. In this study, we evaluated the anesthesiologists’ dilemma with I/R patients due to communication problems during the perioperative period and the suggestions for determined issues. In developed countries where I/R people live intensively, communication issues between physicians and patients have continued to be a serious problem. In a study of better practices for immigrants in health care in European countries, it was stated that the most frequent problem with 95% was language barriers [7]. In a study comparing total knee arthroplasty (TKA) outcomes in English-versus non-English-speaking patients in
Australia, Dowsey et al. found that 34.6% of patients had serious communication problems and reported that speaking in English was a less positive functional outcome predictor after TKA [8]. Akkoç et al. stated that 61% of I/R patients in Turkey have experienced several troubles due to the language problems in health care institutions [9]. In our study, we found that more than half of the anesthesiologists could not communicate with more than half of the I/R patients and that they needed an interpreter. We also found that a quarter of them could not communicate because there was not an interpreter in their institution. During the preoperative evaluation, patients’ chronic diseases, medications, history of operations are some vital importance in determining the type of anesthesia. Taking the necessary precautions in the preoperative process is a serious problem in this group of patients, which may affect the perioperative vital functions. Stefan et al. reported that healthcare providers could not reach medical history in 17% of immigrant patients. They also were concerned that lack of contact details and nationality made decisions regarding consent [7]. Ruppen et al. stated that it was very difficult to explain their diseases and the treatment modalities 378
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to them [10]. In our study, a quarter of the anesthesiologists stated that they could not exactly obtain medical history, fasting and allergy status of these patients during preoperative evaluation. The misunderstanding between patient and physician may cause faults that can not be compensated later. It has been reported some examples of wrong medicine use because of misunderstandings in refugee patients in California residents [11]. Even more Ring et al. pointed out that a 65-year-old female patient had mistakenly an operation in her left-hand instead of a right-hand because of the misconception of the physician [12]. Stefan et al. stated that one of the biggest obstacles to have a good practice for refugees in 16 European countries is the misunderstanding of diseases or treatments [7]. On the other hand, improper planning during preoperative preparation is one of the most important reasons for complications [13]. In the literature, we could not reach any information about complications related to the change in planned anesthesia procedure due to communication problems. In our study, one-fourth of the anesthesiologists stated that they carried out an anesthetic technique according to the appropriate indications while one-third of them could not carry out their planned anesthetic technique due to communication difficulties. This problem was caused by the fact of the inability to provide the necessary and proper position for patients during regional anesthesia. Worse still, 20 anesthesiologists (8.2%) encountered severe morbid events and 2 anesthesiologists (0.8%) faced one event resulted in mortality. Previous studies have reported that some immigrant patients lack confidence in healthcare providers [8]. In this context, it has been reported that patients from countries where political or religious conflict has previously experienced feelings of disbelief against health care providers. Negative attitudes towards healthcare providers or sometimes hostile behavior are largely attributed to cultural differences, misunderstandings, or the feeling of being underestimated. This can often be a result of patients’ previous social experiences or discrimination anxiety. However, the negative behavior of staff towards immigrant patients may also continue this fear of discrimination. Due to inability to understand the language of the host country immigrant patients may also experience discrimination and refusal in the health care system and may be treated unkindly [7]. Sometimes all these factors may turn the physician-patient relationship into situations that result in violence. In a study examining the issues encountered by healthcare providers in Turkey, health workers were exposed to psychological, verbal and physical violence, respectively 22%, 3%, and %1. [9]. In our study, 80.9% of the anesthesiologists were not exposed to any violence by I/R patients, but they were exposed to psychological, verbal and physical violence, respectively 13.8%, 13.4%, and 0.4%. It is necessary to inform patients about the anesthetic procedure and to obtain their informed consent at the end of the preoperative evaluation. Effective preoperative informed consent can lay the groundwork for a less anxious, more knowledgeable, cooperative and satisfied patient profile [14]. Obtaining informed consent for diagnosis and treatment procedures including emergency or elective surgery can be a complex and challenging process in I/R patient. However, this is a necessity for patient safety and critical medical and legal responsibility. In the Guidelines for “Improving Patient Safety Systems with Limited-English Patients Proficiency”, which
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prepared by American Department of Health and Human Services, the poor and inadequate consent form has been assessed in risk management [15]. The American Anesthesiology Ethics Committee states that there are three important elements of a valid informed consent: disclosure/explanation, capacity, and voluntariness [16]. The statement of disclosure/explanation describes the accuracy of information regarding surgical intervention or anesthesia to the patient. Capacity, which encompasses both competence and comprehension is based on the foreign-language consent problem. Voluntariness requires that the patient is making an autonomous decision and is free of coercion. Extra effort may be required during obtaining informed consent in I/R patients due to language and cultural barriers [15]. With similar reasons physicians may also expose to ethical problems due to the patient’s inadequate understanding of the information that transmitted during the appointment [16]. Meghan D Morris et al. stated that patients could not even write their own names on the informed consent form [11]. In our study, we found that 54% of the anesthetists use a consent form that is prepared on a physician’s native language. There are lots of research on the issue of solution regarding the I/R patients’ communication difficulties. Priebe et al.’s study about immigrants has referred to seven components of good practice. These include organizational flexibility, good interpreting services, working with families and social services support, cultural awareness of staff, training programs and information materials for immigrants, positive and stable relationships with staff, and clear guidelines on care entitlements of different group migrants [7]. A good interpreter service may solve communication difficulties in a short term. “International Patient Support Line” in six languages has been created by the Republic of Turkey Ministry of Health in order to overcome these difficulties. Within this scope, a Foreigners Communication Center, which provides service in four languages has been established by AFAD (Disaster and Emergency Management Authority) [18]. However, in our study about half of the anesthesiologists stated that they could not make use of possibilities of telephone interpretation service. For this reason, 84.9% of the anesthesiologists stated that interpreting services must be provided in the hospitals. In many countries where immigrants and refugees live, the communication problems have been solved through professional medical interpretation services. In the United States, the practice guideline for patients with language problems has emphasized that it is necessary to be experienced interpreters [15]. Providing educated medical interpreters for patients who can not speak the language of the healthcare provider has seen as a fundamental component of medical care. All Australian hospitals have telephone translation services provided by experienced medical interpreters [19]. Organizations and programs will be needed to overcome their language barriers [20]. The opening and dissemination of Turkish language training courses in provinces or counties for I/R patients can help solve this problem [9]. On the other hand, holding hospital training programs and information materials for I/R patients can help contribute to solving communication issues. About half of the participants in our study stated that “this is a language problem and the Turkish language education should be extended for them”. Approximately 67.3% of them recommended the arrangement of the hospital training programs and the use of informational materials for these patients. 379
doi: 10.5455/medscience.2018.07.8992
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It has been shown that training of staff on acculturation improves patient-healthcare provider interaction [21]. Especially the promoting staff participation in social and economic assistance programs would likely be necessary to lessen acculturation barriers [11]. In the present study, 20.4% of the participants stated that these problems were cultural-based and that these problems would be resolved with a positive cultural interaction in time. It will also be more appropriate to inform the health care providers about I/R patients and workers’ rights, to give legal and psychosocial support for the problems they have experienced.
4.
Law on foreigners and international protection. http://www.resmigazete.gov. tr/eskiler/2013/04/20130411-2.htm access date 01.11.2018
5.
2017 Migration statistical report of Turkey. https://www.kizilay.org.tr/Upload/ Dokuman/Dosya/38492657_2017-yili-goc-istatistik-raporu-ocak-2018.pdf access date 03.11.2018
6.
Field survey on demographic view, living conditions and future expectations of Syrians in Turkey. https://www.afad.gov.tr/upload/Node/25335/ xfiles/17b-Field_Survey_on_Demographic_View_Living_Conditions_and_ Future_Expectations_of_Syrians_in_Turkey_2017_English_1.pdf access date 05.11.2018
To create a ‘national patient safety guideline’ in order to solve the limited communication and language problems may be one of the most effective practices. Patient safety guidelines for immigrants in the United States and Canada are among the best examples of solving existing problems [15,22]. In our study, there was very few proposals on standardizing a safety system and establishing a guide for I/R patients, which is attributed to the fact that the lack of understanding of such an implementation in our country.
7.
Priebe S, Sandhu S, Dias S et al. Good practice in health care for migrants: views and experiences of care professionals in 16 European countries. BMC Public Health. 2011;11:1-12.
8.
Dowsey MM, Broadhead ML, Stoney JD et al. Outcomes of total knee arthroplasty in English versus non–English-speaking patients. J Orthop Surg. 2009;17:305-9.
9.
Akkoç S, Tok M, Hasiripi A. The problems encountered by healthcare workers while offering an medical care to refugees and asylum seekers. Health Care Acad J. 2017;4:23-7.
There were a few limitations to our study that should be mentioned. Firstly, we sent the questionnaire only to the member of Turkish Society of Anesthesiology and Reanimation. However, we know that the number of anesthesiologists is more than member of Turkish Society of Anesthesiology and Reanimation. If we had reached all of the anesthesiologists, we could achieve better results. Secondly, statements may have been influenced by response tendencies, e.g. in line with the social desirability of answers, and reflect only personal statements. Conclusion The current study reveals that there are serious problems in providing health care services regarding anesthesia to I/R patients especially due to the language barriers. Present study may increase the awareness about this issue and provide a resource for the scientific-based solution suggestions. This article does not contain any studies with human participants or animals performed by any of the authors. Since this study was a survey, informed consent was not obtained from the participants. Competing interests The authors declare that they have no competing interest. Financial Disclosure All authors declare no financial support. Ethical approval The study was approved by the Necmettin Erbakan University Ethical Board.
10. Ruppen W, Urwyler A, Bandschapp O. Language difficulties in outpatients and their impact on a chronic pain unit in Northwest Switzerland. Swiss Med Wkly. 2010;140:260-4. 11. Morris MD, Popper ST, Rodwell TC et al. healthcare barriers of refugees post-resettlement. J Community Health. 2009;34:529-38. 12. Ring DC, Herndon JH, Meyer GS. Case 34-2010 – a 65-year-old woman with an incorrect operation on the left hand. N Engl J Med 2010;363:1950-7. 13. Barash PG, Cullen BF, Stoelting RK. In: Clinical Anesthesia. 5th edition. Lippincott Williams and Wilkins Press, Philadelphia 2006, 257. 14. Shapeton A, O’Donoghue M, Vielen BV, Barnett SR. Anesthesia lost in translation: perspective and comprehension. JEPM. 2017;19:1-8. 15. Improving patient safety systems for patients with limited English proficiency: A guide for hospitals. https://www.ahrq.gov/sites/default/files/publications/ files/lepguide.pdf access date 01.11.2018 16. Asked questions on informed consent for procedures. American Society of Anesthesiologists Committee on ethics. http://www.asahq.org/~/media/sites/ asahq/files/public/resources/faq-anesthesia-consent-ver-1-5.pdf access date 23.11.2016 17. Jones JW, Mccullough LB, Richman BW. Informed Consent: It’s Not Just Signing a Form. Thoracic Surg Clin. 2005;15:451-60. 18. Soysal A, Yağar F. Assessment of the effectiveness of healthcare management about Syrian asylum seekers in Turkey. 2nd Middle East Conferences: Migration Issues in the Context of Conflict in the Middle East, 28-29 April, 2016. Kilis, Turkey, 441-52.
Mehmet Akif Yazar ORCID: 0000-0002-3415-1363 Yasin Tire ORCID: 0000-0002-9905-8856 Betul Kozanhan ORCID: 0000-0002-5097-9291
19. Flores G. The impact of medical interpreter services on the quality of health care: a systematic review. Med Care Res Rev. 2005;62:255-99.
References
20. Palinkas, LA, Pickwell SM. Acculturation as a risk factor for chronic disease among Cambodian refugees in the United States. Social Science & Medicine, 1995;40:1643-53.
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Devi S. Syria’s health crisis: 5 years on. Lancet. 2016;387:1042-3.
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2016 migration report of Turkey. http://www.goc.gov.tr/files/files/2016_yiik_ goc_raporu_haziran.pdf
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Patient rights regulation. http://www.mevzuat.gov.tr/Metin. Aspx?MevzuatKod=7.5.4847&sourceXmlSearch=&MevzuatIliski=0 access date 01.08.1998.
21. Griswold K, Zayas LE, Kernan JB, Wagner CM. Cultural awareness through medical student and refugee patient encounters. J Immigrant Minority Health, 2007:9:55-60. 22. Pottie K, Greenaway C, Feightner J et al. Evidence-based clinical guidelines for immigrants and refugees. CMAJ. 2011;183:824-925.
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ORIGINAL RESEARCH
Medicine Science International Medical Journal
Medicine Science 2019;8(2):381-4
Effects of ketofol and propofol on intubation conditions and hemodynamics without the use of neuromuscular blockers in patients undergoing tympanomastoidectomy Duygu Demiroz Aslan1, Muharrem Ucar2, Mehmet Ali Erdogan2, Mukadder Sanli2, Nurcin Gulhas2, Cemil Colak3, Mahmut Durmus2 Istanbul Training and Research Hospital, Department of Anaesthesiology and Reanimation, Istanbul, Turkey 2 Inonu University, Faculty of Medicine, Department of Anaesthesiology and Reanimation, Malatya, Turkey 3 Inonu University, Faculty of Medicine, Department of Biostatistics, and Medical Informatics, Malatya, Turkey 1
Received 20 March 2019; Accepted 30 April 2019 Available online 13.06.2019 with doi:10.5455/medscience.2019.08.9042 Copyright Š 2019 by authors and Medicine Science Publishing Inc. Abstract The effect of ketofol, a mixture of ketamine and propofol in various ratios, on hemodynamic, for intubation without the use of neuromuscular blockers, has not been elucidated in patients undergoing tympanomastoidectomy. We evaluated the effects of ketofol and propofol on intubation conditions and hemodynamic without the use of a neuromuscular blocker. The prospective randomized, double-blinded study was scheduled for tympanoplasty or mastoidectomy. The patients were divided randomly into a propofol group (Group P) and a ketofol group (Group KP). Intubation conditions, changes in hemodynamics, HR, MAP, systolic arterial pressure (SAP), and SpO2 values were recorded before induction, after induction, after intubation, and at 3-min intervals during the first 30 min, 5-min intervals for the next 30 min, and 10-min intervals after that. In the intragroup evaluation, SAP, DAP, MAP and HR values were lower in both groups compared to the baseline values. Hemodynamic values were significantly lower in Group P than in Group KP after intubation compared to baseline. DAP at 12 and 18 min, DAP and MAP at 24 min, SAP, DAP and MAP at 27 min, and SAP and MAP at 30 min after the start of the operation were significantly lower in Group P than in Group KP. The need for ephedrine and the number of patients who required ephedrine were significantly lower in Group KP than in Group P. Ketofol provided appropriate intubation conditions similar to propofol, without the use of a neuromuscular blocker, and contributed to better hemodynamic conditions in patients undergoing tympanomastoidectomy. Keywords: Ketofol, propofol, hemodynamic, neuromuscular blocker, tympanomastoidectomy
Introduction The use of neuromuscular blocker is not recommended in terms of exposure and protection of the facial nerve in patients undergoing ear surgery [1]. Propofol and thiopental have been used for intubation without the need for neuromuscular blockers. However, propofol reduces heart rate (HR) and mean arterial pressure (MAP) and thiopental is associated with a longer recovery period [2,3]. Ketofol is a mixture of ketamine and propofol in various ratios [4]. Some properties of propofol, including quick recovery due to a short duration of action and decreased nausea-vomiting, compliment several beneficial effects of ketamine, such as long duration of action, analgesic activity, and a hemodynamic stimulatory effect
*Coresponding Author: Duygu Demiroz Aslan, Istanbul Training and Research Hospital, Department of Anaesthesiology and Reanimation, Istanbul, Turkey E-mail: drduygudemiroz@hotmail.com
[4,5]. However, the impact of ketofol on hemodynamics, in the absence of a neuromuscular blocker, has not been elucidated in patients undergoing tympanomastoidectomy. In the study, we evaluated the effects of intubation with propofol or ketofol, without the use of a neuromuscular blocker, on hemodynamic parameters and intubation scores in patients who were scheduled for tympanoplasty and mastoidectomy. Material and Methods The present study was a single-center, cross-sectional observational study conducted at Inonu University Hospital (Malatya, Turkey) between April 2015 and March 2016. After receiving institutional approval from the Ethics Committee of Inonu University Faculty of Medicine (Date/No: 2015/81.) and obtaining written informed consent, 60 patients with American Society of Anesthesiologist physical status and Mallampati scores of I and II, aged between 18 and 65 years and scheduled for elective tympanoplasty or 381
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mastoidectomy, were enrolled in this study. The patients were divided randomly into a propofol group (Group P) and a ketofol group (Group KP). 2 mg/kg propofol Propofol (2 mL/kg), 4 µg/kg remifentanil, and 1 mg/kg lidocaine were administered to Group P. A ketofol solution (1:1, total 20 mL) was prepared for Group KP, comprising 100 mg ketamine (Ketalar 50 mg/mL; Pfizer, Cambridge, MA, USA) and 100 mg propofol (1% propofol; Fresenius, Bad Homburg, Germany), brought up to 20 mL with saline and administered along with 4 µg/kg remifentanil and 1 mg/kg lidocaine. The final concentrations were 5 mg/mL ketamine and 5 mg/mL propofol. Ketofol (0.2 mL/kg; 1 mg/kg ketamine and 1 mg/kg propofol) was administered to the KP group. Three min. later, the patients were intubated with 7–7.5 ID endotracheal tubes. Patients who strained during the intubation were administered 10 mg rocuronium and excluded from the study. Anesthesia was maintained in both groups by infusion with 6–8% desflurane, 50% O2 + 50% air, and 0.025 μg/kg remifentanil. Patients with a history of allergy to the drugs used, severe cardiovascular or pulmonary systemic diseases, hepatic or renal dysfunction, a history of psychiatric disorder, or a body weight < 50 kg or > 90 kg were excluded from the study. The patients were randomized and allocated to groups using computer-generated numbers, via Excel software (Microsoft Corp., Redmond, WA, USA), by an anesthesiologist not participating in the trial. No patients were premedicated. All patients were accepted into the operating room. Electrocardiogram, HR, peripheral arterial oxygen saturation (SpO2), and noninvasive blood pressure were monitored. Following routine monitoring, all parameters were measured three times at 2 min intervals, and the mean values of the measurements were taken as the baseline. The primary outcome was to evaluate the effects of the intubation conditions. The secondary outcome was changes in hemodynamics. HR, MAP, systolic arterial pressure (SAP), diastolic arterial pressure (DAP) SpO2 values were recorded before induction (baseline), after anesthesia induction, after intubation, and at 3-min intervals during the first 30 min, 5-min intervals for the next 30 min, and 10-min intervals after that. If the MAP and HR decreased 20% to the baseline value and 45 beats/min, respectively, 10 mg ephedrine or 0.5 mg atropine was administered. At the end of the operation, all anesthetic agents were discontinued, and the patients were ventilated with 100% oxygen. Initiation of spontaneous respiration, opening of the eyes, tracheal extubation time, responsiveness to commands, and orientation to time, place, and person were recorded. The patients were assessed for consciousness, activity, respiration, circulation, and SpO2 at min 1, 10, and 30 according to the Modified Aldrete Recovery Score. Also, side effects such as nausea, vomiting, sore throat, laryngospasm, hoarseness, and chin laxity, as well as ease of laryngoscopy, vocal cord clearance, and extremity movements, were also recorded. Intubation conditions were evaluated according to the Helbo–Hansen–Raulo intubation scoring system. Surgical satisfaction was assessed with a 3-point scoring system, as follows 1: poor, 2: moderate, 3: good.
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Statistical Analysis SPSS software (ver. 23.0, SPSS Inc., Chicago, IL, USA) was used for the statistical analysis. Continuous quantitative variables are expressed as means and standard deviation and categorical variables as numbers and percentages. The normality of the data was assessed by the Shapiro–Wilk test. Pearson’s chi-square test was used to compare categorical variables. The Mann–Whitney U test or unpaired t-test was used to compare continuous quantitative variables. A p-value < 0.05 was considered statistically significant. Results Sixty-six patients were enrolled in the study. However, four patients did not meet the inclusion criteria, and two patients declined to participate. Demographic data of the study population was shown in Table 1. Table 1. Demographics of the groups Group P (n=30)
Group KP (n=30)
P values
Age, year
28.3 ± 8.8
31.1 ± 9.1
0.221
Gender, Female (n, %)
15 (%50)
12 (%40)
0.604
Height (cm)
167.5 ± 7.0
166.5 ± 7.9
0.593
Weight (kg)
65.1 ± 9.7
68.0 ± 11.6
0.310
20/10
16/14
0.197
ASA I/II
When SAP, DAP, MAP, and HR values were evaluated between groups, it found that all values were lower compared to the baseline values (p < 0.05 for all). SAP, DAP, and HR values were significantly lower in Group P than in Group KP after intubation compared to baseline (p < 0.05) (Table 2). DAP at 12 and 18 min, DAP and MAP at 24 min, SAP, DAP, and MAP at 27 min, and SAP and MAP at 30 min after the start of the operation were significantly lower in Group P than in Group KP (p < 0.05). Table 1. Demographics of the groups Group P (n=30)
Group KP (n=30)
P values
129.7 ± 11.6
129.0 ± 18.9
0.857
Baseline SAP (mmHg) DAP (mmHg)
80.5 ± 9.0
81.3 ± 8.8
0.742
MAP (mmHg)
97.0 ± 11.3
97.9 ± 14.8
0.793
HR (beats/min)
81.2 ± 15.1
84.3 ± 17.5
0.462
SpO2 (%)
99.5 ± 0.8
98.9 ± 1.3
0.047
SAP, (mmHg)
89.8 ± 14.6
100.3 ± 19.5
0.023
DAP, (mmHg)
49.0 ± 10.6
59.5 ± 10.7
< 0.001
MAP, (mmHg)
64.9 ± 11.2
70.5 ± 11.7
0.066
HR, (beats/min)
66.8 ± 12.3
73.6 ± 12.1
0.035
SpO2 (%)
99.6 ± 1.4
97.9 ± 8.8
0.311
SAP (mmHg)
97.6 ± 11.6
98.5 ± 16.7
0.810
DAP (mmHg)
53.9 ± 12.3
62.9 ± 17.1
0.023
MAP (mmHg)
69.7 ± 11.2
73.2 ± 16.1
0.334
HR (beats/min)
70.5 ± 12.2
72.4 ± 13.0
0.564
SpO2 (%)
99.5 ± 1.3
98.4 ± 7.3
0.424
After induction
After Intubation
SAP=Systolic arterial pressure, DAP=Diastolic arterial pressure, MAP=Mean arterial pressure, HR=Heart rate, SpO2= Peripheral Oxygen saturation
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Atropine was not needed in both groups. The need for ephedrine was significantly lower in Group KP (3 patients) than in Group P (12 patients) (p < 0.05). The number of patients who required ephedrine was significantly lower in Group KP than in Group P (p < 0.05). Initiation of spontaneous respiration, eye opening, tracheal extubation time, responsiveness to commands, and orientation to time, place, and person were similar between the groups. Modified Aldrete Recovery Score was significantly higher in Group P than in Group KP at min 30 (p < 0.05) (Table 3). Table 3. Data of Aldrete recovery scores. Group P
Group KP
P values
Aldrete 1st min
7.5 ± 0.8
7.5 ± 0.8
0.999
Aldrete 10th min
8.9 ± 0.6
8.7 ± 0.6
0.243
Aldrete 30th min
9.7 ± 0.4
9.2 ± 0.5
< 0.001
No difference in surgical satisfaction was observed between the groups. The groups were also similar in terms of side effects, such as sore throat, laryngospasm, and hoarseness. The incidence of nausea/vomiting was significantly higher in Group P than in Group KP (p = 0.001). Vomiting/nausea was observed in 18 patients in Group P. No nausea/vomiting was observed in Group KP. Discussion In the present study, ketofol provided better hemodynamic conditions; moreover, vomiting/nausea was observed fewer patients receiving ketofol versus group P. Additionally, the intubation conditions (Helbo–Hansen–Raulo intubation scoring) were similar those achieved with propofol, without the use of a muscle relaxant during tympanomastoidectomy. Several induction agents, such as propofol, thiopentone, and etomidate, in combination with different opioids, such as remifentanil, alfentanil, and fentanyl at different doses, are preferred for laryngoscopy and tracheal intubation without neuromuscular blockers [6-9]. It has been reported that propofol in combination with a short-acting opioid provides satisfactory conditions for tracheal intubation without the use of a neuromuscular blocker [10]. Propofol combined with remifentanil has been used more commonly, and provides more favorable conditions [2,3]. Remifentanil is preferred due to its short halflife, breakdown by esterases, and hemodynamic stability. In addition, biotransformation is sufficiently rapid and complete to render the effect of the duration of remifentanil infusion on wakeup time minimal [11]. In this study, an endotracheal intubation protocol without a neuromuscular blocker was used for anesthetic management of patients scheduled for tympanoplasty or mastoidectomy, to prevent facial nerve paralysis due to surgery and to allow monitoring of complications that may develop. We also used remifentanil as an opioid. Ketamine was added to propofol to provide better hemodynamic stability. Klemola et al. [10] showed that 3.5 mg/kg propofol combined with 4 mg/kg remifentanil provides good or excellent intubation conditions in children. Another study showed excellent intubation conditions with 2 mg/kg propofol combined with 4 mg/kg remifentanil [1]. In the present study, similar intubation doses
Med Science 2019;8(2):381-4
of propofol and remifentanil were used and excellent intubation conditions were achieved, as in other studies [1,10]. Erdoğan et al. [12] compared the effects of propofol and ketofol on laryngeal mask airway insertion conditions and hemodynamics in elderly patients. The same laryngeal mask airway insertion conditions were observed with ketofol and propofol, and the number of patients in need of ephedrine and the total doses of ephedrine were significantly lower in the ketofol group, whereas SAP was significantly higher in the ketofol group than in the propofol group. In the present study, the number of patients in need of ephedrine (3 patients) in Group KP was lower than in Group P (12 patients). This was likely because ketamine stimulates the nervous system and inhibits norepinephrine reuptake. Coadministration of propofol and ketamine is more favorable than propofol alone due to hemodynamic stabilization. Previous studies demonstrated that propofol combined with remifentanil decreases mean blood pressure and HR after induction, without the use of a neuromuscular blocker [1,13,14]. Similarly, in the present study, HR, SAP, and DAP values decreased significantly in Group P after induction compared to baseline, and better hemodynamic stability was provided by ketofol. The likely reason for this is that propofol leads to a loss of sympathetic stimulation on induction. A propofol-opioid-ketamine combination provided better hemodynamic stability, which can be explained by the antagonistic properties of propofol and ketamine. Recovery times were reportedly prolonged in a ketamine/propofol group compared to a alfentanil/propofol [15]. Similarly, in the present study, the Aldrete score was significantly lower in Group KP at 30 min, suggesting that recovery from propofol may be faster because the rate of clearance of the drug exceeds the hepatic blood flow [13]. No nausea/vomiting was observed in Group KP. However, nausea/ vomiting was seen in 18 patients in Group P. This was likely due to the tympanoplasty and mastoidectomy surgeries, which are associated with a high incidence of nausea/vomiting [1618]. We believe that ketamine produces effects, such as stable hemodynamics and inhibition of hypotension and analgesia, which may inhibit nausea/vomiting [19,20]. Conclusion Ketofol provided appropriate intubation conditions similar to propofol, without the use of a neuromuscular blocker and contributed to better hemodynamic conditions in patients undergoing a tympanomastoidectomy. We suggest that the studies should be replicated with larger groups and multicentric studies are required to make a final decision. Financial Disclosure All authors declare no financial support. Ethical approval After receiving institutional approval from the Ethics Committee of Inonu University Faculty of Medicine (Date/No: 2015/81.) Duygu Demiroz Aslan ORCID: 0000-0002-4241-4514 Muharrem Ucar ORCID: 0000-0002-1232-9829 Mehmet Ali Erdogan ORCID: 0000-0002-3860-6919 Mukadder Sanli ORCID: 0000-0003-1009-5536 Nurcin Gulhas ORCID: 0000-0002-2539-9017
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doi: 10.5455/medscience.2019.08.9042 Cemil Colak ORCID: 0000-0001-5406-098X Mahmut Durmus ORCID: 0000-0001-9594-9064
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Ko SH, Kim DC, Han YJ, et al. Small-dose fentanyl: optimal time of injection for blunting the circulatory responses to tracheal intubation. Anesth Analg. 1998;86:658-61.
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Akaslan F, Özcan AT, Canlı Ş, ve ark. Çocuklarda kas gevşeticisiz trakeal entübasyon. Ege J of Med. 2016;55:14-9.
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Jabbour-Khoury SI, Dabbous AS, Rizk LB, et al. A combination of alfentanillidocaine-propofol provides better intubating conditions than fentanyllidocaine-propofol in the absence of muscle relaxants. Canadian J Anesthesia. 2003;50:116-20.
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the use of muscle relaxants: remifentanil or alfentanil in combination with propofol. Acta Anaesthesiol Scand. 2000;44:465–9. 11. Morgan GE, Mikhail MS, Murray MJ, editors. İntravenöz Anestezikler. In: Clinical Anesthesiology 5 th ed. International Edition: Lange Medical Books. 2015;175-88. 12. Erdogan MA, Begec Z, Aydogan MS, et al. Comparison of effects of propofol and ketamine-propofol mixture (ketofol) on laryngeal mask airway insertion conditions and hemodynamics in elderly patients: a randomized, prospective, double-blind trial. J Anesth. 2013;27:12-7. 13. Alexander R, Olufolabi AJ, Booth J, et al. Dosing study of remifentanil and propofol for tracheal intubation without the use of muscle relaxants. Anaesthesia.1999;54:1037-40. 14. Woods AW, Allam S. Tracheal intubation without the use of neuromuscular blocking agents. Brit J Anaesthesia. 2005;94:150-8. 15. St Pierre M, Kessebohm K, Schmid M, et al. Recovery from anaesthesia and incidence and intensity of postoperative nausea and vomiting following a total intravenous anaesthesia (TIVA) with S-(+)-ketamine/propofol compared to alfentanil/propofol. Anaesthesist. 2002;51:973-9. 16. Liu YH, Li MJ, Wang PC, et al. Use of Dexamethasone on the prophylaxis of nausea and vomiting after tympanomastoid surgery. Laryngoscope. 2001;111:1271-4. 17. Eidi M, Kolahdouzan K, Hosseinzadeh H, et al. A comparison of preoperative ondansetron and dexamethasone in the prevention of post-tympanoplasty nausea and vomiting. Iran J Med Sci. 2012;37:166-72. 18. Donlon Jr. JV. Anesthesia for Eye, Ear, Nose, and Throat Surgery. In: Miller RD(ed). Anesthesia. Fifth edition. New York: Churchill Livingstone; 2000, 2173-98.
Gupta A, Kaur R, Malhotra R, et al. Comparative evaluation of different doses of propofol preceded by fentanyl on intubating conditions and pressor response during tracheal intubation without muscle relaxants. Pediatr Anaesth. 2006;16:399-405.
19. White PF, Freire AR. Günübirlik Anestezi. In: Miller RD Edition. Anesthesia. 6th editors Philadelphia- Pennsylvania Churchill Livingstone. 2010:2589635.
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20. Watcha MF, White PF. Postoperative nause and vomiting. Its etiology treatment and prevention. Anesthesiology. 1992;77:162-84.
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Available online at www.medicinescience.org
ORIGINAL RESEARCH
Medicine Science International Medical Journal
Medicine Science 2019;8(2):385-9
Rheumatoid arthritis and ankylosing spondylitis with cervical involvement and characteristics Nevsun Pihtili Tas1, Rabia Aydogan Baykara2, Ayhan Kamanli3
1
Elazig Education and Research Hospital. Department of Physical Medicine and Rehabilitation, Turkey 2 Malatya State Hospital, Department of Physical Medicine and Rehabilitation, Malatya, Turkey 3 Sakarya University Training and Research Hospital, Division of Rheumatology, Department of Physical Medicine and Rehabilitation, Sakarya, Turkey 1
Received 01 October 2018; Accepted 19 December 2018 Available online 30.01.2019 with doi:10.5455/medscience.2018.07.8961 Copyright Š 2019 by authors and Medicine Science Publishing Inc. Abstract Rheumatoid Arthritis and Ankylosing Spondylitis are systemic, inflammatory and chronic diseases. Cervical vertebra involvement is common and may cause disability in patients. The aim of this study; to determine the clinical and radiological features of cervical vertebrae involvement in patients with Rheumatoid Arthritis and Ankylosing Spondylitis and to assess the disability and quality of life of patients with different measurement methods. Forty-two patients with Ankylosing Spondylitis (AS) were diagnosed according to Modified New York criteria and 54 Rheumatoid Arthritis (RA) patients meeting the American College of Rheumatology (ACR) criteria were included. Cervical vertebra joint range of motion and neurological examination of all patients were evaluated. Open odontoid radiographs, lateral cervical graphs in the flexion and extension positions and MRI images were taken. Values such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and Rheumatoid factor (RF) were determined in all patients. Disease activity was assessed in patients with RA using DAS 28 and BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) in AS patients. In the evaluation of quality of life and disability for RA patients, the health assessment questionnaire (HAQ), the Rheumatoid Arthritis Quality of Life Scale (RAQOL), Short Form 36 (SF36), AS patients were interviewed for the Quality of Life Scale-SPA (SPA-QOL), Ankylosing Spondylitis Life Quality Scale (ASQOL), Short Form 36. 48 of the RA patients were female and 8 were female. The average age was 50.7 years Six patients with RA and AS had AAS identified by radiography. Pannus was detected on MRI of 5 patients with RA and 7 patients with AS. 80% of our patients with RA and 71% of our patients with AS who detected pannus formation by MRI were AA joint range was below 3 mm. There was no significant relationship between disease activity criteria and AAS. There was a significant relationship between AAS and age in RA patients (p < 0.05). Patients with RA had a worse quality of life. Cervical vertebral involvement can lead to deterioration of the quality of life of patients. For this reason, cervical spine involvement should be specifically investigated following the disease. Plain radiographs can provide reliable and practical measurements in determining cervical involvement MRI can be consulted if needed. Assessment of atlantoaxial joint integrity in patients with minimal cervical symptoms. Early diagnosis and treatment of cervical spine disorders is important. Keywords: Rheumatoid arthritis, ankylosing spondylitis, cervical vertebrae, cervical MRI, quality of life
Introduction Rheumatoid arthritis (RA) is a symmetric, systemic, chronic, and inflammatory disease that shows the primer effect in synovium. The disease can affect all synovial joints, especially affecting the hands, wrists, and feet. [1] The disease can eventually cause pannus formation in the synovium, leading the destruction of cartilage, bone and other adjacent tissues, and eventually joint deformations. [2] *Coresponding Author: Nevsun Pihtili Tas, Elazig Education and Research Hospital. Department of Physical Medicine and Rehabilitation, Turkey E-mail: nevsunpihtili@gmail.com
Cervical vertebra lesions in RA patients are reported between 25% and 86%. [3-5] The cause is usually seen as a synovial pannus, which is a characteristic lesion of RA. [6] Collagenase and other proteolytic enzymes secreted from pannus tissue cause destructive synovitis, ligamentous laxity, and bone erosions. This can lead to instability and subluxation. [6] The most common cervical involvement is the Atlanto-Axial Subluxation (AAS). [7] Anterior subluxation has been reported in 70% of patients with AAS cases, 20% to lateral, 7% to posterior and Rotational subluxation very rarely. Anterior Atlanto-Dental Interval (AADI) is the most common form of cervical involvement (50-70%). [8] The second most common type of cervical involvement is the 385
doi: 10.5455/medscience.2018.07.8961
superior migration of odontoids. Neurological damage or even death may occur due to direct compression of the brain stem.[9] Subaxial subluxation is seen in 15%. Spinal cord compression, which is less common than AAS, is more severe.[10] Combined anomalies are also very common. [10] Ankylosing spondylitis (AS) of the axial skeleton is mainly known for certain pathologies (sacroiliac joints and spinal joints) from the spondyloarthropathy group seronegative characterized by a chronic rheumatic disease involvement. In about 75% of AS patients chronic back pain and stiffness are the first symptoms.[11] However, sacroiliac joint involvement in this disease and is not limited to dorsal lumbar vertebral joints but include the cervical spine. Cervical vertebra involvement usually manifests itself with neck painful detention. Complications of cervical involvement in stubborn neck pain; fractures, subluxation, and discitis should be considered. Early diagnosis and treatment are important because unimportant trauma in AAS cases can lead to serious neurological findings or even death. [12] In addition, AAS and dislocations should be excluded in cases with AS, because in cases with general anesthesia, neck manipulation may be required during entubation and positioning of the patient. [13] For this reason, cervical vertebrae should be routinely evaluated in the follow-up of RA and AS patients. Plain graphs are very useful for determining the dislocation. The maximal flexion of the neck and the lateral graphs were taken at the extension should be evaluated. The most commonly used radiological measurements to assess the severity of dislocation are; Anterior Atlanto-Dental Interval (AADI), Posterior AtlantoDental Interval (PADI), McGregor Line, Ranawat Index and Redlund - Johnell Line. [10] Generally, RA and AS patients are followed by AADI and it is help to decide for surgery. [10] Magnetic Resonance Imaging (MRI) provides the early detection of pannus formation and changes in synovial tissues with highresolution power on soft tissues. [14] Bone marrow edema is a marker of subsequent erosive injury. [15] Studies suggest that contrast MRI is the gold standard. STIR or T2 fat-printed images have been shown to have high sensitivities in evaluating bone marrow edema and bone erosions. [16] In this study, we aimed to determine the clinical and radiological features of cervical vertebrae in RA and AS patients and to evaluate the disability and quality of life of patients with different measurement methods. Materials and Methods This study protocol was made in line with the approval of the local ethics committee of the Faculty of Medicine of Fırat University in 2008 / 05. This study included 54 RA and 42 AS patients enrolled or newly diagnosed in the polyclinic of Rheumatology Department. A detailed physical examination of patients, neurological findings, socio-demographic characteristics, duration of illness, drugs used and morning prisoner were evaluated.
Med Science 2019;8(2):385-9
Rheumatoid Arthritis Quality of Life Scale (RAQoL), the Health Assessment Questionnaire (HAQ), Short Form 36 (SF 36), Nottingham Health Profile ( NHP) and Disease Activity Score 28 (DAS 28 score) were used for the functional evaluation of patients with RA. BASFI (Bath Ankylosing Spondylitis Functional İndex), Ankylosing Spondylitis Life Quality Scale (ASQoL), Bath Ankylosing Spondylitis disease activity index (BASDAI), HAQ-S, NHP were used in the functional evaluations for AS patients. All patients participating in the study had antero-posterior mouth open and lateral cervical radiographs in flexion and extension (Shimadzu brand radspeed 200 models, Tokyo, Japan) and cervical MRIs were taken. (1.5 Tesla, Signa Excite, GE Healthcare, Milwaukee, USA) the shooting was done in the axial sagittal T1 and T2 image (TR / TE, 660/16, 4800/102 and 700/10, 3340/105, respectively). Radiological measurements of AADi, PADI, McGregor line, Ranawat index, and Redlund - Johnell line were measured with a caliper sensitive to 0.02 mm to assess the severity of dislocation. Patients receiving cervical MRI images were recorded with atlanto- axial subluxation, destruction, and erosion in the dens, an enlargement at the distance of the atlantoaxial joint, and synovial hypertrophy with or without contrast material in the odontoid process. Statistical methods Data are mean ± SD, median (range), what (%) was given as. All statistical analysis SPSS (SPSS version 18, Chicago, IL, USA) was performed. Data was evaluated using the KolmogorovSmirnov test disperses homogenously. The nonhomogeneous distribution shows ESR, CRP, and RF parameters such as duration of illness were assessed with the Mann-Whitney U test. İndicating homogeneous distribution data were analyzed by Student t-test. Categorically Chi-square test was used to compare the data. Pearson correlation test was used for correlation analysis. A P value of <0.05 was considered significant. Results Eight of RA patients (14.8%) were male, 46 (85.2%) were female, their ages were 50.7 ± 10.9 (26 - 75), of the 42 AS patients, 31 (73.8%) were male and 11 (26.2%) female, their ages were 36.3 ± 8.11 (18-60) years. In patients with RA and AS, height, weight, BMI, and the duration of morning arrest were similar (Table1). Table 1. Demographic characteristics of patients (mean ±SD) Age Size (m) weıght(kg) BMI(kg/m2) Duration of illness (Year) Morning stiffness(mn)
RA N=54
AS N=42
50.7±10.9 163.8±7.9 71.6±14.04 26.5±4.4 9.3±7.3 60.09±108.8
36.3±8.1 169.2±10.3 67.7±13.6 23.6±4.17 6.9±5.06 8 0.8±107
BMI: Body mass indeks
DAS28, RAQOL and HAQ scores in patients with rheumatoid arthritis are given in Table 2. 386
doi: 10.5455/medscience.2018.07.8961 Table 2. DAS28. RAQ oL. HAQ scores in RA patients (mean±SD)
Med Science 2019;8(2):385-9
Table 5. Some MRI findings of RA and AS patients (n (%))
RA N=54
RA
AS
24 (75)
20 (64.1)
DAS 28
3.780±1.56
The presence of osteophyte formation
HAQ
0.900±0.78
Degenerative disc disease
13 (40.6)
5 (18.5)
RAQ OL
14.98±9.35
Intervertebral disc herniation
18 (55.2)
16 (59.3)
Spinal stenosis
11 (34.4)
6 (22.2)
Erosion in Dens
6 (18.8)
4 (14.8)
Apex destruction
12 (37.5)
9 (33.3)
Contrast holding synovial hypertrophy
5 (15.6)
7 (25.9)
Contrast keep synovial hypertrophy
9 (28.1)
2 (7.4)
Expansion of the AA joint space
4 (12.5)
3 (11.1)
AA joint space narrowing
2 (6.2)
0 (0)
Cervical axis angulation
1 (3.1)
1 (3.7)
DAS28; Disease Activitiy Score. HAQ. Health Assessment Questionnaire. RAQ OL: Rheumatoid Arthritis Quality of Life Scale
In patients with Ankylosing spondylitis, the BASDAI score was 4.06 ± 2.97 (0-9.46), BASFI score was 3.63±3.40 (0-9.6), ASQOL was 8.61±7.02(0-19), HAQ-S stiffness score last week was 45,8 ± 33.2 (0-100) and HAQ-S total score was measured as 0.98 ± 0.86 (0-3). When the values obtained from measurements of cervical graphs of patients with RA and AS were compared, it was seen that the measurements were similar in RA and AS patients (Table3). Table 3. Measurements in RA and AS patients( mean±SD) RA
AS
AADI flex (mean±SD)
1.52±1.17
1.36±0.97
PADI (mean±SD)
28.8±3.98
30.9±5.13
Ranavat Index(mean±SD)
16.9±3.5
17.9±3.94
Redlund-Johnell Line(mean±SD)
30.2±4.41
31.04±5.74
AADI flex: on flexion graphs Anterior Atlantodental Interval. AADI ext: on extension graphs Anterior Atlantodental Interval padi: posterior atlantodental interval AADI was measured 3 mm and over in 6 patients with Rheumatoid arthritis and AS
The results of the McGregor line used for evaluating superior migration of odontoids and C1 - C2 measurements on the anteriorposterior radiographs for assessment the lateral subluxation are shown in table 4. Table 4. Mc Gregor and C1-C2 measurements in RA and AS patients (mean±SD) RA
AS
Mcgregor line dens of 1-4 mm past >4.5 mm past
17±31.5
11±26.2
Mcgregor line dens of >4.5 mm past
6±11.1
7±16.7
C1-C2 right >2mm
2±3.7
1±2.4
C1-C2 left >2mm
5±9.3
3±7.1
C1-C2 >2mm bilateral
9±16.7
4±9.5
Cervical MRI images of 32 RA and 27 AS patients were obtained. In 6 patients with Rheumatoid Arthritis, in the dens erosion was detected on MRI. 12 patients had apex destruction, 5 patients had contrast-enhanced synovial hypertrophy.( Table5) As a result of interrogation with SF - 36 which is a general quality of life criterion; physical function, vitality, and mental health; It was determined that AS patients were higher than in patients with RA and the difference was statistically significant (p < 0.05) (Table 6). As a result of questioning with the Nottingham Health Profile (NHP), there was a significant difference between the groups in the scores of physical activation and social isolation titles of patients with RA and AS. (p<0.05) Scores were found to be higher in patients with RA (Table 7).
Table 6. SF-36 scores of RA and AS patients (mean±SD) RA
AS
p
SFF
37.62±30.62
58.21±26.61
0.001
SF
39.44±65.85
30.3333±43.31
0.440
SVA
48.92±25.54
41.30±23.75
0.139
SGS
44.31±23.58
47.69±23.4
0.487
SV
35.37±17.23
45.45±23.23
0.017
SSF
57.45±24.13
57.78±27.25
0.950
SER
49.37±66.26
38.72±43.40
0.369
SMS
41.98±16.82
54.19±27.88
0.009
Sd: Standard deviation SGS; SF–36 general health SFF; SF–36 physical function SFR; SF–36 physical role restriction SER; SF–36 emotional role restriction SVA; SF–36 body pain SSF; SF–36 social function SMS; SF–36 mental health SV; SF–36 vitality Table 7. NHP scores of RA and AS patients (mean±SD) RA
AS
P
32.79±33.27
29.84±33.92
0.700
NSİ
39.08±39.19
14.52 ±29.03
0.001
NU
41.2959±34.78
32.54±32.48
0.234
NY
63.31±43.08
50.3±42.7
0.245
NFA
42.46±29.10
33.88±31.74
0.210
NA
44.29±33.22
48.93±37.37
0.427
NER
NA; Nottingham health profile pain NFA; Nottingham health profile physical activity NY: Nottingham health profile fatigue NU: Nottingham health profile SLEEP NSI: Nottingham health profile social isolation NER: Nottingham health profile emotional reactions
Discussion In this study we aimed to investigate cervical region with conventional graphs and MR images in patients with RA and AS who applied to our clinic, to evaluate the effects on the functioning and quality of life of patients determined by different pathologies with different scales. 54 RA and 42 AS patients were included in our study. Measurements were used to determine the severity of cervical involvement and the patients were evaluated for their quality of life. Radiological evaluation was the first and most important step leading us to assess patients AA subluxations. The lateral graphs taken from our patients were evaluated in flexion and extension. 387
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The most commonly used AADI for evaluating AA subluxation was 11.2 % in our patient with RA over than 3 mm. Values were between 3 and 5 mm. They suggested that transverse ligament injury and instability were subluxations in these patients. PADI is directly related to the risk of neurological damage. PADI, which is more valuable than AAS evaluation, was evaluated as 16. 5 mm in one patient. According to the literature, cervical vertebra lesions in RA patients are between 25% and 86%. Cervical subluxation has been reported in 43% to 86% of RA patients. [5,18] We evaluated the AAS ratio in patients with AS as 14.8 %. Values between 3 and 5 mm suggest that the subluxation is due to transverse ligament injury and instability. In a study conducted by Ramos et al. the AAS frequency seen in AS was reported to be 21%. [19] Lateral subluxation occurs because of damage to the joint capsule and bone erosion and anterior-posterior open mouth is best assessed by X-ray light. Chellapandi et al. [20] RA patients show cervical involvement had the rate of 1.3 % lateral subluxation, Agarwal et al. [21] reported in 2%. In our study, the rate of lateral subluxation whıch diagnosed by having a joınt space greater than 2 mm in the anteroposterior radiographs was found to be 16.7 %. This rate may be related to the fact that our patients have a longer disease duration. Vertical subluxation is rarely seen in AS in various studies. [19] In our study, the vertical subluxation rate AS patients was 4.8 %. As a result of odontoid compression in the vertical AAS, 9th, 10th, and 12th cranial nerves can be affected and dysphagia and vocalization can occur. In our study, 14.8 % of patients with RA had a voice depression, and 5.3 % of patients had dysphagia with vertical subluxation and the relation with subluxation was not significant ( p > 0.05). This suggested to us that the complaints may be due to the different involvement of the RA, such as the cricoarytenoid joint. Pannus tissue, soft tissue, nerve tissue and bone that can not be detected on conventional radiographs can be evaluated by MRI which can show more clearly. [22] Einig et al. [23] RA with cervical involvement in their studies of 60 patients are a good amount of assessment and a high rate of MRI results with clinical signs of the disease, they reported that correlated. In our study, we were able to obtain MRI images of 32 RA and 27 AS patients. Limitations of this study were patient’s postural disturbances, claustrophobia, prosthetic presence, and patients’ refusal to take MRI were the reasons that restricted MRI imaging. 80 % of our patients with RA who detected pannus formation by MRI and 71.5 % of our AS patients had an AA joint area of less than 3 mm. This result suggests that we should determine the risk of subluxation of the MRI before detection by radiography and we should be more careful in following the patient. The inflammation in the ligament causing the subluxation as well as the erosions in AS and RA are also increasing the severity of cervical involvement.
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Odontoid erosion or fracture of the posterior subluxation is rare but it is difficult to assess with direct radiography. [17] Erosion was detected with MRI at 14.8 % of AS patients and 18.8 % of patients with RA who received MRI images. In MRI, the relationship between dense erosion presence and AADI measurements was significant. (p < 0.05) This suggests that clinical and MRI compatible results can be obtained in the absence of statistical significance in the detection of AAS with conventional radiographs. Indexes for measuring functional status and quality of life following various diseases have been widely used in recent years. We assessed the effects of cervical involvement on quality of life and functioning in our patient groups evaluated by radiography and MRI images with various quality of life criteria. Neve et al. [24] in RA patients were detected in patients with AAS rate of 38.3 % and reported that the subluxation was worse than the HAQ score. Talamo et al. [25] identified radiographic erosions in patients with RA, SF-36, and worse HAQ score. HAQ scores were higher in patients with RA than patients with AS who had AAS and AA joint space increased. SF 36 physical function, physical role weakness, general health subscale deteriorated (p < 0.005) another RA-specific scale. We found that RAQOL worsening, another specific scale that we used to evaluate functioning in RA, also increased subluxation (r = 325. p >0.05 ). There was no significant deterioration in the quality of life of patients with RA or AS who had pannus formation on MRI. There was a significant deterioration in the quality of life of RA patients with cervical involvement. It should also be noted that the long duration of illness and high disease activity, which are risk factors for cervical involvement, contribute to this situation. BASDAI, HAQ - S changes we evaluated for general outcomes of AS patients and changes in the BASFI scores we evaluated for functioning. No significant effect on the risk of subluxation was found. (p > 0.05). This can be attributed to the fact that the overall condition of our cases is good. Conclusion In conclusion, RA and AS are the most frequent rheumatic diseases affecting the cervical spine. The development of AAS in RA and AS can cause significant morbidity and mortality. Early diagnosis and regular treatment can prevent the development of AAS. At the same time, cervical involvement causes disability and loss of function in patients, which adversely affects the quality of life. Therefore, evaluation of atlantoaxial joint integrity in patients, cervical spine disorders early diagnosis and treatment is important, although cervical symptoms are minimal. Plain radiographs are also a quick, practical and economical method to follow with practical measurements. Competing interests The authors declare that they have no competing interest. Financial Disclosure All authors declare no financial support.
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doi: 10.5455/medscience.2018.07.8961 Ethical approval This study protocol was made in line with the approval of the local ethics committee of the Faculty of Medicine of Fırat University in 2008 / 05. Nevsun Pihtili Tas ORCID: 0000-0003-0202-6426 Rabia Aydogan Baykara ORCID: 0000-0003-0542-266X Ayhan Kamanli ORCID: 0000-0001-5299-7250
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Ergin S. Romatoid artrit ve Sjögren Sendromu. In: Beyazova M, GökçeKutsal Y editörler. Fiziksel Tıp ve Rehabilitasyon 3. Baskı, Ankara: Güneş Kitapevi; 2000;1549-76.
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Kim HJ, Nemani VM, Riew KD et al. Cervical spine disease in rheumatoid arthritis: incidence, manifestations, and therapy. Curr Rheumatol Rep. 2015;17:9. Mukerji N, Todd NV. Cervical myelopathy in rheumatoid arthritis. Neurol Res Int. 2011:153-628.
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Nguyen HV, Ludwig SC, Silber J, et al. Rheumatoid arthritis of the cervical spine. Spine J. 2004;4:329-34.
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Zhang T, Pope J. Cervical spine involvement in rheumatoid arthritis over time: results from a meta-analysis. Arthritis Res Ther. 2015;17:148.
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Gillick JL, Wainwright J, Das K. Rheumatoid arthritis and the cervical spine: a review on the role of surgery. Int J Rheumatol. 2015:252-456.
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Boden SD, Dodge LD, Bohlman HH, et al. Rheumatoid arthritis of the cervical spine. JBJS. 1998;9:693-703.
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Pamela L, Laasonen L, Kankaanpaa E, et al. Progression of cervical spine changes in patients with early rheumatoid arthritis. J Rheumatol. 1997;24:1280-4.
10. Reiter MF, Boden SD. Inflammatory disorders of the cervical spine. Spine. 1998;23:2755-66.
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13. Slobodin G, Shpigelman A, Dawood H et al. Craniocervical junction involvement in ankylosing spondylitis. Eur Spine J. 2015;24: 2986-90. 14. Stiskal MA, Neuhold A, Szolar DH et al. Rheumatoid arthritis of the craniocervical region by MR imaging: detection and characterization. Am J Roentgenol. 1995;165:585-92. 15. Collins DN, Barnes CL, Fitzrandolph RL. Cervical spine instability in rheumatoid patients having total hip or knee arthroplasty. Clin Orthop. 1991;272:127-35. 16. Jacobsen EA, Riise T. MRI of the cervical spine with flexion and extension used in patients with rheumatoid arthritis. Scand J Rheumatol. 2000;29:249-54. 17. Narvaez JA, Narvaez J, Serrallonga M et al. Cervical spine involvement in rheumatoid arthritis: correlation between neurological manifestations and magnetic resonance imaging findings. Rheumatology. 2008;47:1814-9 18. Del Grande M, Del Grande F, Carrino J et al. Cervical spine involvement early in the course of rheumatoid arthritis. Semin Arthritis Rheum 2014;43:738-44. 19. Ramos-Remus C, Gomez- Vargas A, Guzman-Guzman JL, et al. Frequency of atlantoaxial subluxation and neurologic involvement in patients with ankylosing spondylitis. J Rheumatol. 1995;22:2120-5. 20. Chellapandian D, Rajendran Panchapekesa C, Rajan Rukmangatha S. The cervical spine involvement in rheumatoid arthritis and its correlation with disease severity. Indian Rheumatol Assoc. 2004;12:2-5. 21. Aggarwal A, Kulshrestha A, Chaturvedi V et al. Cervical spine involvement in rheumatoid arthritis: Prevalence and relationship with overall disease severity. J Assoc Phys India. 1996;44:468-71. 22. Kramer J, Jolesz F, Kleefield J. Rheumatoid arthritis of the cervical spine. Rheum Dis Clin North Am. 1991;3:757-71. 23. Einig M, Higer HP, Meairs S et al. Magnetic resonance imaging of the craniocervical junction in rheumatoid arthritis: value, limitations, indications. Skeletal Radio1. 1990;19:341-6.
11. Haroon N. Ankylosis in ankylosing spondylitis: current concepts. Clin Rheumatol. 2015;34:1003-7.
24. Neva MH, Hakkinen A, Makinen H et al. High prevalence of asymptomatic cervical spine subluxation in patients with rheumatoid arthritis waiting for orthopedic surgery. Ann Rheum Dis. 2006;65:884-8.
12. Khan MA, Hochberg MC, Silman AJ, et al. Clinical features of ankylosing spondylitis. Rheumatology. Mosby, Philadelphia. 2003:1161-81.
25. Talamo J, Frater A, Gallivan S et al. Use of the short form for health status measurement in rheumatoid arthritis. Brit J Rheumatol. 1997;36:463-9.
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Available online at www.medicinescience.org
ORIGINAL RESEARCH
Medicine Science International Medical Journal
Medicine Science 2019;8(2):390-4
A single-center experience with resin adsorption hemoperfusion combined with continuous veno-venous hemofiltration for septic shock patients Baris Arslan1, Cagatay Kucukbingoz1, Mustafa Kutuk1, Hasan Murat Gunduz2 Adana Numune Training and Research Hospital, Department of Anesthesia and Intensive Care, Adana, Turkey 2 Cukurova University Medical Faculty, Department of Anesthesia and Intensive Care, Adana, Turkey
1
Received 21 November 2018; Accepted 10 December 2018 Available online 26.12.2018 with doi:10.5455/medscience.2018.07.8950 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract Our primary goal was to investigate whether treatment of CVVH-HP in patients with septic shock caused decreased vasoconstrictor and inotropic drug requirements. As a secondary objective, to determine whether CVVH-HP had an effect on inflammatory biomarkers and mortality. 11 septic shock patients who received CVVH-HP treatment within 12 months were included in the study. The following parameters were taken from patients’ medical records; hemodynamic parameters, infection markers, inotropes and vasopressors use. Also, Intensive care mortality and duration of ICU stay were assessed. The survival rate after the 24 hours from the start of treatment was 63.6% and 28 days survival rate was 36.4%. Four of the remaining seven survivors at the 24 hours were discharged home. CVVH- HP treatment was associated with an increase of mean arterial pressure, reduction of vasoconstrictor/ionotropic requirement, reduction of C-reactive protein and procalcitonin levels. In our retrospective study, we found that patients treated with CVVH-HP treatment had approximately 40% reduction in norepinephrine and dopamine requirement in the first 24 hours and patients had higher mean arterial pressures. Keywords: Adsorption, hemofiltration, hemoperfusion, septic shock
Introduction Sepsis is the most leading cause of death in the intensive care units (ICU) resulting from the injury triggered by the body infection [1-3]. High mortality and morbidity rates of sepsis reveal the necessity of a serious clinical approach [4]. Response induced by the proinflammatory, anti-inflammatory cytokines and the activated immune cells generally result in multiple organ dysfunction [2,5]. Moreover, the level of this inflammation is also closely related to sepsis mortality [6,7]. While the mortality associated with septic shock rises to 54%, this rate reaches up to 80% with the increasing need for vasopressor and organ dysfunction [8]. Such high mortality has forced the clinicians to search for different and innovative treatment methods. Methods which reduce endotoxin and cytokine levels are thought to possibly be effective on treatment of septic shock. Anti-endotoxin monoclonal antibodies, cytokine antagonists, coupled plasma filtration adsorption (CPFA) and Polymyxin B immobilized direct hemoperfusion (PMX-DHP) are *Coresponding Author: Baris Arslan Adana Numune Training and Research Hospital, Department of Anesthesia and Intensive Care, Adana, Turkey E-mail: arslanbarismed@gmail.com
a few of these treatment methods [2,3]. Classical hemoperfusion is the direct contact of blood with the sorbents in the extracorporeal system [1]. Being a new hemoperfusion method, “HA 330 type resin cartridge” is produced from a polymer material and removes mediators, molecular toxins and cytokines by using neutral microporous resin according to the adsorption principles [2,3]. While HA 330 type resin cartridge can be used alone using a device in sepsis patients for hemoperfusion, it can also be used in renal failure by integrating into the CVVH treatment. Moreover, it is offered as a therapeutic option for sepsis as CVVH removes -at low amounts though- tumor necrosis alpha and some proinflammatory cytokines [6]. In theory, hemoperfusion combined with CVVH (CVVH-HP) can remove higher amounts of mediators and cytokines, as a result, can positively affect the clinical results. Use of HA 330-type resin cartridge is a new method in hemoperfusion treatment and there are only a limited number of clinical studies on its clinical effectiveness and reliability. This study aimed to investigate the effectiveness of the CVVHHP method in patients with septic shock. The primary goal of the study was to investigate whether treatment of CVVH-HP method caused decreased vasoconstrictor and inotropic drug requirements 390
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in septic shock patients. As a secondary objective, the study aimed to determine whether CVVH-HP had an effect on inflammatory biomarkers and mortality. Material and Methods This retrospective, single-center study was conducted on all the patients who received HA-type resin cartridge combined with CVHH for hemoperfusion within the first 12 months (January 2016 – December 2016) of the start of the use of HA 330 type resin cartridge in Adana Numune Hospital. The study was approved by the Ethics and Scientific Board of Adana Numune Hospital with the Dossier No of ref:51. In our clinic, the decision of hemoperfusion begins with the decision of the intensive care specialist and the following written standard protocols are applied. Firstly all patients diagnosed with sepsis receives an appropriate treatment regarding last Sepsis Surviving Campaign guidelines including [10] ; 1-Initial fluid resuscitation aiming; Central venous pressure (CVP) 8–12 mm Hg b) MAP ≥ 65 mm Hg c) Urine output ≥ 0.5 mL/kg/hr d) Central venous oxygen saturation ≥ 70 2- Administration of effective intravenous antimicrobials as soon as recognition of septic shock 3- a) Norepinephrine as the first choice vasopressor as needed to target a mean arterial MAP of 65 mm Hg b) Epinephrine or dopamine when an additional agent is needed to maintain adequate blood pressure. Our hemoperfusion therapy is performed only patients who give no response to the septic shock treatment applied by the ICU physician according to the Sepsis Surviving Campaign (SSC) Goal-Directed Protocol [10] If there is no response to conventional treatment, hemoperfusion is initiated in the following situations. 1- Use of high-dose vasopressor or dual vasopressor, 2- Dysfunction of 2 organs ≥ , 3- Presence of suspected or proved gram-negative infection. Hemoperfusion method is performed using HA 330 resin cartridge (Jafron Biomedical Co., Ltd Zhuhai, Guangdong, China) by following the use instructions. Hemoperfusion is performed once a day for three consecutive days. Dual lumen catheter 12 F is placed in the right jugular vein or femoral vein with the Seldinger method. CVVH-HP is performed using the same hemodiafiltration (HDF) machine. Blood filter (HF-1200, Baxter, America) is used for CVHH. The CVVHH procedure is performed on the patients simultaneously using the prismaflex device. Blood flow rate is adjusted at 100 ml/min-150ml/min. Each hemoperfusion procedure lasts at least 2 hours. Hemofiltration continues after the hemoperfusion. Hemofilter is replaced once in 72 hours or whenever occluded by coagulation. Anticoagulation is achieved using citrate. Hemoperfusion and hemofiltration may be applied separately
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or together. In our clinic, all hemoperfusion therapy are applied together with hemofiltrations. Even if hemofiltration is not performed before hemoperfusion, it is wanted to continue until the filter is clogged because of the blood purification effect it provides. Patient Evaluations Since lactic acid level could not be measured in our intensive care in the concerned date interval, septic shock was diagnosed as the case which is characterized by the circulation failure accompanied by persistent arterial hypotension which cannot be explained by another reason [9]. Following parameters were collected from the medical records of the patients. The Acute Physiology and Chronic Health Enquiry (APACHE) 2 score of each patient, (measured in the first 24 hours of stay in the ICU) was used to evaluate the severity of the disease. Changes in the sequential organ dysfunction assessment (SOFA) score were recorded before the hemoperfusion treatment and at the 24th and 72nd hours after completion of the treatment. Heart rate (HR), systolic blood pressure, diastolic blood pressure and mean artery pressure (MAP) were recorded. Dopamine, dobutamine and noradrenaline infusion dosages; leucocytes and thrombocytes counts; procalcitonin and CRP levels; and arterial pH; pO2/FiO2 rate were measured on daily basis. ICU mortality and the duration of stay in the ICU were evaluated. Statistical Analysis Statistical analyses were performed using SPSS 20.0 software (SPSS Inc. Chicago, IL, USA). Student’s independent and paired t-test was applied for the parametric data and Mann-Whitney U test for the non-parametric data. Results are presented with “mean +standard deviation”. Statistical significance was set at P<0.05. Results 7 male and 4 female, totally 11 septic shock patients (age 51.3± 21.7 years) were included in the study scope. Most frequent reasons for ICU stay were found to be pneumonia and head trauma. Basic and clinical features of the patients are presented in Table 1. While gram-negative bacteria was isolated most, the most frequent source of sepsis was respiratory system infections (Table 2.) In 5 patients (45.5 %), gram-negative bacteria and Candida spp. were isolated together. Each patient was administered 2.18±0.9 hemoperfusion treatment on average. Table 1. Patient demographics and the severity of their disorders Male:Female (%)
7:4 (63.6:36.4)
Age (years)
51.3± 21.7
Number of failed organs
3.09±0.8
Acute renal failure (%)
7 (63.6)
Apache† II score
31.4±11.3
Diagnosis at ICU admission Traumatic brain injury (%)
4 (36.4)
Pneumonia (%)
4 (36.4)
Intra-abdominal sepsis (%)
2 (18.2)
Acute renal failure (%)
1 (9.1)
†APACHE Acute Physiologic and Chronic Health Evaluation; ‡ Intensive Care Unit
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doi: 10.5455/medscience.2018.07.8950 Table 2. Etiology of the infections Source Abdominal cavity (%)
1 (9.1 %)
Respiratory system (%)
9 (81.8 %)
Urosepsis (%)
3 (27.3%)
Central venous catheter-related blood infection (%)
2 (18.2 %)
Causative microorganism Gram-negative bacteria (%)
9 (81.8%)
Acinetobacter baumannii (%)
8 (72.7%)
Gram-negative bacteria+fungus (%)
5 (45.5 %)
Gram-negative bacteria+fungus+gram-positive bacteria (%) Unrecognized
3 (27.3% ) 2 (18.2%)
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Four (4) of 11 patients (41.7 %) lost their lives within 24 hours by completing only one CVVH+HP treatment. Survival rate at the 24th hour of treatment start was found to be 63.6 % and survival rate in 28 days to be 36.4 %. Table 3 shows the comparison of the pre-hemoperfusion clinical and laboratory parameters of the surviving patients. Evaluation of the hemodynamic parameters shows similarities between the mean arterial pressure and pulse rate of the non-survivors and the survivors. Compared to the survivors, non-survivors had statistically significantly higher procalcitonin values (25.5±31.5 vs. 2.8±3 p=0.03), SOFA scores (14.4±3.6 vs. 8.2±3.6 p=0.042) and APACHE 2 scores (38.4±7.2 vs. 19.2±1.7 p=0.006). Meanwhile, non-survivors had statistically the significantly lower number of leucocytes (10.1±5 vs. 18.3±4.9, p=0.042) and arterial pH values (7.13±0.1 vs. 7.37±0.07, p=0.012).
Table 3. Comprasion of clinical and laboratory parameters between survivors and non-survivors before hemoperfusion Survivors (n=4)
Non Survivors (n=7)
P value
Mean blood pressure, (mm Hg)
78.1±12.4
73±7.5
0.648
Heart rate (beat/min)
88.5±18.7
107.3±24.2
0.164
Platelet count (x109/L)
337.2±124.1
139.4±131.6
0.073 0.042*
White cell blood count (x 109/ L)
18.3± 4.9
10.1±5
CRP† ( mg/dL)
25.5±13.3
27±12.9
0.570
PCT ‡ (ng/ml)
2.8±3
25.5±31.5
0.012* 0.012*
pH
7.37±0.07
7.13±0.1
PaO2/FiO2
226.7±170
131.5±114
0.109
SOFA§ score
8.2±3.8
14.4±3.6
0.042*
Dose of dopamine (μg/kg/min )
15±12.9
14.3±6.7
0.927
0.42±0.39
0.41±0.21
Dose of noradrenaline (μg/kg/min )
APACHE # II score 19.2±1.7 38.4±7.2 Data in the table are presented as mean ± SD. Survivors vs. Non Survivors (p < 0.05) , † CRP C-reactive protein; ‡ PCT Procalcitonin, # APACHE Acute Physiologic and Chronic Health Evaluation; § SOFA Sequential Organ Failure Assessment
Reduction of the procalcitonin and CRP values after the CVVHHD treatment are presented in Figure 1. Procalcitonin value was measured as 18.3 ±28.7 before the treatment, started to decrease to 7.04±7.8 on the first day and measured as 2.4±3.3 on the 7th day after the treatment. The decrease recorded in the procalcitonin levels of the surviving patients at the 1st day after the treatment was found to be statistically insignificant (2.8±3 vs. 0.74 ±0.28 p=0.285). Similarly, a comparison of the pre- and post-CRP values of the surviving group produced no statistically significant difference (26.9±12.9 vs. 18±11.22, p=0.075).
0.923 0.006*
Need for dopamine infusion decreased from 14.54±9.07 mcg/kg/ min in the pre-CVVH-HP period to 8.8±11.5 mcg/kg/min at the 1st day and to 1±2.4 mcg/kg/min at the 3rd day after the treatment. Similarly, norepinephrine need was reduced from 0.41±0.27 mcg/ kg/min in the pre-treatment period to 0.25±0.31 mcg/kg/min at the 1st day and to 0.2±0.31 mcg/kg/min at the 3rd day after the treatment. Unlike the decrease in the vasoconstrictor requirement, MAP value progressively increased from the pre-treatment value of 75.2±0.4 to 82±19.1 on the 3rd day after the treatment. PaO2/ FiO2 ratio started to increase just after the CVVH- HP treatment. Thrombocyte count of the patients who survived after the first 24 hours decreased firstly and then started to rise again. It decreased from 211.9±196.14 to 170.14±123.3 at the 24th hour after the treatment and then increased up to 229.8±165.9 on the 7th day after the treatment. Discussion
Figure 1. The changes of biomarkers after hemoperfusion. C-reactive protein and procalcitonin daily reduced after resin adsorption theraphy.
This retrospective study presents CVVH+HP procedure as a rescue treatment for 11 septic shock patients who did not respond to the goal-oriented treatment and who required vasopressor. It was observed that the norepinephrine and dopamine need of the patients decreased by 40% and their mean arterial pressure (MAP) values increased within the first 24 hours following the CVVH+HP treatment. Moreover, CVVH-HP treatment was shown by this study to improve hemodynamic parameters, to decrease 392
doi: 10.5455/medscience.2018.07.8950
vasopressor requirement and to improve oxygenation in patients who did not respond to the conventional treatment [11]. Similarly, a study which used resin adsorption revealed a 60% decrease in the norepinephrine and dopamine need and improved mean arterial pressure values [2]. Restoration of hemodynamic stability by the HA 330 hemoperfusion treatment can be partially explained by the reduced pro- and anti-inflammatory mediators the blood thanks to the treatment, which resulted in less vasodilation. By this way, manipulation of the mediators via removal may lead to downregulation of systemic inflammation and restoration of homeostasis of the organism [5]. In patients who were subjected to a resin adsorption procedure, IL-6 and IL-8 levels were observed to decrease approximately by 50% on the 3rd day of the procedure [2]. Similarly, among the proinflammatory mediators, IL-6 ve TNF-alpha levels were found to be statistically significantly lower in the group receiving HP treatment in the scope of the peritoneal sepsis model developed. Moreover, after the treatment, compared to the other group, the HP group produced a lower number of bacteria colonies [5]. 28-day hospital mortality rate of the present study was recorded to be lower than the mortality rate estimated by the APACHE 2 score (which was 73.3%). However, the mortality rate varies in 20.9%-45% range in the blood purification methods [2,8,12]. Compared to the previous studies, the present study produced higher mortality rates, which may have resulted from four main reasons. Firstly, the patients of the present study had higher APACHE 2 scores. Secondly, nearly all of the present study patients developed a gram-negative infection. In addition to the gram-negative organisms, they developed fungal-polymicrobial infections at higher rates. Besides, the rate of intra-abdominal infection, on which blood purification techniques are thought to be more effective, was low in the patient group of the present study. Rather, this study had a higher rate of pneumonia-induced sepsis (recorded as 81%). Finally, in terms of exclusion criteria, this study included all patients who were administered hemoperfusion while the compared studies are observed to have excluded some patients with prospective bad prognosis. Hemoperfusion treatment is actually known to be more effective when initiated at early stages. It may be less effective in late cases with prospective bad prognosis. This difference in patient selection may be the reason behind the high mortality rates recorded in the present study. Since CVVH-HP treatment is not a widely-accepted treatment at the moment, it is referred to as the last option in the study clinic in line with the regulations of the Ministry of Health and ethical rules. Rather than this practice, if the patients who were estimated to die at early stages (for instance within the first 24 hours) were excluded from the scope of this study, as done in the compared studies, the 28-day mortality rate would be 36.4%, a rate comparable with the other studies. Procalcitonin is known to be helpful in prognosis in presence of systemic bacterial infection [13]. Compared to the CRP, procalcitonin is a better marker in both diagnosing serious sepsis and mortality. Both CRP and procalcitonin values decreased after the treatment both in non-survivors and survivors. However, while the procalcitonin value was statistically significantly higher in the patients to have lost their lives within the first 24 hours, it was observed to be still high, not at a statistically significant level though, in the patients who lost their lives at later periods when compared to the survivors. The changes recorded in the oxygenation, thrombocyte count and
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vasopressor requirement by this study were observed to be similar with those recorded in the previous studies conducted by using different methods and filters. In parallel with the similar studies, the PaO2/FiO2 rate increased immediately after the treatment [2,14,15]. This improvement in oxygenation may have resulted from the decrease in the extravascular lung water (16). CVVHHP treatment may create the estimated result (in the mechanism of the ARDS induced by the gram-negative bacteria) of reducing the alveolocapillary permeability caused by the activated immune cells by removing endotoxin and key mediators in the blood [17]. Further search should be made to find the reason behind oxygenation improvement. While the thrombocyte count decreased immediately after the treatment, it was observed to reincrease up to the pre-treatment levels. Although the literature presents no explanation for this result, it may have resulted from the direct contact of thrombocytes with the cartridge in the extracorporeal system. It does not seem to be the HeparinInduced Thrombocytopenia (HIT), moreover, since the CVVH treatment was performed using citrate; HIT seems to be a low probability. It should be noted that serious thrombocytopenia and leukopenia developed in the first hemoperfusion applications [16]. With the introduction of the biocompatible coating systems offered by the technological developments, on the other hand, no serious thrombocytopenia is observed anymore. Still, it should be considered before the treatment that it will reduce thrombocyte count of the patients with thrombocytopenia or bleeding disorder. Sepsis is the leading reason for acute renal failure and death in the ICU [1]. Acute renal failure increases alone the mortality and morbidity [13]. ICU patients with acute renal failure should be treated with CRRT (Continuous Renal Replacement Therapies). CRRT treatment restores fluid and electrolyte balance in the hemodynamically unstable patients. Moreover, continuous fluid removal ensures sufficient calorie intake. Despite all these advantages, CRRT has a little or no clinical effectiveness as a blood purification method. Although hemofiltration does not decrease mortality alone, it has been observed to further increase the effectiveness of hemoperfusion[11]. In a meta-analysis where 16 studies were analyzed, approximately 15% decrease was recorded in the mortality rate (35.7% vs. % 50.1) of the patients who were treated with a blood purification method [7]. Blood purification therapy techniques ensure non-specifically removal of many inflammatory mediators from the blood by using extracorporeal device [5]. Different blood purification methods have been developed for sepsis. Some of them are high volume hemofiltration, high adsorption hemofiltration, high cut-off membrane hemofiltration, plasma exchange, and hybrid systems like coupled plasma filtration adsorption. Blood purification methods have diversified in parallel with the technological developments and, mortality decreased has been achieved in the literature studies; however, it has not started to be used widely. In the scope of this study, a new hemofiltration filter â&#x20AC;&#x153;HA 330â&#x20AC;? was used in integration with the CVVH treatment in the study clinic. Recently, an international guideline for the management of sepsis and septic shock was published, and sepsis campaign recommends initiation of fluid resuscitation, source control and administration of timely antibiotics (within 1 hour of suspected sepsis) if the refractory use of vasoactive agents [18]. While CVP is no 393
doi: 10.5455/medscience.2018.07.8950
longer recommended alone in the evaluation of fluid therapy. It is proposed to take into account dynamic measurements such as passive leg raise. This study has some limitations which have to be pointed out. Firstly, the small patient population, no control group and the retrospective nature of the study do not allow us to figure out a conclusion about the effectiveness of CVHH-HP. Secondary, at the beginning of the study, lactate measurement could not be effectively performed in our intensive care unit, which is now an important parameter for diagnosis and follow-up.
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2.
Huang Z, Wang SR, Su W, et al. Removal of humoral mediators and the effect on the survival of septic patients by hemoperfusion with neutral microporous resin column. Ther Apher Dial. 2010;14:596–602.
3.
Liu LY, Zhu YJ, Li XL, et al. Blood hemoperfusion with resin adsorption combined continuous veno-venous hemofi ltration for patients with multiple organ dysfunction syndrome. World J Emerg Med . 2012;33:44–8.
4.
Cader RA, Gafor HA, Mohd R, et al. Coupled plasma filtration and adsorption (CPFA): A single center experience. Nephrourol Mon. 2013;5:891–6.
5.
Namas RR, Zamora R, Namas RR et al. Sepsis: Something old, something new, and a systems view. J Crit Care. 2012;27:314.e1-314.e11.
6.
Mao HJ, Yu S, Yu XB et al. Effects of coupled plasma filtration adsorption on immune function of patients with multiple organ dysfunction syndrome. Int J Artif Organs. 2009;32:31–8.
7.
Zhou F, Peng Z, Murugan R, et al. Blood purification and mortality in sepsis: a meta-analysis of randomized trials. Crit Care Med. 2013;41:2209–20.
8.
Scielzo R, Caramazza L, Circone R, et al. Intravenous immunoglobulin in the prevention of infections in high-risk pediatric neurosurgery. Minerva Anestesiol. 1992;58:235–8.
9.
Levy MM, Fink MP, Marshall JC et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med. 2003;31:1250–6.
Conclusion The mean APACHE II scores of the patients in our study were 31.4±11.3. Mortality rate with CVVH-HP treatment lower than the mortality rate estimated by the APACHE II score was observed. it was concluded that these findings need to be tested with multicenter prospective randomized controlled trials. Sepsis is a complex disease and blood purification is a complex intervention. Factors of the host, as well as the pathogenic factors, are effective on the course of sepsis. Sepsis factors may vary from one center to the other. For this reason, it may not be right to generalize the blood purification methods. Moreover, as well as the epidemiological factor, antibiotic preferences may also differ between the centers. Blood purification methods can have some effects on this situation. primary goal was to investigate whether treatment of CVVH-HP in patients with septic shock caused decreased vasoconstrictor and inotropic drug requirements. As a secondary objective, to determine whether CVVH-HP had an effect on inflammatory biomarkers and mortality.
10. Dellinger RP, Levy MM, Rhodes A et al. Surviving sepsis campaign. Crit Care Med. 2013;41:580–637. 11. Singer M, Deutschman CS, Seymour CW et al. The Third International consensus definitions for Sepsis and septic shock (Sepsis-3). Jama. 2016;315:801–10. 12. Nakada T, Oda S, Ken-ichi M et al. Continuous hemodiafiltration with PMMA hemofilter in the treatment of patients with septic shock. Mol Med. 2008;14:257-63.
Competing interests The authors declare that they have no competing interest
13. Hassan J, Abdul Cader R, Kong NCT, et al. Coupled plasma filtration adsorption (CPFA) plus continuous veno-venous Haemofiltration (CVVH) versus CVVH alone as an adjunctive therapy in the treatment of sepsis. EXCLI J. 2013;12:681–92.
Financial Disclosure The financial support for this study was provided by the investigators themselves.
14. Franchi M, Giacalone M, Traupe I et al. Coupled plasma filtration adsorption improves hemodynamics in septic shock. J Crit Care. 2016;33:100–5.
Ethical approval The study was approved by the Ethics and Scientific Board of Adana Numune Hospital with the Dossier No of ref:51. Baris Arslan ORCID: 0000-0001-9386-514X Cagatay Kucukbingoz ORCID: 0000-0002-2527-3510 Mustafa Kutuk ORCID: 0000-0002-4546-519X Hasan Murat Gunduz ORCID: 0000-0002-0373-892X
References 1.
Ronco C, Brendolan A, Dan M et al. Adsorption in sepsis. Kidney Int. 2000;58:148–55.
15. Adamik B, Zielinski S, Smiechowicz J, et al. Endotoxin elimination in patients with septic shock: an observation study. Arch Immunol Ther Exp (Warsz). 2015;63:475–83. 16. Shum HP, Yan WW, Chan TM. Extracorporeal blood purification for sepsis. Hong Kong Med J. 2016;22:478–85. 17. Stanley TH, Sperry RJ, editors. Anesthesia and the Lung. Springer Science & Business 1992. 18. Rhodes A, Evans LE, Alhazzani W et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock. Intensive Care Med.2016;33:304-77.
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Available online at www.medicinescience.org
ORIGINAL RESEARCH
Medicine Science International Medical Journal
Medicine Science 2019;8(2):395-400
The effects of thyroid hormones levels on prognosis after pediatric heart surgery Engin Gurcu1, Ahmet Yuksel2, Yusuf Velioglu2, Isik Senkaya Signak3 1
Canakkale Mehmet Akif Ersoy State Hospital, Department of Cardiovascular Surgery, Canakkale, Turkey Abant Izzet Baysal University Faculty of Medicine, Department of Cardiovascular Surgery, Bolu, Turkey. 3 Uludag University Faculty of Medicine, Department of Cardiovascular Surgery, Bursa, Turkey
2
Received 26 November2018; Accepted 19 December 2018 Available online 08.02.2019 with doi:10.5455/medscience.2018.07.8969 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract In this study, we aimed to evaluate the effects of thyroid hormone levels on the prognosis of patients who underwent congenital heart surgery under cardiopulmonary bypass. A total of 40 children who underwent congenital heart surgery were enrolled to this prospective study. The patients were divided into two groups according to the presence or absence of postoperative low cardiac output state. Plasma free thyroxine, free triiodothyronine and thyroid stimulating hormone levels were measured preoperatively and at 24 and 48 hours postoperatively. Postoperative low cardiac output state was observed in five patients (12.5 %). Preoperative free thyroxine levels were significantly higher in the low cardiac output state group (p=0.021). Postoperative free triiodothyronine and free thyroxine levels were significantly lower, and lactate levels, inotropic index were significantly higher in the low cardiac output state group. Duration of mechanical ventilation, intensive care unit stay, operation and cardiopulmonary bypass were significantly higher in the low cardiac output state group. Four patients (10 %) died in the early postoperative period, and all of them were in the low cardiac output state group. Our findings showed that the occurrence of low cardiac output state after congenital heart surgery was associated with the high levels of preoperative free thyroxine and the reduction in percentage of free triiodothyronine and free thyroxine levels at the 24th and 48th hours postoperatively. Keywords: Cardiopulmonary bypass, pediatric heart surgery, thyroid hormones, prognosis
Introduction Despite the recently developed diagnosis and treatment methods, congenital heart diseases continue to be one of the most important causes of death in the first year of life after birth [1]. Low cardiac output state (LCOS) might occur following a congenital heart surgery under cardiopulmonary bypass (CPB). This adverse state occurs 9-12 hours after the CPB is over and cardiac functions resumes normally in 24 hours. The decrease in cardiac output elicites clinical evidences such as hypotension, tachycardia, bradycardia, inotropic drug requirement for maintaining normal blood pressure (dopamine > 5 µg/kg/min or any dose of dobutamine, epinephrine, norepinephrine infusion), oliguria, anuria, acidosis, respiratory failure, confusion, central hyperthermia, peripheral hypothermia, and gastrointestinal disorders [2-4]. An inotropic index is defined as the support of the cardiovascular system with inotrop medicine in the cases of decreased cardiac output [5]. Many studies show that inotropic index is an important independent indicator in the mortality and the morbidity of children operated for congenital heart disease [5,6].
*Coresponding Author: Ahmet Yuksel, Abant Izzet Baysal University Faculty of Medicine, Department of Cardiovascular Surgery Bolu, Turkey E-mail: ahmetyuksel1982@mynet.com
Many studies show that in cases of congenital heart diseases after surgeries under CPB, thyroid hormone levels are depressed [7-9]. The changes in thyroid hormone levels during CPB is described as sick euthyroid syndrome type-1 or nonthyroidal illness syndrome (NIS). NIS is a malfunction in the hypothalamus-pituitarythyroid axis which may be in a low form with only a decrease in triiodothyronine (T3) levels or which may be in a more complex form with a decrease at T3 and thyroxine (T4) levels at the same time [10,11]. NIS developing after cardiac surgery under CPB is believed that hemodilution non-pulsatil flow usage, systemic heparinization and hypothermia are responsible for its development and it results in a decrease in cardiac contractility and an increase in peripheral vascular resistance [12,13]. In this study, we aimed to evaluate the relationship between thyroid hormone levels on prognosis in infant patients undergoing congenital heart surgery under CPB and the possible LCOS after surgery. Material and Methods The patients’ parents were informed about the study, and their written consents were obtained. The study protocol was approved by the institutional ethics committee. This study was conducted in accordance with the principles of the Helsinki Declaration. 395
doi: 10.5455/medscience.2018.07.8969
A total of 40 children that were planned to undergo congenital heart surgery under CPB at our hospital were included in this prospective study. Firstly, the demographic and clinical characteristics of patients were recorded, then intraoperatif data and postoperative outcomes of patients were also recorded. In addition to preoperative data, the recorded perioperative parameters were as follows: CPB time, aortic cross clamp time, duration of surgery, duration of mechanical ventilation, inotropic index, length of stay in intensive care unit (ICU), length of stay in hospital, amount of diuresis per hour, and plasma lactate levels in arterial blood gas measured 6 times in 24 hours, as well as in-hospital mortality. The patients were divided into two groups according to the presence or absence of postoperative LCOS, and were then compared with each other. The patients with the absence of LCOS were named as Group 1, whereas the patients with the presence of LCOS were named as Group 2. The patients who had previous thyroid illness or had used thyroid hormones before the surgery were excluded from the study. Operations were performed by same cardiothoracic surgery team. All operations were performed through median sternotomy under general anaesthesia, and normothermic conditions with no ultrafiltration during CPB. Blood samples were collected from patients preoperatively and postoperatively at the 24th and 48th hours. Thyroid stimulating hormone (TSH), free thyroxine (fT4) and free triiodothyronine (fT3) levels were measured with the Electro Chemi Luminesence Immuno Assay (ECLIA) method. Statistical Analysis The Statistical Package for Social Sciences (SPSS) version 20 was used for the analysis. Mann-Whitney U or independent sample t tests were used for differences in continuous variables between the groups, while Fisher’s exact test was used for differences in categorical variables. Spearman correlation analysis was used to show the relationships between variables. Continuous variables were presented as mean ± Standard deviation or median (minimum-maximum), whereas categorical variables were
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presented as frequency and percentage. A p value of less than 0.05 was considered as statistically significant. Results Cardiac output did not decrease in 35 of 40 cases in the study group (87.5 %), whereas 5 of the cases (12.5 %) had LCOS. Four of the cases (10 %) died. Those who died were all in the group with the presence of LCOS (80 %). Table 1 shows both the names of the diseases and the operations that the cases in the study groups had. Procedures performed on the four cases that have died were; ventricular septal defect was closed in one patient, tetralogy of Fallot was corrected in one patient, total anomalous pulmonary venous connection was corrected in one patient, total cavopulmonary shunt was performed in one patient. Table 2 shows the median, minimum and maximum values and p values of the patients’ preoperative data. Twenty five of 40 patients in the study group (62.5 %) consisted of the boys, whereas other 15 of patients (37.5 %) were girls. The youngest patient was 1 month old, whereas the oldest one was 171 months old (median=37 months). Weights were ranging between 4 and 64 kg (median=12 kg), heights were ranging between 50 and 168 cm (median=90.5 cm) and the body surface areas (BSA) were ranging between 0.21 and 1.72 (median=0.53). When patients were compared according to their ages, weights, heights, BSA and genders, no statistically significant difference was found. Preoperative fT3 value of the patients was 3.70 (2.64 - 4.82) pg/dL in Group 1, whereas it was 3.72 (2.76 - 3.99) pg/dL in Group 2. There was no statistically significant difference in terms of preoperative fT4 between two groups (p=0.781). Preoperative fT4 value was found to be 1.33 (0.9 - 1.98) ng/dL in Group 1 and 1.60 (1.32 - 1.74) ng/dL in Group 2 with a statistically significant high level of preoperative fT4 in Group 2 (p=0.021). Preoperative TSH value was found to be 2.66 (1.07 - 13.24) μIU/mL in Group 1 and 3.10 (2.43 - 6.57) μIU/mL in Group 2 with no statistically significant difference between two groups (p=0.317).
Table 1. Diseases and operations of patients Disease
Operation
VSD ASD TOF AVSD Subaortic stenosis Single ventricle, RV hypoplasia TAPVD VSD + Subaortic stenosis ASD + Pulmonary stenosis Supra-annular aortic stenosis ALCAPA RV hypoplasia, BCPC Operated AVSD, Mitral regurgitation Pulmonary conduit stenosis Pulmonary stenosis c-TGA, VSD, Glenn shunt
VSD closure ASD closure Total correction Total correction Resection of the stenosis BCPC Total correction VSD closure, resection of the stenosis ASD closure, reconstruction of the RVOT Aortoplasty Transposition TCPC Mitral valve repair Pulmonary conduit replacement Reconstruction of the RVOT Fontan circulation
Group 1 (n=35)
Group 2 (n=5)
8 7 5 3 3 1
1
1 1 1 1 1 1 1 1
1
1 1
1
VSD: Ventricular septal defect, ASD: Atrial septal defect, TOF: Tetralogy of Fallot, AVSD: Atrioventricular septal defect, BCPC: Bidirectional cavapulmonary circulation, TAPVD: Total anomalous pulmonary venous return, RVOT: Right ventricular outflow tract, ALCAPA: Anomalous Left Coronary Artery From the Pulmonary Artery, RV: Right ventricle, TCPC: Total cavapulmonary circulation, c-TGA: Corrected transposition of the great arteries
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doi: 10.5455/medscience.2018.07.8969 Table 2. Preoperative data of groups
Table 3. Intraoperative and postoperative data of groups
Group 1 (n=35)
Group 2 (n=5)
p value
Age (month)
42 (4-171)
18 (1-45)
0.170
Height (cm)
96 (55-168)
72 (50-105)
0.094
Weight (kg)
14 (5-64)
9 (4-19)
0.103
0.58 (0.27-1.72)
0.41 (0.21-0.73)
0.113
BSA Gender Male
1.00
Group 1 (n=35)
Group 2 (n=5)
p value
CPB time (min)
86.6 ± 37.4
138.4 ± 35.5
0.007
Aortic cross clamp time (min)
46.6 ± 28.7
67.2 ± 16.5
0.086
Duration of surgery (min)
170.2 ± 43.6
236 ± 81.7
0.038
8.8 ± 7.2
146.0 ± 80.0
<0.001
35.7 ± 16.6
106.4 ± 79.6
0.002
5.6 ± 3.0
11.2 ± 11.1
0.968
0 (0-7)
50 (9-100)
<0.001
Plasma lactate levels (mg/dL)
23.1 ± 9.7
54.8 ± 26.3
0.005
Diuresis (mL/h)
56.6 ± 39.2
23.6 ± 13.7
0.018
13 (86.7%)
2 (13.3%)
22 (88%)
3 (12%)
fT3
3.70 (2.64-4.82)
3.72 (2.76-3.99)
0.781
fT4
1.33 (0.9-1.98)
1.60 (1.32-1.74)
0.021
Length of hospital stay (days)
TSH
2.66 (1.07-13.24)
3.10 (2.43-6.57)
0.317
İnotropic index
Female
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Duration of MV (h)
BSA: Body surface area, fT3: Free triiyodothyronine, fT4: Free thyroxine, TSH: Thyroid stimulating hormone.
Table 3 shows intraoperative and postoperative data of patients. CPB time was found to be significantly higher in Group 2 (p=0.007). No statistically significant difference was found between two groups in aortic cross clamp time (p=0.086). Operation time was found to be significantly higher in Group 2 (p=0.038). Duration of mechanical ventilation was found to be significantly higher in Group 2 (p<0.001). Duration of ICU stay was found to be significantly higher in Group 2 (p=0.002). No significant difference was found between two groups for inhospital stay duration (p=0.968). Inotropic index was found to be significantly higher in Group 2 (p<0.001). Plasma lactate level in Group 2 was found to be significantly higher (p=0.005). Diuresis was found to be significantly higher in Group 2 (p=0.018).
Length of ICU stay (h)
CPB: Cardiopulmonary bypass, ICU: İntensive care unit, MV: Mechanical ventilation.
Percentage changes (PC) between the preoperative and postoperative results of patients’ thyroid hormone values were calculated. The change between preoperative median value and postoperative 24th hour median value was named as PC1. The change between preoperative median value and postoperative 48th hour median value was named as PC2. The results according to groups are shown in Table 4 as median, minimum and maximum values with their p values. The course of thyroid hormones levels, and percentage changes are also shown in Figure 1.
Figure 1. The course of thyroid hormones levels and percentage changes
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doi: 10.5455/medscience.2018.07.8969
Discussion
Table 4. Postoperative quantitative data of groups
fT3 PC1
Med Science 2019;8(2):395-400
Group 1 (n=35)
Group 2 (n=5)
p value
-44.8 (-73, 0)
-61.6 (-75, -48)
0.018 0.053
fT3 PC2
-49.4 (-77, -22)
-71.7 (-76, -34)
fT4 PC1
-3.4 (-38, +126)
-30 (-52, -15)
0.002
fT4 PC2
-8.1 (-41, +16)
-25 (-58, -19)
0.006
TSH PC1
-43.7 (-94, +179)
-75.1 (-90, -28)
0.058
TSH PC2
-27.2 (-94, +224)
-76.1 (-94, +1624)
0.123
fT3: Free triiyodothyronine, fT4: Free thyroxine, TSH: Thyroid stimulating hormone, PC: Percentage change.
A correlation analysis was conducted between preoperative values of thyroid hormones and inotropic index which is an independent indicator in LCOS presence. No statistically significant relationship was found between inotropic index and preoperative fT3 and TSH values. A statistically significant positive relationship was found between inotropic index and preoperative fT4 value (Table 5). Table 5. Results of the correlation analysis of preoperative values of thyroid hormones and inotropic index fT3
fT4
TSH
r
0.28
0.373
0.141
p
0.864
0.018
0.385
fT3: Free triiyodothyronine, fT4: Free thyroxine, TSH: Thyroid stimulating hormone.
Table 6 shows the results of the percentage changes of inotopic index and thyroid hormones in the correlation analysis. A statistically significant negative relationship was found between intropic index and fT3 PC1, fT3 PC2, fT4 PC1, fT4 PC2 and TSH PC1 values. No significant relationship was found between inotropic index and TSH PC2 value. Table 6. Results of the correlation analysis of percentage changes of inotopic index and thyroid hormones fT3 PC1
fT3 PC2
fT4 PC1
fT4 PC2
TSH PC1
TSH PC2
r
-0.385
-0.358
-0.426
-0.322
-0.398
-0.278
p
0.014
0.023
0.006
0.043
0.011
0.082
fT3: Free triiyodothyronine, fT4: Free thyroxine, TSH: Thyroid stimulating hormone, PC: Percentage change.
Table 7 shows the results of the correlation analysis between inotropic index and peroperative and postoperative variables. A statistically significant positive relationship was found between intropic index and CPB time, aortic cross clamp time, duration of ventilation and duration of ICU stay. No significant relationship was found between inotropic index and operation duration. Table 7. Results of the correlation analysis between inotopic index and preoperative and postoperative variables CPB time
Aortic cross clamp time
Operation time
MV time
ICU time
r
0.392
0.331
0.214
0.659
0.615
p
0.012
0.037
0.185
<0.001
<0.001
CPB: Cardiopulmonary bypass, MV: Mechanical ventilation, ICU: Intensive care unit.
Heart surgery techniques have improved since that the CPB has been in place in heart surgery practice, but at the same time some side effects caused by extracorporeal circulation have been also seen. To prevent or minimize these side effects, many studies have been performed and are still being performed. As the studies on congenital heart surgery have increased, our knowledge have also increased and we have tried to define the preoperative risk factors more clearly. In human physiology, T4 concentration in blood is approximately 70 times more than T3. After secreted from thyroid gland T3 and T4 are quickly attached to plasma proteins. Only a very small amounts of T3 and T4 are found free form in blood. This free fraction determines the metabolic activity of the hormones. Compared to T4, T3 is 4 times more active. Three plasma proteins which are called thyroid binding globulin, thyroid binding prealbumin and albumin, carry the thyroid hormones in bind. Although not accepted as an inotrop, positive inotropic effects of thyroid hormones are known. T3 improves the contractility of the heart muscle by stimulating the transcription of myosin heavy chain α and inhibiting myosin heavy chain β. It increases β-adrenergic receptors and G proteins by changing the isoforms of Na-K-ATP-ase genes. In this way, it makes positive inotropic and chronotropic effects in the heart. Thyroid hormones increase the β-adrenergic receptors in heart and skeleton muscles while decreasing α adrenergic receptors in heart muscles. They also increase the effect of catecholamines by increasing adenylcyclase activation and cAMP production in postreceptor levels [14-16]. In our study, LCOS was observed in 5 of 40 patients (12.5 %), whereas in other 35 of them (87.5 %) it was not observed. Four of all patients (10 %) died. Those who died were all in the group with the presence of LCOS (80 %). In their study with 36 infant patients who had congenital heart surgery under CPB, Plumpton and Haas [17] found that the extension in CPB period was related with low preoperative fT3 and TSH values. The study also showed that babies younger than 3 months had low preoperative fT3 values and they had the need for mechanical ventilation for more than 48 hours. In another study with 16 infant patients who had congenital heart surgery under CPB, McMahon et al. [18] reported a similar relationship between CPB period and total plasma T3 value. In our study, we found no statistically significant difference between both groups in terms of the demographic features including age, gender, weight, height and body surface area. In addition, we found that preoperative fT4 level is significantly higher in the group with the presence of LCOS than in the group with the absence of LCOS. No significant difference was found between two groups regarding the preoperative fT3 and TSH values. Moreover, it was found that perioperative CPB time and operation time were significantly longer in patients with the presence of LCOS and aortic cross clamp timed was longer in cases with the presence of LCOS but that was not significant. Also the duration of mechanical ventilation and the duration of ICU stay were found to be significantly longer in patients with the presence of LCOS whereas there was not a significant difference between two groups for the duration of in-hospital stay. It was found that thyroid hormones 398
doi: 10.5455/medscience.2018.07.8969
decreased postoperatively in both groups. It was seen that in the group with the presence of LCOS, fT3 had decreased significantly more in postoperative 24th hour borderline significantly decreased further in postoperative 48th hour. It was also seen that in the group with the presence of LCOS, fT4 had decreased significantly more in postoperative 24th and 48th hour and TSH had borderline significantly decreased more in postoperative 24th hour but not significantly decreased in postoperative 48th hour. It was seen that postoperative lactate level had increased in both groups in the first 24 hours but the increase in the group with the presence of LCOS was found to be significantly higher. Also the inotropic index was found to be significantly higher in the group with the presence of LCOS. In a study in which children with congenital heart diseases had operations under CPB, Baysal et al. [19] demonstrated that plasma fT3, total T3 and total T4 values had decreased, TSH and fT4 values had no significant change, fT3 and total T3 values in the postoperative 48th hour had significantly decreased in children with the presence of LCOS and preoperative total T4 level was an independent indicator of LCOS. In another study in which 20 infants had congenital heart operation under CPB and ultrafiltration, Bartkowski et al. [20] reported the decreased postoperative thyroid hormone levels in plasma, and the authors also found thyroid hormones in the dialysis ultrafiltrate. It was seen that the recovery period was longer for the patients who had more decrease in T3 levels, therefore they suggested that T3 replacement therapy could be beneficial for the postoperative recovery. In a randomized controlled study in which 20 patients had congenital heart operations under CPB and received T3 treatment for 5 days, Bettendorf et al. [21] showed the increased average cardiac index in patients who had T3 treatment and increased systolic function for especially the ones whose CPB time was lasted longer. In a study performed by Talwar et al. [8] in which 100 infant patients had congenital heart operations under CPB, the authors evaluated thyroid hormones, survival, inotropic score, duration of mechanical ventilation and postoperative complications and found the decreased thyroid hormones levels postoperatively in all patients. They found that the patients who died in the first postoperative 72 hours had lower total T4 levels when compared to the patients who did not die. For the patients who who did not die, total T4 levels were found to be lower in the ones with the presence of complications when compared to the ones with the absence of complication. They also found that total T4 level had a significant inverse correlation with inotropic score and borderline significant inverse correlation with mechanical ventilation. They stated that to improve the postoperative results, more researches should be conducted on prophylactic management of total T4. In our study, we also found that the inotropic index was significantly positively correlated with preoperative fT4, inversely correlated with PC in fT3 and fT4, and PC in TSH in postoperative 24th hour, and it was not correlated with the PC in TSH in postoperative 48th hour. Limitations of the Study This present study had several limitations. The major limation of the study was small sample size. The other important limitations were non-randomized study design or lack of adjustment in comparability between the groups, heterogeneity and irregular
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distribution of the groups in terms of both the wide range of disease spectrum and patient numbers of groups, and the lack of the mid and long-term outcomes of patients. Conclusion Our findings showed that the development of LCOS after a pediatric heart surgery was related with the increase of preoperative fT4 and the decrease in fT3 and fT4 levels in the first postoperative 24 and 48 hours. As a result, in our study with the patients who had congenital heart surgery under CPB, we found a decrease in thyroid hormone levels and determined that this could be related to deterioration of myocardial function. Therefore, we believe that preoperative and postoperative thyroid hormone levels of the patients could be used in intensive care and clinical follow-ups. There is not enough studies and meta-analyzes on patients who had congenital heart surgery comparing thyroid hormone levels with prognosis; but in view of the available data in the literature, there is a belief that the thyroid hormone tests might be important tools at early diagnosis for preventing the development of LCOS. In accordance with these data, the follow-up of thyroid hormone levels might be an important parameter in the establishment of proactive treatment. As we had a limited number of patients in our study, we believe that more researches should be done on the related topic and the findings should be supported with wider studies. Competing interests The authors declare that they have no competing interest Financial Disclosure This study was supported by the konya education and research hospital. Ethical approval Available from Uludag University Medical Research Ethics Committee (Decision number: 2012-24/5 and date: November 06, 2012). Engin Gurcu ORCID: 0000-0001-6729-1541 Ahmet Yuksel ORCID: 0000-0003-0021-6509 Yusuf Velioglu ORCID: 0000-0003-4709-4705 Isik Senkaya Signak ORCID: 0000-0003-4030-7827
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10. Börner U, Klimak M, Schoengen H, et al. The influence of various anesthetics on the release and metabolism of thyroid hormones: Results of two clinical studies. Anesth Analg. 1995;81:612-8. 11. Oyama T, Shibata S, Matsuki A, et al. Thyroxine distribution during halothane anesthesiain man. Anesth Analg. 1969;48:715-9. 12. Lyerly HK. The thyroid gland physiology. Textbook of surgery Sabiston DC. 14th edition. Philadelphia: WB Sounders CO; 1991. p: 560-8. 13. Bird CG, Hayward I, Howells TH, et al. Cardiac arrythmias during thyroid surgery. Anaesthesia. 1969;24:180-9. 14. Bostancı N. Tiroid ve paratiroid hastalıkları. Endokrinoloji II. İstanbul: Bozak Matbaası, 1979.
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15. The Merck of diagnosis and therapy. Section 2, Chapter 8. Thyroid disorders; 2011. 16. Greenspan FS, Gardner DG. Basic and clinical endocrinology. 8. edition. Norwalk: McGraw-Hill Companies; 2001. p: 902-8. 17. Plumpton K, Haas NA. Identifying infants at risk of marked thyroid suppression post-cardiopulmonary bypass. Intensive Care Med. 2005;31:581-7. 18. McMahon CK, Klein I, Ojamaa K. Interleukin-6 and thyroid hormone metabolism in pediatric cardiac surgery patients. Thyroid. 2003;13:301-4. 19. Baysal A, Saşmazel A, Yıldırım Aİ, et al. The effects of thyroid hormones and interleukin-8 levels on prognosis after congenital heart surgery. Turk Kardiyol Dern Ars. 2010;38:537-43. 20. Bartkowski R, Wojtalik M, Korman E, et al. Thyroid hormones levels in infants during and after cardiopulmonary bypass with ultrafiltration. Eur J Cardiothorac Surg. 2002;22:879-84. 21. Bettendorf M, Schmidt KG, Grulich-Henn J, et al. Triiodothyronine treatment in children after cardiac surgery: a double-blind, randomised, placebocontrolled study. Lancet. 2000;356:529-34.
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ORIGINAL RESEARCH
Medicine Science International Medical Journal
Medicine Science 2019;8(2):401-6
Effects of L-Carnitine and N-Acetylcysteine on nonalcoholic hepatic steatosis in rats Cemal Nas1, Mehmet Tahir Gokdemir2, Naime Canoruc3, Mehmet Yaldiz4 Health Sciences University, Gazi Yasargil research and training Hospital, Department of Biochemistry, Diyarbakir, Turkey 2 Health Sciences University, Gazi Yasargil research and training Hospital, Department of Emergency, Diyarbakir, Turkey 3 Ankara University, Elderly Care School, Ankara, Turkey 4 Mersin University, Faculty of Medicine, Department of Pathology, Mersin, Turkey
1
Received 16 Octaber 2018; Accepted 28 November 2018 Available online 18.02.2019 with doi:10.5455/medscience.2018.07.8982 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract This study was performed to investigate whether the antioxidants L-carnitine and N-acetylcysteine (NAC) have therapeutic effects on Nonalcoholic hepatic steatosis (NHS) in rats with carbon tetrachloride (CCl4)-induced fatty liver disease. Twenty-four healthy male and female Wistar Albino rats, weighing 220–250 g and obtained from our university health research institute, were used in this study. The animals were divided into four groups of six rats each: Group 1 [Diet + normal saline solution (NSS), control group], Group 2 [Diet + CCl4], Group 3 [Diet + CCl4 + L-carnitine] and Group 4 [Diet + CCl4 + NAC]. For biochemical examinations blood samples were obtained from the right ventricle of the heart and liver samples for histopathological were also obtained. The mean Aspartate aminotransferase (AST) (P = 0.043) and lactate dehydrogenase (LDH) levels (P=0.021) were significantly lower in rats with l-carnitine treatment. The mean ALT level were significantly lower in rats with NAC and (P = 0.014). Microscopic steatosis severity was decreased in the rats with NAC treatment than the controls. However administration of l-carnitine did not sufficiently prevent hepatic steatosis or inflammation. Our study showed that L-carnitine and NAC treatment resulted in significant regression of steatosis in rats with NHS. However, these findings must be confirmed by further studies including larger populations. Keywords: L-Carnitine, N-Acetylcysteine, nonalcoholic hepatic steatosis, rats
Introduction Nonalcoholic hepatic steatosis (NHS) is an important health problem, the prevalence of which has been gradually increasing with the general increase in the rate of obesity. There have been a number of recent improvements in the diagnosis and treatment of NHS, which is a type of hepatitis observed in people who do not consume alcohol that shares histopathological features with alcoholic fatty liver disease [1]. Although this pathological entity was previously referred to as pseudo-alcoholic liver disease, fatty liver hepatitis, diabetic nonalcoholic Laennec’s disease, and steatonecrosis, the term “nonalcoholic steatohepatitis” was adopted in the 1980s. Finally, the term “NHS” was applied [2]. Pharmacological therapies for NHS include lipid-lowering agents, such as statins and fibrates; metformin; insulin sensitizers, such as thiazolidinedione; cytoprotective and antioxidant agents,
such as bile acid and vitamin E; and anti-obesity drugs, such as orlistat. However, these drugs are not specific to the liver, and side effects associated with prolonged use may occur. Triglyceride (TG) accumulation in hepatocytes, and inflammation of the liver parenchyma, play roles in the pathogenesis of hepatic steatosis [3]. Future treatment approaches will focus on agents capable of preventing the release of proinflammatory cytokines and TG accumulation. Previous studies indicated that N-acetylcysteine (NAC) and carnitine have anti-inflammatory effects [4]. Therefore, as L-carnitine deficiency is the primary defect in hepatic steatosis, the necessity of L-carnitine treatment has been emphasized in these patients. NAC and L-carnitine may be options for treatment of NHS. This study was performed to investigate whether the antioxidants L-carnitine and NAC have therapeutic effects on NHS in rats with carbon tetrachloride (CCl4)-induced fatty liver disease. Material and Methods
*Coresponding Author: Mehmet Tahir Gokdemir, Health Sciences University, Gazi Yasargil research and training Hospital, Department of Emergency, Diyarbakir, Turkey, E-mail: drtahirgokdemir@gmail.com
Twenty-four healthy male and female Wistar Albino rats, weighing 220–250 g and obtained from our university health research 401
doi: 10.5455/medscience.2018.07.8982
institute, were used in this study. The rats were kept in cages and fed at the Health Sciences Research Center of the Faculty of Medicine of our university. The animals were divided into four groups of six rats each: Group 1 [Diet + normal saline solution (NSS)]: rats received 1 ml of NSS for 4 weeks intraperitoneally (i.p.). Group 2 [Diet + CCl4]: rats received a single i.p. injection of CCl4 (0.5 ml/rat) in week 1. Throughout the following 4 weeks, 40% CCl4 solution in olive oil was injected (0.3 ml/rat) i.p., twice weekly. Group 3 [Diet + CCl4 + L-carnitine]: rats received i.p. CCl4 injections in the first 4 weeks, and a single dose of 100 mg/kg L-carnitine (CARNITENE®; Santa Farma Ilaç AS, Istanbul, Turkey) was administered i.p. in the last week (week 5). These animals underwent the same fattening procedure as Group 2 and the same dose of CCl4 was administered. Group 4 [Diet + CCl4 + NAC]: rats received intraperitoneal CCl4 injections in the first 4 weeks and a single dose of 150 mg/kg NAC (ASIST®; Hüsnü Arsan Ilaç AS, Istanbul, Turkey) was administered i.p. in the final week (week 5). These animals underwent the same fattening procedure as Group 2 and the same dose of CCl4 was administered. The ethical rules were applied in the study.Ethical date 16 April 2002, Ethics committee approval number: 1496 Diet The rats received a diet consisting of a mixture of 79.5% corn, 20% animal fat, and 0.5% CCL4 for 2 weeks. In the last week, the feed was changed to corn only. Animals received medications according to their group allocation. At 24–48 hours following the end of medication period, the rats in the four groups were anesthetized with xylazine (Rompun, 1 ml/rat, intramuscularly [i.m.]) + ketamine hydrochloride (Ketalar, 1 ml/rat, i.m.) on the day of the experiment for biochemical and histopathological examinations, and blood samples were obtained from the right ventricle of the heart by opening the thoracic cavity. Liver samples were also obtained. Following these procedures, the animals were sacrificed by exsanguination from the carotid artery. Blood samples obtained from the rats were transferred into plain tubes for biochemical analysis, and the serum was separated by centrifugation at 3,500 rpm for 5 minutes. A portion of the liver tissue was placed in 10% formaldehyde solution for histopathological examination, and the remaining tissue was kept at −80°C until the day of analysis of malondialdehyde (MDA) levels. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), albumin, bilirubin (total and direct), total cholesterol (TC), highdensity lipoprotein-cholesterol (HDL-C), low-density lipoproteincholesterol (LDL-C), very low-density lipoprotein (VLDL), TG, total protein, and lactate dehydrogenase (LDH) levels in the serum samples were analyzed using an Auto Analyzer (Toshiba, Tokyo, Japan) operating based on the principles of Abbott enzymaticcolorimetric chemical measurement.
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Histopathological examination Liver tissues that had been kept in 10% formaldehyde solution were stained with hematoxylin and eosin, and histopathological examination was performed under a light microscope in the Department of Pathology at our university. On histopathological examination, the samples were graded according to Angulo’s fatty liver grading system [5]. The study protocol was approved by the Ethics Committee of our university (Approval No: 2002/1496). Statistical analysis SPSS software (ver. 11.5; SPSS Inc., Chicago, IL, USA) was used for statistical analysis. The results of biochemical tests are expressed as means and standard deviation. Due to the small number of rats in each group, the median, minimum, and maximum values were also calculated. The Mann–Whitney U test was used for comparison of test results among groups. In all analyses, P < 0.05 was taken to indicate statistical significance. Results The mean, standard deviation, median, and minimum–maximum values of the biochemical tests in Groups 1 and 2, and the significance of differences in values between the two groups, are presented in Table 1. As shown in Table 2, the mean AST (187 ± 52.74 U/L vs. 392 ± 232.31 U/L, P = 0.043) and LDH (582.75 ± 320.88 U/L vs. 1263.25 ± 131.5 U/L, P = 0.021) levels were significantly lower in rats with L-carnitine treatment (Group 3) than in rats without L-carnitine treatment (Group 2). The results of biochemical analyses of Groups 4 and 2 are presented in Table 3. The mean ALT level was 64.25 ± 28.89 U/L in Group 4 and 232.4 ± 76.19 U/L in Group 2, and this difference was significant (P = 0.014). Results of histopathological examinations The liver parenchyma, portal area, and sinusoidal structure of rats in Group 1, which were treated with saline only, were determined to be normal (Figure 1). On histopathological examination, CCl4 was found to cause grade 2 macrovesicular steatosis and grade 4 inflammation according to the fatty liver grading system described by Angulo et al. (5) (Figure 2a–b). Figures 2a (×10 magnification) and 2b (×20 magnification) show tissue sections of the liver from rats in Group 2 that had been treated with CCl4. Microscopic examination showed moderate macrovesicular steatosis around both periportal and central veins. Swelling was seen in the hepatocytes, the sinusoidal structure was partially disrupted, and patchy mononuclear cell infiltration was detected in the portal area. Administration of L-carnitine did not sufficiently prevent hepatic steatosis or inflammation in Group 3 (CCl4 + L-carnitine) (Fig. 3a–b). Moderate macrovesicular steatosis was observed, which was more prominent around the central vein. The rats in Group 3 showed no decrease in steatosis grade compared to those in Group 2. 402
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The results of microscopic examination of liver tissue sections from rats in Group 4 (CCl4 + NAC) are presented in Figs. 4a–b. NAC was shown to improve the histopathological features, with reduction in histological grade by 1. Moderate diffuse macrovesicular steatosis, disruption of the sinusoidal structure of the liver, swelling in the hepatocytes, and mild congestion in the portal area were observed. The rats in Group 4 showed a decrease in steatosis severity compared to those in Group 2.
Figure 1. Normal histopathological image in group 1 Table 1. Distribution of biochemical values for Groups 1 and 2
a
GROUP 1 (Mean ± SD) Median(Min-Max)
GROUP 2 (Mean ± SD) Median(Min-Max)
P
TBIL, mg/dl
0.1 ± 0.0
0.1 ± 0.0
0.999
DBIL, mg/dl
0.1(0.1-0.1) 0.0 ± 0.0
0.1(0.1-0.1) 0.05 ± 0.057
0.127
TESTS
AST, U/L ALT, U/L ALP, U/L LDH, U/L GGT, U/L TP, g/dl ALB, g/dl CHOL, mg/dl TG, mg/dl HDL, mg/dl LDL, mg/dl
0.0(0.0-0.0)
0.05(0.0-0.1)
173 ± 32.83 182.5(126-201) 58.25 ± 17.6 60.5(36-76) 218.5 ± 109.98 206(108-354) 1007.25 ± 127.2 1058.5(818-1094) 0.9 ± 0.2 0.8(0.8-1.2) 6.75 ± 0.78 6.45(6.2-7.9) 1.25 ± 0.17 1.3(1-1.4) 52.25 ± 12.28 47.5(44-70) 77.25 ± 43.46 60.5(48-140) 21.75 ± 5.56 19.5(18-30)
187 ± 52.74 185.0(140-238) 64.25 ± 28.89 57(38-105) 367.75 ± 81.13 381(257-452) 582.75 ± 320.88 518.5(265-1029) 7.25 ± 8.13 7.25(1.5-13) 5.75 ± 0.77 5.4(6.2-7.9) 1.12 ± 0.22 1.1(0.9-1.4) 80 ± 27.86 82(47-109) 41 ± 13.6 44(24-52) 39.25 ± 12.68 40.5(24-52)
14.97 ± 4.57
32.65 ± 15.26
b
Figure 2. Figure 2a (small magnification, ×10) - 2b (high magnification, ×20): Microscopic examination showed moderate macrovesicular steatosis around both periportal and central vein in Group 2 (CCl)
0.564 0.999 0.083 0.043
a
0.146 0.378
b
Figure 3. Fig. 3a -3b show moderate macrovesicular steatosis in rat liver tissue sections in Group 3 (CCl + L-carnitine)
0.146 0.243 0.043 0.083
13.75(11-21.4) 35.35(12.9-47) VLDL, mg/dl 15.4 ± 8.7 8.17 ± 2.73 0.248 12.05(9.5-28) 8.7(4.8-10.5) MDA, nmol/g 39.98 ± 14.17 5.99 ± 6.03 0.021 39.32(26.56-54.74) 73.8(71.61-84.77) ALB: Albumin, ALT: Alanine Aminotransferase, ALP: Alkaline Phosphatase, AST: Aspartate Aminotransferase, TBIL: Total Bilirubin, DBIL: Direct Bilirubin, GGT: Gamma Glutamyl Transferase, HDL: High-Density Lipoprotein, CHOL: Cholesterol, LDH: Lactate Dehydrogenase, LDL: Low-Density Lipoprotein, MDA: Malondialdehyde, TP: Total Protein, TG: Triglyceride, and VLDL: Very Low-Density
a
b
Figure 4. Fig. 4a-4b: show moderate diffuse macrovesicular steatosis, disruption in sinusoidal structure of liver, swelling in the hepatocytes, and mild congestion in the portal area in Group 4 (CCl4 + NAC)
403
doi: 10.5455/medscience.2018.07.8982 Table 2. Distribution of biochemical values for Groups 2 and 3
GROUP 3 (Mean ± SD) Median(Min-Max)
GROUP 4 (Mean ± SD) Median(Min-Max)
P
TBIL, mg/dl
0.14 ± 0.054
0.1 ± 0.0
0.176
DBIL, mg/dl
0.1(0.1-0.2) 0.14 ± 0.054
0.1(0.1-0.1) 0.05 ± 0.057
0.190
0.1(0.0-0.2)
0.05(0.0-0.1)
422.4 ± 211.0 468(188-682) 232.4 ± 76.19 247(114-298) 363.8 ± 114.09 366(235-524) 914.2 ± 589.9 745(353-1865) 6.3 ± 0.534 6.4(5.8-7.1) 1.24 ± 0.089 1.3(1.1-1.3) 57.2 ± 6.41 55(51-65) 30.6 ± 9.3 25(23-45) 28.2 ± 3.42 28(25-33)
187 ± 52.74 185(140-238) 64.25 ± 28.89 57(38-105) 367.75 ± 81.13 381(257-452) 582.75 ± 320.88 518.5(265-1029) 5.75 ± 0.77 5.4(5.3-6.9) 1.12 ± 0.22 1.1(0.9-1.4) 80 ± 27.86 82(47-109) 80 ± 27.86 44(24-52) 39.25 ± 12.6 40.5(24-52)
23.04 ± 5.01
32.65 ± 15.26
GROUP 3 (Mean ± SD) Median(Min-Max)
P
TBIL, mg/dl
0.14 ± 0.054
0.1 ± 0.0
0.317
DBIL, mg/dl
0.1(0.1-0.2) 0.14 ± 0.054
0.1(0.1-0.1) 0.05 ± 0.057
0.096
0.1(0.0-0.2)
0.05(0.0-0.1)
422.4 ± 211.0 297.5(236-737) 128 ± 78.69 90(86-246) 282.25 ± 80.26 270.5(209-379) 1263.25 ± 131.5 1247.5(1128-1430) 6.3 ± 0.42 6.15(6-6.9) 1.1 ± 0.14 1.05(1-1.3) 58.25 ± 22.36 57.5(32-86) 36.5 ± 10.78 39.5(21-46) 27.5 ± 9.67 26.5(17-40)
187 ± 52.74 185(140-238) 64.25 ± 28.89 57(38-105) 367.75 ± 81.13 381(257-452) 582.75 ± 320.88 518.5(265-1029) 5.75 ± 0.77 5.4(5.3-6.9) 1.12 ± 0.22 1.1(0.9-1.4) 80 ± 27.86 82(47-109) 41 ± 13.6 44(24-52) 39.25 ± 12.68 40.5(24-52)
0.043
AST, U/L
0.149
ALT, U/L
0.149
ALP, U/L
0.021
LDH, U/L
0.186
TP, g/dl
0.999
ALB, g/dl
0.248
CHOL, mg/dl
0.561
TG, mg/dl
0.191
HDL, mg/dl
23.3 ± 10.5
32.65 ± 15.26
0.248
LDL, mg/dl
AST, U/L ALT, U/L ALP, U/L LDH, U/L TP, g/dl ALB, g/dl CHOL, mg/dl TG, mg/dl HDL, mg/dl LDL, mg/dl
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Table 3. Distribution of biochemical values for Group 2 and Group 4
GROUP 2 (Mean ± SD) Median(Min-Max)
TESTS
TESTS
0.110 0.014 0.806 0.221 0.138 0.381 0.221 0.217 0.219 0.221
23.05(10.8-36.3) 35.35(12.9-47) VLDL, mg/dl 7.3 ± 2.18 8.17 ± 2.73 0.564 7.9(4.2-9.3) 8.7(4.8-10.5) MDA, nmol/g 53.2 ± 16.7 75.99 ± 6.03 0.149 48.85(39.96-75.19) 73.8(71.61-84.77) ALB: Albumin, ALT: Alanine Aminotransferase, ALP: Alkaline Phosphatase, AST: Aspartate Aminotransferase, TBIL: Total Bilirubin, DBIL: Direct Bilirubin, GGT: Gamma Glutamyl Transferase, HDL: High-Density Lipoprotein, CHOL: Cholesterol, LDH: Lactate Dehydrogenase, LDL: Low-Density Lipoprotein, MDA: Malondialdehyde, TP: Total Protein, TG: Triglyceride, and VLDL: Very Low-Density
21.9(16.4-28.3) 35.35(12.9-47) VLDL, mg/dl 6.12 ± 1.83 8.17 ± 2.73 0.221 5.1(4.7-9) 8.7(4.8-10.5) MDA, nmol/g 63.96 ± 12.28 75.99 ± 6.03 0.086 65.95(45.85-80) 73.8(71.61-84.77) ALB: Albumin, ALT: Alanine Aminotransferase, ALP: Alkaline Phosphatase, AST: Aspartate Aminotransferase, TBIL: Total Bilirubin, DBIL: Direct Bilirubin, GGT: Gamma Glutamyl Transferase, HDL: High-Density Lipoprotein, CHOL: Cholesterol, LDH: Lactate Dehydrogenase, LDL: Low-Density Lipoprotein, MDA: Malondialdehyde, TP: Total Protein, TG: Triglyceride, and VLDL: Very Low-Density
Discussion
and releasing free radicals. Collagen synthesis in the liver increases according to the period and dose of CCl4 administration, leading to fibrosis and eventually, the development of cirrhosis. Following experimental administration of CCl4 to animals, necrosis, centrilobular degeneration and steatosis develop in the third zone of the liver [8]. Grade 2 macrovesicular steatosis was seen in the third zone of the liver on liver sections from rats in the control group treated with CCl4.
This study was performed to evaluate the effects of L-carnitine and NAC on hepatic steatosis in rats given various treatments. Significant decreases in blood LDH and AST levels were observed in NHS-induced rats that received L-carnitine (Group 3) compared to those in Group 2 treated with CCl4, whereas no significant improvement was observed on histopathological examination of the liver. Histopathological examination indicated that the serum ALT level was decreased, and hepatic steatosis improved, in NHSinduced rats administered NAC (Group 4). Nonalcoholic fatty liver disease (NAFLD) is an important health problem, the prevalence of which has gradually increased with increasing rates of obesity. There have been a number of recent improvements in the diagnosis and treatment of NAFLD, which manifests with various symptoms. NAFLD is thought to be more prevalent than previously estimated, and is it known to be associated with many different agents and diseases [7]. CCl4 induces fatty degeneration and necrosis of the liver. It damages the membrane structure by increasing lipid peroxidation
Accumulation of free fatty acids in the liver may be responsible for liver dysfunction, because they are highly reactive and may damage biological membranes. Acute and chronic increases in liver fat have been reported to lead to lipid peroxidation, the severity of which is closely correlated to the amount of fat in the liver. Lipid peroxidation leads to the release of toxic substances (MDA and 4-hydroxynonenal), which may trigger inflammatory responses in the liver. These toxic substances lead directly to cell damage, or induce an inflammatory response by attracting inflammatory cells to the liver parenchyma [9]. However, isolated fatty liver in the absence of hepatitis occurs more frequently than steatohepatitis. Therefore, there is some doubt as to whether fat accumulation in the liver is responsible for inflammation, but experimental findings 404
doi: 10.5455/medscience.2018.07.8982
suggest that increases in fatty acid levels lead to increased fibrous tissue formation in the liver [2]. TG accumulation and severe mitochondrial β-oxidation insufficiency are the most likely reasons for liver pathology [10]. L-Carnitine plays an important role in the transportation of longchain fatty acids into the mitochondria from the cytoplasm. This transport induces β-oxidation of fatty acids. Therefore, energy production occurs with the entry of fatty acids into the Krebs and citric acid cycles. In addition, L-carnitine plays a role in the elimination of toxic metabolites. In L-carnitine deficiency, which may occur due to various etiologies and genetic defects, long-chain fatty acids that do not enter the mitochondria from the cytoplasm, and that are not metabolized, lead to fatty liver by accumulating as a single fat lobule, and then accumulating in the liver [11]. There have been very few studies of fatty liver resulting from L-carnitine deficiency, and few reports regarding its treatment, in contrast to the large numbers of studies on alcoholic fatty liver [7]. The levels of L-carnitine in human subjects with type 1 diabetes have been shown to be decreased due to increased urinary excretion of L-carnitine [11]. In a randomized controlled clinical study, elevations in AST and ALT levels compared to the control group were significantly attenuated by L-carnitine treatment. The same study demonstrated that high serum ALT levels in 89.7% (35/39 persons) of patients treated with L-carnitine-orotate complex normalized after 12 weeks of treatment. Computed tomography of the liver demonstrated an increase in the liver attenuation index of subjects administered L-carnitine-orotate complex compared to placebo controls, and a significant change was reported in the liver attenuation index following 12 weeks of therapy [12]. In the present study, a single i.p. dose of 200 mg/kg L-carnitine was administered to rats. Significant decreases were detected in LDH and AST levels compared to the control group. However, no significant improvement was observed on histopathological examination of the liver compared to the control group. L-Carnitine increases the activities of antioxidant enzymes, such as glutathione peroxidase, catalase, and superoxide dismutase, and has metal ion-chelating activity (i.e., ferrous) that catalyzes the production of reactive oxygen species (ROS). Their antioxidant activities can be compared to those of standard antioxidant agents, such as alpha-tocopherol, and may alleviate ischemia-reperfusion injury by decreasing the inhibitory effects of ROS on aerobic metabolism [13,14]. In another study, mitochondrial dysfunction was induced in rats fed a high-fat diet (48 kcal% fat) for 6 weeks. The mitochondrial functions of these rats were shown to improve following L-carnitine (100 mg/kg/day) administration via oral gavage for 2 weeks [10]. Amin et al. reported that L-carnitine supplementation resulted in significant decreases in serum TG, VLDL, TC, and LDL-C levels, and significant increases in HDL-C levels, in obese mice [15]. There have been a few studies regarding the treatment of fatty liver resulting from L-carnitine deficiency [12,15]. Acetyl-L-carnitine produced dose-dependent improvements in the liver tissue of rats with experimentally induced fatty liver [5]. The necessity for L-carnitine treatment may be due to the principal defect in fatty liver being L-carnitine deficiency. Further controlled and experimental studies are needed to investigate the effects of L-carnitine in fatty liver disease caused by L-carnitine deficiency and other etiologies.
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Oxidative damage and glutathione-sulfate consumption are known to be due to the effects of cytokines [13]. This leads to reduced antioxidant capacity and a genetic predisposition toward NAFLD. Studies on the use of substances with known antioxidative effects, such as vitamins E and C, selenium, and NAC, for the treatment of NAFLD are of great interest [8,16]. NAC is a thiol-containing agent that eliminates free oxygen radicals, binds directly to reactive metabolites, and replenishes mitochondrial and cytosolic glutathione stores by acting as a glutathione substitute, thereby preventing hepatic damage. Decreased glutathione levels and marked increases in oxidative stress parameters were observed in alcoholic liver disease, similar to what is seen in paracetamol intoxication [12]. In the present study, we examined the effects of NAC on rats in an experimental setting, as a strong antioxidant that can replenish glutathione stores in NAFLD, the pathogenesis of which is similar to that of alcoholic liver damage. In a prospective randomized case-control study, Nabi et al. demonstrated significant improvement in the survival of patients treated with NAC, and a lower mortality rate, of 53%, in the control group compared to 28% in patients treated with NAC. In the same study, the use of NAC was concluded to be safe and was shown to decrease the length of hospital stay [8]. NAC is an antioxidant, and a reducing and chelating agent, which replenishes glutathione stores except in the case of acetaminophen intoxication [12]. Zhou et al. compared NAC-treated rats to controls and demonstrated that NAC reduced ALT and AST activity, decreased TG and LDL-C levels, and improved the liver tissue to varying degrees [16]. In the present study, a single dose of 150 mg/kg NAC was administered i.p., and the serum ALT level was significantly decreased compared to the control group. On histopathological examination, NAC was shown to decrease fatty liver. One of the major limitation of our study was that it was planned in 2002 and it was studied in 2004. Although more than a decade of work has been done, studies on L-Carnitine and N-Acetylcysteine are still up to date. However, this can be considered as an important limitation. Conclusion In conclusion, elucidation of the etiopathogenesis of, and new treatment approaches for, NHS are crucial because this condition can result in serious diseases, such as cirrhosis. Changes in the levels of oxidative stress parameters may be important for the diagnosis of liver damage caused by NHS, as well as for prediction of its prognosis. Our study showed that L-carnitine and NAC treatment resulted in significant regression of steatosis in rats with NHS. However, these findings must be confirmed by further studies including larger populations. Acknowledgment We are grateful to Santa Farma Ilaç A.S. for providing CARNITINE® ampoules and Hüsnü Arsan Ilaç A.S. for providing ASSIST® ampoules (NAC) Competing interests The authors declare that they have no competing interest. Financial Disclosure All authors declare no financial support. Ethical approval Consent of ethics was approved by the local ethics committee.
405
doi: 10.5455/medscience.2018.07.8982 Cemal Nas ORCID: 0000-0002-5616-8625 Mehmet Tahir Gokdemir ORCID: 0000-0002-5546-9653 Naime Canoruc ORCID: 0000-0001-5987-9812 Mehmet Yaldiz ORCID: 0000-00030640-4551
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13. Bae CJ, Lee WY, Yoon KH et al. Improvement of nonalcoholic fatty liver disease with carnitine-orotate complex in type 2 diabetes (CORONA): a randomized controlled trial. Diabetes Care. 2015;38:1245-52.
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Zarei M, Barroso E, Palomer X et al. Hepatic regulation of VLDL receptor by PPAR β/δ and FGF 21 modulates non-alcoholic fatty liver disease. Mol Metabol. 2018;8:117-31.
14. Shaw S, Rubin KP, Liyeber CS. Depressed hepatic glutathione and increased diene conjugates in alcoholic liver disease: evidence of lipid peroxidation. Dig. Dis. Sci. 1983;28:585-9.
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Bodaghi-Namileh V, Sepand MR, Omidi A et al. Acetyl-L-carnitine attenuates arsenic-induced liver injury by abrogation of mitochondrial dysfunction, inflammation, and apoptosis in rats. Environ. Toxicol. Pharmacol. 2018;58:1120.
15. Gokdemir MT, Karakilcik AZ, Gokdemir GS. Prognostic importance of paraoxonase, arylesterase and mean platelet volume efficiency in acute ischaemic stroke.J Pak Med Assoc. 2017;67:1679-83.
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Angulo P, Deach JC, Batts KP, et al. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology. 1999;30:1356-62.
16. Amin Ka, Nagy MA. Effect of Carnitine and herbal mixture extract on obesity induced by high fat diet in rats. Diabetology & Metabolic Syndrome. 2009;1:17.
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S Yuan D, Xiang T, Huo Y. Preventive effects of total saponins of Panax japonicus on fatty liver fibrosis in mice. Arch Med Sci. 2018;14:396–406..
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Nabi T, Nabi S, Rafiq N, et al. Role of N-acetylcysteine treatment in nonacetaminophen-induced acute liver failure: A prospective study. Saudi. J. Gastroenterol. 2017;23:169-75.
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Peverill W, Powell LW, Skoien R. Evolving concepts in the pathogenesis of NASH: beyond steatosis and inflammation. Int J Mol Sci. 2014;15:8591-638.
12. Moghaddas A, Dashti-Khavidaki S. Potential protective effects of L-Carnitine against neuromuscular ischemia-reperfusion injury: From experimental data to potential clinical applications. Clin. Nutr. 2016;35:783-90.
17. Chheda TK, Shivakumar P, Sadasivan SK et al. Fast food diet with CCl4 micro-dose induced hepatic-fibrosis a novel animal model. BMC Gastroenterol. 2014;14:89. 18. Zhou H, Shi T, Yan J et al. Effects of activated carbon N acetylcysteine sustained release microcapsule on dipeptidyl peptidase IV expression in young rats with non alcoholic fatty liver disease. Exp. Therap. Med. 2017;14:4737-44.
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ORIGINAL RESEARCH
Medicine Science International Medical Journal
Medicine Science 2019;8(2):407-11
Diagnostic utility of microhematuria in renal colic patients in emergency medicine: correlation with findings from multidetector computed tomography Murat Das1, Okan Bardakci1, Ersan Yurtseven1, Canan Akman1, Yavuz Beyazit2, Okhan Akdur1 Canakkale Onsekiz Mart Universty, Faculty of Medicine, Department of Emergency Medicine, Canakkale, Turkey 2 Canakkale Onsekiz Mart Universty, Department of Internal Medicine, Canakkale, Turkey
1
Received 19 November2018; Accepted 28 December 2018 Available online 30.01.2019 with doi:10.5455/medscience.2018.07.8974 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract Although urine analysis is a simple and inexpensive method for the initial evaluation of renal colic patients presenting in emergency departments, it is regarded as unreliable for an exact diagnosis of urinary system stones. The aim of the present study is to assess the association between clinical demographics, and stone size and location, with the combined utility of urinalysis and unenhanced multidetector computed tomography (MDCT) in the emergency department. After gaining local Ethics Committee approval, a retrospective study was conducted with data from 186 patients who presented at our emergency service with flank pain and documented urolithiasis. Stone location and size was determined by MDCT, and the presence of microhematuria confirmed by urinalysis. The presence of hydronephrosis and clinical complaints were also recorded. A total of 186 patients were included in the present study, in which an absence of microhematuria was recorded in 24.7% patients. Urine density was found to be elevated in the microhematuria group (p=0.001). Upper urinary tract stones and hydronephrosis were found to be associated with the presence of microhematuria. Although statistically insignificant, an increased trend of microhematuria was observed with stones over 5 mm in size. Urinary stone size and location are directly associated with the incidence of microhematuria. Absence of microhematuria does not preclude MDCT imaging, however, especially in cases where stones are suspected in patients with renal colic. Keywords: Unenhanced MDCT, renal colic, emergency department
Introduction Urinary stones are globally one of the most common medical problems to have increased in prevalence over the past three decades [1]. The reported lifetime prevalence of urinary stones varies between 10 and 20% of the population, with a relapse rate of 50% within 5–10 years, and 75% within 20 years [2,3]. This worldwide trend has been demonstrated by studies conducted in Turkey [4,5] and elsewhere.
regarded as a simple, easy to apply, and inexpensive diagnostic tool for urolithiasis, but one involving several disadvantages, among them constraints and unreliability. Unfortunately, the absence of microhematuria does not always exclude the possibility of urinary stones, and nearly 10% of patients with urinary lithiasis have negative urinary testing on initial admission to emergency clinics [8].
Urolithiasis is the most commonly encountered cause of flank pain in emergency medical settings [6,7]. Although a diagnosis of urolithiasis is generally based on the history, clinical symptoms, and physical exam¬ination of the patient, an additional diagnostic work-up is usually required to reach a definitive conclusion. In this context, microhematuria as determined by urinalysis can be
Unenhanced multidetector computed tomography (MDCT) is a universally accepted gold standard diagnostic method for detecting urolithiasis [9]. At our institution, all patients who presented to the emergency service with flank pain and suspicion of a urinary stone are routinely evaluated with a computed tomography (CT) scan. The main advantage of CT scanning over intravenous urography and urinary system ultrasound is its superior accuracy for definitive detection of urolithiasis and the ruling out of alternative diagnoses that could account for the patient’s clinical presentation [10,11].
*Coresponding Author: Murat Das, Canakkale Onsekiz Mart Universty, Faculty of Medicine, Department of Emergency Medicine, Canakkale, Turkey E-mail: muratdas58@gmail.com
Considering the important role of emergency departments in the diagnosis and management of renal colic patients, the value of clinical, laboratory, and imaging data from emergency clinics has 407
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been under-studied in Turkey. Therefore, the objective of the present study is to evaluate distinct variables, including demographics, admission symptoms, laboratory results, and imaging findings in symptomatic renal colic patients with the presence of urinary stones confirmed by MDCT. Material and Methods Subjects This study is undertaken after the approval from local institutional ethics board. We have performed a retrospective analysis of 1027 patients who were admitted to the emergency department of Canakkale Onsekiz Mart University Hospital between January 2016 and December 2017 with flank colic pain. Out of these 1027 patients, only 518 was found to receive an unenhanced MDCT scan because of suspicion of an urinary stone. From 518 patients, we have excluded 332 patients due to lack of complete blood cell counts, biochemical evaluations or urinanalysis. In overall, 186 patients were included in the final analyses. Study design Demographic characteristics, urinalysis results, the presence of hydronephrosis, clinical complaints, alternative diagnoses, and the presence or absence of urolithiasis as revealed by MDCT, were recorded for each patient. The number and the size of the stones were also recorded for further analysis. Patients with a history of renal/ureteral operations with or without use of ureteric stents were excluded. Moreover, a history of lithotripsy was also considered an exclusion criterion. Urinalysis included microscopic examination of urine within 2h of emergency admission. Patients were classified by the status of red blood cells on urinalysis in two groups: those with five or fewer erythrocytes per high power field were taken as the absence-ofhematuria group (Group I); those with more than five red blood cells per high-power field were regarded as the microhematuria group (Group II).
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All multi-detector CT scanner (Toshiba® Asteion TSX-021B) images were obtained without oral or intravenous contrast. Scans were obtained which covered the entire urinary tract (from the upper borders of the kidneys to the lower aspect of the symphysis pubis) with a narrow collimation of 1 mm and the remainder with 3 mm sections. The size and location of each calculus was determined using information from the radiology report. Stone size was categorized as either ≤5mm or >5mm (with a cutoff representing median stone size). The location of the stones was categorized either as ‘lower’ (below two-thirds of the distal portion of the ureter) or ‘upper’. Statistical analyses The data were analyzed with SPSS 20.0 software. Numbers, percentages, means, and standard deviations were used in the presentation of values. The Mann Whitney U test was applied as the non-parametric test when the data was not normally distributed. The Chi square test was applied for categorical data analysis. When the p value was under 0.05, the result was regarded as statistically significant. Results During the enrollment period, a total of 1027 patients were admitted to our tertiary referral center complaining of renal colic. Of these, 518 underwent unenhanced MDCT. Of this number, 332 patients were excluded from the present study due to lack of complete blood cell counts, biochemical evaluations, or urinalysis. In total, therefore, the study population consisted of 186 patients with a mean age of 44.8±16.1 years, comprising 57 (30.6%) females and 129 (69.4%) males. Figure 1 presents a flow diagram of the study. According to the urinalysis, 140 (75.3) patients had microhematuria, and 46 (24.7%) patients had no microhematuria. The demographic and laboratory characteristics of the patients are presented in Table 1. Only urine density was found to be significant in both groups (p=0.001).
Table 1. Demographic, clinical, and laboratory characteristics of study population Group I (Without Hematuria)
Group II (With Hematuria)
Mean±SD
Mean±SD
Age (years)
48.5±17.0
43.6±15.7
0.067
Urine density
1014.6±7.2
1018.1±5.7
0.001
Urea (mg/dL)
31.8±9.8
34.2±11.4
0.275
Creatinine (mg/dL)
0.9±0.3
1.0±0.6
0.416
p
ALT (U/L)
23.7±25.8
22.2±15.9
0.455
AST (U/L)
23.8±16.7
20.4±8.4
0.516
Sodium (mmol/L)
140.2±2.7
140.2±3.4
0.759
Chloride (mmol/L)
100.8±3.2
100.6±3.9
0.832
Potassium (mmol/L)
4.3±0.4
4.2±0.4
0.194
Calculi size (mm)
4.4±2.9
4.5±3.4
0.527
SD: Standard deviation, p: Mann Whitney U Test ALT: Alanine amino transferase, AST: Aspartate amino transferase
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Patients were classified according to their presenting symptoms, the most common of which was flank, inguinal, and supra-pubic pain. Statistical analysis revealed no significant difference between the two groups in terms of presenting symptoms (Table 2). Groups were also evaluated according to hydronephrosis. The presence of hydronephrosis between Group I and Group II was statistically significant (p=0.001). Microhematuria patients were found to be more likely to present with hydronephrosis (Table 3).
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From assessment of unenhanced MDCT results, urinary tract stones were evaluated as having either a ‘lower’ or ‘upper’ urinary tract location. The patients in the absence-of-hematuria group were more likely to have a lower stone location (76.1% vs. 23.9%, p=0.006). The incidence of microhematuria seemed to increase in patients with stones over 5 mm in size; however, the correlation between the size of the stone and microhematuria was insignificant (Table 3).
Table 2. Pain localization with accompanying clinical characteristics related to hematuria status Group I (Without Hematuria) n(%)
Group II (With Hematuria) n(%)
46 (24.7)
140 (75.3)
Number of Patients
p
Sex Female
19 (33.3)
38 (66.7)
Male
27 (20.9)
102 (79.1)
Flank pain
39 (24.4)
121 (75,6)
Inguinal pain
3 (21.4)
11 (78,6)
Supra-pubic pain
1 (33.3)
2 (66,7)
Other pain
3 (33.3)
6 (66,7)
Drug use
11(24.6)
34 (75.4)
1.000
Chronic illness
1(33.3)
2(66.7)
1.000
0.105
Pain localization
n: Number, %: Row Percentage, p: Chi square test
Table 3. Correlations between stone size, position of stone, and hydronephrosis in the two study groups. Group I (Without Hematuria) n(%)
Group II (With Hematuria) n(%)
No
22 (47.8)
29 (20.7)
Yes
24 (52.2)
111(79.3)
Lower urinary tract
35 (76.1)
74 (52.9)
Upper urinary tract
11 (23.9)
66 (47.1)
p
Hydronephrosis 0.001
Stone localization 0.006
Stone size ≤5 mm
37 (80.4)
99 (70.7)
>5 mm
9 (19.6)
41 (29.3)
0.197
n: Number, %: Column Percentage, p: Chi square test
Discussion This single-center retrospective study has revealed that a lower urine density and lower urinary stone location are both associated with the absence of hematuria in patients presenting with urinary system stone disease. Moreover, renal complications such as hydronephrosis were found to be significantly related to the presence of hematuria.
a recent study by Muslumanoglu et al. [4], the prevalence rate of urolithiasis in Turkey was reported to increase gradually with age in both men and women, varying from 8% in the younger group (<25 years) to 26.6% in the 45-to-55 year group. Authors have concluded that 11.1% of the population have a history of urinary stone disease, as diagnosed by a physician, and an additional 2.1% have had at least one episode of renal colic. These patients have elevated rates of emergency medical admission.
Renal colic is one of the most frequently encountered issues treated in emergency departments globally [12]. Although the reported lifetime incidence varies across different populations, the estimated annual incidence of urolithiasis is 240 per 100,000 of the population in the United States [13]. Urolithiasis is also a severe problem in Turkey, with high prevalence and incidence rates. In
As a further point, it is important to note that clinicians need to obtain diagnostic certainty prior to initiating optimal treatment. For this reason, simple and effective diagnostic tools are essential in the emergency setting. Our results demonstrate the importance of CT scanning in the diagnosis of renal colic, even in the absence of microhematuria. Although it is not suggested here that every 409
doi: 10.5455/medscience.2018.07.8974
physician should perform a non-contrast CT scan in order to diagnose a urinary tract stone, the importance of CT scanning in order to diagnose urolithiasis cannot be exaggerated. Low-dose unenhanced CT (UHCT) visualization is considered a state-ofthe-art method for diagnosing urinary stones [14]. As with most comparable institutions and practices, our center has in recent years replaced intravenous urography with UHCT as the primary diagnostic modality. The main underlying reason for this shift is the superior ability of CT scanning in the detection of urinary stones, regardless of size, location, and composition, with a sensitivity and specificity exceeding >95% [15,16]. Moreover, non-contrast CT scanning avoids the risk of contrast reactions and is able to diagnose other disease conditions that can cause flank pain. However, it should be noted that non-contrast CT scanning can underestimate ureteral stone size by up to 12% [17]. In the present study, we define microscopic hematuria as a detection of more than five red blood cells per high-power field in the urinalysis. It is important to determine the presence of hematuria in urinalysis, in the diagnostic workup of cases of suspected renal colic; however, the sensitivity of microhematuria presence in this patient group can vary between 69% and 84% [18,19]. Nevertheless, it is considered here that a simple urinalysis is practical on account of its reproducibility, rapidity, low cost, and widespread availability in almost all emergency departments. The results of the present study do reveal, however, that the absence of hematuria does not exclude a diagnosis of urolithiasis â&#x20AC;&#x201C; nor does it help indicate the exact location of a urinary stone. Moreover, it should be noted that the presence of a lower urinary tract stone in renal colic patients seems to go hand-in-hand with a higher incidence of the absence of hematuria. Elevated rates of hydronephrosis constitute another complication that this study detected in renal colic patients with hematuria. This is understandable in that the presence of increased size of urinary stones in this patient group can easily lead to the complication of hydronephrosis. Contrary to these findings, however, are those of Mefford et al. [18]. These researchers proposed that microscopic hematuria is less sensitive in detecting urolithiasis in patients with obstructive uropathy. Though unable to provide an exact rationale for this finding, they did propose that larger ureteral stones may obstruct bleeding, resulting in the absence of hematuria on urinalysis. In the present study, it was also demonstrated that the size of the stones (measured in mm) is correlated with the presence of microhematuria. In agreement with the current study, Lallas et al. [20] demonstrated that stones â&#x2030;Ľ8mm were more than twice as likely to be associated with microhematuria. In another study, Argyropoulos et al. [21] demonstrated the efficacy of a stone size cut-off point of 6 mm in determining microhematuria through use of a urine dipstick test. Thus, the results of the current study can be seen to be in agreement with the literature. It is also noteworthy that stone size and location were seen to be correlated with the hallmark signs of urolithiasis, including renal colic, urinary urgency, fever, and hematuria [22]. The location of the stone is also associated with patient symptoms such as pain in the flank, inguinal, and supra-pubic areas. Elton and colleagues [23] found that unilateral flank pain was a predominating symptom in 89% of 206 emergency department patients with a diagnosis of ureteral
Med Science 2019;8(2):407-11
calculus. Interestingly, Lallas et al. [20] reported in their study that urinary stones located in the renal calyces were the least symptomatic (16.9%) when compared to those situated in the renal pelvis (58.8%) or ureter (82.4%). In contrast, in the present study no symptomatic differences were observed between the patient groups. This might have been due to our relatively small patient groups and the retrospective nature of the study. The results of the present study should be carefully evaluated in the context of several limitations. First, retrospective nature of the study may lead to selection bias and statistical underpowering. Second, although this is study is one of the largest study in literature exploring the urinary stone patients with no absent hematuria, it is obvious that a large sample size should increase the value of the study. Finally, it must be noted that different centers have used different criterias for labeling a urinalysis result as negative or positive for hematuria, and the methods for measuring hematuria are not precise. Conclusion In conclusion, the presence of microhematuria can vary depending on the size and location of the urinary stone. In addition, it is suggested that non-contrast CT should be applied in all suitable cases, even in the absence of microhematuria. Competing interests The authors declare that they have no competing interest Financial Disclosure All authors declare no financial support. Ethical approval Ethics committee decision number: 2011-KAEK-27/2018-E.1800154812 receives approval from the ethics committee. Murat Das ORCID: 0000-0003-0893-6084 Okan Bardakci ORCID: 0000-0001-6829-7435 Ersan Yurtseven ORCID: 0000-0003-0469-5260 Canan Akman ORCID: 0000-0002-3427-5649 Yavuz Beyazit ORCID: 0000-0001-6247-2714 Okhan Akdur ORCID: 0000-0003-3099-6876
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Xafis K, Thalmann G, Benneker LM, et al. Forget the blood, not the stone! Microhaematuria in acute urolithiasis and the role of early CT scanning. Emerg Med J. 2008;25:640-4.
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Ahn JH, Kim SH, Kim SJ, et al. Diagnostic performance of advanced modeled iterative reconstruction applied images for detecting urinary stones on submillisievert low-dose computed tomography. Acta Radiol. 2018;59:1002-9.
10. Goldstone A, Bushnell A. Does diagnosis change as a result of repeat renal colic computed tomography scan in patients with a history of kidney stones? Am J Emerg Med. 2010;28:291-5. 11. Westphalen AC, Hsia RY, Maselli JH, et al. Radiological imaging of patients with suspected urinary tract stones: national trends, diagnoses, and predictors. Acad Emerg Med. 2011;18:699-707.
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16. Xafis K, Thalmann G, Benneker LM, et al. Forget the blood, not the stone! Microhaematuria in acute urolithiasis and the role of early CT scanning. Emerg Med J. 2008;25:640-4. 17. Dundee P, Bouchier-Hayes D, Haxhimolla H, et al. Renal tract calculi: comparison of stone size on plain radiography and noncontrast spiral CT scan. J Endourol. 2006;20:1005-9. 18. Mefford JM, Tungate RM, Amini L, et al. Comparison of Urolithiasis in the Presence and Absence of Microscopic Hematuria in the Emergency Department. West J Emerg Med. 2017;18:775-9. 19. Eray O, Ă&#x2021;ubuk MS, Oktay C, et al. The efficacy of urinalysis, plain films, and spiral CT in ED patients with suspected renal colic. Am J Emerg Med. 2003;21:152-4.
12. Luchs JS, Katz DS, Lane MJ, et al. Utility of hematuria testing in patients with suspected renal colic: correlation with unenhanced helical CT results. Urology. 2002;59:839-42.
20. Lallas CD, Liu XS, Chiura AN, et al. Urolithiasis location and size and the association with microhematuria and stone-related symptoms. J Endourol. 2011;25:1909-13.
13. Miller OF, Rineer SK, Reichard SR, et al. Prospective comparison of unenhanced spiral computed tomography and intravenous urogram in the evaluation of acute flank pain. Urology. 1998;52:982-7.
21. Argyropoulos A, Farmakis A, Doumas K, et al. The presence of microscopic hematuria detected by urine dipstick test in the evaluation of patients with renal colic. Urol Res. 2004;32:294-7.
14. Tack D, Sourtzis S, Delpierre I, et al. Low-dose unenhanced multidetector CT of patients with suspected renal colic. AJR Am J Roentgenol. 2003;180:30511.
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ORIGINAL RESEARCH
Medicine Science International Medical Journal
Medicine Science 2019;8(2):412-7
Efficacy and safety of intravitreal aflibercept therapy in diabetic macular edema Ali Cihat Aslan, Serkan Erdenoz, Akin Cakir, Burak Erden, Cetin Akpolat, Mustafa Nuri Elcioglu Okmeydani Training and Research Hospital, Department of Ophthalmology, Istanbul, Turkey Received 01 December 2018; Accepted 29 December 2018 Available online 29.01.2019 with doi:10.5455/medscience.2018.07.8976 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract To conduct a retrospective evaluation of the efficacy and safety of intravitreal aflibercept treatment in diabetic macular edema. Patients treated with intravitreal aflibercept for diabetic macular edema participated in this study. Three injections were administered to the previously untreated 76 eyes of 50 patients for 3 consecutive months with one-month interval. The results were evaluated retrospectively by analyzing the patients’ medical records. The patients’ values of ‘‘best corrected visual acuity” inverted according to Snellen chart, and their central macular thickness and intraocular pressure were compared before and after treatment. The average age of the patients was 57.2 ± 10.1. Of the cases, 77.6% were phakic, and 22.4 % were pseudophakic. The increases in “best corrected visual acuity” in the first month after each injection and at the end of the third month were statistically significant (p < 0.001). The mean central macular thickness was 405.63 ± 106.93 μm before treatment and 288.83 ± 62.49 μm after the third injection. This reduction in the mean central macular thickness was statistically significant (p < 0.05). During and after the three-month follow-up of the injection application process, the most common observed ocular side effect was subconjunctival hemorrhage (34.2%). During or after the applications, no systemic side effects, such as sudden death, thromboembolic events, or myocardial infarction, were seen. Functionally and anatomically, intravitreal aflibercept injection therapy in diabetic macular edema is an effective treatment option because it improves visual acuity and decreases central macular thickness. Keywords: Central retinal thickness, diabetic retinopathy, vascular endothelial growth factor, aflibercept
Introduction Depending on the reduced synthesis of the insulin hormone or the resistance of the peripheral tissues to the insulin hormone, diabetes mellitus (DM) is a multisystemic disease characterized by chronic hyperglycemia; changes in carbohydrate, fat, and protein metabolism; impaired capillary membranes; and subsequent accelerated atherosclerosis [1-3].
these patients. In patients with non-insulin dependent diabetes, the incidence of DR is 23% at 11–12 years, 60% at 16 and more years. After 16 years, the incidence of PDR has been found to be 3% [5,6]. DR is divided into non-proliferative diabetic retinopathy (NPDR) and PDR. In NPDR, the lesions manifest only as local pathologies in retinas whereas the lesions in PDR also spread to the vitreous [7].
Besides the prevalence of DM varies among different populations, it is 1–2% [3]. The most important risk factor for the development of diabetic retinopathy (DR) is the total duration of the disease [4]. The incidence of retinopathy is very low in individuals who have had Type I DM (insulin-dependent DM) for less than five years.
Diabetic macular edema (DME) can develop at any stage of DR, and it is one of the most important causes of vision loss from DR. The frequency of macular edema increases with the severity of DR. DME was reported in 3% of mild NPDR cases, 38% of moderate or severe NPDR cases, and 71% of PDR cases [8,9].
It is present in 27% of those who have had Type I DM for 5–10 years and 71–90% of those who have had Type I DM longer than 10 years. The incidence increases to 95% after 20–30 years, with proliferative diabetic retinopathy (PDR) developing in 30–50% of
DME is caused by retinal microangiopathy, which is treated by laser photocoagulation, anti-vascular endothelial growth hormone (anti-VEGF), intravitreal corticosteroids, and combinations of these treatments.
*Coresponding Author: Ali Cihat Aslan, Okmeydani Training and Research Hospital, Department of Ophthalmology, Istanbul, Turke E-mail: alicihataslan@gmail.com
In this study, following the administration of repeated intravitreal injections, the effects of the anti-VEGF agent aflibercept on visual acuity, intraocular pressure (IOP), and central macular thickness (CMT) were investigated. 412
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Material and Methods Prior to the study, approval was obtained from the local Ethics Committee. The study included patients who received intravitreal aflibercept (IVA) treatment for DME. In this retrospective study, 76 eyes of 50 patients with Type 1 and Type 2 diabetes were evaluated. Inclusion criteria: ● Macular edema associated with DM ● CMT values of ˃260 μm ● Three injections over 3 consecutive months Exclusion criteria: ● Macular edema other than DR (uveitis, retinal vein occlusion, etc.) ● History of glaucoma ● Cataract or vitreoretinal surgery interventions in the previous 6 months ● Focal or grid laser treatments in the previous 3 months The patients’ files were analyzed to obtain the recorded visual acuity, CMT, and IOP parameters required for the study. Before the IVA injection was administered to the patients and four weeks after each application, the best corrected visual acuity (BCVA) was determined in converted logMAR unit according to the Snellen chart. The CMT values were measured with optical coherence tomography (OCT) (Cirrus SD-OCT Model 4000, Carl Zeiss Meditec, Dublin), and the IOP values were measured by Goldmann applanation tonometry. Optical Coherence Tomography Measurement Method The measurement was performed using the fast-macular thickness protocol of the Cirrus SD-OCT Model 4000 device. The pupil diameter of ≥5 mm required for optimum measurement was obtained in all patients because detailed biomicroscopic and fundoscopic examinations were performed at the beginning of the study. The fundus was imaged by Cirrus SD-OCT with a modified ETDRS grille (6 × 6 mm), and values such as the retinal thickness and macular volume (MV) between the inner limiting membrane (ILM) and retinal pigment epithelium (RPE) were obtained. Images with artefacts resulting from unintentional eye movements and images with signal levels of 0.22 logMAR or worse were not included. These image captures were repeated. The modified ETDRS grid (Figure 1) was divided into nine independent sectors. These circular maps consist of three interlaced circles with diameters of 1 mm, 3 mm, and 6 mm. From the center of the fovea are a central sector (Cen) with a radius of 500 μm, an inner sector 500 μm–1,500 μm from the foveal center divided into four quadrants (Sin, Tin, Iin, and Nin) and an outer sector 1500 μm–3,000 μm from the foveal center also divided into four quadrants (Sout, Tout, Iout, and Nout). These are all represented in the grid [10]. The central subfield thickness and the volume cube parameters were subtracted from the data obtained by Cirrus SD-OCT. The parameter measured as the central subfield thickness corresponds to the 1 mm area of the modified ETDRS grid. This is indicated in the current study as the CMT. The volume cube represents the retinal volume in the 6 mm diameter central portion of the macula. This value was defined as the MV.
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Method for Intravitreal Injections An IVA injection was administered by an experienced physician under sterile conditions following pupillary dilatation. After the periocular skin was cleaned with 10% povidone iodide, the patient was dressed with a sterile drape, and a sterile retractor was fixated. Prior to receiving the injections, the patients were given proparaine drops as a topical anesthetic. In addition, 2 mg aflibercept was injected into the vitreous with a 30-gauge needle 3.5 mm behind the limbus in patients who had undergone cataract surgeries, and 4 mm was injected behind the limbus in patients who had not undergone cataract surgery. Immediately after the needle was pulled back following injection, short-term pressure was gently applied with a cotton tipped applicator to the injection point to prevent the backflow of the drug or vitreous and to prevent conjunctival hemorrhage. After injection, the patients were prescribed moxifloxacin drops 8 times per day for 7 days. The patients were told to be on the alert for symptoms such as sudden and unexpected vision loss, pain, and redness. They were checked for infection and other complications on the first day of follow-up. From the first month, the patients were examined after the administration of each injection. At each visit, detailed ophthalmologic examinations were performed, the same parameters were studied, and the OCT measurements were repeated. The fundus examination findings were recorded following the dilatation of the pupils. The patients with IOP higher than 21 mmHg were planned to be started on anti-glaucomatous treatment. Complications were also noted. Statistics IBM SPSS Statistics version 18.0 for Windows was used to evaluate the data obtained in the study. In addition to descriptive statistical methods, the paired sample t-test was used for the intra-group comparison of the normal distributed parameters, the Wilcoxon sign test was used for the intra-group comparison of the non-normal distributed parameters, and the Friedman test was used for comparing two or more interrelated distributions. Multivariate linear regression analysis was used to investigate the predictive factors affecting CMT reduction and BCVA gain. A p value of <0.05 was considered statistically significant Results This study assessed 76 eyes of 50 patients: both eyes of 26 patients and a single eye of 24 patients. Of these patients, 26 (34.22%) eyes belonged to females, and 50 (65.78%) belonged to males. In the study, 59 (77.63%) of the eyes were phakic, and 17 (22.37%) eyes were pseudophakic. In addition, 56 (73.7%) of the eyes had NPDR, and 20 (26.4%) had PDR. The mean duration of DM in these 50 patients was 11.83 years. The mean BCVA at baseline was 0.38 ± 0.26 logMAR. It was 0.53 ± 0.32 logMAR 4 weeks after the first injection, 0.57 ± 0.34 logMAR 4 weeks after the second injection, and 0.64 ± 0.33 4 weeks after the third injection (Figure 1). The mean CMT was 405.63 ± 106.93 μm at baseline, 328.58 ± 77.824 μm after the first injection, 299.96 ± 66.25 μm after the second, and 288.53 ± 62.49 μm after the third (Figure 2). The mean MV values were as follows: 12.55 ± 1.91 mm3 at baseline, 11.83 ± 1.54 mm3 after the first injection, 11.36 ± 1.19 mm3 after the second injection, 413
doi: 10.5455/medscience.2018.07.8976 and 11.23 ± 1.10 mm3 after the third injection (Figure 4.3). The mean IOP was 15.53 ± 3.44 mmHg before treatment, 15.21 ± 3.25 mmHg after the first injection, 15.21 ± 3.25 mmHg after the second injection, and 15.14 ± 3.20 mmHg after the third injection.
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The statistical analysis revealed significant alterations in the BCVA, CMT, and MV values at all visits (p < 0.001); however, there were no statistical changes in the mean IOP values (p = 0.724). (Table 1)
Table 1. The alteration of the data during follow up Baseline
Month1
Month 2
Month 3
P value
0.38±0.26
0.53±0.32
0.57±0.34
0.64±0.33
<0.001
CMT (μm)
405.63±106.93
328.57±77.82
299.96±66.25
288.57±62.49
<0.001
MV (mm3)
12.55±1.91
11.83±1.54
11.36±1.19
11.23±1.10
<0.001
IOP (mmHg)
15.53±3.44
15.21±3.25
15.21±3.25
15.14±3.20
0.724
BCVA (logMAR)
BCVA: Best corrected visual acuity, CMT: Central macular thickness, MV: Macular volume, IOP: Intraocular pressure
There was a statistically significant difference in the monthly evaluation of the CMT and MV mean values (p < 0.05). Other than the insignificant difference between the first and second months (p = 0.053), there was a significant difference (p < 0.05) in the mean values of the BCVA. (Table 2)
When the correlation of the BCVA gain with the other parameters was assessed, the baseline BCVA (R=−0.228, p=0.024) was found to be statistically significant but slightly correlated with the baseline CMT (R=0.242, p=0.018) and the baseline MV (R=0.304, p=0.004). (Table 3)
Table 2. Evaluation of differences using binary comparison (Wilcoxon Test) CMT1- Baseline CMT
CMT2- Baseline CMT
CMT3- Baseline CMT
CMT2-CMT1
CMT3-CMT1
CMT3-CMT2
0.000
0.000
0.000
0.000
0.000
0.020
BCVA1-Baseline BCVA
BCVA2- Baseline BCVA
BCVA3- Baseline BCVA
BCVA2-BCVA1
BCVA3-BCVA1
BCVA3-BCVA2
0.000
0.000
0.000
0.053
0.001
0.015
MV1-Baseline MV
MV2- Baseline MV
MV3- Baseline MV
MV2-MV1
MV3-MV1
MV3-MV2
0.000
0.000
0.000
0.000
0.000
0.008
P value
P value
P value
BCVA: Best corrected visual acuity, CMT: Central macular thickness, MV: Macular volume, 1: First month, 2: Second month, 3: Third month
Table 3. Parameters related to visual acuity gain (pearson correlation analysis) Parameters
R value
P value
Age
-0.092
0.216
Gender
-0.130
0.132
Baseline BCVA
-0.228
0.024
Baseline CMT
0.242
0.018
Baseline MV
0.304
0.004
Edema Type
-0.092
0.216
Diabetes Type
-0.078
0.251
BCVA: Best corrected visual acuity, CMT: Central macular thickness, MV: Macular volume
When the predictive values, which were effective on the final BCVA were examined, the baseline BCVA was observed to be statistically significant (B coefficient=0.766, p < 0,001). Thus, when the baseline BCVA increased by 1 unit, the final BCVA increased by 0.766 units. In addition, another parameter that was observed to be closest to statistical significance was the baseline
MV (coefficient B=0.044, p=0.082). When the baseline MV increased by 1 unit, the final BCVA increased by 0.044 units. When the predictive values that could affect BCVA gain were examined, the baseline BCVA was observed to be the closest value to statistical significance (B coefficient=−0.234, p=0.072). When the baseline BCVA increased by 1 unit, the BCVA gain decreased by 0.234 units. Thus, a higher BCVA gain was achieved in the cases with a lower baseline BCVA. Another parameter that was observed to be close to statistical significance was the initial MV (coefficient B=0.044, p=0.082). When the baseline MV increased by 1 unit, the gain of the BCVA increased by 0.044 units. When the predictive values that could be effective on the final CMT were examined, only the baseline CMT was found to be statistically significant (B coefficient=0.274, p=0.007). When the baseline CMT increased by 1 unit, the final CMT increased by 0.274 units. Thus, the higher the baseline CMT, the higher the final CMT. When the effective predictive values on CMT recovery were examined, only the baseline CMT was statistically significant (B coefficient: 0.726, p < 0.001). When the baseline CMT increased by 1 unit, the CMT gain was 0.726 units. Thus, higher CMT gains were observed in cases with higher CMT values. (Table 4) 414
doi: 10.5455/medscience.2018.07.8976 Table 4. Predictive factors (multiple linear regression analysis table)
Final BCVA BCVA Gain Final CMT CMT Gain
Parameter
B coefficient
P value
Baseline BCVA
0.766
0.000
Baseline MV
0.044
0.082
Baseline BCVA
-0.234
0.072
Baseline MV
0.044
0.082
Baseline CMT
0.274
0.007
Baseline CMT
0.726
0.000
BCVA: Best corrected visual acuity, CMT: Central macular thickness, MV: Macular volume
Figure 1. The odified ETDRS grid
Med Science 2019;8(2):412-7
have been conducted. In the DA VINCI study, an average of 11.4 letters of visual acuity were gained with an average of 5.5 injections at week 24. The VISTA study in the United States and the VIVID study in Europe were conducted with a similar arrangement. The general information obtained from these studies is that approximately 2 lines of visual acuity gain were observed with 8–12 injections at week 52 [18]. An objective the DRCR.net Protocol T study was to compare the effect of three anti-VEGFs. Bevacizumab (1.25 mg), ranibizumab (0.3 mg), and aflibercept (2 mg) were randomly injected into 660 patients. In the first year, gains of 9.7 letters in the bevacizumab group, 11.2 in the ranibizumab group, and 13.3 in the aflibercept group were achieved. In the second year, the gains in letters were 10, 12.3, and 12.8 in the bevacizumab, ranibizumab, and aflibercept groups, respectively. The average number of injections performed in the first year was reported as 10 for each of bevacizumab and ranibizumab and 9 of aflibercept. The average number of injections in the second year was reported as 6 each of bevacizumab and ranibizumab and 5 of aflibercept [19,20]. Aflibercept and focal or grid laser therapy were compared in a study conducted by Do et al. [21] The randomized multicentered double-blind study comprised 221 patients. Depending on the administration of aflibercept at different doses and intervals, the gain in visual acuity for the aflibercept group was reported as 9.7–13.1 letters at the end of the first year. A reduction of 1.3 letters was reported for the laser group. The decrease in central retinal thickness was 127–194 μm in the aflibercept group, but it remained at 67.9 μm in the laser group. This study, which included naive patients with DME, aimed to investigate the effects of 2 mg IVA injections on visual acuity, CMT, MV, and IOP. In addition, it assessed the possible complications.
Figure 2. Molecular structure of aflibercept
Discussion Treatment approaches for DME vary because of the differences in the mechanisms of macular edema. They can be grouped into three main categories: laser photocoagulation, intravitreal steroid injection, and intravitreal anti-VEGF injection [11,12]. Treatment success is assessed through OCT, and the treatment options can be changed on the basis of the OCT results. Significant ocular problems can occur when DME is not treated. When untreated, 24% of eyes with clinically significant macular edema (CSME) and 33% of eyes with centralized CSME will have moderate vision loss within 3 years [13,14]. Aflibercept consists of an IgG backbone fused to extracellular VEGF receptor sequences of human VEGFR1 and VEGFR2 (Figure 2). As a soluble trap receptor, it binds to VEGF-A with greater affinity than its natural receptors. Aflibercept’s high affinity to VEGF prevents the signaling and activation of the natural VEGF receptors. Reduced VEGF activity leads to decreased angiogenesis and decreased vascular permeability. In addition, the inhibition of PIGF and VEGF-B also contributes to antiangiogenesis [15-17]. Aflibercept has been used prospectively in some studies on DME as an anti-VEGF, And DA VINCI, VIVID, and VISTA studies
A statistically significant decrease in CMT values was observed at all visits, and the mean decrease of 117 μm at the end of the third month was found to be statistically significant. These results were similar to those of previous studies. Because the MV represents a wider area, 6 mm diameter, of the macula as opposed to a 1 mm diameter area of the central macula represented by the CMT, the MV might be an ancillary parameter to the CMT in treatment follow-up and planning. Although there was not a significant decrease in CMT in some of the cases, there was a significant decrease in MV. In contrast, in the current study, the analysis of the predictive factors affecting BCVA gain and final BCVA indicated that the most significant parameter after the baseline BCVA was the baseline MV. Paracentral scotomas have an important role in the reading difficulty of patients with decreased visual acuity. It is likely that the decrease in MV is an indirect parameter indicating a decrease in paracentral scotomas. Thus, MV reduction might have a positive effect on the evaluation of patients’ general reading activities (e.g., newspapers and magazines). When the BCVA gain was correlated with the other parameters of the cases, it was found to be statistically significant but slightly associated with the baseline BCVA, baseline CMT, and baseline MV. The worse the baseline BCVA, the higher the BCVA gain. 415
doi: 10.5455/medscience.2018.07.8976
The greater the baseline CMT and the baseline MV, the higher the BCVA gain. Age, sex, type of edema, and diabetes type had no significant effect on visual acuity outcomes. In this study, the statistically significant parameter affecting the final BCVA was found to be the baseline BCVA, and the baseline MV parameter was the closest to statistical significance on the final BCVA. Thus, the better the baseline BCVA, the better the final BCVA; however, an opposite finding drew attention to BCVA gain. Patients with a worse baseline BCVA had a higher BCVA gain (peak effect), but they did not achieve the final BCVA values reached by patients with a higher baseline BCVA. The parameter closest to significance level on BCVA gain was the baseline MV, which had a positive correlation with BCVA gain. The only statistically significant parameter on the final CMT was the baseline CMT: namely, the higher the baseline CMT, the higher the final CMT. In contrast, the patients with a higher baseline CMT had a greater CMT gain. However, these patients did not achieve the optimal CMT values reached by the patients with a lower baseline CMT.
Med Science 2019;8(2):412-7
as hypertension and lipid profile, that could increase the severity of macular edema, the relatively small number of patients, and the short duration of the follow-up are among the limitations of this study. Thus, prospectively designed studies should be conducted. Competing interests The authors declare that they have no competing interest Financial Disclosure All authors declare no financial support. Ethical approval Consent of Ethics was approved by local ethics committee. Ali Cihat Aslan ORCID: 0000-0001-5889-0462 Serkan Erdenoz ORCID: 0000-0002-8673-6101 Akin Cakir ORCID: 0000-0001-5880-283X Burak Erden ORCID: 0000-0003-0650-4552 Cetin Akpolat ORCID: 0000-0002-7443-6902 Mustafa Nuri Elcioglu ORCID: 0000-0002-8238-9106
References 1.
Klein R, Klein BEK, Moss SE, et al. The Wisconsin epidemiologic study of diabetic retinopathy IV: diabetic macular edema. Ophthalmol. 1984;91:1464–74.
In sum, early diagnosis in the treatment of DME and, therefore, early anti-VEGF treatment are very important. The final BCVA was at the highest levels and the final CMT was at the most optimal levels with intravitreal aflibercept treatment initiation when the BCVA was not yet greatly decreased and the CMT was not yet greatly increased. However, in patients with delayed admission or onset of symptoms, the baseline BCVA was much worse, and the baseline CMT was much higher. Despite the increased letter gain with late treatment, the final BCVA levels were never as good as those of the patients with a better baseline BCVA. Likewise, when the baseline CMT was higher, the CMT gain was greater than in patients with a lower baseline CMT. However, the higher baseline CMT values did not fall to the optimum levels like those of the patients with lower CMT.
2.
Kalantzis G, Angelou M, Poulokau E. Diabetic retinopathy: an historical assessment. Hormones (Athens). 2006;5:72–5.
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Ola M, Nawaz M, Siddiquei M, et al. Recent advances in understanding the biochemical and molecular mechanism of diabetic retinopathy. J Diabetes Complications. 2012;26:56-64.
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Aiello LP, Gardner TW, King GL, et al. Diabetic retinopathy. Diabetes Care. 1998;21:143-56.
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Klein R, Klein B, Moss S, et al. The Wisconsin epidemiologic study of diabetic retinopathy. XIV. Ten-year incidence and progression of diabetic retinopathy. Arch Ophthalmol. 1994;112:1217-28.
6.
The Diabetic Retinopathy Study Research Group. Photocoagulation treatment of proliferative diabetic retinopathy: The second report of diabetic retinopathy study findings. Ophthalmology. 1978;85:82-106.
Although a statistically significant decrease in CMT levels was observed each month, a correlated increase in CMT was not seen during this period. There might be a relationship between the reduction in CMT and the improvement in BCVA. Because anatomical correction does not always provide functional improvement, a significant change in BCVA was not observed between the first and second months. A lack of immediate improvement in BCVA in response to a decrease in CMT could lead a delay period, and this could result in a negative interpretation of patients’ functional outcomes. Thus, according to the PRN treatment protocol, an anti-VEGF indication in patients with or without a loss in BCVA should be noted if an increase in CMT is observed at clinic visits.
7.
Klein R, Klein B. Epidemioloy of proliferative diabetic retinopathy. Diabetes Care. 1992;1875-91.
8.
Hikichi T, Fujio N, Akiba Y, et al. Association between the short-term natural history of diabetic macular edema and the vitreomacular relationship. Ophthalmology. 1997; 104:473-8.
9.
Williams R, Airey M, Baxter H et al. Epidemiology of diabetic retinopathy and macular oedema: a systematic review. Eye. 2004;18:963-83.
In this study, subconjunctival hemorrhage (34.2%) was the most common complication from the injection technique. Although some side effects have been reported in the literature, no endophthalmitis, TRD, retinal tear, glaucoma, vitreous hemorrhage, or local or systemic side effects were observed in any of the patients [22,23].
12. Tetikoğlu M, Kurt MM, Sağdık HM, et al. Retrospective analysis of the effect of aflibercept loading dose on the retinal vessel diameters in patients with treatment-naive neovascular AMD. Cutan Ocul Toxicol. 2018; 37:84-9.
Conclusion
14. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study Report Number 1. Early Treatment Diabetic Retinopathy Study research group. Arch OphthalmolArch Ophthalmol. 1985;103:1796806.
In conclusion, IVA injection can be considered an effective and safe treatment option for DME. The absence of additional factors, such
10. Ishikawa H, Stein DM, Wollstein G, et al. Macular segmentation with optical coherence tomography. Invest Ophthalmol Vis Sci. 2005;46:2012-7. 11. Kurt MM, Çekiç O, Akpolat Ç, Elçioglu M. Effects of intravitreal ranibizumab and bevacizumab on the retinal vessel size in diabetic macular edema. Retina. 2018;38:1120-6.
13. Osaadon P, Fagan XJ, Lifshitz T, et al. A review of antiVEGF agents for proliferative diabetic retinopathy. Eye (Lond). 2014;28:510–20.
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15. Vincenti V, Cassano C, Rocchi M, et al. Assignment of the vascular endothelial growth factor gene to human chromosome 6p21.3. Circulation. 1996;93:1493-5.
20. Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a Comparative Effectiveness Randomized Clinical Trial. Ophthalmol. 2016;123:1351-9.
16. Senger D, Galli S, Dvorak A, et al. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983; 219: 983â&#x20AC;&#x201C;5.
21. Do D, Schmidt-Erfurth U, Gonzalez VH, et al. The DA-VINCI Study: phase 2 primary results of VEGF Trap-Eye in patients with diabetic macular edema. Ophthalmol. 2011;118:1819-26.
17. Bhisitkul RB. Vascular endothelial growth factor biology: clinical implications for ocular treatments. Br J Ophthalmol. 2006;90:1542-7. 18. Do DV, Nguyen QD, Boyer D, et al. One-year outcomes of the da Vinci Study of VEGF Trap-Eye in eyes with diabetic macular edema. Ophthalmol. 2012;119:1658-65. 19. Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015;372:1193-203.
22. Arevalo JF, Maia M, Flynn Jr HW, et al. Tractional retinal detachment following intravitreal bevacizumab (Avastin) in patients with severe proliferative diabetic retinopathy. Br J Ophthalmol. 2008;92:213-6. 23. Hoang QV, Tsuang AJ, Gelman R et al. Clinical predictors of sustained intraocular pressure elevation due to intravitreal anti-vascular endothelial growth factor therapy. Retina. 2013;33:179-87.
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Available online at www.medicinescience.org
ORIGINAL RESEARCH
Medicine Science International Medical Journal
Medicine Science 2019;8(2):418-21
Reactivation risk of Hepatitis B Virus in both HBsAg negative and HBcIgG positive patients with solid malignancy. Is antiviral prophylaxis really necessary? Murat Araz1, Ismail Beypinar2, Tarik Demir3, Hacer Demir2, Mukremin Uysal2 1 Necmettin Erbakan University, Faculty of Medicine, Department of Medical Oncology, Konya, Turkey Afyon Health Sciences University, Faculty of Medicine, Department of Medical Oncology, Afyonkarahisar, Turkey 3 Bezmialem VakÄąf University, Department of Medical Oncology, Istanbul, Turkey
2
Received 14 January 2019; Accepted 21 January 2019 Available online 21.02.2019 with doi:10.5455/medscience.2019.08.9009 Copyright Š 2019 by authors and Medicine Science Publishing Inc. Abstract Prophylactic antiviral treatment is controversial due to a lack of studies in both HBsAg negative/HBcIgG positive patients who treated conventional chemotherapy with solid malignancy, unlike HBsAg positive. In this cross-sectional and retrospective study, we analyzed that the reactivation risk of Hepatitis B Virus (HBVr) of totally 457 HBcIgG positive patients with solid cancer in archives records between 2011 and 2018 years of two different centers. Totally 217 HBcIgG positive patients with solid cancer were included in the study. Anti-HBs positive and negative patients were 119 (54.8%) and 98 (45.2%), respectively. Frequent diagnosis of the patients was lung (28.1%), colorectal (19.4%), breast (17.5%) and hepatobiliary tract cancers (8.3%), respectively. Most of the study population had stage 4 disease (48.8%) and received palliative chemotherapy. When the patients were stratified due to American Gastroenterological Association Institute (AGA) guideline, HBVr risk of chemo regimen was moderate in 21 patients (17.5%), low in 8 patients (3.7%). The majority of the patients were undefined risk group (78.8%). We did not determine any HBVr in the patients who have received different conventional chemotherapy regimens and have different primer tumor site despite all the patients did not receive the prophylactic antiviral drug. Keywords: Antiviral prophylaxis, Hepatitis B virus, reactivation risk, solid malignancy
Introduction Hepatitis B Virus (HBV) related clinical pictures are one of the most important public health problems due to one-third of the World population had an interaction with it [1]. Reactivation of HBV (HBVr) under treatment with immunosuppressive or chemotherapy is well known in HBsAg positive patients. The HBVr may result in the discontinuation of treatment and can cause increased morbidity and mortality related to the primary disease and liver damage [2]. The HBVr risk is closely associated with viral serology, baseline serum HBV DNA level, kind of drug and treatment intensity, and underlying malignancy, inflammatory, and autoimmune diseases [3]. While HBsAg positive patients with hematopoietic stem cell
*Coresponding Author: Murat Araz, Necmettin Erbakan University, Faculty of Medicine, Department of Medical Oncology, Konya, Turkey E-mail: zaratarum@yahoo.com
and organ recipients, and hematological malignancies have a higher risk, HBsAg positive patients with solid malignancy are accepted as moderate HBVr risk. The reactivation risk of HBsAg positive patients is known as approximately eight times higher than in HBsAg negative/HBcIgG positive [2,3]. Although HBsAg positive patients have a higher risk to have an HBVr, HbsAg negative/HBcIgG positive patients more likely to be seen in the population [4]. The HBVr risk in solid tumor quite varies by the administered systemic chemotherapy agents [5]. Although there is a high risk (>10%) in HBsAg negative patients who are treated with T and B cell depleting agents like rituximab and anthracycline derivates, the risk of reactivation decreases to a moderate level (1-10%) in HBsAg negative/HBcIgG positive patients with solid malignancy for anthracycline derivates. However, HBVr risk of conventional chemotherapy agents such as taxans, platins, fluorouracil which frequently used for the treatment of solid malignancies have not been well defined in American Gastroenterological Association Institute (AGA) guideline drug list, unlike anthracycline derivatives [6]. 418
doi: 10.5455/medscience.2019.08.9009
Recently published two metanalyses [7,8] have shown that antiviral prophylaxis treatment provides a statistically significant reduction of HBV reactivation risk in HBsAg positive patients with a solid tumor. Therefore, this patient population is indicated to have HBV prophylaxis with anti-viral drugs. However, prophylactic antiviral treatment is controversial due to a lack of studies in both HBsAg negative/HBcIgG positive patients who treated conventional chemotherapy with solid malignancy [2]. In this study, we aimed to analyze the HBV reactivation risk in the HBsAg negative and HBcIgG positive patients who received conventional chemotherapy for the treatment of solid malignancy. Material and Methods Patient Selection In this cross-sectional study, 4651 patientâ&#x20AC;&#x2122;s records in archives of two different centers between 2011 and 2018 were retrospectively scanned. HBcIgG positive 457 patients were found. When the patients who were HBsAg positive or not received chemotherapy or lost follow-up were excluded, the rest of 217 patients were enrolled in the study. The patient characteristics, the HBVr risk of chemotherapy regimens, the number of cycles patients received were recorded. The HBVr ratio of chemotherapy regimens was evaluated according to the recommendations of AGA Guideline in 2015. Also the baseline International Normalized Ratio (INR), aminotransferase level, albumin levels analyzed for an unknown hepatic disease. The aminotransferase levels of the patients were recorded at baseline before the initiation of chemotherapy, at the third cycle and sixth cycle of the chemo and the control times after the complete treatment. The aminotransferase levels during chemotherapy and observation recorded as numbers and categorized as normal, between two to five, five to ten and above the tenfold from the normal range. The duration of the observation period, antiviral prophylaxis status, and reactivation status for each patient were recorded.
Med Science 2019;8(2):418-21
Statistical analysis The SPPS 22.0 programme was used for the statistical analysis. The parameters tested for normal distribution with KolmogorovSmirnov and Shapiro-Wilk tests. The descriptive statistics were analyzed. Results The majority of 217 patients including the study were male (138 patients). The mean age of male patients was 63 years, and female patients were 58 years. The most frequent diagnosis of the patients was lung (28.1%), then colorectal (19.4%), breast (17.5%) and hepatobiliary tract cancers (8.3%), respectively. Most of the study population had stage 4 disease (48.8%) and had received palliative chemotherapy. The median chemotherapy cycles were 6. Doublet chemotherapeutic combinations have been administered primarily for the treatment of colorectal and lung cancer patients. When the chemotherapy regimens compared, most of the patients received platinum-based treatment (42%). The rates of other combined chemo regimen with anthracycline, taxane, and anti-metabolites were 18%, 20.7%, and 22.6%, respectively. Most of the patients had received only one line chemotherapy, and only the minority of the patients had received third or fourth line chemotherapy. Anti-HBs positive and negative patients were 119 (54.8%) and 98 (45.2%), respectively. When the patients were stratified due to AGA guideline, HBVr risk of chemo regimen was moderate in 21 patients (17.5%), low in 8 patients (3.7%). The majority of the remain patients were undefined risk group (78.8%). Moderate risk group patients had received mostly as adjuvant anthracycline-containing chemo regimen for breast cancer treatment â&#x20AC;&#x201D; the median observation time after chemotherapy was four months which differed from 0 to 36 months. Any patients had received antiviral prophylactic medication. All the patientâ&#x20AC;&#x2122;s characteristics were shown in the Table 1.
Table 1. The Characteristics of The Patients Age n:217
Female 58t
Male 63.7t
79 Stage 1 3 (1.4%) Lung 61 (28.1%) Positive 119 (54.8%) Neoadjuvant 8 (3.7%) High 0 Monotherapy 40 (18.4%) Albumin 4.07* Diagnosis n: 217 18* Platinum 92 (42%) First line 159 (73.3%)
138 Stage 2 20 (9.2%) Colorectal 42 (19.4%) Negative 98 (45.2%) Adjuvant 84 (38.7%) Moderate 38 (17.5%) Doublet Triplet 177 (81.6%) INR 1.02* 3th Cycle n:212 18* Taxane 45 (20.7%) Second line 55 (25.3%)
Gender n:217 Stage n:217 Diagnosis n:217 Anti-HBs n:217 Aim of Chemother-apy n:217 Risk of Reactivation n:217 Chemotherapy type n:217 Parameters at Diag-nosis n:217 ALT levels (U/L)
Combination Chemo regimens Based on.. n (%) Line of Treatments n (%) t: Mean *: Median
Stage 3 88 (40.6%) Breast 38 (17.5%)
Stage 4 106 (48.8%) Pankreatobilier 18 (8.3%)
Palliative 116 (53.5%) Low 8 (3.7%)
Chemoradiotherapy 9 (4.1%) Undefined 171 (78.8%)
6thCycle n:158 20* 5-FU 49 (22.6%) Third line 2 (0.9%)
After Chemo n:158 19* Anthracycline 39 (18%) Fourth line 1 (0.5%)
Others 58 (26.7%)
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We did not detect any HBVr in the HBsAg negative and HBcIgG positive patients with solid malignancy who treated with conventional chemotherapy. Whether HBsAb positive or negative did not affect this result. Discussion In the study, we aimed to evaluate the HBVr status of solid organ malignancy patients who have HBcIgG positive. We did not determine any HBVr in the patients who have received different conventional chemotherapy regimens and have different primer tumor site despite all the patients did not receive the prophylactic antiviral drug. While the HBVr in solid tumor treatment is thought much lower than stem cell/organ transplantation and hematologic cancer, the absolute risk with conventional chemotherapeutic agents using for solid cancer treatment is still unclear. In a meta-analysis, the reactivation rates in HBsAg positive and HBsAg negative/HBc IgG positive patients with solid malignancy were median 25% (ranged from 4-68%) and 3%(ranged from 0.3-9%), respectively [7]. Recently, in a systematic comparativesystematic review [4] including 55 studies with a total of 3640 HBsAg negative/HBcIgG positive patients who received immunosuppressive therapy, Cholongitas et al. showed that HBVr rate was detected as 10.9% in patients with hematological diseases and 3.6% in patients with non-hematological diseases. However, the majority of patients with non-hematological diseases were constituting with rheumatic disease (975 patients) in the study. The other non-hematological diseases were including gastrointestinal diseases (105 patients), dermatological diseases (88 patients), various diseases (67 patients), and solid cancer (114). Solid cancer patients were only a small part of the study population (<10%). Also, patients with rheumatic, dermatologic, gastrointestinal, and various nonhematological disease had been received tumor necrosis factor alfa inhibitors (anti-TNF) or rituximab containing treatment. Rituximab and anti-TNF inhibitors are two essential immunosuppressive drugs that well known associated with HBVr in isolated HBc IgG positive patients [9]. In a multicentre and prospective study, Fukuda et al. [10]. found that the incidence of HBVr in patients with HBsAg negative/HBcIgG positive under immunosuppressive therapy for the rheumatic disease was 1.9%. Although anti-TNF agents-associated HBVr risk which accepted with moderate risk is well known, conventional chemotherapy agents have quite variable HBVr risk, and data is limited with heterogenous small case series [2]. Therefore, HBVr risk levels of these drugs, unlike anthracycline derivates, could not be classified in the guidelines [6]. While anthracyclines derivates and cyclophosphamide may cause HBVr in HBsAg positive patients via inducing lymphodepletion, there is very limited data with topoisomerase inhibitors and an antimetabolite agents fluorouracil [5]. When comparing patients regarding detectable and undetectable serum baseline HBV DNA in the study of Cholongiatis et al. [4], HBVr rate was significantly higher in non-hematological diseases (14.2% vs. 2.0%, P=0.001; respectively), but, this difference was not significant in the sensitivity analysis (p=0.090). Although detectable serum baseline HBV DNA had numerically higher reactivation than undetectable HBV DNA (21.9% vs. 11.3%,
Med Science 2019;8(2):418-21
P=0.173; respectively), there was no statistically meaningful difference in patients with hematological disease (P=0.938). HBVr rate was numerically higher in patients treated with rituximabcontaining (9.7% vs. 4.1 %, P=0.056) and significantly higher in patients with detectable baseline serum HBV DNA treated with rituximab-free regimens (14.0% vs. 2.6%, P=0.003; respectively). However, no such difference was seen in patients treated with rituximab-containing regimens (11.7% vs. 11.6 %, P=0.997; respectively). Also, they showed that anti-HBs seropositivity is protective for HBVr in all studies (5.2% vs. 17%, p<0.001) regardless of underlying disease and rituximab treatment. However, the protective effect on HBVr of anti-HBs is very controversial in the literature [11]. However, HBsAb positivity had not affected our results and also, baseline HBV DNA levels of the patients were not available in our study. A relationship between the intensity or multi-line of conventional chemotherapy administration and HBVr is not clearly defined. In both studies of Paul et al. [7] and our, doublet or triplet chemo regimens or increased lines of therapies were not correlated with HBVr. Also, Patullo et al. suggest that some mutation of HBV gene in patients with HBsAg negaÂŹtive/HBcIgG positive may be related to increased HBVr risk. However, this issue is not clearly determined [3]. Consequently, this issue has still so many restricted factors for the quality of the study results from such as incomplete data from retrospective trials, heterogeneity of study populations, and heterogeneity of chemotherapy drugs. From their results, Cholongitas et al. suggest that antiviral prophylaxis should be given in HBsAg negative, HBcIgG positive patients with non-hematological diseases including solid malignancies who have detectable baseline HBV DNA [4]. However, AGA [6] and recently published Turkish Consensus Report [2] do not recommend the routinely using antiviral prophylaxis before the initiate conventional chemo regimen which has low HBVr risk regardless baseline HBV DNA level. If we use routinely prophylactic antiviral drugs in this low-risk group, it will cause an increased economic burden and treatment-related adverse events, especially in HBV endemic countries [7]. Retrospective design, unknown basal HBV DNA level, and short observation duration after chemotherapy of patients were study limitations of our study. Notably, in metastatic patients, cancerrelated high mortality rates in short time after disease progression were related to low observation periods. Conclusion Reactivation risk of hepatitis B virus in both HBsAg negative and HBcIgG positive patients with solid malignancy is very rarely under treatment with conventional chemotherapy regimens. Therefore, we think that antiviral prophylaxis is usually unnecessary. However, in this area have still need comparative and prospective trials. Acknowledge We thank the Afyon Kocatepe University and Bezmialem VakÄąf University for let us collecting the data of their cancer patients. Competing interests The authors declare that they have no competing interest. Financial Disclosure All authors declare no financial support.
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Ethical approval The study was approved by the local ethics committee of Afyon Kocatepe University and was conducted by fo llowing the Helsinki Declaration principles.
5.
Voican CS, Mir O, Loulergue P, et al. Hepatitis B virus reactivation in patients with solid tumors receiving systemic anticancer treatment. Ann Oncol. 2016;27:2172-84.
Murat Araz ORCID:0000-0002-4632-9501 Ismail Beypinar ORCID:0000-0002-0853-4096 Tarik Demir ORCID:0000-0001-6334-4079 Hacer Demir ORCID:0000-0003-1235-9363 Mukremin Uysal ORCID:0000-0002-8524-0665
6.
Reddy KR, Beavers KL, Hammond SP, et al. American Gastroenterological Association Institute guideline on the prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology. 2015;148:215-9.
7.
Paul S, Saxena A, Terrin N, et al. Hepatitis b virus reactivation and prophylaxis during solid tumor chemotherapy: A systematic review and meta-analysis. Ann Intern Med. 2016;164:30-40.
8.
Xu Z, Dai W, Wu YT, et al. Prophylactic effect of lamivudine on chemotherapy-induced hepatitis B virus reactivation in patients with solid tumour: A meta-analysis. Eur J Cancer Care (Engl). 2018;27:e12799.
9.
Wu T, Kwok RM, Tran TT. Isolated anti-HBc: The Relevance of Hepatitis B Core Antibody—A Review of New Issues. Am J Gastroenterol. 2017;112:1780-8.
References 1.
Borentain P, Colson P, Coso D, et al. Clinical and virological factors associated with hepatitis B virus reactivation in HBsAg-negative and anti-HBc antibodies-positive patients undergoing chemotherapy and autologous stem cell transplantation for cancer. J Viral Hepat. 2010;17:807-15.
2.
Aygen B, Demir AM, Gumuş M, et al. Immunosuppressive therapy and the risk of hepatitis B reactivation: Consensus report. Turk J Gastroenterol 2018;29:259-69.
3.
Pattullo V. Prevention of Hepatitis B reactivation in the setting of immunosuppression. Clin Mol Hepatol. 2016;22:219-37.
4.
Cholongitas E, Haidich A, Apostolidou-kiouti F, et al. Hepatitis B virus reactivation in HBsAg-negative , anti-HBc-positive patients receiving immunosuppressive therapy: a systematic review. 2018;480-90.
10. Fukuda W, Hanyu T, Katayama M, et al. Incidence of hepatitis B virus reactivation in patients with resolved infection on immunosuppressive therapy for rheumatic disease: A multicentre, prospective, observational study in Japan. Ann Rheum Dis. 2017;76:1051-6. 11. Feld JJ. Hepatitis B Reactivation: The Controversies Continue. Dig Dis. 2017;35:351–8.
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ORIGINAL RESEARCH
Medicine Science International Medical Journal
Medicine Science 2019;8(2):422-4
Frequency of lysosomal acid lipase deficiency in patients with primary hyperlipidemia Bahri Evren1, Yılmaz Bilgic2, Feyza Firat Atay3, Ayse Nuransoy Cengiz4, Yasir Furkan Cagin2 1 Inonu Universty Faculty of Medicine, Department of Endocrinology Malatya Turkey Inonu Universty Faculty of Medicine, Department of Gastroenterology Malatya Turkey 3 Kovancilar State Hospital, Clinic of Internal Medicine, Elazig Turkey 4 Inonu Universty Faculty of Medicine, Department of Internal Medicine Malatya Turkey 2
Received 27 January 2019; Accepted 17 February 2019 Available online 10.05.2019 with doi:10.5455/medscience.2019.08.9025 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract The aim of our study was to investigate the prevalence of LAL (lysosomal acid lipase) deficiency in patients with primary hyperlipidemia. Twenty-four patients with primary hyperlipidemia were included in the study. The gender, age, height, weight, body mass index and waist circumference of the patients were recorded. Lipid profiles, glucose, transaminases and LAL enzyme profiles were evaluated. LAL enzyme deficiency was not detected in patients with primary hyperlipidemia. In our study, when we investigated LAL deficiency in primary hyperlipidemic patients, we could not find a relationship between them. As a result of our study, LAL deficiency was not detected in patients with primary hyperlipidemia. However, in this context, there is a need to work with a large number of patients. Keywords: Primary hyperlipidemia, lysosomal acid lipase deficiency
Introduction
Material and Methods
Lysosome is a membrane-associated, acidic organelle found in animal-related cells. Its lead to the breakdown of biological macromolecules (mucopolysaccharides, sphingolipids, glycoproteins, triglycerides, cholesterol esters) which are produced both from the outside and within the cell by the acid hydrolases ıts contain [1]. Lysosomal storage diseases (LSD), which the lack of enzymes involved in the catabolism of macromolecules is a group of diseases caused by the defect of the transports that cause the lysis of the lysosomes to function out of the cell due to the accumulation of specific substrates. Clinical findings vary according to the substance stored. Because the accumulated molecules are highly heterogeneous, clinical presentations are also heterogeneous [2]. Lysosomal Acid Lipase (LAL) deficiency is a rare autosomal recessive, lysosomal lipid storage group. It is characterized by progressive cholesterol ester and triglyceride accumulation in liver, spleen and other organs (central system, gis …) [3].
Twenty-four patients with primary hyperlipidemia who were admitted to the endocrinology and metabolism outpatient clinic of Inonu University between June 2016 and September 2017 and who were diagnosed with secondary hyperlipidemia such as type 2 diabetes mellitus, nephrotic syndrome, hypothyroidism and primary biliary cirrhosis were included in the study. The gender, age, height, weight, body mass index and waist circumference of the patients were recorded. Lipid profiles, glucose, transaminases and LAL enzyme profiles were evaluated. LAL enzyme deficiency was not detected in patients with primary hyperlipidemia. Exclusion criteria are given in the material method part of our study. LAL activity was measured by using Dried Blood Spot Test (DBS). The results are given in nanomol / punch / hour. In our study, the mean + standard deviations of the data were given as statistical analysis. Since there was no LAL deficiency in our patients, no specific statistical method was used. Results
*Coresponding Author: Yilmaz Bilgiç, Inonu Universty, Faculty of Medicine Department of Endocrinology Malatya Turkey E-mail: drybilgic1975@hotmail.com
When the laboratory and anthropometric results of the patients with primary hyperlipidemia were evaluated, the mean age was found to be 38.55 ± 10.7 years. The mean weight and body mass index of the patients were 72.42 ± 11.4 kg and 26.72 ± 5.2 kg 422
doi: 10.5455/medscience.2019.08.9025
/ m2, respectively. The waist circumference of the patients was calculated without gender discrimination and the mean was 84.41 ± 12.8 in both sexes. For the exclusion of diabetes mellitus, a cause of secondary hyperlipidemia, fasting blood glucose was also included in our study and mean fasting glucose was measured as 86 ± 9.5 mg / dl. Liver enzymes were also studied to determine whether there was a high liver enzyme elevation in LAL deficiency. The mean AST 27 ± 7.2 UI / L and ALT 24 ± 6.3 UI / L were determined. In our study, mean blood lipids were 244 ± 54.2 mg / dl for total cholesterol, 121 ± 44.7 mg / dl for triglyceride, 51.4 ± 10.3 mg / dl for HDL cholesterol and 182 ± 39.4 mg / dl for LDL cholesterol (Table 1). Table 1. Laboratory and anthropometric results of patients with primary hyperlipidemia Parameters
Patients with primary hyperlipidemia (n = 24)
Age (years)
38.55 ± 10.7
Height (cm)
157.2 ± 6.1
Weight (kg)
72.42 ± 11.4
BMI (kg/m2)
26.72 ± 5.2
Waist circumference
84.41 ± 12.8
Glucose (mg/dl)
86 ± 9.5
AST
27 ± 7.2
ALT Total cholesterol (mg/dl)
24 ± 6.3 244 ± 54.2
Triglyceride (mg/dl)
121 ± 44.7
HDL cholesterol (mg/dl)
51.4 ± 10.3
LDL cholesterol (mg/dl)
182 ± 39.4
LAL (nmol/punch/h.)
0.74 ± 0.68
Discussion LAL is a rare lipid storage disease and its prevalence is approximately 1 / 40.000 depolama1 / 350.000 in newborns. Diagnostic images such as liver ultrasound and biopsy are important, which show changes in hepatic morphology such as microvescular steatosis with Kupffer cell involvement, fibrosis and cholesterol-estercrystal accumulation. These findings should suggest LAL disease. Because the disease is manifested as idiopathic microvesicular hepatosteatosis disease [4]. As the disease progresses in patients with initially indeterminate complaints, some clinical symptoms, such as rough facial, skeletal dysplasia, and developmental delay, stimulate a lysosomal depot disorder. Different lysosomal storage disorders share common symptoms and symptoms [5]. LAL deficiency is a disease associated with progressive hepatic insufficiency accompanied by increased atherosclerosis, cardiovascular disease, hepatomegaly, and increased liver enzyme deficiency, with dyslipidemia frequently associated with. LAL deficiency in adults and children shows very different clinical features and heterogeneous course. While the age at onset may occur in late age as 44 years in men and 68 years in women, the mean age at which onset of symptoms is 5 years in both sexes [3]. Hepatomegaly is the most common clinical manifestation of lysosomal storage disease. High serum total cholesterol, LDL cholesterol, triglyceride high together with hepatomegaly are among the most characteristic findings [6]. Definitive diagnosis is the measurement of enzyme activity in leukocytes, cutaneous fibroblasts or dry blood samples from peripheral blood samples. The values below 0.03 (nmol / punch / h) in LAL activity were
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inadequate in LAL activity, values in the range of 0.03-0.15 (nmol / punch / hour) were defined as LAL activity at the border. The values between 0.15-0.37 (nmol / punch / hour) with highly reduced LAL activity, 0.37-0.50 (nmol / punch / hour) values are considered as LAL activity in the transition zone [7,8]. In the treatment, cholestyramine and statins can be given. Although hematopoietic stem cell transplantation is potentially curative in patients with LAL deficiency, it is often not a good option because it carries high risks, including fatal complications. The main treatment consists of the enzyme replacement sebelipase alfa, which was approved in 2015. Sebelipase alpha is a recombinant human lysosomal acid lipase that replaces incomplete LAL enzyme activity and thereby reduces hepatic fat content and elevated transaminases [9]. Conclusion Lysosomal acid lipase deficiency; in patients with high LDL and / or low HDL levels, hepatomegaly and / or high transaminase levels without obesity or metabolic syndrome should be considered. In our study, the use of lipid electrophoresis in the diagnosis of primary hyperlipidemia is one of the weaknesses of our study. In our study, we could not find any relationship between these two diseases. As a result of our study, LAL deficiency was not detected in patients with primary hyperlipidemia. However, because the incidence of LAL deficiency is very low, large-volume clinical studies are needed to evaluate the frequency of patients with primary hyperlipidemia. Competing interests The authors declare that they have no competing interest. Financial Disclosure All authors declare no financial support. Ethical approval Ethics committee approval was obtained. Bahri Evren ORCID: 0000-0001-7490-2937 Yılmaz Bilgic ORCID: 0000-0002-2169-5548 Feyza Firat Atay ORCID 0000-0002-2841-2985 Ayse Nuransoy Cengiz ORCID: 0000-0001-9133-8602 Yasir Furkan Cagin ORCID: 0000-0002-2538-857X
References 1.
Zeynep Büşra Aksoy, Ege soydemir. Lizozomal aktivite. Güncel Gastroenteroloji. 2016;4:345-52.
2.
Futerman AH, Van Meer G. The cell biology of lysosomal storage disorders. Nat Rev Mol Cell Biol. 2004;5:554-65.
3.
Bernstein DL, Hulkova H, Bialer MG, et al. Cholesteryl ester storage disease: review of the findings in 135 reported patients with an underdiagnosed disease. J Hepatol. 2013;58:1230-43.
4.
Botero V, Garcia VH, Gomez-Duarte C, et al. Lysosomal acid lipase deficiency, a rare pathology: The first pediatric patient reported in colombia. Am J Case Rep. 2018;19:669-72.
5.
Andria, g. & parini, Lysosomal storage diseases early diagnosıs and new treatments edited by: rossella parini, generoso andriat. lysosomal storage d apa (american psychological assoc.). 2010.
6.
Lipiński P, Ługowska A, Zakharova EY, et al. Diagnostic algorithm for cholesteryl ester storage disease: Clinical presentation in 19 Polish Patients. J Pediatr Gastroenterol Nutr. 2018;67:452-47.
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8.
Wierzbicka-Rucińska A, Jańczyk W, Ługowska A, et al. Diagnostic and therapeutic management of children with lysosomal acid lipase deficiency (LAL-D). Review of the literature and own experience. Dev Period Med. 2016;20:212-5. Hamilton J, Jones I, Srivastava R, et al. A new method for the measurement of lysosomal acid lipase in dried blood spots using the inhibitor Lalistat 2. Clin
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Chim Acta. 2012;413:1207-10. 9.
Canbay A, Müller MN, Philippou S, et al. Cholesteryl ester storage disease: fatal outcome without causal therapy in a female patient with the preventable sequelae of progressive liver disease after many years of mild symptoms. Am J Case Rep. 2018;19:577-81.
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ORIGINAL RESEARCH
Medicine Science International Medical Journal
Medicine Science 2019;8(2):422-5
Comparison of ultrasound images obtained by different disinfection methods used Eyup Aydogan, Betul Kozanhan, Selver Can Konya Training and Research Hospital, Clinic of Anesthesiology and Reanimation, Konya, Turkey Received 09 August 2018; Accepted 21 September 2018 Available online 26.12.2018 with doi:10.5455/medscience.2018.07.8946 Copyright Š 2019 by authors and Medicine Science Publishing Inc. Abstract Ultrasonography-guided regional anesthesia (UGRA) applications are important in the practice of anesthesiology in the world. Despite the positive effect on patient care, there is concern that ultrasound (US) probes may be used repeatedly and assume a vector role in pathogen transport. There is no consensus on how to preserve US probes and use of gels against probing surface damage with pre-UGRA probe disinfection, agents used, and is still a research topic. Methods: Five different disinfection methods were compared via image quality by experienced anesthesiologists. Evaluators has been wanted to score the image that was recorded with using a defined disinfection method. Evaluators were blind while scoring the image. As a mean of 4,65 (US probe non-sterile stretch film coating and antiseptic spray(10% povidone-iodine) on the stretch film) Method 3 has been the most preferred one. The use of proven disinfection methods in UGRA interventions will be beneficial in terms of cost-effectiveness. According to study results, Method 3 (US probe non-sterile stretch film coating and antiseptic spray(10% povidone-iodine) on the stretch film) was observed to provide best image quality and cause the least cost for long-term use. Keywords: Regional anesthesia, ultrasound-guided, antiseptic
Introduction Ultrasonography-guided regional anesthesia (UGRA) applications are important in the practice of the anesthesiology in the world [15]. In addition, patient-centered ultrasonography (USG) methods have become a cornerstone in the diagnosis and treatment of patients in internal medicine, pediatrics, and emergency services. Despite the positive effect on patient care, there is concern that ultrasound (US) probes may be used repeatedly and assume a vector role in pathogen transport. The sterilization principles, which is a basic prerequisite for invasive interventional procedures, may not be respected sometimes during UGRA. For this reason, it has been reported that patients are exposed to ultrasound (US) probes that have been reused after UGRA and have not been adequately sterilized, may be a vector for pathogens [6]. However, there is no consensus on how to preserve US probes and use of gels against probing surface damage with pre-UGRA probe disinfection, agents used, and is still a research topic [7]. In the study, it was aimed to compare the image quality characteristics of the US images obtained from the axillary region with the proven disinfection methods used in the UGRA attempts *Coresponding Author: Eyup Aydogan, Konya Training and Research Hospital, Clinic of Anesthesiology and Reanimation, Konya, Turkey E-mail: eypaydogan@hotmail.com
by the anesthesiologists with at least 5 years UGRA experience with the Likert scale method. Material and Methods Different disinfection techniques are available for UGRA initiatives. Each method has sufficient disinfection, with advantages and disadvantages, and sufficient image for the users is provided. The aim of our study is to evaluate US images obtained using five proven effluent disinfection methods by anesthesia specialists with more than 5 years UGRA experience. Evaluators have been wanted to score the image that was recorded using a defined disinfection method. Evaluators were blind while scoring the image. The effects of the disinfectant agents to be used have been tested by the preliminary study. Our purpose in this preliminary study is; It is in vitro testing whether microorganisms that may be present the US probes are the cause of the infection during the interventions. (Povidone 10%), 70% 2-Propanol + Chlorhexidine digluconate (SteridinÂŽ) and 0.1% Octenidine Hydrochloride + 2% Phenoxyethanol (OctenidineÂŽ), respectively, after first obtaining a swab culture over the stretched film coated on the probe. After waiting for a while, individual swab cultures were taken. Cultures were evaluated after incubation for 24 hours on sheep blood agar media. A number of colony coagulase-negative Staphylococcus 422
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(S.) productions were detected in the culture from the stretch film, but no growth was detected using disinfectants. It was then aimed to test the effect of disinfectants by forming an infected probe. In this second phase of our study, gram-positive bacteria were used from multiple isolates of S. aureus from clinical isolates from institutional microbiology laboratory. Firstly, a suspension of S. aureus was prepared at a density of 0.5 McFarland. The suspension was then sown on a probe coated with a stretch film. Secondly, after taking the sample of the swab from the stretch film, all the disinfectants were applied separately and waited for the necessary time and then swab samples were taken. As in the first study, samples were seeded on sheep blood agar medium and incubated for 24 hours. When we evaluated after incubation, only S. aureus was observed in the swab culture which we made through the bag, but none of the swab cultures taken after the disinfectant application was produced. The same study was repeated with Pseudomonas aeruginosa in isolates common in intensive care units and the same results were obtained. There was no difference between the disinfectants. Obtaining Image The ESAOTE brand MyLabFive model (Esaote Europe BV Philipsweg 1 6227 AJ Maastricht The Netherlands) was used by an experienced expert with at least 5 years of experience to measure the ultrasonic device linear US probe at a supine position, 30 degrees counter-rotated to the lateral side, placed in the interscalene region at the level of the cervical 6th vertebra, and the nerve, muscle and vascular tissue images were taken about the 15 Mhz frequency. In this way, images obtained from the same anatomical region for each of the asepsis methods described below are recorded. Each image is numbered and transferred to the computer. It has been transferred with a resolution of 1152x864 pixels. In the name of objective evaluation, the evaluating anesthesiologists had not known that which number belongs to which asepsis technique used and they evaluated the images blindly. Totally 38 experienced anesthesiologists evaluated the images. Evaluation of image quality The obtained 5 different images were evaluated by a total of 38 anesthetists who were experienced in UGRA and who have more than 5 years experience. Likert scale was used for evaluation. (Score: 1: insufficient image, 2: reasonable image, 3: good image, 4: fairly good, 5: ideal/optimal image - Likert scale). Disinfection methods were used; Method 1: Placing the US probe inside a sterile glove Method 2: Place the US probe inside the sheath/camera sheath Method 3: US probe sterile non-stretch film coating and antiseptic spray(10% povidone-iodine) on stretch film Method 4: US sterilization with a sterile sponge with antiseptic solution(10% povidone-iodine) Method 5: US probe directly sprayed with 2% chlorhexidine, 70% isopropyl alcohol (Opacjel 2-70®) antiseptic solution The antiseptic agents used for the applications were applied by spraying on the method used or casting on a sponge. Agents used Opakjel 2-70® (2% chlorhexidine, 70% isopropyl alcohol), Poviodine 10% (10% povidone iodine).
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Pouring; 10 cm above the sponge directly from the package or swollen and in total 20 ml in bulk, Spraying; For the US probe, the probe is placed at the right angle, with the probe being held upright, and the light-labeled portion of the probe at 12 o’clock in the clockwise direction at times 12, 3, 6, 9 with a right angle of 3 times and a probe angle of 45 degrees Spraying will be applied 3 times from 15 cm. Spray 3 times 15 cm from the surface for each surface (5 ml per spray). Disinfection with sterile sponge; 10 ml disinfectant applied sterile sponge will be wiped from the center of the application point to the periphery without wiping again from the same point. Transmission gel to be used: NatuRel® 1 liter brand and packing, 2 ml for transmission gel application. The area to be applied shall be used by dropping at a distance of 10 cm. In the case of a sterile sheath (Medbar® Sterile Camera Sheath), the material to be used will be taken sterile by the applicator wearing sterile gloves and applied to the US probe. Stretch film application; The Sera® brand 40 cm wide and 9 micrometers thick, 30 cm long piece will be placed on the full midpoint probe and will be folded towards the top of the stretch film probe and the other disinfecting applications will be applied as described. Results The mean values of the scores of the methods used by anesthesiologists; Method 1: 4,02 (Placing the US probe inside a sterile glove ) Method 2: 3.57 (Place the US probe inside the sheath/camera sheath ) Method 3: 4,36 (US probe non-sterile stretch film coating and antiseptic spray(10% povidone-iodine) on the stretch film) Method 4: 4,18 (US sterilization with sterile sponge with antiseptic solution(10% povidone-iodine)) Method 5: 4,26 (US probe directly sprayed with 2% chlorhexidine, 70% isopropyl alcohol (Opacjel 2-70®) antiseptic solution) According to the results of the study, the least preferred method was method 2 and most preferred method 3. Method 2 is the least preferred method and that was statistically significant. There was no statistically significant difference in preference of other methods. Statistical analyses have been performed with SPSS 15.0 software (SPSS Institute, Chicago, IL, USA). Continuous data have been tested for normality. Normally distributed data have been summarized using mean and standard deviation and have been compared using One-way Anova test. Bonferroni correction has been used. A P-value less than 0.05 have been considered statistically significant. Discussion As it was observed in the results, the worst choice is method 2 and the best is method 3 according to evaluators views, however, it should be emphasized that scores of method 1,3,4 and 5 are not very different from one another. Low image quality score of method 2 was thought to be because of the thickness of the sheath/ camera sheath. It was reported that subcutaneous fat layer(s) and 423
doi: 10.5455/medscience.2018.07.8946
poor transducer contact may cause low image quality [8-10]. The thickness of the camera sheath is not more than a sterile glove but it was thought that sterile glove provides a better contact surface and better image. As it was observed, the sterile camera sheath has more rigid structure than sterile gloves (more flexible), and these structural properties may cause the difference. On the other hand, the measured(measured via micrometric caliper) thickness
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of sterile gloves is 100-150 micrometer (mcm), similarly camera sheet is in 100 mcm thickness nearly. However, the thickness of the stretch film coating is 9 mcm(producer asset). According to evaluators views, scores of different methods seem to be similar except method 2, then it should be evaluated in term of cost of each method. Tabel 1 refers to institutional costs;
Table 1. Products used and prices invoiced to the institution (2017) Povidone-iodine 1L 10% (containing 10% free iodine, 10% iodine complex)
0.04 $/20 ml
Octenidine 1 L 0.1% Octenidine Hydrochloride, 2% Phenoxyethanol
0.57 $/20 ml
US gel (non-steril) 1 L
0.01 $/20 ml
US gel (steril 20 ml )
1$
stretch film coating
0.01 $/meter
steril camera sheet
6.5 $
steril surgical gloves
0.15 $
steril sponge (steril package containing 5 pieces)
0.06 $
(All costs were calculated with current exchange rate United States dollar ($): Turkish lira (TL) and the amount for single use)
As it was seen in table 1 sterile camera sheet is the most expensive and the least preferred method according to the evaluators of the study. Then the most cost-efficient method is method 4, according to scores of the evaluators. However, it should be emphasized that antiseptic solutions may harm the US probe with direct contact and lead to decrease in sonographic resolution [6,11,12]. It has been emphasized that an US probe cleaning method needs to be tailored to the clinical situation to achieve an appropriate cost-tobenefit ratio while applying UGRA [13]. The linear US probe that has been used in our clinic has a price more than 9000 $, then the safety of US probe becomes significant. These findings make method 5 to have increased costs so, although method 5 provides high image quality according to evaluators scores, it is not the best method with real lowest-cost. Method 4 carries similar features, however, it carries the similar risks such as US probe damage and it has been emphasized that US probes have to be protected. It has been maintained that covering US probe also provides sterility of the interventional field, the un-sterile probe has to be covered with a sterile cover such as double layer probe cover [14,15] or sterile drape for ultrasound probe [16]. It sholud not be ignored that sterility of the interventional field was the first and indispensable point of UGRA. As a result, the methods which include a barrier such as method 1, method 2 and method 3 seem to have the advantage to prevent US probe from chemical damage and providing sterility of the interventional field. Then the method 3 becomes the real costeffective disinfection choice that it is cheaper, easy to get, proved to prevent infection.
The manuscript was presented as a poster in the 33th. Turkish Cardiology Congress with International Participation. Competing interests The authors declare that they have no competing interest Financial Disclosure The financial support for this study was provided by the investigators themselves. Ethical approval Not applicable. Eyup Aydogan ORCID: 0000-0003-3432-4946 Betul Kozanhan ORCID: 0000-0002-5097-9291 Selver Can ORCID: 0000-0002-5370-9422
References 1.
Yoshida T, Nakamoto T, Kamibayashi T. Ultrasound-guided obturator nerve block: a focused review on anatomy and updated techniques. Biomed Res Int. 2017;2017:7023750.
2.
Bromberg AL, Dennis JA, Gritsenko K. Exparel/peripheral catheter use in the ambulatory setting and use of peripheral catheters postoperatively in the home setting. Curr Pain Headache Rep. 2017;21:13.
3.
Volk T, Kubulus C. Regional anesthesia - are the standards changing? Anaesthesist. 2017;66:904-9.
4.
Koköfer A, Nawratil J, Opperer M. Regional anesthesia for carotid surgery : An overview of anatomy, techniques and their clinical relevance. Anaesthesist 2017;66:283-90.
5.
Sargin M, Sarıtas TB, Sarkilar G, ve ark.. Multi travmalı bir olguda infraklaviküler blok deneyimimiz. Bakırköy Tıp Dergisi. 2017;13:110-2.
Conclusion
6.
Marhofer P, Schebesta K, Marhofer D. Hygiene aspects in ultrasound-guided regional anesthesia. Anaesthesist. 2016;65:492-8.
The study includes 38 experienced anesthesiologists, however, we believe that working in larger groups will give more inclusive results. In our country, we believe that the use of proven disinfection methods in UGRA interventions will be beneficial in terms of cost-effectiveness. According to study results, Method 3 (US probe non-sterile stretch film coating and antiseptic spray(10% povidone-iodine) on the stretch film) was observed to provide best image quality and cause the least cost for long-term use.
7.
Fuzier R, Lammens S, Becuwe L, et al. The use of ultrasound in France: a point of view from experienced regional anesthesiologists. Acta Anaesthesiol Belg. 2016;67:9-15.
8.
Amin V, Wilson D, Rouse G. USOFT: An ultrasound image analysis software for beef quality research. 1998.
9.
Metcalfe SC, Evans JA. A study of the relationship between routine ultrasound quality assurance parameters and subjective operator image assessment. Br J Radiol. 1992;65:570-5.
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doi: 10.5455/medscience.2018.07.8946 10. Thijssen JM, Weijers G, de Korte CL. Objective performance testing and quality assurance of medical ultrasound equipment. Ultrasound Med Biol. 2007;33:460-71. 11. Koibuchi H, Fujii Y, Kotani K, et al. Degradation of ultrasound probes caused by disinfection with alcohol. J Med Ultrason. 2011;38:97-100. 12. Shokoohi H, Armstrong P, Tansek R. Emergency department ultrasound probe infection control: challenges and solutions. Open Access Emerg Med. 2015:7;1-9.
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13. Mirza WA, Imam SH, Kharal MS, et al. Cleaning methods for ultrasound probes. J Coll Physicians Surg Pak. 2008;18:286-9. 14. Gharib M. A new and improved sterile ultrasound probe cover comprising two layers . United States Patent Application Publication, Pub. No.: US 2016/0135784, 2016. 15. Sharon M. “Cover for ultrasound probe.” U.S. Patent No. 6,132,378, 2000. 16. Taylor, RH. “Sterile drape for ultrasound probe.” U.S. Patent No. 4,887,615, 1989.
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ORIGINAL RESEARCH
Medicine Science International Medical Journal
Medicine Science 2019;8(2):425-9
Evaluating clinical and radiological results following surgical treatment of patella fractures Sadullah Turhan1, Yetkin Soyuncu2 SBU Antalya Training and Research Hospital, Clinic of Orthopedics and Traumatology, Antalya, Turkey Akdeniz University, Faculty of Medicine, Department of Orthopedics and Traumatology, Antalya, Turkey
1 2
Received 29 January 2019; Accepted 07 Febuary 2019 Available online 20.03.2019 with doi:10.5455/medscience.2019.08.9015 Copyright Š 2019 by authors and Medicine Science Publishing Inc. Abstract The aim of treating patella fractures is to restore the integrity of the extensor mechanism. Various treatment methods applied include fastening techniques with different wires, fastening with screws, a combined tension band method and screw technique, segmental patellectomy, a combined tension band method and segmental patellectomy technique, and total patellectomy. Fifty-two patients underwent surgery for isolated closed patella fractures between 2002 and 2012 at the Department of Orthopaedics and Traumatology. Of these 52 patients, 23 patients who completed their follow-up were clinically, radiologically, and retrospectively evaluated. Of the 23 patients, 13 (57%) were male and 10 (43%) were female. The functional status was regarded as excellent in 16 (70%) patients, good in six (26%), and unsatisfactory in one (4%) post-surgery. Radiological evaluation of the patients showed that there was type 1 PFA in five (22%) patients, type 2 PFA in five (22%), type 3 PFA in eight (35%), and type 4 PFA in five (22%). The degree of union was radiologically evaluated in all patients during the follow-ups. Implant irritation, implant migration, and fractures were the most frequently observed complications. Keywords: Bostrom classification, Iwano evaluation scale, modified tension band method, patellofemoral arthrosis, patella fractures
Introduction The patella is the biggest sesamoid bone in the body. Due to its location, it completes the extensor mechanism of the knee joint. Patella fractures are frequently observed around the age of 40. They constitute approximately 1% of skeletal system injuries [1]. Patella fractures may occur due to direct trauma or indirectly from the pulling force of the quadriceps and patellar tendon. The aim of treating patella fractures is to restore the integrity of the extensor mechanism. Opinions differ on the approach for surgical treatments. Various treatment methods applied include fastening techniques with different wires, fastening with screws, a combined tension band method and screw technique, segmental patellectomy, a combined tension band method and segmental patellectomy technique, and total patellectomy. The anterior tension band technique used by Pauwel in 1950s for the treatment of the patella fractures was accepted and developed by the Arbeitsgemeinschaft fĂźr Osteosyntesefragen (AO) group [2]. The purpose of this study is to evaluate the clinical and radiological results following surgery using the modified anterior band method *Coresponding Author: Sadullah Turhan, SBU Antalya Training and Research Hospital, Clinic of Orthopedics and Traumatology, Antalya, Turkey E-mail:sturhan@dr.com
to treat isolated closed patella fractures after at least a 2-year follow-up period. Material and Methods Fifty-two patients underwent surgery for isolated closed patella fractures between 2002 and 2012 at the Department of Orthopaedics and Traumatology . Ethical protocol number of the research is 2014-232. Of these 52 patients, 23 patients who completed their follow-up were clinically, radiologically, and retrospectively evaluated. Patients who had surgery for same-side femur and/or tibia fractures together with their patella fracture were excluded from the evaluation. Patients who had ligament injury in the ipsilateral knee to the patella fracture and were not included in a rehabilitation program were also excluded from this study. Furthermore, patients in whom wound site infections developed post-surgery and patients who had head trauma or history of pregnancy were excluded as well. For all patients who were evaluated in the emergency department and whose physical examinations were completed, an anteroposterior (AP) and lateral knee radiograph was taken and classifications were made according to AO [2]. Following this, the 425
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affected leg was put in a long leg splint to keep the knee in full extension. The average time period between injury and surgery was 2 (1–6 ± 1.4) days. The average hospitalization period was 3.6 (3–8 ± 1.2) days. Surgery Technique Of the 23 patients, 10 were operated under general anesthesia, 12 under spinal anesthesia, and the remaining 1 under epidural block anesthesia. Two K-wires were run in a distal to proximal direction to reduce the bone fragments anatomically. The wires were sent from the third closed to the knee joint. This was done in three equal pieces in the sagittal plane of the patella, as parallel as possible. Cerclage wires (loop 18 G) were passed from the bonding place of the quadriceps tendon as far as possible, from the bottom of the K-wires going out and passed from the front face of the patella using the tension ban method (Zuggurtung method) in a figureof-eight configuration. Applying the cannula screw in the tension band method, two pieces of 4.5 mm cannula screws were sent from the third part closed to the knee joint. This was done in three equal pieces in the sagittal plane of the patella, as parallel as possible. Cerclage wires (loop 18G) were passed from the inside of the cannula screws and passed from the front face of the patella in a figure-of-eight configuration.
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Table 1. Bostman Scoring Form A) MOVEMENT WIDTH (ROM) a) Full extension, ROM > 120°
6
b) Full extension, ROM 90–120°
3
c) Loss of full extension, ROM < 90°
0
B) PAIN a) None or minimal on exertion
6
b) Moderate on exertion
3
c) In daily activity
0
C) WORK a) Original job
4
b) Different job
2
c) Unable to work
0
D) ATROPHY a) <12 mm
4
b) 12–25 mm.
2
c) >25 mm
0
E) SUPPORT USAGE a) None
4
b) Assistance required sometimes
2
c) Assistance required always
0
F) EFFUSION a) None
2
b) Reported to be present
1
Follow-up Protocol With stable fracture fastening provided during surgery, patients in splints were mobilized by crutches. Segmental load was given at a tolerable rate starting from day two post-surgery. Follow-ups were conducted at 1 month, 2 months, 3 months, 6 months, 12 months, and 24 months post-surgery.
c) Present
0
After radiological confirmation of union and clinical determination of reduced effusion in the knee, absence of wound site problems, passive joint movement width >90 degrees, tolerable pain, progression toward normal quadriceps power within 18–24 months on average, progressively active exercises were commenced in the patients. Quadricep power was evaluated by measuring the femoral diameter in each patient.
a) Normal
2
b) Difficult
1
c) Disabling
0
Patients were clinically and radiologically evaluated against controls. While evaluation of the degree of union was conducted using AP and auxiliary radiographs, functional evaluation of tangential patella radiographs was conducted using the Bostman scoring form [3] (table 1). Evaluation of the degree of PFA was performed using the Iwano evaluation scale [4] (Figure 1).
G) KNEE GIVING WAY a) None
2
b) Sometimes
1
c) In daily life
0
H) GOING UP AND DOWN THE STAIRS
The results were reported as follows: 28–30 points as excellent, 20–27 points as good, and <20 points as unsatisfactory. Statistical Evaluation All values including means, standard deviations, frequencies, and percentages were derived from descriptive statistics. The relationship between the fracture types and functional results and between degree of PFA and functional results were evaluated using both Kruskal Wallis and Spearman Correlation analyses. A p-value ≤0.05 was determined as statistically significant. Statistical analysis was done using the SPSS (Statistical Package for Social Sciences for Windows 18.0) software program. Results A total of 23 patients who completed their follow-ups, including 13 (57%) males and 10 (43%) females, were evaluated.
Figure 1. Classification of patellofemoral joint arthrosis (Iwano evaluation scale)
The average age of all patients included in the study was 48.4±15.3 (21–70) years. For all male patients, the average age was 47.2±17.4 (23 to 70 years). The average age for female patients was 49.9±14.3 426
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(21 to 66 years) in the females. We observed that patella fractures occurred earlier (20 to 45 years) in male patients and later (45 to 70 years) in female patients. Following evaluation of the fractures in accordance with the AO classification, 5 (22%) fractures were determined to be extraarticular (34-A1) and 18 (88%) fractures were intra-articular. 13 (57%) of the patients were operated due to left patella fractures, and 10 (43%) of the patients were operated due to right patella fractures. The average follow-up duration was 48.2±12.3 (25 to 124) months. The length of time between injury and surgery was an average of 2 (1-6 ± 1.4) days. Average hospitalization period was 3.6 (3-8±1.2) days. In 17 patients, the modified anterior tension band method was applied. Modified tension combined with peripheral wiring was applied in two patients. Fastening with screws was used in two patients. Peripheral wiring was used in another two patients. Functional results were obtained from all patients. Results were determined to be excellent in 16 (70%) patients, good in 6 (26%) patients, and unsatisfactory (4%) in one patient. In the patient with unsatisfactory results, there was a delay in rehabilitation because of a cerebrovascular event (CVE) post-surgery. Knee extension was >120 degrees in 21 patients and between 90 and 100 degrees in two of them. No patient experienced full loss of knee extension. Following radiological evaluation of the patients, it was observed that all fractures achieved full union. The degree of PFA was also evaluated. Type 1 PFA was observed in 5 (21%) patients, type 2 in 5 (22%) patients, type 3 in 8 (37%) patients, and type 4 in the remaining 5 (21%) patients. Of the 23 fractures, 18 were intra-articular and five were extraarticular. There was no statistically significant relationship between the functional results of the patients post-surgery and the fracture type (intra-articular or extra-articular) (p=0.651). After examining the effect of patella fracture type on the development of PFA, it was determined that PFA severity increased as the complexity of the fractures increased. This relationship was statistically significant (p≤0.05).
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The role of the patella in knee function is a major talking point in the treatment of patella fractures. Some authors suggest that the patella may not be necessary for knee function, and it could be excised, if fractured. Others maintain that the patella has an important place in knee function, and claim that it should be protected [6]. Although there is a consensus on the indications for surgical treatment in patella fractures, the rationale for selecting the surgical method of choice remains variable. Surgical methods are preferred in open patella fractures, patella fractures with retinaculum tear, patella fractures with displacement greater than 3 mm, and patella fractures with articular incongruity greater than 2 mm [5]. Yesiller et al compared Magnuson’s technique with the Mini External Fixator (MEF), the AO stretching band, and the modified AO stretching band techniques in a biomechanical study performed using five cadaveric knees. They determined that fixation with MEF provided the most stability, followed by the AO stretching band technique [7]. Burvant et al compared the modified tension band technique with the modified tension band technique with screws. They determined that the modified tension band with screws technique performed significantly better than did the modified tension band [8]. Of a total of 42 patients, Cakici et al applied fastening with the modified anterior tension band technique in 34 cases, fastening with the peripheral cerclage method in three cases, butterfly fixation fastening in two cases, fastening with the indirect reduction method in two cases and fastening with the external fixator in one case. Of the 34 cases in which the modified anterior tension band method was applied, results obtained were determined as excellent in 26 cases, good in six cases, and unsatisfactory in two cases [9]. Sim et al applied a combined modified tension band with cerclage method to a total of 22 patients including 16 with transverse patella fractures and six multi-part patella fractures. The results obtained were determined as excellent in 20 patients and good in two patients. It was thought that good stability positively impacted functional levels [10].
The primary goals in the treatment of the patella fractures are to provide anatomical reduction, mobilize the patient early, prevent the development of joint stiffness, and provide the best functional results possible.
In their study of 27 patients, Esenkaya et al utilized central transverse in 12 cases, subpolar “apical” in nine cases and segmental fracture fastening in six cases. They performed osteosynthesis including Magnuson’s technique for two patients (7.4%), standard tension band for 8 (29.6%) patients, and modified AO tension band method for 17 (63%) patients. The results observed in the last control of the cases were determined as excellent in 15 (55.6%) cases, good in 8 (29.6%) cases, and unsatisfactory in 4 (14.8%) cases, as determined by the Levack scoring system [11]. Of the four patients with unsatisfactory results, three of them had additional fractures in other bones. The fourth patient had a reoccurrence of the fracture because of a fall and underwent another surgery. Atrophic changes were observed radiologically in 8 (29.6%) cases, and required medication in some of the cases.
Treatment of patella fractures may be done conservatively or surgically. While conservative methods have been shown to be effective in non-displaced patella fractures, surgery should be the first treatment option in displaced patella fractures [5].
The initial fracture type has been considered as the most important factor affecting functional results post-surgery. It has been suggested that functional results obtained in transverse fractures were better than those obtained in segmental fractures. Saltzman
The degree of PFA was evaluated. It was determined that five patients were in phase 1, five patients were in phase 2, eight patients were in phase 3, and five patients were in phase four. It was observed that the degree of PFA did not affect the functional status of the patients (p≤0.515). Discussion
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et al showed that initial fracture type was the sole factor that affected their results [12]. In segmental fractures, poor fastening and rehabilitation insufficiency have been cited in literature as common reasons for failure. Of the 23 cases in our study, there were 18 intra-articular and five segmental fractures. Following evaluation by Bostman scoring, results obtained from our study were determined as excellent in 14 (76%) patients, good in 4 (19%) patients, and unsatisfactory in 1 (5%) patient. Although our sample size was smaller, fracture type did not statistically influence functional results. In the single patient with poor functional level in our study, we suspect that a combination of the patientâ&#x20AC;&#x2122;s age and immobilization following a cerebrovascular event may have been contributed to this unsatisfactory result. Of the ten patients treated by the peripheral cerclage wire method, Dimiski et al obtained results determined as good in three patients and unsatisfactory in two patients [13]. They suggested that the high percentage of unsatisfactory results using the peripheral cerclage wire method was due to poor fixation. Yang et al operated on 21 patients with multi-part patella fractures. They applied the tension band method using titanium cables. They determined the functional levels to be excellent in 17 patients and good in four patients. They attributed their successful results to the early commencement of exercises in the post-surgical period [14]. In our study, the cerclage method was applied in two patients, with excellent result in one and good in the other. Both fractures were intra-articular in nature. One of the fractures was a segmental fracture. Although this method did not provide optimum stability, we believe that early movement and appropriate rehabilitation had a positive effect on the results. Yavarikia et al applied diagnostic arthroscopy to 22 patients with transverse patella fractures. Surgeries were conducted using the modified tension band method. A normal patellofemoral cartilage finding was observed in five patients. Phase I chondral lesions were observed in 10 patients, phase II chondral lesions in four patients, and phase III chondral lesions in three patients. There was no statistically significant relationship between the functional level of the patients and the radiologic findings observed [15]. Tukenmez et al operated on 50 patients with patella fractures including 27 segmental (satellite) fractures, 13 transverse fractures, 8 distal pole fractures, 1 chondral fracture, and one longitudinal fracture. Of the 50 cases, osteosynthesis with modified AO tension band technique was applied in 25 (50%) cases, osteosynthesis with screw, and Kirschner wires was applied in 10 (20%) cases, segmental patellectomy was used in 6 (12%) cases, tension band combination was used in 8 (16%) cases, and arthroscopic manipulation was applied in 1 (2%) case. Results obtained from this study were determined as unsatisfactory in 13 (26%) cases, good in 21 (42%) cases, and excellent in 16 (32%) cases [16]. Additional pathologies in three patients and an open fracture in another patient may have contributed to the number of unsatisfactory results obtained. Degeneration of the patellofemoral joint was observed in only four patients. In our study, the degree of patellofemoral arthrosis was determined
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as type 1 in 5 patients, type 2 in 5 patients, type 3 in 8 patients, and type 4 in 5 patients. Although the fracture type negatively affected the degree of PFA, we determined that the degree of PFA did not have a negative effect on the functional level observed in the patients. We think the most important reason here that lending assistance of the surgery method applied in feeding the cartilage and forming the joint surface by allowing to the early movement and in protecting the knee movement width with the early rehabilitation. Karim et al operated on 18 patients with transverse closed isolated patella fractures. Surgeries were performed using the modified tension band method. The following complications were observed: superficial infection in three patients, wire migration in two patients, wire fracture in three patients, and displacement greater than 2 mm in one patient [17]. Following antibiotic treatment, infections observed were resolved. Additional surgical intervention was not necessary for any of the observed complications. An extension constraint of 25 degrees was observed in patients whose displacement was â&#x2030;Ľ 2 mm. In our study, there were no occurrences of union delay or failure of union among our patients. Implant irritation occurred in eight patients. of these 8 patients, the implants had to be removed from four of them. Wire migration was observed in three patients, and wire rupture occurred in two patients. The implants in these 5 patients had to be removed, as they caused pain and extension constraint during movements of the knee joint. Conclusion In conclusion, we evaluated clinical and radiological results following surgical treatment of patella fractures using peripheral wiring, modified anterior tension band, and cannula screw methods. Our results in the medium term are good. We also observed that fracture type did not affect the clinical results, although it was positively correlated with the degree of PFA. However, we believe that the degree of PFA does not affect the functional results of the patients. Finally, we believe that early commencement of knee joint rehabilitation exercises post-surgery is an important factor in achieving good clinical results. Financial Disclosure All authors declare no financial support. Ethical approval Ethical approval: This article contains studies with human participants and This article does not contain any studies or animal participant performed by any of the authors. Sadullah Turhan ORCID:0000-0003-2186-6519
References 1.
Canale ST, Beaty JH. Campbellâ&#x20AC;&#x2122;s operative orthopaedics: expert consult premium edition-enhanced online features, Elsevier Health Sciences 2012.
2.
Suh KT, Suh JD, Cho HJ. Open reduction and internal fixation of comminuted patellar fractures with headless compression screws and wiring technique. J Orthop Sci. 2018;23:97-104.
3.
Wild M, Fischer K, Hilsenbeck F, et al. Treating patella fractures with a fixedangle patella plate-A prospective observational study. Injury. 2016;47:173743.
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4.
Grelsamer RP, Dejour D, Gould J. The pathophysiology of patellofemoral arthritis. Orthop Clin North Am. 2008;39:269-74.
11. Esenkaya I, Kafadar A, Bombaci H, et al. The results of the surgical treatment of patellar fractures. Acta Orthop Traumatol Turc. 2004;28:366-9.
5.
Blum L, Hake M. ORIF patella fracture with a tension band construct. J Orthop Trauma. 2017;31 Suppl 3:8-9.
6.
Ege R. Diz Anatomisi. Diz sorunları. Editör Ege R. 1998;3:27-54.
12. Saltzman C, Goulet J, McClellan R, et al. Results of treatment of displaced patellar fractures by partial patellectomy. J Bone Joint Surg Am. 1990;72:1279-85.
7.
Yesiller E, Durmaz H, Cakmak M, et al. A Biomechanical study on a new mini external fixator developed in our clinics for transverse patellar fractures. Acta Orthop Traumatol Turc. 2004;24:163-7.
13. Dimiski G, Akan KH, Poyanli OS, et al. Results of surgical treatment in patellar fractures. Acta Orthop Traumatol Turc. 2004;30:377-80. 14. Yang L, Yueping O, Wen Y. Management of displaced comminuted patellar fracture with titanium cable cerclage. Knee. 2010;17:283-6.
8.
Burvant JG, Thomas KA, Alexander R, et al. Evaluation of methods of internal fixation of transverse patella fractures: a biomechanical study. J Orthop Trauma. 1994;8:147-53.
15. Yavarikia A, Davoudpour K, Amjad GG. Patella on patellofemoral articular cartilage in follow up arthroscopy. Pak J Biol Sci. 2010;13:235-9.
9.
Çakıcı ÇT, Behçet S. Patella kırıklarının cerrahi tedavisi. Turkis J Arthrop Arthroscop Surg. 2000;11:18-23.
16. Cekin T, Tukenmez M, Tezeren G. Comparison of three fixation methods in transverse fractures of the patella in a calf model. Acta Orthop Traumatol Turc. 2004;40:248-51.
10. Sim JC, Ha SS, Hong KD, et al. Circumferential wiring combined with tension band wiring in the operative treatment of patella fracture. J Korean Fracture Society. 2014;27:65-71.
17. Karim MRU, Rahman M, Howlader MAR, et al. Fracture patella-outcome of early movement of knee after stable fixation. Journal of Armed Forces Medical College, Bangladesh. 2009;5:11-3.
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ORIGINAL RESEARCH
Medicine Science International Medical Journal
Medicine Science 2019;8(2):426-9
Evaluation of 62 bullous pemphigoid patients Ibrahim Halil Yavuz1, Goknur Ozaydin Yavuz1, Serap Gunes Bilgili1, Kubra Tatar1, Irfan Bayram2 1
Yuzuncu Yil University Faculty of Medicine, Department of Dermatology, Van, Turkey 2 Yuzuncu Yil University Faculty of Medicine, Department of Pathology, Van, Turkey Received 29 August 2018; Accepted 24 September 2018 Available online 13.11.2018 with doi:10.5455/medscience.2018.07.8927 Copyright Š 2019 by authors and Medicine Science Publishing Inc.
Abstract Bullous pemphigoid (BP) is an acquired autoimmune disease often manifesting with subepidermal bullae. Autoantibodies against hemidesmosomes constitute the main cause of BP. In this study, we aimed to evaluate the clinical and histopathological characteristics of BP patients and to discuss them in light of the studies conducted in Turkey and around the world. The retrospective study included 62 patients that were diagnosed with BP in our clinic between 2005 and 2017. Diagnosis of BP was established based on clinical, histopathological, and DIF microscopy findings. Age, gender, duration of disease, presence of pruritus, peripheral eosinophilia, significant histopathological findings, history of smoking, and family history were recorded for each patient. Patients under 18 years of age were excluded from the study. The 62 patients comprised 24 (38.7%) men and 38 (61.3%) women with a median age of 72.0 years. The male-to-female ratio was 1.5. The median age at disease onset was 67.0 (range, 50-75) years and the median duration of disease was 1.0 (0.5-3.0) years. Of the 62 patients, 35 (56.5%) had a history of smoking and mucosal involvement was found in 27 (43.5%) patients. BP is a disease of the elderly and more common in women than in men. Oral mucosa should be an integral part of the physical examination in BP patients. Pruritus is a significant clinical symptom and eosinophilia is an important laboratory marker in the diagnosis of BP, particularly in patients with difficult diagnosis. Keywords: Bullous pemphigoid, smoking, pruritus
Introduction Bullous pemphigoid (BP) is an acquired autoimmune disease that often manifests with subepidermal bullae and is characterized by linear deposition of immunoglobulin G (IgG) and/or C3 along the epidermal basement membrane zone. Autoantibodies against hemidesmosomes constitute the main cause of BP. BP mostly affects the elderly and is more common in women than in men. Moreover, it is a common disease around the world and also the most common immunobullous disease in Europe [1]. Bullous pemphigoid (BP) may start with pruritus in the prodromal stage, which may last for several days to several months. Classical BP is characterized by tense, hemorrhagic bullae of 1-3 cm diameter that appear on erythematous skin. BP mostly involves the axillae, groins, legs, and lower abdomen. The bullae in BP *Coresponding Author: Ibrahim Halil Yavuz, Yuzuncu Yil University Faculty of Medicine, Department of Dermatology, Van, Turkey E-mail: ihalilyavuz@gmail.com
typically heal without scars after becoming eroded and crusted areas. Skin or mucosal lesions are often not life-threatening, but mortality rate is relatively higher in the elderly [2]. Diagnosis of BP is based on clinical features, direct immunofluorescence (DIF) microscopy, and presence of circulating autoantibodies. Laboratory tests can be normal in 10% of the patients [3]. Bullous pemphigoid (BP) is a self-limiting disease which may last from several months to a few years. BP may relapse in some patients during the first year of treatment. The primary step in the treatment of BP is to stop the provoking drug and treat underlying malignancy, if identified any. Mainstay treatment of BP includes immunosuppressive drugs, mostly including topical corticosteroids [2,4]. In this study, we aimed to evaluate the clinical and histopathological characteristics of BP patients and to discuss them in light of the studies conducted in Turkey and around the world. 426
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Material and Methods The retrospective study included 62 patients that were diagnosed with BP in our clinic between 2005 and 2017. Diagnosis of BP was established based on clinical, histopathological, and DIF microscopy findings. Typical histopathological features of BP included subepidermal splitting and mixed inflammatory infiltrate, whereas typical DIF microscopy pattern was linear deposition of IgG and/or C3 along the epidermal basement membrane zone. Patients with nonbullous BP, those that could not be diagnosed histopathologically, and patients under 18 years of age were excluded from the study. Age, gender, duration of disease, presence of pruritus, peripheral eosinophilia, significant histopathological findings, history of smoking, and family history were recorded for each patient. The study was conducted in accordance with the Helsinki Declaration and was initiated after an approval was obtained from the local ethics committee. Statistical Analysis Data were analyzed using SPSS for Windows version 17.0 (SPSS Inc. Co, Chicago, IL, USA). Normal distribution of data was tested using histogram plots and the Kolmogorovâ&#x20AC;&#x201C;Smirnov test. Descriptive statistics were expressed as median and percentiles (25-75). Results The 62 patients comprised 24 (38.7%) men and 38 (61.3%)
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women with a median age of 72.0 years. The male-to-female ratio was 1.58. DIF microscopy indicated C3 deposition in 12 (19.4%), C3 + IgG deposition in 30 (48.4%), IgG deposition in 6 (9.7%), and no deposition in 14 (22.6%) patients. Although no comorbidity was found in 28 (45.2%) patients, brain tumor was found in 1 (1.6%), diabetes mellitus (DM) in 12 (19.4%), hypertension (HT) in 11 (17.7%), and cerebrovascular diseases (CVDs) in 10 (16.1%) patients. Of the 62 patients, 27 (43.5%) patients were using less than 3 drugs, 19 (30.6%) were using 3-5 drugs, 4 (6.5%) were using more than 5 drugs, and 12 (19.4%) had no drug history. The bullae were localized in the extremities + body in 21 (30.6%), extremities only in 35 (56.4%), and body only in 6 (9.7%) patients. Of the 62 patients, 35 (56.4%) had a history of smoking and mucosal involvement was found in 27 (43.6%) patients. The most common drugs used in the treatment of BP were systemic steroids (n= 36; 58.1%), followed by topical steroids (n=19; 30.6%), topical antibiotics (n=3; 4.8%), intravenous immunoglobulin (IVIG) (n=2; 3.2%), and dapsone (n=1; 1.6%). Pruritus was present in 51 (82.3%), treatment-related complications occurred in 2 (3.2%), and eosinophilia occurred in 25 (33.9%) patients. The skin lesions manifested with bullae in 10 (16.130%), polymorphic lesion in 25 (40.322%), eroded plaques in 1 (1.613%), eroded-ulcerated lesions in 1 (1.613%), and vesicular bullae in 25 (40.322%) patients. The median age at disease onset was 67.0 (range, 50-75) years and the median duration of disease was 1.0 (0.5-3.0) years (Table 1, Table 2).
Table 1. Demographic, laboratory, and clinical characteristics - 1 n
%
Male
24
(38.7)
Female
38
(61.3)
Age (years) DIF findings
Comorbidity
Drug usage
Lesion site
Smoking Mucosal involvement
72.00
(54.00-78.00)
C3 deposition
12
(19.4)
C3 + IGG deposition
30
(48.4)
IGG deposition
6
(9.7)
No deposition
14
(22.6)
None
28
(45.2)
Brain tumor
1
(1.6)
DM
12
(19.4)
HT
11
(17.7)
CVD
10
(16.1)
None
12
(19.4)
Less than 3 drugs
27
(43.5)
3-5 drugs
19
(30.6)
More than 5 drugs
4
(6.5)
Extremities + Body
21
(30.6)
Extremities
35
(56.4)
Body
6
(9.7)
No
27
(43.5)
Yes
35
(56.5)
No
35
(56.5)
Yes
27
(43.5)
HT: hypertension; DM: Diabetes mellitus; for quantitative variables, median was used in lieu of n value and percentiles (25-75) were used in lieu of %.
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Table 2. Demographic, laboratory, and clinical characteristics - 2
Drugs
Pruritus Treatment complications Eosinophilia
Lesions
n
%
Dapsone
1
(1.6)
IVIG
2
(3.2)
Systemic steroids
36
(58.1)
Topical antibiotics
3
(4.8)
Topical steroids
19
(30.6)
No
11
(17.7)
Yes
51
(82.3)
No
60
(96.8)
Yes
2
(3.2)
No
41
(66.1)
Yes
21
(33.9)
Bullae
10
(16.130)
Polymorphic lesion
25
(40.322) (1.613)
Eroded plaques
1
Eroded-ulcerated lesions
1
(1.613)
Vesicular bullae
25
(40.322)
Age at disease onset (years)
67.0
(50.0-75.0)
Duration of disease (years)
1.0
(0.5-3.0)
For quantitative variables, median was used in lieu of n value and percentiles (25-75) were used in lieu of %.
Discussion
median rate between the rates reported by other studies.
The results indicated that BP is a disease of the elderly and mucosal involvement can be commonly seen in BP patients. Although BP can be seen at any age, it mostly affects patients older than 60 years of age [2,3]. Banihashemi et al. [1] reported that more than 78% of their patients were aged over 60 years and Fรถrsti et al. [5] reported a mean age of 77 years for their patients. In our patients, mean age was 72 years, which was consistent with the literature.
Pruritus is known to be a significant clinical symptom in BP patients. Yazici et al. [12] detected pruritus in 73%, Akay et al. [9] detected in 77.4%, Ekiz et al. [10] detected in 82.8% , and Pascal et al. [4] detected in 93% of the patients. In our study, pruritus was detected in 82.3% of the patients, which suggests that pruritus is a significant clinical symptom in BP patients.
Bullous pemphigoid (BP) is more common in women than in men. However, a study conducted in Switzerland [6] reported that there was a male preponderance in their BP patients and another study that was conducted in USA [7] reported that the male-to-female ratio was similar. Nevertheless, a study conducted in Kuwait [8] revealed that BP was five times more common in women than in men among their patients. In our study, the female-to-male ratio was 1.58, which confirms the hypothesis that autoimmune diseases are more common in women than in men. Mucosal involvement in BP can be seen in 10-30% of the patients. Akay et al. [9] reported that mucosal involvement was present in 12.9% and Ekiz et al. [10]. reported that mucosal involvement was found in 17.2% of their patients. In our study, mucosal involvement was present in 43.5% of the patients, which was remarkably higher than the rates reported in previous studies. Both our study and the previous studies indicate that mucosal involvement should be taken care of during the physical examination of BP patients. Bullous pemphigoid (BP) typically manifests with vesicles and bullae that appear on erythematous skin. Esmaili et al. [11] and Banihashemi et al. [1] both evaluated BP in Iranian patients and reported that bullae were detected in 97.5% and 27.3% of the patients, respectively. In our study, bullae accompanied by vesicles or bullae alone were detected in 56.4% of the patients, which was a
Peripheral eosinophilia and elevated serum total immunoglobulin E (IgE) levels have been implicated in some BP patients (2). Esmaili et al. [11] found peripheral eosinophilia in 30.3% , a Taiwanese study [13] found in 22.1%, and Kizilyel et al. [14] found in 13.2% of the patients. In our study, peripheral eosinophilia was detected in 33.9% of the patients. Taken together, all these rates implicate that peripheral eosinophilia can be a supportive diagnostic marker of BP, particularly in patients with difficult diagnosis. Smoking is a significant factor for the development of BP. A history of smoking was detected in 24% of the patients in the study by Akarsu et al. [15] and in 23.6% of the patients evaluated by Alexandre et al. [16]. However, in our study, 56.5% of the patients had a history of smoking, which was higher than the rates reported by other studies. All these rates implicate that smoking is an aggravating factor for BP. Bullous pemphigoid (BP) is a chronic disease with varying duration of disease. Sophan et al. [17] reported that the mean duration of disease was 2.1 months, Ekiz et al. [10] reported a mean duration of 15.4 months, and Yazici et al. [12] reported a mean duration of 9.8 months for their patient series. In our study, the mean duration of disease was 1 year, which was consistent with the literature. Coexistence of BP with various diseases has been reported in numerous studies. These diseases mainly include neuropsychiatric 428
doi: 10.5455/medscience.2018.07.8927
disorders, tumors, DM, HT, and autoimmune diseases [2,3]. Kibsgaard et al. [18] evaluated 98 patients with BP and reported that 70 patients were accompanied by cardiovascular diseases, 37 patients by neurologic disease, 15 patients by DM, and 14 patients by cancer. Similarly, Kizilyel et al. [14] evaluated 46 patients with BP and revealed that 28 patients had HT, 21 patients had CVD, 17 patients had DM, and 4 patients had cancer. In our study, 12 patients had DM, 11 patients had HT, 10 patients had CVD, and 1 patient had tumor. Although these rates were similar to those reported in the literature, the only difference was that the incidence of cancer in our patients was relatively lower. Factors that facilitate BP in genetically predisposed individuals are various. These are drug intake (eg, furosemide, enalapril, ıbuprofen, ampicillin, sulfonamide), physical agents (eg, ultraviolet, thermal or electrical burns, or surgical procedures), vaccinations (eg, antiinfluenza vaccine, tetanus toxoid), diet (eg, gluten), infections (eg, cytomegalovirus, epstein-barr virus, HHV-6, hepatitis B and C viruses, helicobacter pylori, toxoplasma gondii) [19]. In our study, the majority of patients were taking medication. Especially the use of antihypertensive drugs was high. But we could not detect many of the other triggering agents. Common agents used in the treatment of BP include topical corticosteroids, systemic corticosteroids, azathioprine, mycophenolate mofetil, methotrexate, dapsone, intravenous immunoglobulin, plasmapheresis, rituximab, and omalizumab [2,3,20]. Ekiz et al. [10] reported that 37% of the patients received topical corticosteroids and 34.5% of the patients received systemic corticosteroids. Moreover, Kibsgaard et al. [18] reported that 67.3% of the patients received topical corticosteroids. In our study, 30.6% of the patients received topical corticosteroids and 58.1% of the patients received systemic corticosteroids. These findings implicate that corticosteroids are the mainstay treatment of BP. Our study was limited in several ways. First, it was a single-center study. Secondly, it had a relatively small patient series. Thirdly, no evaluation was performed for serum IgE levels. Conclusion In conclusion, BP is a disease of the elderly and more common in women than in men. Oral mucosa should be an integral part of the physical examination in BP patients. Pruritus is a significant clinical symptom and eosinophilia is an important laboratory marker in the diagnosis of BP, particularly in patients with difficult diagnosis. However, further multicenter, prospective studies are needed to substantiate our findings. Competing interests The authors declare that they have no competing interest Financial Disclosure The financial support for this study was provided by the investigators themselves. Ethical approval Our study was approved by the local ethics review board. Ibrahim Halil Yavuz ORCID: 0000-0003-0819-2871 Goknur Ozaydin Yavuz ORCID: 0000-0002-8500-315X Serap Gunes Bilgili ORCID ID: 0000-0002-4685-885X
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Kubra Tatar ORCID: 0000-0001-5014-0069 Irfan Bayram ORCID: 0000-0001-5014-0070
References 1.
Banihashemi M, Zabolinejad N, Vahabi Set al. Survey of bullous pemphigoid disease in northern Iran. Int J Dermatol. 2015;54:1246-9.
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Bağcı IS, Horváth ON, Ruzicka T, et al. Bullous pemphigoid. Autoimmun Rev. 2017;16:445-55.
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Bernard P, Antonicelli F. Bullous pemphigoid: A review of its diagnosis, associations and treatment. Am J Clin Dermatol. 2017;18:513-28.
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Joly P, Baricault S, Sparsa A, et al. Incidence and mortality of bullous pemphigoid in France. J Invest Dermatol. 2012;132:1998-2004.
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Försti AK, Jokelainen J, Timonen M, et al. Increasing incidence of bullous pemphigoid in Northern Finland: a retrospective database study in Oulu University Hospital. Br J Dermatol. 2014;171:1223-6.
6.
Marazza G, Pham HC, Schärer L, et al. Autoimmune bullous disease Swiss study group. Incidence of bullous pemphigoid and pemphigus in Switzerland: a 2-year prospective study. Br J Dermatol. 2009;161:861-8.
7.
Colbert RL, Allen DM, Eastwood D, et al. Mortality rate of bullous pemphigoid in a US medical center. J Invest Dermatol. 2004;122:1091-5.
8.
Nanda A, Al-Saeid K, Al-Sabah H, et al. Clinicoepidemiological features and course of 43 cases of bullous pemphigoid in Kuwait. Clin Exp Dermatol. 2006;31:339-42.
9.
Akay BN, Bodamyalı P, Şanlı H, et al. Büllöz pemfigoidli hastalarda 10 yıllık gözlem. Turkderm. 2010;44:61-4.
10. Ekiz Ö, Bülbül Şen B, Rifaioğlu EN, et al. Büllöz pemfigoidli hastalarda 3 yıllık gözlem: 29 olgu. Turkderm. 2013;47:205-8. 11. Esmaili N, Hallaji Z, Soori T, et al. Bullous pemphigoid in Iranian patients: a descriptive study on 122 cases. Acta Med Iran. 2012;50:335-8. 12. Yazıcı S, Başkan EB, Tunalı Ş, et al. Retrospective analysis of forty-six patients with bullous pemphigoid followed-up in our clinic. Turkderm. 2016;50:114-8. 13. Chang YT, Liu HN, Wong CK. Bullous pemphigoid: a report of 86 cases from Taiwan. Clin Exp Dermatol. 1996;21:20-2. 14. Kızılyel O, Elmas ÖF, Bilen H, et al. Bullous pemphigoid in Erzurum:A 10 year retrospective study. Turkderm. 2015;49:66-9. 15. Akarsu S, Özbağçivan Ö, Dolaş N, et al. Possible triggering factors and comorbidities in newly diagnosed autoimmune bullous diseases. Turk J Med Sci. 2017;47:832-40. 16. Alexandre M, Brette MD, Pascal F, et al. A prospective study of upper aerodigestive tract manifestations of mucous membrane pemphigoid. Medicine (Baltimore). 2006;85:239-52. 17. Sobhan M, Farshchian M, Tamimi M. Spectrum of autoimmune vesiculobullous diseases in Iran: a 13-year retrospective study. Clin Cosmet Investig Dermatol.2016;9:15-20. 18. Kibsgaard L, Bay B, Deleuran M, et al. A retrospective consecutive caseseries study on the effect of systemic treatment, length of admission time, and co-morbidities in 98 bullous pemphigoid patients admitted to a tertiary centre. Acta Derm Venereol. 2015;95:307-11. 19. Lo Schiavo A, Ruocco E, Brancaccio G, et al. etiology, pathogenesis, and inducing factors: facts andcontroversies. Clin Dermatol. 2013;31:391-99. 20. Daye M, Mevlitoğlu İ, Esener S. Bullous disorders in Konya: A study of 93 cases: Turkderm. 2013;47:200-4.
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Available online at www.medicinescience.org
ORIGINAL RESEARCH
Medicine Science International Medical Journal
Medicine Science 2019;8(2):430-5
Nutritional status of elderly people living in nursing home and some related factors Recep Bentli1, Nese Karakas2, Betul Firinci3, Serdar Deniz4 1 Inonu University, Faculty of Medicine, Department of Internal Medicine, Malatya, Turkey Inonu University, Vocational School of Health Services, Department of Health Care Services, Malatya, Turkey 3 Inonu University, Faculty of Medicine, Department of Public Health, Malatya, Turkey 4 Malatya Provincial Directorate of Health, Malatya, Turkey
2
Received 10 April 2019; Accepted 25 April 2019 Available online 30.05.2019 with doi:10.5455/medscience.2019.08.9039 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract The aim of this research is to evaluate the nutritional status of elderly people residing in a nursing home and to examine the relationship of the results with chronic diseases. The sampling of the descriptive and cross-sectional research consists of 65 nursing home residents. The data of the research were collected through the Personal Information Form, Mini Nutritional Assessment Test (MNA), Hand Grip Strength Test, Activities of Daily Living Scale and Geriatric Depression Scale. In the analysis of the data, p<0.05 value was accepted as statistically significant. The mean MNA score of the participants was calculated as 22.24±4.8; malnutrition was found in 15.4% and malnutrition risk was detected in 41.5%. There was a statistically significant positive relationship between the MNA scores and hand grip strengths of the participants (r=0.299, p<0.05). Low hand grip strength was discovered in 52.3% of the participants. There was no significant difference among the distribution of MNA scores according to the chronic diseases of the participants (p>0.05). MNA scores of the participants who had depression were found to be significantly low (p<0.05). As the dependency level in the activities of daily living increased, hand grip strength (r=-362, p˂0.01) and MNA scores (r=-596, p˂0.01) decreased significantly. Keywords: Malnutrition, nutrition, nursing home, elderly people
Introduction Demographic aging is the decrease in the rate of children and young people in the total population and the increase in the rate of elderly population [1]. Turkey is one of the countries that experience the most rapid demographic aging process. In Turkey, the rate of the people over 65 was specified as 8.5% in 2017. According to population projections, this rate is expected to reach 10.2% in 2023 and 22.6% in 2060 [2]. The main topic coming to the forefront in the increase in the expected length of life after birth and the increase in the rate of elderly people in the society is healthy aging, i.e., the quality of aging. The factors effective in the quality of aging are healthy eating, physical activity, being a non-smoker, regular physical activity, and control of chronic diseases [3]. The deficiency, excesses or imbalances in energy and/or food intake are defined as malnutrition [4,5]. Although malnutrition affects every age group, it is more complicated in elderly people than young people. The studies conducted reveal that malnutrition reduces the quality of life in the elderly; and it is *Coresponding Author: Nese Karakas, Inonu University, Vocational School of Health Services, Department of Health Care Services, Malatya, Turkey E-mail: nese.karakas@inonu.edu.tr
the determinant of morbidity and mortality [6,7]. The presence of comorbidity in elderly people, level of functional dependency, bereavement of spouse, low level of education were associated with malnutrition [8,9]. Early diagnosis and effective treatment of malnutrition can prevent potential morbidity and mortality [10]. The most frequently used screening tool for the screening of malnutrition in elderly people is the Mini Nutritional Assessment Test. In addition, since muscle function is affected by malnutrition in early period, it is recommended that hand grip strength should be used as an early diagnostic tool in the determination of malnutrition risk [10-12]. The aim of this study is to evaluate the nutritional status of people living in Malatya Nursing Home and to analyze the relationship between the results and chronic diseases. Material and Methods The research was conducted in descriptive and cross-sectional type in Malatya Nursing Home between 01-15 November 2018. The universe of the research consists of the elderly people (n= 80) residing in Malatya Nursing Home on the dates when the research was conducted. The research aims to reach the whole universe without using any sampling method. 65 (81.0%) nursing home 430
doi: 10.5455/medscience.2019.08.9038
residents who accepted to participate in the research were included in the research. Data collection tools The data of the research were collected through the Personal Information Form, Mini Nutritional Assessment Test, Hand Grip Strength Test, Activities of Daily Living Scale and Geriatric Depression Scale. Mini Nutritional Assessment Test (MNA): MNA test consists of 18 questions as 15 verbal and 3 anthropometric measurements. The first section of the MNA test consists of 6 questions, and those receiving a score of 11 and below out of 14 scores are considered as risky groups in terms of malnutrition and they continue to the second section of the test with 12 questions. The total MNA score between 23.5-30.0 is accepted as normal nutritional status, a score between 17.0-23.0 is accepted as malnutrition risk, and a score lower than 17.0 is accepted as malnutrition [11,12]. The Turkish validity and reliability of the test was performed by Sarıkaya [13].
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was taken from Malatya Provincial Directorate of Family and Social Policies in order to conduct the research in Malatya Nursing Home. Results The age means of the nursing home residents in the research were 77.4±8.7 and 60% of them were 85 years old and above. 52.3% of the participants were women, 52.3% were divorced or their spouse had died, and 40% were illiterate. Participants’ MNA score means were 22.24±4.8; malnutrition was observed in 15.4% and the risk of malnutrition in 41.5% (Figure 1).
Hand Grip Strength Measurement Test: Hand grip strength measurement of the participants was performed by Jamar Hydraulic Hand Dynamometer. The hand grip strength of the participants was determined by calculating the mean of the values by measuring three times from the dominant hand. In this research, <20 kg in females and <30 kg in males were accepted as low hand grip strength in line with the literature [14,15]. Activities of Daily Living Scale (ADL): It is a 9-item scale that questions the functions of dressing, eating, toilet, transfer, personal hygiene, bed movement, locomotion and continence. Each item is evaluated through 3 points (0= independent, 1= controlled, 2= assisted, 3= dependent). It is accepted that the functional capacity decreases as the score increases in the ADL scale [16,17]. Geriatric Depression Scale (GDS): It was developed by Yesavage et al. in 1983 for the depression scanning of the elderly population. In terms of its ease of use, Burke et al. proved the validity and reliability of the 15-item short form [18,19]. The Turkish validity and reliability of the test was performed by Ertan et al. [20]. In this research, the short form of GDS was used and the scores above 5 were accepted as depression risk.
Figure 1. Distribution of Nutritional Status by MNA Scores
The mean hand grip strength of the nursing home residents in the research was found as 21.08±11.09. Low hand grip strength was discovered in 52.3% of the participants. As seen in Figure 2, there is a statistically significant positive relationship between the MNA scores and the hand grip strengths of the participants (r=0.299, p ˂0.05).
Statistical assessment of the data SPSS 21.0 (Statistical Package for Social Sciences) was used for the analysis of the data obtained. The research data did not exhibit a normal distribution according to the Kolmogorov-Smirnov test, and they were not homogenous in respect to Levene’s test (p<0.05). The Man-Whitney U test and the Kruskal-Wallis test were used for discovering the difference between the groups in the independent samplings. The Tamhane test was used to specify between which groups there was a significant difference in more than two independent samplings. The Spearman Correlation coefficient was used in the analysis of the continuous variables. The chi-square test was used for the assessment of the categorical data. p<0.05 was considered statistically significant. Research ethics The ethics committee approval was received from the NonInterventional Research Ethics Committee of İnönü University before beginning the research (2018/12-12). A written permission
Figure 2. Relationship Between Hand Grip Strength and MNA Scores
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The comparison of the MNA scores is given according to the defining characteristics of the participants in Table 1. While the MNA score distribution of the participants did not differ as to the conditions of gender, age, marital status, education, having
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children and smoking (p˃0.05), the distribution of their MNA scores differed according to their condition of doing physical activities; the group which created difference was the one who went walking regularly (p˂0.05).
Table 1. Comparison of MNA scores according to descriptive characteristics of nursing home residents n
Gender
Age
Educational Background
Marital Status
Smoking
%
Median
Min.- Max.
Female
34
52.3
24.50
12.00-29.00
Male
31
47.7
22.00
7.50-28.50
60-74 years
6
9.2
24.75
75-84 years
20
30.8
21.50
7.50-29.00
85 years and above
39
60.0
24.50
13.00-28.00
Statistical values z
p
-1.348
0.178
KW
p
3.732
0.155
KW
p
2.103
0.349
KW
p
2.103
0.349
KW
p
3.864
0.144
KW
p
8.417
0.015
17.00-26.50
Illiterate
26
40.0
22.15
7.50-28.50
Primary School
30
46.2
23.75
13.50-29.00
Secondary school and above
9
13.8
25.00
19.50-27.00
Single
20
30.8
23.05
14.50-24.50
Married
11
16.9
27.20
7.50-28.00
Other
34
52.3
34.73
8.00-29.00
Yes
14
21.5
24.50
16.50-27.50
No
36
55.4
21.50
8.00-29.00
I quit
15
23.1
25.00
7.50-28.00
* Regular walking
25
38.5
35.04
13.00-28.50
Occasionally walking
28
43.1
37.23
8.00-29.00
No walking
12
18.5
18.88
7.50-26.50
*the group creating the difference KW=Kruskal-Wallis Test Z=Mann-Whitney U Test
The distribution of the MNA scores is given in Table 2 with respect to the chronic diseases of the nursing home residents. 50.8% of the participants had hypertension, 26.2% had osteoarthritis, 21.5% had diabetes, 18.5% had COPD, and there were no significant differences between the MNA score distributions according to these chronic diseases (p>0.05). But there were significant differences between the MNA score distributions according to dementia (p˂0.05). The GDS could be applied to 59 participants due to their cognitive conditions and depression was observed in 11.9%. The MNA scores of those with the diagnosis of depression were found significantly low (p˂0.05). As seen in Figure 3, as the ages of the nursing home residents in the research increased, their hand grip strengths decreased (r=-0.253, p ˂0.05). As presented in Table 3, the low hand grip strength ratio was significantly higher in male participants than the female ones.
(X2= 23.667, p˂0.01). When the hand grip strength means were examined according to the chronic diseases of the participants, it was seen that the hand grip strengths of the participants with depression were lower than the ones without depression (Table 4). When we categorized the nursing home residents in the research as to their levels of executing activities of daily living, 76.9% were independent, 13.8% were completely dependent. The relationship between the dependency levels, nutritional status and hand grip strengths of the nursing home residents is given in Table 5. As the dependency level in the activities of daily living increased, hand grip strength (r=-362, p˂0.01) and MNA scores (r=-596, p˂0.01) decreased significantly. 432
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Table 2. Comparison of MNA scores according to chronic diseases of nursing home residents
Hypertension Osteoarthritis Diabetes COPD Dementia Depression
n
%
Median
Min.- Max.
Yes
33
50.8
22.30
13.50-29.00
No
32
49.2
23.75
7.50-28.00
Yes
17
26.2
21.50
12.00-29.00
No
48
73.8
22.35
7.50-28.50
Yes
14
21.5
23.65
15.50-28.00
No
51
78.5
23.00
7.50-29.00
Yes
12
18.5
23.00
7.50-29.00
No
53
81.5
24.50
17.50-28.00
Yes
8
12.3
18.50
12.00-27.00
No
57
87.7
23.50
7.50-29.00
Yes
7
11.9
18.00
8.00-25.00
52
88.1
24.50
7.50-29.00
z
p
-0.47
0.636
-0.62
0.325
-0.47
0.482
-1.21
0.226
-1.97
0.048
-2.27
0.023
Z=Mann-Whitney U Test Table 3. Distribution of Hand Grip Strengths according to gender of nursing home residents
Gender
Low Hand Grip Strength
Normal Hand Grip Strength
n
%
n
%
X2
p
Female
8
23.5
26
76.5
23.667
˂0.001
Male
26
83.9
5
16.1
Table 4. Comparison of hand grip strengths according to chronic diseases of nursing home residents
Hypertension Osteoarthritis Diabetes COPD Dementia Depression
n
%
Median
Min-Max
Yes
35
50.8
17.30
2.00-40.00
No
30
49.2
24.30
1.00-41.00
Yes
17
26.2
15.30
3.60-32.00
No
48
73.8
24.45
1.00-51.00
Yes
14
21.5
19.80
4.30-40.0
No
51
78.5
21.30
1.00-41.00
Yes
12
18.5
15.30
4.30-44.00
No
53
81.5
22.00
1.00-41.00
Yes
8
12.3
15.45
1.00-32.00
No
57
87.7
22.00
2.00-51.00
7
11.9
22.50
3.60-41.00
52
88.1
17.30
7.30-32.60
Yes
z
p
-2.198
0.028
-1.1911
0.560
-0.056
0.955
-1.133
0.257
-1.108
0.268
-2.223
0.824
Z=Mann-Whitney U Test
Table 5. The Relationship between ADL Scale Total Score and MNA Scores and Hand Grip Strengths MNA ADL scale total score
Hand Grip Strength
r
-.569
-.362
p
0.000
0.003
Discussion Malnutrition is an important public problem observed more frequently in elderly people compared to the general population [4,5]. Whereas the malnutrition and malnutrition risk ratio is stated as 5-15% in the general population, this ratio is reported to be 10-
38% in elderly people living in the society and increase up to 85% in elderly people at hospital or nursing homes when it comes to old population [22]. Küçük and Kapucu stated the malnutrition ratio as 28.6% and the malnutrition risk ratio as 44.5% in elderly people who stayed in nursing homes; it was revealed in a study conducted in India that 70% of the old population was under the malnutrition risk and malnutrition was observed in 19.5% [23,24]. In our study, the MNA score means of the nursing home residents are 22.24±4.84; malnutrition was encountered in 15.4% of the participants and the malnutrition risk in 41.5%. Sarcopenia is defined as “the loss of skeletal muscle mass and strength occurring with the increasing age” [25]. The hand grip strength is suggested to be used as an early diagnostic tool in 433
doi: 10.5455/medscience.2019.08.9038
malnutrition because the muscle function is affected by inadequate nutrition at an early time [14,15]. In our study, the hand grip strengths of the nursing home residents increased as their MNA scores increased (r=0.299, p ˂0.05). Saka et al. reported in their study on nursing home residents that the malnutrition ratio was higher in the nursing home residents who were thought to be sarcopenic according to the hand grip strength measurements (p< 0.001) [11]. Demir referred to a statistically significant relationship between the hand grip strength and the MNA in his study conducted on the patients above 60 years of age who were staying at hospital (p< 0.001) [26]. No statistically significant relationships were discovered between the ages of the participants and the MNA scores in this study (p˃0.05). However, as the ages of the participants in the research increased, their hand grip strengths decreased (r=-0.253, p ˂0.05). It was stated in the literature that the hand grip strength decreased with the age [27,28]. The MNA score distributions of the nursing home residents in the research did not differ according to the participants’ characteristics of gender, marital status, education and smoking (p˃0.05). While Maderia et al. revealed that the malnutrition/malnutrition risk in women was higher than men (p<0.05), no significant difference was reported between the genders in the studies conducted in Turkey (p˃0.05) [29,30]. Dişçigil and Sökmen state that the low hand grip strength is higher in women [31]. Contrary to the literature, the low hand grip strength ratio was higher in male participants in our study (X2= 23.667, p˂0.01). MNA score distribution of the nursing home residents in the research differed as to their levels of doing physical activities and the group which created difference was the one who went walking regularly (p˂0.05). Similarly, Slavíková et al. referred to a positive relationship between physical activity and MNA scores in their study [32]. It is stated in the study conducted by Ongan in 25 nursing homes of Turkey that the chronic diseases mostly observed in the nursing home residents were hypertension (60.3%), cardiovascular disease (34.3%), rheumatic diseases (29.8%) and diabetes (29.4%) [20]. It was reported that the nursing home residents in this research had mostly hypertension (50.8%), osteoarthritis (26.2%), diabetes (21.5%) and COPD (18.5%). Ayraler et al. stated that the malnutrition and malnutrition risk distribution was not statistically significant according to the presence of chronic diseases (p>0.05), however, the malnutrition and malnutrition risk ratio was higher in participants with hypertension [33].In this research, no significant difference was discovered between the chronic diseases and the MNA score distributions of the nursing home residents (p>0.05), but the nursing home residents with hypertension had lower hand grip strengths (p<0.05). In this study, depression was found in 11.9% of the participants according to the GDS. While the MNA score means of the group with the diagnosis of depression were statistically and significantly low (p<0.05), no statistically significant difference was discovered between the hand grip strength means (p>0.05). Saka et al. reported in their study that they observed depression in 15.7% of the nursing home residents and found no significant relationship between depression and malnutrition/malnutrition risk in participants (p˃0.05) [11]. Balcı et al. state in their study
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conducted on elderly people who lived with their families that 7.9% of the participants had depressive complaints. Moreover, it was reported in the same study that the depression score (towards depression) increased as the MNA score decreased (malnutrition) [34]. Contrary to our study, it is stated in some studies that the hand grip strength is lower in elderly people with depression or anxiety disorder compared to the control group [35-37]. It is reported in the literature that malnutrition leads to direct or indirect decrease in the activities of daily living and people who are dependent in executing the activities of daily living have a higher malnutrition risk [38,39]. 13.8% of the nursing home residents in this research were completely dependent in executing the activities of daily living and the hand grip strength (r=-362, p˂0.01) and the MNA scores (r=-596, p˂0.01) significantly decreased as the dependency level of the participants in the activities of daily living increased. Conclusion Consequently, the malnutrition ratio found in the nursing home residents in the research is similar to the one in the studies conducted on the nursing homes of our country. As the MNA score of the participants diminished, the hand grip strength decreased. As the functional capacities of the participants increase, their MNA scores and hand grip strengths also increase. Routine screening can be suggested for the low functional capacity and depression symptoms in addition to the nutritional disorders for the early diagnosis and treatment of malnutrition. Because the data we obtained as a result of the study are limited to only one nursing home, it can be suggested to work with wider sampling groups. Competing interests The authors declare that they have no competing interest. Financial Disclosure All authors declare no financial support. Ethical approval Before the study, permissions were obtained from local ethical committee Recep Bentli ORCID: 0000-0002-7205-0379 Nese Karakas ORCID: 0000-0003-0737-0541 Betul Firinci ORCID: 0000-0001-5685-4142 Serdar Deniz ORCID: 0000-0002-6941-4813
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Available online at www.medicinescience.org
ORIGINAL RESEARCH
Medicine Science International Medical Journal
Medicine Science 2019;8(2):436-9
Investigation of antidepressant -like effect of pari-flo product on forced swimming test in balb-c mice Ismet Yilmaz1 , Ahmet Berk2 Inonu University, Faculty of Pharmacy, Department of Pharmacology, Malatya Turkey 2 Elazig Fethi Sekin City Hospital, Department of Pharmacy, Elazig, Turkey
1
Received 12 Febuary2019; Accepted 04 March2019 Available online 27.03.2019 with doi:10.5455/medscience.2019.08.9022 Copyright Š 2019 by authors and Medicine Science Publishing Inc. Abstract Pari-flo is a commercial preparation in the form of a solution containing standardized Passiflora incarnata plant extract. We hypothesized that Pari-flo may have antidepressant potential with its content. Therefore, the aim of this study was investigation of the antidepressant-like effect of Pari-flo product comparing with imipramine based on Forced Swimming Test (FST) in Balb-c Mice. Forty-two male Balb-c mice were divided into 6 equal groups as follows: group 1 (control) were fed with normal rat chow and tap water, groups (2, 3, 4 and 5) were given 125, 250, 500 and 1000 mg/kg/day dose Pari-flo respectively, group (6) were given 15 mg/kg/day dose imipramine. After 7 days of treatment, the FST was carried out. Pari-flo significantly reduced the immmobility time while increased the climbing time in FST at the dose of 500 and 1000 mg/kg/day. At the 1000 mg/kg/day dose of Pari-flo was increased the swimming time in FST. Imipramine was also increased the swimming and climbing time, while reduced the immobility time. Based on FST test results, it is concluded that Pari-flo product has antidepressant-like activity comparable to those of imipramine in experimental animal models. Keywords: Antidepressant, Forced Swimming Test, Pari-flo, Mice
Introduction Affecting millions of people per year, depression is a serious psychiatric problem with lifetime prevalence of 2% to 15% globally, and a major contributor to the global burden of disease and disability [1]. Many drugs and herbal extracts are being tested to use in the treatment of depression since the current treatment approaches remain insufficient [2,3]. For this purpose, we have tested Pari-flo product in animal model of depression in this study. Pari-flo is a commercial preparation in the form of a solution containing 200 mg/ml standardized Passiflora incarnata plant extract, 20 mg/ml L-Glycine, 30 mg/ml magnesium L-threonate and 0,1 mg/ml L-methylfolate. The main component of the Pariflo, P. incarnata, a perennial herb, is used as an ornamental plant in Turkey. The plant, which has major active ingredients as flavonoids and alkaloids, is also used for complaints such as restlessness, anxiety, insomnia, epilepsy, various disorders in menstruation and menopausal periods, and known to have antitussive, antiastmatic, aphrodisiac and anti-inflammatory effects [4,5]. Although P. incarnata extract has been tested in many preclinical studies, its *Coresponding Author: Ismet Yilmaz, Inonu University, Department of Pharmacology, Faculty of Pharmacy, Malatya Turkey E-mail: yilmaz.ismet@inonu.edu.tr
mechanism of action is still being discussed. The sedative effects of P. incarnata have been showed in rodents [6]. Furthermore, P. incarnata was found to have anxiolytic effects [7-10]. The effect of L-methylfolate, which is one of the other substances in the content of the product, can support the sufficient synthesis of biochemical compounds, such as serotonin, norepinephrine and dopamine, which are necessary for the alleviation of depression [11]. Other substance of the product, L-Glycine, reduces emotional stress, increases mental efficiency, improves nervous system metabolism, as well as having anti-stress and sedative effects [12]. Among the other substances of preparation, magnesium plays a critical role in some brain-related and neurological disorders such as depression, anxiety, bipolar disorder, schizophrenia, and L-methylfolate, is known to be effective in the treatment of depression, dementia and schizophrenia, in addition, it increases the effect of serotonin and norepinephrine reuptake inhibitors (SNRI) and selective serotonin reuptake inhibitors (SSRI) [13,14]. In our literature research, we did not find any study about investigating of antidepressant effect of Pari-flo in Mice. According to above information, we hypothesized that Pari-flo may have antidepressant potential with its content and therefore, we aimed to investigate (as a preliminary study) the antidepressant-like effect of Pari-flo product at four different doses comparing with imipramine based on FST in mice. 436
doi: 10.5455/medscience.2019.08.9022
Material and Methods
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(p<0.05) compared with control group.
Animals: Forty-two male Balb-c mice, weighing 34–38 g, were provided from the Experimental Animal Research and Production Center of Inonu University and the study protocol was approved by the Ethic Comittee of Inonu University Faculty of Medicine (2018/A-26). They were randomly divided into six groups (n=7 mice in each group). Animals were treated humanely in accordance with the NIH Guide for the Care and Use of Laboratory Animals and were housed at room temperature (21 °C ± 2 °C) with relative humidity of 52% ± 3% with a 12 h light/dark cycle. Experimental Design Forty-two male Balb-c mice were divided 6 equal groups as follows: group 1 (control) were fed with normal rat chow and tap water, group 2 were given 125 mg/kg/day, group 3 were given 250 mg/kg/day, group 4 were given 500 mg/kg/day, and group 5 were given 1000 mg/kg/day dose Pari-flo (Grand Medical Group/ İstanbul/Türkiye) via drinking water, group 6 were given 15 mg/ kg/day dose imipramine (Novartis Pharmaceuticals) via drinking water. Before we started this study, daily water consumption of mice was measured and found to be an average of 7 ml per animal/day. Dose adjustments of animals were made based on this measurement. After 7 days of treatment, the forced swimming test (FST) was carried out with pretest. The number of animals in each group, the doses and administration times of pari-flo and imipramine were determined by considering similar studies [15, 16]. Forced swimming test (FST) FST was performed according to the method of Porsolt et al. [17]. Mice were forced to swim in a cylindrical tank filled with 15 cm deep water, 18 cm in diameter and 40 cm in height. In the 5-min test, the animals’ swimming, climbing, and immobility times were measured with the help of a stopwatch. When each animal test was completed, the water in the tank was changed so that the mice were not affected from each other. Animals were accepted as immobile when they remained motionless and only doing those movements necessary to keep the noise above the water. Statistical Analysis GraphPad Instat Version 3.10 package software was used for statistical analyses. The data were expressed as mean ± standard error of mean (± SEM). Significance between the groups was analyzed using the one-way variance analysis (ANOVA). Comparisons of groups with significant differences were made using the Tukey-Kramer test. A value of p<0.05 was considered statistically significant.
Figure 1. Effects of imipramine (15 mg/kg/day) and Pari-flo (125, 250, 500 and 1000 mg/kg/day) on immobility time in the forced swimming test. (IM: imipramine treated group, P125: 125 mg/kg/day Pari-flo treated group, P250: 250 mg/kg/day Pari-flo treated group, P500: 500 mg/kg/day Pari-flo treated group, P1000: 1000 mg/kg/day Pari-flo treated group, *p<0.05, significant change vs. contol group; **p<0.01, significant change vs. control group, ***p<0.001, significant change vs. control group).
Figure 2. Effects of imipramine (15 mg/kg/day) and Pari-flo (125, 250, 500 and 1000 mg/kg/day) on swimming time in the forced swimming test. (IM: imipramine treated group, P125: 125 mg/kg/day Pari-flo treated group, P250: 250 mg/kg/day Pari-flo treated group, P500: 500 mg/kg/day Pari-flo treated group, P1000: 1000 mg/kg/day Pari-flo treated group, *p<0.05, significant change vs. contol group; ***p<0.001, significant change vs. control group).
Results Figure 1 shows the immobility time of mice in FST. Significant reduction in immobility time was noted in the animals treated with 15 mg/kg/day imipramine (p<0.001), 1000 mg/kg/day Pariflo (p<0.01) and 500 mg/kg/day Pari-flo (p<0.05) compared with control group. Figure 2 shows the swimming time of mice in FST. Significant increase in swimming time was noted in the mice treated with 15 mg/kg/day imipramine (p<0.001) and Pari-flo1000 mg/kg/day (p<0.05) compared with control group. Figure 3 shows the climbing time of mice in FST. Significant increase in climbing time was noted in the animals treated with imipramine (p<0.001), 1000 mg/kg/day Pari-flo (p<0.01) and 500 mg/kg/day Pari-flo
Figure 3. Effects of imipramine (15 mg/kg/day) and Pari-flo (125, 250, 500 and 1000 mg/kg/day) on climbing time in the forced swimming test. (IM: imipramine treated group, P125: 125 mg/kg/day Pari-flo treated group, P250: 250 mg/kg/day Pari-flo treated group, P500: 500 mg/kg/day Pari-flo treated group, P1000: 1000
437
doi: 10.5455/medscience.2019.08.9022 mg/kg/day Pari-flo treated group, *p<0.05, significant change vs. contol group; **p<0.01, significant change vs. control group, ***p<0.001, significant change vs. control group).
Discussion Forced swimming test is one of the most commonly used animal models for investigating the antidepressant-like effects of conventional drugs and herbal substances in mice and rats. This model is sensitive to the effects of drugs and herbal extracts [18]. While decreasing the duration of immobility in FST is considered as an indicator of antidepressant-like effect, it has been suggested that the increase in noradrenergic activity induces the climbing behavior of animals, and increase in serotonergic activity may be related to swimming behavior [19]. In our study, imipramine reduced the immobility times of animals as in other studies [20]. As a tricyclic andtidepressant, imipramine increased both swimming and climbing behavior, which may be due to its effect on noradrenergic and serotonergic pathways. Pari-flo was also found to decrease the immobility time of mice as dosedependent manner, which indicating antidepressant-like effect. It was observed that Pari-flo increased both swimming and climbing behavior, and the effect on climbing behavior was more pronounced, which may be attributed to a prominent noradrenergic effect. The major component of Pari-flo, P. incarnata plant extract, known to contain alkaloids such as harmaline, harmine and harmalol, which are the irreversible monoamine oxidase-A (MAO-A) inhibitors, and known to have have antidepressant properties [21,22]. These alkaloids may have played a major role in antidepressant-like activity. Besides MAO-A inhibition, P. incarnata plant extract is known to have an effect on GABAergic system, which may have contributed to antidepressant activity [23,24]. Some studies have shown that P. incarnata plant extract has no significant effect on swimming behavior in FST when used alone [15]. This difference may indicate that the other components in the content of Pari-flo have contributed to the antidepressantlike effect, via augmenting the serotonergic mechanisms, further studies are needed to determine the exact mechanism of Pariflo. In addition, we believe that determining of the components responsible for pharmacological activity in Pari-flo, and removal of other substances will improve the formulation. Conclusion It is concluded that Pari-flo may have antidepressant-like effects comparable to those of imipramine in experimental animal models of Mice. However, this issue should be investigated with further experimental and clinical studies to determine the action mechanism and/or efficacy of Pari-flo as an antidepressant in the treatment of depression. Acknowledgments This work was supported by Grand Medical Group, Istanbul, Turkey.
Med Science 2019;8(2):436-9
Ismet Yilmaz ORCID:0000-0001-8680-3098 Ahmet Berk ORCID: 0000-0002-0828-6520
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Competing interests The author confirms that this article content has no conflict of interest.
17. Porsolt RD, Anton G, Blavet N, et al. Behavioural despair in rats: a new model sensitive to antidepressant treatments. Eur J Pharmacol. 1978;47:379-91.
Financial Disclosure All authors declare no financial support.
18. Petit-Demouliere B, Chenu F, Bourin M. Forced swimming test in mice: a review of anti-depressant activity. Psychopharmacol. 2005;177:245-55.
Ethical approval Inonu University and the study protocol was approved by the Ethic Comittee of Inonu University Faculty of Medicine (2018/A-26).
19. Castagne V, Moser P, Roux S, et al. Rodent models of depression: forced swim and tail suspension behavioral despair tests in rats and mice. Current
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doi: 10.5455/medscience.2019.08.9022 protocols in neuroscience. 2011;Chapter 8:Unit 8 10A. 20. Fiebich BL, Knorle R, Appel K, et al. Pharmacological studies in an herbal drug combi-nation of St. Johnâ&#x20AC;&#x2122;s Wort (Hypericum perforatum) and passion flower (Passiflora incarnata): in vitro and in vivo evidence of synergy between Hypericum and Passiflora in antidepressant pharmacological models. Fitoterapia. 2011;82:474-80. 21. Bennati E. Quantitative determination of harmane and harmine in the extract of Passi-flora incarnata. Boll Chim Farm.1971;110:664-9.
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22. Callaway JC, McKenna DJ, Grob CS, et al. Pharmacokinetics of Hoasca alkaloids in healthy humans. J Ethnopharmacol. 1999;65:243-56. 23. Grundmann O, Wang J, McGregor GP, et al. Anxiolytic activity of a phytochemically characterized Passiflora incarnata extract is mediated via the GABAergic system. Planta Med. 2008;74:1769-73. 24. Lolli LF, Sato CM, Romanini CV, et al. Possible involvement of GABA A-benzodia-zepine receptor in the anxiolytic-like effect induced by Passiflora actinia extracts in mice. J Ethnopharmacol. 2007;111:308-14.
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ORIGINAL RESEARCH
Medicine Science International Medical Journal
Medicine Science 2019;8(2):440-4
Comparison of the effects of head & down and head-up position on intraocular pressure and haemodynamics during laparoscopic abdominal surgery Zinet Asuman Arslan Onuk Antalya Training and Research Hospital, University of Health Science, Department of Anesthesiology, Antalya, Turkey Received 18 April 2019; Accepted 22 May 2019 Available online 30.05.2019 with doi:10.5455/medscience.2019.08.9040 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract The aim of our study was to compare intraoperative changes on the haemodynamics and intraocular pressure in the head-up and head-down position in laparoscopic cholecystectomy and gynaecologic surgery. This cohort study (prospective observational study) was made in Antalya Education and Research Hospital (Turkey) between 2015 and 2017. Seventy seven patients undergoing laparoscopic cholecystectomy (head-up position, n=42 ) and laparoscopic gynecology operations (head-down position=35) were included. The intraocular pressure (IOP) was measured for both eyes at defined intervals during the procedure with Schiotz tonometer. During of surgery, heart rate, mean arterial blood pressure, sistolic arterial blood pressure, diastolic arterial blood pressure and ETCO2 were also recorded. IOP was detected to be higher in Group II at the 5th minute of CO2 insufflation (17.17±2.91) and at the 5th minute of head-down position (17.97±2.83), P<0.05. In addition, IOP measurements were recorded 14.79±4.92 for group I and 17.17±3.03 for group II significally higher immediately before post-op CO2 desufflation (P<.0.05). Statistically meaningful difference was detected between groups in terms of operation and anaesthesia processes (P=0.044, P<0.001 respectively). The patient’s position during surgery may represent a stronger risk factor for IOP increase than pneumoperitoneum-related intraabdominal pressure in surgical operations which are expected to last longer than two hours and in old patients. IOP increases with head-down position. We recommend preoperative and peroperative IOP measurement in laparascopic and robotic surgery attempts, in surgical operations which are expected to last long and in old patients whether or not they have eye disease anamnesis. Keywords: Intraocular pressure, head-down, head-up, laparoscopy, haemodynamics
Introduction Laparoscopic surgical procedures are minimal invasive methods using intraperitoneal carbondioxide (CO2) insufflation. Wide range, less blood loss and postoperative pain, shorter hospitalization interval and faster recovery are the advantages of this technique [1]. Many factors such as general anaesthesia application, patient position during surgery and increase in intraabdominal pressure may affect hemodynamics [2-4]. General surgeries, including laparoscopic, spinal and cardiac procedures, especially, with their demand for steep trendelenburg or prolonged prone positioning and hypotensive anesthesia, can induce intraocular pressure changes and ocular perfusion imbalance [5]. Laparascopic surgery generally performed in head-up and headdown positions depending on the type of operation. These positions cause undesirable hemodynamic and intraocular pressure (IOP) changes [6-8]. *Coresponding Author: Zinet Asuman Arslan Onuk, Antalya Training and Research Hospital, University of Health Science, Department of Anesthesiology, Antalya, Turkey, E-mail: asumanonuk@hotmail.com
Laparoscopic attempts, routinely used for gynecologic operations can be extended safely for cholecystectomy in uncomplicated cholelithiasis [9] . The aim of our research is to compare head-down in gynecologic procedures and head-up in cholelithiasis laparascopic surgeries using same anaesthetic methods with regards to IOP (intraocular pressure) and hemodynamic changes. Material and Methods This cohort study (prospective observational study) was made in Antalya Education and Research Hospital (Turkey) between 2015 and 2017. 77 patients (58 F, 19 M) belonging to ASA I-II groups were included in the research after ethical board approval and patient consents. Patients who underwent laparascopic cholecystectomy in head-up position were acknowledged as Group I (head-up n=42) and patients who underwent laparascopic gynecological surgery in head-down position were acknowledged as Group II (head-down n=35). Patients with eye surgery history, cardiovascular disease, diabetes mellitus, chronic obstructive lung disease and high IOP anamnesis were excluded from the research. Patients had no premedication and anaesthesia induction obtained with 2,5 mg/kg propofol and 2µg/kg fentanyl and 440
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0,6 mg/kg rocuronium bromide (esmeron) and patients were intubated. Anaesthesia maintenance was obtained with 6-10 mg/ kg/hr propofol, esmeron and intermittent fentanyl bolus (1µg/kg). Mechanical ventilation was supplied with 40-60% of air in order to procure 30-40 mmHg EtCO2. Pneumoperitoneum was created as previously recommended [8,9] and intraperitoneal insufflation of CO2 was performed via a Palmer needle with the patient in the supine position. Throughout surgery, intraperitoneal pressure was maintained automatically at 12 mmHg by a CO2 insufflator. During surgery intraocular pressure (IOP), mean arterial pressure (MAP), systolic arterial pressure (SAP), diastolic arterial pressure (DAP), heart rate (HR), end-tidal CO2 (EtCO2) measured in both groups at the following time points: (T1) One minute of intubation in supine position (group I and II) (T2) 5th minute of insufflation CO2 in head-down (group II) and head-up (group I) position (T3) 5th minute of head-down (group II) and head-up (group I) position, (T4) 10th minute head-down (group II) and head-up (group I) position, (T5) 20th minute head-down (group II) and head-up (group I) position, (T6) CO2 desufflation,head-down (group II) and head-up (group I) position, (T7) before extubation in supin position.(grup I and grup II) IOP measurements were recorded for each eye in previously determined 7 different time zones (Table 2, figure 1). IOPs were measured with a Schiotz tonometer. The tonometer was calibrated and sterilized (alcohol swap or merthiolate solution) before each reading. In each patient, IOP was measured by 5,5 scala of Schiotz tonometer and the average of the two measurements was calculated for each eye; the mean of the IOPs for both eyes was used as the patient’s . Statistical Analysis Paired t-test was used in intergroup comparisons and independent sample t-test was used in intragroup comparisons. P<0.05 was considered to be significant. Results Average age of the patients was 40.52±7.57 years in group I (headup) and 50.45±1.31 years in group II (head-down), No statistically significant difference was found between the two groups. (P>0.05, P=0.06 table 1). Anaesthesia duration in group I was 119.78±41.97 min, surgery duration was 104.50±36.88 min (P<0.05, P=0.044) whereas anaesthesia duration in group II was 64.25±25.98 min, surgery duration was 70.60±99.61 min (P<0.05, P=0.001). There were statistically significant differences in anesthesia and surgery times between groups Our research compares cholecystectomic (n=42) and gynecologic (n=35) operations for head- up and head-down positions respectively. Minimal invasive gynecologic surgical operations are common. Gynecological surgeries operated in head-down position
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in our research are minimal invasive interferences (cystectomy, myomectomy, hysterectomy). We correspondingly detected that anaesthesia and operation durations were shorter in group II (headdown). Statistically meaningful difference was detected amongst groups in terms of operation and anaesthesia duration (P=0.044; P=0.001 respectively). 9 of 77 ASA I-II patients were hypertensive (7 patients in group I; 2 patients in group II). At a result of the blood pressure; systolic arterial pressure (SAP) measurements in the first moment of intubation in group II (in head-down position) were recorded as high (P<0.05). As we evaluated the diastolic arterial pressure (DAP) measurements, we did not find statistically meaningful differences both in intergroup (P>0.05) and intragroup values (P>0.05). Similary, we did not find statistically meaningful differences both in inter group (P>0.05) and intragroup values with respect to mean arterial pressure (MAP) (P>0.05). Nevertheless, SAP and MAP measurements in 1st minute of the operation were detected higher in head-down group (P<0.05, table 2). Upon the evaluation of heart rate evaluations; heart rate in the first minute of intubation in group I was detected lower. Statistically meaningful changes were obtained in 10th minute after positioning the patient (P<0.05, table 2). As we evaluated the intraocular pressure changes; we determined that IOP increased in head-down position. IOP in 5th minute of CO2 insufflation 17.17±2.91 mmHg and in 5th minute of head-down position 17.97±2.83 mmHg was recorded higher in Group II (Head down group). Statistically meaningful difference was detected among groups (P<0.05) (Figure 1, table 2). After positioning the patients in the following of the surgical preocedure, 20th minute IOP measurements were both detected in group I in head-up position and in group II in head-down position. We thought that CO2 insufflation was also effective in IOP along with positioning in both groups. We also thought that increase in intraabdominal pressure was related with CO2 insufflation. 20th minute IOP measurements 16.20±5.02 mmHg in group I; 16.98±3.45 mmHg in group II, in head-up and head-down positions and 5th minute CO2 insufflation values 14.82±4.90 mmHg in group I; 17.17±2.91 mmHg in group II were recorded meaningfully high (P<0.05, table 2, figure 1). In addition, IOP measurements 14.79±4.92 mmHg in group I; 17.17±3.03 mmHg in group II) just before CO2 desufflation at the end of surgical operation were recorded meaningfully high (P<0.05, table 2, figure 1). In consequence of EtCO2 measurements; EtCO2 values were detected to be high in group II. Difference between group I (head-up) and group II (head-down) measurements was statistically meaningful (P<0.05). All measurements were normal values in the first moment of intubation. As we evaluated the measurements of SAP, MAP, IOP and EtCO2, values of head-up group were determined them to be lower (P<0.05, table 2). 1st minute measurements of intubation were detected higher than after CO2 desufflation measurements in group II (P<0.05). Both 441
doi: 10.5455/medscience.2019.08.9040
intragroup and intergroup measurements were detected statistically meaningfully high (P<0.05). These are related to high pressure associated with intubation. EtCO2 values before intubation was detected statistically meaningfully higher that values of 1st minute
Med Science 2019;8(2):440-4
of the intubation in each groups (P<0.05). EtCO2 values before intubation was detected higher in group II (P<0.05). Difference between groups were detected as statistically meaningful (P<0.05, table 2).
Table 1. Demographic data Grup I (head-up) n=42
Grup II (head-down) n=35
P
Age
40.5(7.57)
50.45(1.31)
P=0.060
Sex
23 male,19 female
35 female
Duration of anesthesia (min)
119.78(41.97)
64.25(25.98)
P=0.001
Duration of operation min)
104.50(36.88)
70.60(99.61)
P=0.044
7/42
2/35
Hypertension
Data are presented as the mean±standard deviation where indicated. P<0.05 was accepted to be statistically significant Table 2. Hemodynamic Variables and Intraocular Pressure Values in Laparoscopic Surgery Operation stages (measurement time) Hemodynamic variables (group I and group II)
Intubation.1.minute
CO2 insufflation (5.minute)
Position (5.minute)
Position (10.minute)
Position (20.minute)
CO2 desufflatio
Pre-extubation
Mean(SD)
Mean(SD)
Mean(SD)
Mean(SD)
Mean(SD)
Mean(SD)
Mean(SD)
SAP Head-up
128.38(19.45)
133.24(28.71)
138.19(28.27)*
130.74(21.28)
129.43(21.50)
130.19(23.59)
147.21(23.38)*
Head-down
150.31(22.00)
130.51(27.47)*
136.63(25.85)*
136.83(23.30)*
136.43(29.65)*
137.91(30.53)*
155.60(32.35)
Head-up
87.38(21.75)
92.90(21.43)
92.02(20.19)
83.98(18.10)
81.14(18.14)*
81.50(15.18)
89.67(15.43)
Head-down
89.63(13.86)
85.06(17.37)
83.74(16.66)
83.09(11.60)*
82.06(12.33)*
79.06(12.57)*
92.54(13.63)
Head-up
101.40(21.21)
107.67(23.98)
106.86(22.20)
100.33(18.18)
98.83(17.95)
97.29(18.94)
113.43(23.16)*
Head-down
112.69(14.01)
103.63(20.40)*
102.31(16.51)*
102.17(13.77)*
101.80(15.22)*
100.71(17.14)*
114.03(18.41)
Head-up
88.64(11.60)
77.86(13.07)*
76.62(13.07)*
74.05(11.53)*
73.43(12.98)*
73.71(15.47)*
85.76(16.62)
Head-down
83.62(16.70)
78.54(13.62)
80.00(18.75)
81.80(20.06)
78.43(17.33)
74.34(16.00)*
88.86(16.37)
Head-up
12.75(4.19)
14.82(4.90)*
14.33(4.20)*
15.81(4.47)*
16.20(5.02)*
14.79(4.92)*
16.31(6.30)*
Head-down
15.03(2,81)
17.17(2.91)*
17.97(2.83)*
16.14(2.03)*
16.98(3.45)*
17.17(3.03)*
17.65(3.80)*
Head-up
32.38(2.56)
31.43(3.78)
31.60(4.20)
31.64(4.90)
31.38(4.89)
31.80(3.62)
35.83(7.169)*
Head-down
35.09(4.88)
33.74(4.89)*
34.91(5.51)
35.31(5.18)
36.71(5.28)
37.83(5.37)*
40.83(7.670)*
DAP
MAP
Heart Rate
IOP
EtCO2
Groups: Group I: Head-up group, Group II: Head-down group, SAP: Systolic arterial pressure, DAB: diastolic arterial pressure, MAP: Mean arterial pressure (mmHg), HR: Heart Rate (beat /minute), EtCO2: end-tidal CO2, IOP: Intraocular Pressure, Position 5., 10., 20. Minutes : head up and head down position, #P<0.05 intergroup comparison , *P<0.05 intragroup comparison (Head-up and Head-down groups ). (compared to the 1.minute of intubation)
Discussion Our research was made on laparascopic cholecystectomy and gynecology patients operated in head-up or head-down positions. Pneumoperitoneum and head-up and head-down positions trigger changes in hemodynamics and IOP in patients under the effect of anaesthesia [5]. Limited data suggest that it is also useful as propofol for the maintanence of IOP during anesthesia [10,11]. We used propofol in the induction and maintenance of anaesthesia.
Figure 1 . Time-dependent change in IOP in Head-up group and Head-down group
IOP measurements in the 1st minute of intubation were recorded 12.75±4.19 mmHg in head- up group and 15.03±2.81 mmHg in head-down group. In addition to this we recorded higher 442
doi: 10.5455/medscience.2019.08.9040
measurements of SAP, MAP and EtCO2 in head-down group. These measurements which were not related to the positioning was thought to be related with the high preoperative values of the patient and with the anaesthesia induction. Cheng and Young-Chul Yoo revealed that propofol might suppress IOP increase caused by perioperative hemodynamics, intubation and extubation under general anaesthesia in ophtalmic patients [7]. In our research, we detected that propofol infusion was useful to diminish the increase of IOP caused by head-down and head-up position and CO2 insufflation in laparascopic surgeries. Hwank et al. investigated effects of surgical position and anaesthesia type on pneumoperitonium depended IOP in laparascopic surgeries. IOP was detected as low in laparascopy patients operated in reverse trendelenburg position independently of anaesthetic agent whereas IOP showed significant increase in desflurane applied pelvic laparascopic surgeries. They ultimately thought that effect of anaesthetics in laparascopic surgeries to IOP was related to position and propofol was effective to increase IOP [3]. In addition, some researches stated that IOP increase was timedependent and it deteriorated with excessive head-down position. Basal IOP values were detected to increase with age and systolic blood pressure was stated to be an effective factor on IOP values as it increased with age [7]. Rubin et al. recorded increase on heart rate and diastolic blood pressure, slight decrease in systolic blood pressure, and stable mean arteriel pressure in head-up position [12]. In our study, 9 of patients was hypertensive and mean arterial pressures of the patients were recorded similar at the time of measurement. Intraocular pressure was significantly negatively correlated with systolic blood pressure [13] . These patients belonged to two seperate groups. We did not excluded the hypertensive patients from the evaluation. There was no statistically significant difference in intragroup and intergroup comparison in terms of MAP (P>0.05). Systolic arteriel pressure was detected high during the 1st minute intubation measurements in group II (head-down position) (P<0.05). We found low heart rate in the first minute measurement of intubation in cholecystectomy operations performed in head-up position (P<0.05). As Montazeri et al. suggested for opthalmic surgeries, perioperative IOP measurement might be useful in need of laparascopic surgery in trendelenburg position in which IOP increase expected to ocur [14]. Borahay et al. detected that IOP increased significantly in laparoscopic and robotic hysterectomy patients in head-down position [13]. Even tough further researches are needed to define this procedure, when aging population of patients with high risk of glaucoma are regarded, evaluation of preoperative eye health should be executed [14,15]. We also think that preoperative IOP measurement is beneficial in surgical interventions with positioning. Slight decrease was reported in blood pH with the increase of EtCO2 and PCO2 levels caused by CO2 pneumoperitoneum in laparoscopic surgeries [1618].
Med Science 2019;8(2):440-4
We observed normal range of EtCO2 levels in both positions but increase was meaningful in head-down position (P<0.05). We excluded patients with eye surgery history, cardiovascular disease, diabetes mellitus, chronic obstructive lung disease and high IOP anamnesis from the research. Pinkney et al. stated that elevated IOP was detected in laparoscopic colorectal surgery patients in head down and prone position and perioperative vision loss might ocur [19]. Preoperative IOP was recorded as 9-28 mmHg in head-down position and 120 minutes later IOP increased to 25-54 mmHg, ocular perfusion pressure (OPP) was recorded as 50-82 mmHg at the beginning and decreased to 21-75 mmHg in 120th minute. Increasing IOP and decreasing OPP was stated as statistically meaningful in headdown position (P<0.01). Recently, Yoo and friends defended that propofol and consistent deep neuromuscular blockage during laparoscopic radical prostatectomy had decreasing effect on IOP [20]. They defended the idea that perioperative vision loss was a catastrophic complication and surgeons should realise this. In our research we did not observed any complaints about eye and any pathological examination findings in 24 hours of postoperative term. Carey et al. investigated the effect of head-up position on IOP and they observed that IOP decreased in time [21]. These results were similar to our research. Kyoichi Mizumoto et al. reported significantly meaningful timedependent IOP increase in laparascopic radical prostatectomy patients operated with 30 degrees head-down trendelenburg position (8.3±12.5 right after induction in supin position, 19.7±23.8 right after head-down position, 27.6±31.5 in head-down position right before supin position) [22]. Results of this research is similar to our results. We detected statistically meaningful IOP increase with head-down position. IOP was high in group II at the 5th minute of CO2 insufflation (17.17±2.91) and in head down position (17.97±2.83) at the 5th minute (P<0.05). IOP at 20th minute was detected as high in both groups in reverse trendelenburg (Group I; head-up) and in trendelenburg (Group II; head down). Position and CO2 insufflation are effective factors in IOP increase of both groups. Andrea Grosso et al. detected slight and reversible increase in IOP in neutral position with standart pneomoperitoneum (<14 or =14 mmHg) in 45-85 years old colorectal surgery patients but they stated higher rate of IOP increase in head-down operated patients. 17 of 29 patients in head-down position showed 5 mmHg IOP increase which was stated to be statistically meaningful (P=0.020). They finally defend that headdown position was more risky than pneumoperitonum [23]. A large study (458 patients) by Sanaa A. et al showed no statistically significant differences between intraocular pressures of men (15 mm Hg, range:6-28) and women (16 mm Hg, range:6-28) (P=0.26). Therefore, we did not discriminate between male and female gender in cholecystectomy surgery [24]. 443
doi: 10.5455/medscience.2019.08.9040
Conclusion In our research, we detected increase for IOP with head-down position. We think that CO2 insufflation is also effective on IOP with head-down position. We recommend preoperative and peroperative IOP measurement in laparascopic and robotic surgery attempts, in surgical operations which are expected to last longer than two hours and in old patients whether or not they have eye disease anamnesis. Financial Disclosure All authors declare no financial support. Ethical approval The study was approved by the Ethics Committee of Antalya Education and Research Hospital and written informed consent from patients. Zinet Asuman Arslan Onuk ORCID: 0000-0002-9189-2926
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11. Mowafi HA, Al-Ghamdi AJ, Rushood A. Intraocular pressure changes during laparoscopy in patients anesthetized with propofol total intravenous anesthesia versus isoflurane inhaled Anesthesia. Anesthesia&Analgesia. 2003;97:471-4. 12. Rubin AM, Rials SJ, Marinchak RA, et al. The head-up tilt table test and cardiovascular neurogenic syncope. Am Heart J. 1993;125:476-82. 13. Borahay MA, Pooja R, Patel MD. Intraocular pressure and steep trendelenburg during minimally invasive gynecologic surgery: is there a risk? J Minim Invas Gynecol. 2013;20:819-24. 14. Montazeri K, Dchghan A, Akbari S. Increase in intraocular pressure is less with propofol and remifentanil than isoflurone with remifentanil during cataract surgery: A randomized controlled trial. Adv Biomed Res.2015;4:55. 15. Kayacan N, Arici G, Akar M, et al. The effect of pneumoperitoneum and head-down position on intraocular pressure. Gynaecol Endos. 2002;11:383-7. 16. Goepfert CE, Ifune C, Tempelhoff R. Ischemic optic neuropathy: are we any further? Curr Opin Anaesthesiol. 2010;23:582-57. 17. Awad H, Santilli S, Ohr M. The effects of steep trendelenburg positioning on intraocular pressure during robotic radical prostatectomy. Anesth Analg. 2009;109:473478. 18. Sator S1, Wildling E, Schabernig C. et al. Desflurane maintains intraocular pressure at an equivalent level to isoflurane and propofol during unstressed non-ophthalmic surgery. Br J Anaesth. 1998;80:243-4. 19. Pinkney TD, King AJ, Walter C, et al. Raised intraocular pressure (IOP) and perioperative visual loss in laparoscopic colorectal surgery: a catastrophe waiting to happen? A systematic review of evidence from other surgical specialities. Tech Coloproctol. 2012;16:331-5. 20. Yoo YC, Kim NY, Shin S. The intraocular pressure under deep versus moderate neuromuscular blockade during low-pressure robot assisted laparoscopic radical prostatectomy in a randomized trial. PLoS One. 2015;10:e0135412. 21. Carey TW, Shaw KA, Weber ML, et al. Effect of the degree of reverse Trendelenburg position on intraocular pressure during prone spine surgery: a randomized controlled trial. Spine J. 2014;14:2118-26. 22. Mizumoto K, Gosho M, Iwaki M, et al. Ocular parameters before and after steep Trendelenburg positioning for robotic-assisted laparoscopic radical prostatectomy. Clin Ophthalmol.2017;11:1643-50.
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ORIGINAL RESEARCH
Medicine Science International Medical Journal
Medicine Science 2019;8(2):484-8
Evaluating clinical and radiological results following surgical treatment of patella fractures Sadullah Turhan1, Yetkin Soyuncu2 SBU Antalya Training and Research Hospital, Clinic of Orthopedics and Traumatology, Antalya, Turkey Akdeniz University, Faculty of Medicine, Department of Orthopedics and Traumatology, Antalya, Turkey
1 2
Received 29 January 2019; Accepted 07 Febuary 2019 Available online 20.03.2019 with doi:10.5455/medscience.2019.08.9015 Copyright Š 2019 by authors and Medicine Science Publishing Inc. Abstract The aim of treating patella fractures is to restore the integrity of the extensor mechanism. Various treatment methods applied include fastening techniques with different wires, fastening with screws, a combined tension band method and screw technique, segmental patellectomy, a combined tension band method and segmental patellectomy technique, and total patellectomy. Fifty-two patients underwent surgery for isolated closed patella fractures between 2002 and 2012 at the Department of Orthopaedics and Traumatology. Of these 52 patients, 23 patients who completed their follow-up were clinically, radiologically, and retrospectively evaluated. Of the 23 patients, 13 (57%) were male and 10 (43%) were female. The functional status was regarded as excellent in 16 (70%) patients, good in six (26%), and unsatisfactory in one (4%) post-surgery. Radiological evaluation of the patients showed that there was type 1 PFA in five (22%) patients, type 2 PFA in five (22%), type 3 PFA in eight (35%), and type 4 PFA in five (22%). The degree of union was radiologically evaluated in all patients during the follow-ups. Implant irritation, implant migration, and fractures were the most frequently observed complications. Keywords: Bostrom classification, Iwano evaluation scale, modified tension band method, patellofemoral arthrosis, patella fractures
Introduction The patella is the biggest sesamoid bone in the body. Due to its location, it completes the extensor mechanism of the knee joint. Patella fractures are frequently observed around the age of 40. They constitute approximately 1% of skeletal system injuries [1]. Patella fractures may occur due to direct trauma or indirectly from the pulling force of the quadriceps and patellar tendon. The aim of treating patella fractures is to restore the integrity of the extensor mechanism. Opinions differ on the approach for surgical treatments. Various treatment methods applied include fastening techniques with different wires, fastening with screws, a combined tension band method and screw technique, segmental patellectomy, a combined tension band method and segmental patellectomy technique, and total patellectomy. The anterior tension band technique used by Pauwel in 1950s for the treatment of the patella fractures was accepted and developed by the Arbeitsgemeinschaft fĂźr Osteosyntesefragen (AO) group [2]. The purpose of this study is to evaluate the clinical and radiological results following surgery using the modified anterior band method *Coresponding Author: Sadullah Turhan, SBU Antalya Training and Research Hospital, Clinic of Orthopedics and Traumatology, Antalya, Turkey E-mail:sturhan@dr.com
to treat isolated closed patella fractures after at least a 2-year follow-up period. Material and Methods Fifty-two patients underwent surgery for isolated closed patella fractures between 2002 and 2012 at the Department of Orthopaedics and Traumatology . Ethical protocol number of the research is 2014-232. Of these 52 patients, 23 patients who completed their follow-up were clinically, radiologically, and retrospectively evaluated. Patients who had surgery for same-side femur and/or tibia fractures together with their patella fracture were excluded from the evaluation. Patients who had ligament injury in the ipsilateral knee to the patella fracture and were not included in a rehabilitation program were also excluded from this study. Furthermore, patients in whom wound site infections developed post-surgery and patients who had head trauma or history of pregnancy were excluded as well. For all patients who were evaluated in the emergency department and whose physical examinations were completed, an anteroposterior (AP) and lateral knee radiograph was taken and classifications were made according to AO [2]. Following this, the 484
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affected leg was put in a long leg splint to keep the knee in full extension. The average time period between injury and surgery was 2 (1–6 ± 1.4) days. The average hospitalization period was 3.6 (3–8 ± 1.2) days. Surgery Technique Of the 23 patients, 10 were operated under general anesthesia, 12 under spinal anesthesia, and the remaining 1 under epidural block anesthesia. Two K-wires were run in a distal to proximal direction to reduce the bone fragments anatomically. The wires were sent from the third closed to the knee joint. This was done in three equal pieces in the sagittal plane of the patella, as parallel as possible. Cerclage wires (loop 18 G) were passed from the bonding place of the quadriceps tendon as far as possible, from the bottom of the K-wires going out and passed from the front face of the patella using the tension ban method (Zuggurtung method) in a figureof-eight configuration. Applying the cannula screw in the tension band method, two pieces of 4.5 mm cannula screws were sent from the third part closed to the knee joint. This was done in three equal pieces in the sagittal plane of the patella, as parallel as possible. Cerclage wires (loop 18G) were passed from the inside of the cannula screws and passed from the front face of the patella in a figure-of-eight configuration.
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Table 1. Bostman Scoring Form A) MOVEMENT WIDTH (ROM) a) Full extension, ROM > 120°
6
b) Full extension, ROM 90–120°
3
c) Loss of full extension, ROM < 90°
0
B) PAIN a) None or minimal on exertion
6
b) Moderate on exertion
3
c) In daily activity
0
C) WORK a) Original job
4
b) Different job
2
c) Unable to work
0
D) ATROPHY a) <12 mm
4
b) 12–25 mm.
2
c) >25 mm
0
E) SUPPORT USAGE a) None
4
b) Assistance required sometimes
2
c) Assistance required always
0
F) EFFUSION a) None
2
b) Reported to be present
1
Follow-up Protocol With stable fracture fastening provided during surgery, patients in splints were mobilized by crutches. Segmental load was given at a tolerable rate starting from day two post-surgery. Follow-ups were conducted at 1 month, 2 months, 3 months, 6 months, 12 months, and 24 months post-surgery.
c) Present
0
After radiological confirmation of union and clinical determination of reduced effusion in the knee, absence of wound site problems, passive joint movement width >90 degrees, tolerable pain, progression toward normal quadriceps power within 18–24 months on average, progressively active exercises were commenced in the patients. Quadricep power was evaluated by measuring the femoral diameter in each patient.
a) Normal
2
b) Difficult
1
c) Disabling
0
Patients were clinically and radiologically evaluated against controls. While evaluation of the degree of union was conducted using AP and auxiliary radiographs, functional evaluation of tangential patella radiographs was conducted using the Bostman scoring form [3] (table 1). Evaluation of the degree of PFA was performed using the Iwano evaluation scale [4] (Figure 1).
G) KNEE GIVING WAY a) None
2
b) Sometimes
1
c) In daily life
0
H) GOING UP AND DOWN THE STAIRS
The results were reported as follows: 28–30 points as excellent, 20–27 points as good, and <20 points as unsatisfactory. Statistical Evaluation All values including means, standard deviations, frequencies, and percentages were derived from descriptive statistics. The relationship between the fracture types and functional results and between degree of PFA and functional results were evaluated using both Kruskal Wallis and Spearman Correlation analyses. A p-value ≤0.05 was determined as statistically significant. Statistical analysis was done using the SPSS (Statistical Package for Social Sciences for Windows 18.0) software program. Results A total of 23 patients who completed their follow-ups, including 13 (57%) males and 10 (43%) females, were evaluated.
Figure 1. Classification of patellofemoral joint arthrosis (Iwano evaluation scale)
The average age of all patients included in the study was 48.4±15.3 (21–70) years. For all male patients, the average age was 47.2±17.4 (23 to 70 years). The average age for female patients was 49.9±14.3 485
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(21 to 66 years) in the females. We observed that patella fractures occurred earlier (20 to 45 years) in male patients and later (45 to 70 years) in female patients. Following evaluation of the fractures in accordance with the AO classification, 5 (22%) fractures were determined to be extraarticular (34-A1) and 18 (88%) fractures were intra-articular. 13 (57%) of the patients were operated due to left patella fractures, and 10 (43%) of the patients were operated due to right patella fractures. The average follow-up duration was 48.2±12.3 (25 to 124) months. The length of time between injury and surgery was an average of 2 (1-6 ± 1.4) days. Average hospitalization period was 3.6 (3-8±1.2) days. In 17 patients, the modified anterior tension band method was applied. Modified tension combined with peripheral wiring was applied in two patients. Fastening with screws was used in two patients. Peripheral wiring was used in another two patients. Functional results were obtained from all patients. Results were determined to be excellent in 16 (70%) patients, good in 6 (26%) patients, and unsatisfactory (4%) in one patient. In the patient with unsatisfactory results, there was a delay in rehabilitation because of a cerebrovascular event (CVE) post-surgery. Knee extension was >120 degrees in 21 patients and between 90 and 100 degrees in two of them. No patient experienced full loss of knee extension. Following radiological evaluation of the patients, it was observed that all fractures achieved full union. The degree of PFA was also evaluated. Type 1 PFA was observed in 5 (21%) patients, type 2 in 5 (22%) patients, type 3 in 8 (37%) patients, and type 4 in the remaining 5 (21%) patients. Of the 23 fractures, 18 were intra-articular and five were extraarticular. There was no statistically significant relationship between the functional results of the patients post-surgery and the fracture type (intra-articular or extra-articular) (p=0.651). After examining the effect of patella fracture type on the development of PFA, it was determined that PFA severity increased as the complexity of the fractures increased. This relationship was statistically significant (p≤0.05).
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The role of the patella in knee function is a major talking point in the treatment of patella fractures. Some authors suggest that the patella may not be necessary for knee function, and it could be excised, if fractured. Others maintain that the patella has an important place in knee function, and claim that it should be protected [6]. Although there is a consensus on the indications for surgical treatment in patella fractures, the rationale for selecting the surgical method of choice remains variable. Surgical methods are preferred in open patella fractures, patella fractures with retinaculum tear, patella fractures with displacement greater than 3 mm, and patella fractures with articular incongruity greater than 2 mm [5]. Yesiller et al compared Magnuson’s technique with the Mini External Fixator (MEF), the AO stretching band, and the modified AO stretching band techniques in a biomechanical study performed using five cadaveric knees. They determined that fixation with MEF provided the most stability, followed by the AO stretching band technique [7]. Burvant et al compared the modified tension band technique with the modified tension band technique with screws. They determined that the modified tension band with screws technique performed significantly better than did the modified tension band [8]. Of a total of 42 patients, Cakici et al applied fastening with the modified anterior tension band technique in 34 cases, fastening with the peripheral cerclage method in three cases, butterfly fixation fastening in two cases, fastening with the indirect reduction method in two cases and fastening with the external fixator in one case. Of the 34 cases in which the modified anterior tension band method was applied, results obtained were determined as excellent in 26 cases, good in six cases, and unsatisfactory in two cases [9]. Sim et al applied a combined modified tension band with cerclage method to a total of 22 patients including 16 with transverse patella fractures and six multi-part patella fractures. The results obtained were determined as excellent in 20 patients and good in two patients. It was thought that good stability positively impacted functional levels [10].
The primary goals in the treatment of the patella fractures are to provide anatomical reduction, mobilize the patient early, prevent the development of joint stiffness, and provide the best functional results possible.
In their study of 27 patients, Esenkaya et al utilized central transverse in 12 cases, subpolar “apical” in nine cases and segmental fracture fastening in six cases. They performed osteosynthesis including Magnuson’s technique for two patients (7.4%), standard tension band for 8 (29.6%) patients, and modified AO tension band method for 17 (63%) patients. The results observed in the last control of the cases were determined as excellent in 15 (55.6%) cases, good in 8 (29.6%) cases, and unsatisfactory in 4 (14.8%) cases, as determined by the Levack scoring system [11]. Of the four patients with unsatisfactory results, three of them had additional fractures in other bones. The fourth patient had a reoccurrence of the fracture because of a fall and underwent another surgery. Atrophic changes were observed radiologically in 8 (29.6%) cases, and required medication in some of the cases.
Treatment of patella fractures may be done conservatively or surgically. While conservative methods have been shown to be effective in non-displaced patella fractures, surgery should be the first treatment option in displaced patella fractures [5].
The initial fracture type has been considered as the most important factor affecting functional results post-surgery. It has been suggested that functional results obtained in transverse fractures were better than those obtained in segmental fractures. Saltzman
The degree of PFA was evaluated. It was determined that five patients were in phase 1, five patients were in phase 2, eight patients were in phase 3, and five patients were in phase four. It was observed that the degree of PFA did not affect the functional status of the patients (p≤0.515). Discussion
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et al showed that initial fracture type was the sole factor that affected their results [12]. In segmental fractures, poor fastening and rehabilitation insufficiency have been cited in literature as common reasons for failure. Of the 23 cases in our study, there were 18 intra-articular and five segmental fractures. Following evaluation by Bostman scoring, results obtained from our study were determined as excellent in 14 (76%) patients, good in 4 (19%) patients, and unsatisfactory in 1 (5%) patient. Although our sample size was smaller, fracture type did not statistically influence functional results. In the single patient with poor functional level in our study, we suspect that a combination of the patientâ&#x20AC;&#x2122;s age and immobilization following a cerebrovascular event may have been contributed to this unsatisfactory result. Of the ten patients treated by the peripheral cerclage wire method, Dimiski et al obtained results determined as good in three patients and unsatisfactory in two patients [13]. They suggested that the high percentage of unsatisfactory results using the peripheral cerclage wire method was due to poor fixation. Yang et al operated on 21 patients with multi-part patella fractures. They applied the tension band method using titanium cables. They determined the functional levels to be excellent in 17 patients and good in four patients. They attributed their successful results to the early commencement of exercises in the post-surgical period [14]. In our study, the cerclage method was applied in two patients, with excellent result in one and good in the other. Both fractures were intra-articular in nature. One of the fractures was a segmental fracture. Although this method did not provide optimum stability, we believe that early movement and appropriate rehabilitation had a positive effect on the results. Yavarikia et al applied diagnostic arthroscopy to 22 patients with transverse patella fractures. Surgeries were conducted using the modified tension band method. A normal patellofemoral cartilage finding was observed in five patients. Phase I chondral lesions were observed in 10 patients, phase II chondral lesions in four patients, and phase III chondral lesions in three patients. There was no statistically significant relationship between the functional level of the patients and the radiologic findings observed [15]. Tukenmez et al operated on 50 patients with patella fractures including 27 segmental (satellite) fractures, 13 transverse fractures, 8 distal pole fractures, 1 chondral fracture, and one longitudinal fracture. Of the 50 cases, osteosynthesis with modified AO tension band technique was applied in 25 (50%) cases, osteosynthesis with screw, and Kirschner wires was applied in 10 (20%) cases, segmental patellectomy was used in 6 (12%) cases, tension band combination was used in 8 (16%) cases, and arthroscopic manipulation was applied in 1 (2%) case. Results obtained from this study were determined as unsatisfactory in 13 (26%) cases, good in 21 (42%) cases, and excellent in 16 (32%) cases [16]. Additional pathologies in three patients and an open fracture in another patient may have contributed to the number of unsatisfactory results obtained. Degeneration of the patellofemoral joint was observed in only four patients. In our study, the degree of patellofemoral arthrosis was determined
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as type 1 in 5 patients, type 2 in 5 patients, type 3 in 8 patients, and type 4 in 5 patients. Although the fracture type negatively affected the degree of PFA, we determined that the degree of PFA did not have a negative effect on the functional level observed in the patients. We think the most important reason here that lending assistance of the surgery method applied in feeding the cartilage and forming the joint surface by allowing to the early movement and in protecting the knee movement width with the early rehabilitation. Karim et al operated on 18 patients with transverse closed isolated patella fractures. Surgeries were performed using the modified tension band method. The following complications were observed: superficial infection in three patients, wire migration in two patients, wire fracture in three patients, and displacement greater than 2 mm in one patient [17]. Following antibiotic treatment, infections observed were resolved. Additional surgical intervention was not necessary for any of the observed complications. An extension constraint of 25 degrees was observed in patients whose displacement was â&#x2030;Ľ 2 mm. In our study, there were no occurrences of union delay or failure of union among our patients. Implant irritation occurred in eight patients. of these 8 patients, the implants had to be removed from four of them. Wire migration was observed in three patients, and wire rupture occurred in two patients. The implants in these 5 patients had to be removed, as they caused pain and extension constraint during movements of the knee joint. Conclusion In conclusion, we evaluated clinical and radiological results following surgical treatment of patella fractures using peripheral wiring, modified anterior tension band, and cannula screw methods. Our results in the medium term are good. We also observed that fracture type did not affect the clinical results, although it was positively correlated with the degree of PFA. However, we believe that the degree of PFA does not affect the functional results of the patients. Finally, we believe that early commencement of knee joint rehabilitation exercises post-surgery is an important factor in achieving good clinical results. Financial Disclosure All authors declare no financial support. Ethical approval Ethical approval: This article contains studies with human participants and This article does not contain any studies or animal participant performed by any of the authors. Sadullah Turhan ORCID:0000-0003-2186-6519
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Canale ST, Beaty JH. Campbellâ&#x20AC;&#x2122;s operative orthopaedics: expert consult premium edition-enhanced online features, Elsevier Health Sciences 2012.
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Suh KT, Suh JD, Cho HJ. Open reduction and internal fixation of comminuted patellar fractures with headless compression screws and wiring technique. J Orthop Sci. 2018;23:97-104.
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Wild M, Fischer K, Hilsenbeck F, et al. Treating patella fractures with a fixedangle patella plate-A prospective observational study. Injury. 2016;47:173743.
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Grelsamer RP, Dejour D, Gould J. The pathophysiology of patellofemoral arthritis. Orthop Clin North Am. 2008;39:269-74.
11. Esenkaya I, Kafadar A, Bombaci H, et al. The results of the surgical treatment of patellar fractures. Acta Orthop Traumatol Turc. 2004;28:366-9.
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Blum L, Hake M. ORIF patella fracture with a tension band construct. J Orthop Trauma. 2017;31 Suppl 3:8-9.
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Yesiller E, Durmaz H, Cakmak M, et al. A Biomechanical study on a new mini external fixator developed in our clinics for transverse patellar fractures. Acta Orthop Traumatol Turc. 2004;24:163-7.
13. Dimiski G, Akan KH, Poyanli OS, et al. Results of surgical treatment in patellar fractures. Acta Orthop Traumatol Turc. 2004;30:377-80. 14. Yang L, Yueping O, Wen Y. Management of displaced comminuted patellar fracture with titanium cable cerclage. Knee. 2010;17:283-6.
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Burvant JG, Thomas KA, Alexander R, et al. Evaluation of methods of internal fixation of transverse patella fractures: a biomechanical study. J Orthop Trauma. 1994;8:147-53.
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Available online at www.medicinescience.org
CASE REPORT
Medicine Science International Medical Journal
Medicine Science 2019;8(2):445-8
Treatment of the left and the right coronary arteries’ ostial lesions by stenting in a patient with ımmune thrombocytopenic purpura Selda Morrad1, Bektas Morrad2 Viransehir Government Hospital Department of Cardiology, Sanlıurfa-Turkey 2 Kadirli Government Hospital Department of Cardiology, Osmaniye-Turkey
1
Received 27 June 2018; Accepted 27 July 2018 Available online 11.09.2018 with doi: 10.5455/medscience.2018.07.8896 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract Immune thrombocytopenic purpura is an autoimmune disease which is characterized with a decrease in number of platelets in blood. Gathering ITP and coronary artery disease are a rare situation. These patients are treated with percutaneous, surgery or medical therapy. Our patient is 61 years old female who resting angina pectoris (Canada classification class 4). She has immun trombocytopenic purpura for 5 years. Her hematological investigation showed thrombocyte counts 40x10^9/L. We performed coronary angiography after hematology counsultation. Coronary angiography showed left main coronary artery ostial 99% stenosis, right coronary artery ostial 90% stenosis. At the same section, we implanted bare metal stent 4.0x12 mm for right coronary artery and 4.5x15 mm for left main coronary artey ostial lesions, respectly. Angina of the patient disaapeared and she was discharged next day. There was no any problems at 6th month outpatient control. Keywords: Immune thrombocytopenic purpura, coronary artery disease, percutaneous coronary intervention
Introduction
Case Report
Immune thrombocytopenic purpura (ITP) is an autoimmune disease characterized by decrease platelet count in blood. Autoantibodies are formed against patients’ platelet membrane antigens and these platelets are subjected to phagocytosis by mononuclear macrophage system in spleen. As a result of shortened life span of thrombocytes in blood and failure of bone marrow, megakaryocytes producing thrombocytes, the number of thrombocytes is decreased by time [1]. Development of atherosclerosis and myocardial infarction in patients with ITP are quite low. In addition, the application of percutaneous coronary intervention in these patients is lower than other patients due to concerns with bleeding risk [2].
A 61-years-old female patient who was diagnosed with ITP five years ago. She was admitted to our hospital with complaints of chest pain. From the patient’s history it was learned that she has been suffering from Diabetes Mellitus for 15 years, ITP for 5 years and coronary artery disease for 4 years. On physical examination, she was anaemic and had dullness in upper left quadrant due to splenomegaly. Her blood pressure was 90/60 mmHg, and heart rate was 108 beats / min. Laboratory examinations revealed hemoglobin (HB) 5.9 g / dl, platelet 40x10 ^ 9 / L.
We report an ITP patient with refractory, whose ostial lesions of Left Main Coronary Artery (LMCA) and Right Coronary Artery (RCA) were treated with stent.
*Coresponding Author: Selda Morrad, Viransehir Government Hospital Department Of Cardiology, Sanlıurfa-Turkey E-mail: selda.eraslan@hotmail.com
The patient was hospitalized and up on the Hematology Department’s recommendations two units of fresh whole blood were given. In post-transfusion blood control, hemoglobin increased to 8.1 g / dL and platelet to 42x10^9/L. Coronary angiography was performed. There were 99% ostial lesion in LMCA and 90% ostial lesion in RCA (Figure 1). Acording syntax score coronary artery bypass grafting was planned but according to recommendation of hematology it may have high risk of bleeding and on the other hand patient did not accept cardiac surgery, because of that we opt PCİ. Intervention started first to RCA and then to LMCA. 48 hours before the procedure the patient was started on ASA 100 mg / day and Clopidogrel 75 mg / day as anti-aggregate treatment. It 445
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was adjusted in RCA ostium with JR4 side hole guiding catheter passing through 6F femural sheath. After giving 5,000 units unfractionated heparin intracoronary, a soft wire was passed through RCA ostial lesion and then dilated with 3.0x12mm N / C balloon (Sprinter). After that to align the stent in proximal part of aorta, a second soft wire was sent to aorta through the catheter. After that, 4.0x12mm bare metal stents (Integrity) at 20 atmospheres was transferred to aorta 3mm and was implanted in RCA ostium. Providing a complete restoration in right coronary (Figure 2), intervention started to LMCA. JL4 was adjusted in LMCA ostium with side hole guiding catheter half selectively. A soft wire was sent to LAD and a second soft wire was sent to CX. Then a balloon sent over the wire which had been sent to LAD and then LMCA lesion dilated with 3.5x12 mm N/C balloon (Sprinter), after that 4.5x15 mm bare metal stents (Integrity) at 18 atmospheres was implanted in LMCA ostium (Fiure 3). Femoral artery sheath was removed 4 hours after the procedure and 20 minutes femoral artery compression applied by hand to make sure bleeding has fully stopped. Patient with Angina completely recovered and was discharged the next day. In followup after six months angiography done, it showed the stents were open (Figure 4) and there were no additional problems.
Figure 3. Ostium of left main coronary artery after stenting
Figure 1. Ostial lesions of left main coronary artery and right coronary artery
Figure 4. The final view of left main coronary artery
Discussion
Figure 2. Ostium of right coronary artery after stenting
Application of percutaneous coronary intervention for the treatment of coronary artery disease in a patient with hematological problem and then taking of antiplatelet therapy regimes leads to some difficulties due to increased bleeding and risk of thrombosis (ITP) is an autoimmune disease in which autoantibodies are formed against patientsâ&#x20AC;&#x2122; platelet membrane antigens. As a result, platelets are destroyed rapidly by the immune system and the numbers of platelets are reduced in blood. It is well known that in patients diagnosed with ITP there is not only decrease in platelet counts but also function disorders [1]. There is no common consensus about percutaneous coronary intervention or bypass surgery in ITP patients with coronary artery disease. In literature, there is no clear limit regarding the safe platelet number in terms of bleeding 446
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complications after percutaneous coronary intervention. In this subject, the most important studies done by Park and colleagues on 22 patients who undergone PCI was reviewed. The patients average thrombocyte was 66±8310^9/L, 80 % of the patients’ approach were femoral, 87 % of the patients’ have received unfractioned heparin during procedure, and 83 % of the patient’ have received mono or dual antiplatelet therapy. They showed that bleeding can be controlled by hand compression after percutaneous coronary intervention and after 6 months follow up any major complication was seen [1]. Rossi et al in another study on this subject > 50x10 ^ 9 / L platelets from patients with wigs or surgical intervention can be applied safely showed [1]. There is another study by Rossu and colleagues showing that PCI and surgical intervention can be done safely in patients who has > 50x10 ^ 9 / L platelets. Our patient’s platelet count before the operation was 42x10 ^ 9 / L and no pre-treatment was given in order to increase the platelet count. 48 hours before the procedure Clopidogrel 75 mg / day and ASA 100 mg / day was started. In this way we aimed to reduce the risk of bleeding by avoiding giving Clopidogrel-loading dose. The operation was planned to perform from radial artery but it was failed, because of that we performed on the right femoral artery using a 6F sheath. 100 U/kg (5,000 units) UFH anticoagulation was given intracoronary and then the stent procedure performed. Following that antiplatelet therapy was dual oral antiplatelet therapy Clopidogrel 75 mg / day and ASA 100 mg / day) in the first month, after that it was continued only with ASA 100 mg / day. There was no development of complications associated with bleeding. Coronary artery disease (in a patient with ITP) can be seen in form of stable angina or acute coronary syndrome (ACS). This issue is related to the case reports of patients with ACS and ITP [6,7]. The basic mechanisms for ACS development is the growth of platelet or fibrin plug over a ruptured or eroded atherosclerotic plaque to develop an acute occlusion in coronary artery. Besides high count of platelet being responsible for acute coronary events, there are also many other factors effective for. Rituximab and IVIG therapy in patients with ITP due to anti-IIb / IIIa antibodies, highness of anti-phospholipid antibodies and other different factors the thrombotic events are more frequent comparing to normal population. Therefore, in ITP patients we should not ignore the high risk of thrombosis as well as bleeding complications after PCI. Especially patients treated with IVIG and rituximab are noted at higher risk in terms of developing thrombotic events. Our patient did not receive any of these treatments. Some points should be considered to reduce the risk of developing complications during and after the CAG process in patients with ITP. The most important one is the location of the operation. To provide a better compression the radial artery is preferred more than the femoral artery. However, due to good application of compression a good haemostasis has been achieved by patients who have preferred the femoral artery in some cases [5,7]. Another important point is the size of the sheath being used. The use of the smallest sheath can reduce the development of bleeding complications. The other important point, as our patient has, is that, if more than one vascular intervention is needed that should be done at one scene We preferred 6F sheath and applied stents in RCA and LMCA lesions at once. During PCI, antiplatelet and anticoagulant therapy management is one of the important points
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of bleeding. Unfractionated heparin has been safely used [8]. There are case reports showing that the dose of heparin in patients with high risk of bleeding has been reduced. Neskovic and colleagues have showed that half-dose heparin and fondaparinux can be used together by over 80 years for the treatment of acute coronary syndrome without any complications. Regarding Glycoprotein IIb IIIA, Stouffer and colleagues have used Eptifibatide and Clopidogrel together for treatment of ACS in patients with ITP and no bleeding complications have developed. Yagmur and colleagues have used Tirofiban for treatment of ACS in patients with ITP. It has been reported that the number of platelets was steady, furthermore, there was no bleeding. The third important point is the selection of the stent. Bare metal stents in order to shorten the time of dual anti-platelet could be preferred than the drug-coated stents. In 2 cases, Estelle and colleagues have applied drug-coated stents and have followed with Asetilsalisilik Acid and Clopidogrel. They have not seen any bleeding complications during the follow-up [9]. In another case study drug coated stents have been implanted in 2 patients. As a result of early stopping of antiplatelet therapy there was the need to repeat revascularization due to acute stent thrombosis [9]. Bleeding risk is high in these patients and there is a possible need to discontinue antiplatelet therapy. Therefore, (bare metal stent) should be considered as a priority for these patients. In our case, both in RCA and LMCA bare metal stents have been implanted. Afterward, in first month the antiplatelet therapy continued with two medication and then only with Aspirin 100 mg / day. At six months follow-up, angiography showed that both stents are open and there were no bleeding complications. As a result, PCI can be performed safely in patients with ITP whose platelet count is >30 x10 ^ 9 / L.
Conclusion To reduce the risks of procedure-related complications, the operators could be careful about using of small sheaths, operation area and individualizing of the antiplatelet therapy. Competing interests The authors declare that they have no competing interest. Financial Disclosure The financial support for this study was provided by the investigators themselves. Selda Morrad ORCID:0000-0002-6564-7185 Bektas Morrad ORCID:0000-0002-3935-0222
References 1.
Gracia MC, Cebollero IC, Lezcano JS, et.al. Invasive treatment performed for acute myocardial infarction in a patient with immune thrombocytopenic purpura. Int J Cardiol. 2008;127:183-5
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Fuchi T, Kondo T, Sase K, et.al. Primary percutaneous transluminal coronary angioplasty performed for acute myocardial infarction in a patient with idiopathic thrombocytopenic purpura. Jpn Circ J. 1999;63:133-6.
3.
Kikuchi S, Hayashi Y, Fujioka S, et al. A case of intracoronary stent implanted for acute myocardial infarction in an elderly patient with idiopathic thrombocytopenic purpura. Nippon Ronen Igakkai Zasshi. 2002;39:88-93.
4.
Hun-Jun P, Ki-Bae S, Pum Joon K, et al. Intracoronary stent deployment without antiplatelet agents in a patient with idiopathic thrombocytopenic purpura. Korean Circ J. 2007;37:87-90.
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Russo A, Cannizzo M, Ghetti G, et al. Idiopathic thrombocytopenic purpura and coronary artery disease: comparison between coronary artery bypass grafting and percutaneous coronary interventionInteract. Cardiovasc Thorac Surg. 2011;13:153-7.
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Renard D1, Cornillet L, Castelnovo G. Myocardial infarction after rituximab infusion. Neuromuscular Disorders. 2013;23:599-601.
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Caputo RP, Abraham S, Churchill D.Transradial coronary stent placement in a patient with severe idiopathic autoimmune thrombocytopenic purpura. J Invasive Cardiol. 2000;12:365-8.
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8.
Sandeep K D, Edwin L, John F, et al. Acute ST elevation myocardial infarction in patients with immune thrombocytopenia purpura: a case report. Cardiol Res. 2011;2:42-5.
9.
Estelle T, Harout Y, Donald M, James L. Two Cases and Review of the Literature: Primary Percutaneous Angiography and Antiplatelet Management in Patients with Immune. Thrombocytopenic Purpura. 2013;2013:174659.
10. Yagmur J, Cansel M, Acikgoz N et al. Multivessel coronary thrombosis in a patient with idiopathic thrombocytopenic purpura. Texas Heart Institute J. 2012;39:881-3.
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CASE REPORT
Medicine Science International Medical Journal
Medicine Science 2019;8(2):449-50
Management of obsessive compulsive disorder induced by the use of clozapine Yunus Emre Donmez1, Ozlem Ozcan2, Fatma Kartal Sarioglu3, Sumeyra Gungoren4 1Malatya Training and Research Hospital, Clinic of Child and Adolescent Psychiatry, Malatya,Turkey 2 Inonu University, Faculty of Medicine, Department of Child and Adolescent Psychiatry, Malatya, Turkey 3 Inonu University, Faculty of Medicine, Department of Psychiatry, Malatya, Turkey 4 Harran University, Faculty of Medicine, Department of Child and Adolescent Psychiatry, Sanliurfa, Turkey Received 17 July 2018; Accepted 19 September2018 Available online 26.10.2018 with doi:10.5455/medscience.2018.07.8920 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract The second generation antipsychotic of clozapine has superior efficacy compared to other antipsychotics especially for treatment-resistant schizophrenia. In up to 20% of patients receiving clozapine treatment, the side effect of obsessive compulsive symptoms or obsessive compulsive disorder occurs. These obsessive compulsive side effects sometimes cause cessation of the use of clozapine and sometimes causes difficulties in treating the psychotic symptoms due to dose reductions. This manuscript presents a case with resistant schizophrenia who developed obsessive compulsive disorder secondary to clozapine treatment and was successfully treated with clomipramine and aims to discuss the case accompanied by the literature. Keywords: Atypical antipsychotics, clozapine, obsessive compulsive disorder, clomipramine, adolescent
Introduction
Case Report
The second generation antipsychotic of clozapine has superior efficacy compared to other antipsychotics especially for treatmentresistant schizophrenia [1]. In up to 20% of patients receiving clozapine treatment, the side effect of obsessive compulsive symptoms (OCS) or obsessive compulsive disorder (OCD) occurs [2,3]. These obsessive compulsive side effects sometimes cause cessation of the use of clozapine and sometimes causes difficulties in treating the psychotic symptoms due to dose reductions. Additionally these obsessive compulsive side effects linked to clozapine may be interpreted as a worsening of the psychotic symptoms and clozapine dose may be increased and this results in a worsening of OCS/OCD. In the literature there are very few case reports about approaches to OCS/OCD linked to clozapine [4]. This manuscript presents a case with resistant schizophrenia who developed OCD secondary to clozapine treatment and was successfully treated with clomipramine and aims to discuss the case accompanied by the literature.
The sixteen-year old male patient was monitored by our clinic for early-onset schizophrenia diagnosis. Psychiatric examinations of the patient observed that self-care had reduced, he had distrustful opinions, disorganized talk, grandiose and nihilistic delusions, visual and auditory hallucinations, and blunted affect. With no history of alcohol, drug or chronic medication use and with no chronic disease, the patient’s family also had no history of psychiatric disease. The patient was examined by the neurology clinic for organic etiology and neurological pathology wasn’t detected. The patient did not benefit from 4 mg/day risperdal treatment and treatment was discontinued because of the extrapyramidal system side effects. After the risperidon treatment the patient used haloperidol 10 mg / day, arirpiprazole 20 mg / day and olanzapin 15 mg/day respectively. But the patient did not benefit from these treatments and some extrapyramidal side effects have been observed. As a result, in the fourth month the patient began clozapine treatment. Before the patient began clozapine treatment positive and negative syndrome scale (PANSS) scores were 53 for negative symptoms and 66 for positive symptoms. With periodic controlled dose increases, in two weeks the clozapine dose reached 225 mg. The patient responded positively to 225 mg/day clozapine dose and PANSS scores reduced to 25 for negative symptoms and 39 for positive symptoms. In the second
*Coresponding Author: Yunus Emre Donmez, Malatya Training and Research Hospital, Clinic of Child and Adolescent Psychiatry, Malatya,Turkey E-mail: dryemredonmez@gmail.com
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week of 225 mg/day clozapine treatment, the patient was observed cleaning and religious obsessions with hand washing and praying compulsions. As the patient had not responded to any other antipsychotics other than clozapine, treatment changes were not made and considering the benefit of 225 mg/day clozapine dose it was not reduced. The patient began clomipramine treatment of 75 mg/day for treatment of OCS. The patient’s psychotic and obsessive-compulsive symptoms were monitored along with the possible hematologic side effects of clozapine and the possible cardiac side effects of clomipramine. Clomipramine dose was increased to 150 mg/day within two weeks. During six weeks of monitoring, the patient’s psychotic symptoms were not observed to increase, with OCS largely reducing. With Children’s Yale-Brown Obsessive-Compulsive Scale score of 27 before clomipramine treatment, scores reduced to 13 due to treatment. No side effects due to clomipramine were observed during the treatment of the patient. But depending on the use of clozapine, hypersalivation was observed. The patient’s treatment successfully continues.
A study by Lin et al. about clozapine treatment of 102 schizophrenia patients reported the prevalence of OCS was 38.2%. Of patients 28.4% began to have OCS after clozapine treatment, with 5.9% developing OCD [7]. Ertugrul et al. in a study of 50 schizophrenia patients receiving clozapine treatment reported 20% of these patients had OCS after clozapine [8]. The OCS mechanism due to clozapine is not fully known. However, it is proposed that 5HT2A receptor antagonsim in key brain regions related to OCD including the anterior singulate cortex, dorsal lateral prefrontal cortex and orbitofrontal cortex may cause OCS [9,10]. Additionally a variety of gene (SLC1A1, GRIN2B and GRIK2) polymorphisms have been proposed to cause clozapine-sourced OCS/OCD [11]. Strategies applied in clozapine induced OCS management at case reports may be listed as reducing the clozapine dose, use of serotonergic antidepressants and electroconvulsive therapy [4]. In some case reports, dose reductions facilitated by augmentation with valproic acid have also been shown to improve OCS outcomes [12,13]. In the literature there are two case reports encountered where clozapine-linked OCS was treated with clomipramine [14, 15]. However, these two cases were adult patients, with our case being the first adolescent case report in the literature treated with clomipramine for clozapine-linked OCS. There is only one case report of the treatment of clozapine-linked OCS in the adolescent age group in the literature, and sertaline was used for treatment
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[16]. In the light of the case and literature data that we have shared, we are in the opinion that clozapine linked OCS/OCD can be treated by the use of clomipramine in adolescents and further studies regarding this matter are required. Competing interests The authors declare that they have no competing interest Financial Disclosure The financial support for this study was provided by the investigators themselves. Yunus Emre Donmez ORCID:0000-0002-7785-2805 Ozlem Ozcan ORCID:0000-0003-3267-2648 Fatma Kartal Sarioglu ORCID:0000-0002-5379-0021 Sumeyra Gungoren ORCID:0000-0002-2806-807X
References 1.
Kane J, Singer MD, Meltzer MD. Clozapine for the treatment-resistant. Arch Gen Psychiatry. 1988;45:789-96.
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Bleakley S, Brown D, Taylor D. Does clozapine cause or worsen obsessive compulsive symptoms? An analysis and literature review. Ther Adv Psychopharmacol. 2011;1:181-8.
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Schirmbeck F, Zink M. Clozapine-induced obsessive-compulsive symptoms in schizophrenia: a critical review. Curr Neuropharmacol. 2012;10:88-95.
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Fonseka TM, Richter MA, Müller DJ. Second generation antipsychoticinduced obsessive-compulsive symptoms in schizophrenia: a review of the experimental literature. Curr Psychiatry Rep. 2014;16:510.
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Swets M, Dekker J, van Emmerik-van Oortmerssen K, et al. The obsessive compulsive spectrum in schizophrenia, a meta-analysis and meta-regression exploring prevalence rates. Schizophr Res. 2014;152:458-68.
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Sterk B, Lankreijer K, Linszen DH, et al. Obsessive–compulsive symptoms in first episode psychosis and in subjects at ultra high risk for developing psychosis; onset and relationship to psychotic symptoms. Aust N Z J Psychiatry. 2011;45:400-6.
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Lin SK, Su SF, Pan CH. Higher plasma drug concentration in clozapinetreated schizophrenic patients with side effects of obsessive/compulsive symptoms. Ther Drug Monit. 2006;28:303-7.
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Ertugrul A, Yagcioglu AEA, Eni N, et al. Obsessive-compulsive symptoms in clozapine-treated schizophrenic patients. Psychiatry Clin Neurosci. 2005;59:219-22.
9.
Milad MR, Rauch SL. Obsessive-compulsive disorder: beyond segregated cortico-striatal pathways. Trends Cogn Sci. 2012;16:43-51.
Discussion In 25-64% of schizophrenia patients, OCS are observed and of these 8-26% abide by the criteria for clinically significant OCD [4]. A combinatorial meta-analysis and meta-regression study identified the OCD incidence with schizophrenia as 13.6% with OCS incidence of 30.3% [5]. Additionally only 1.7-14% of OCD patients have psychotic symptoms and 4-12% occur comorbidly with schizophrenia [4]. OCS are observed continuously during the progression of schizophrenic disorder, and may occur more clearly during chronic or late stage schizophrenia. The prevalence in first-attack patients is low, with rates of nearly 9% for OCS and 1.5% for OCD [6]. The low incidence of OCS and OCD in early schizophrenia is proposed to be linked to drug naivety or shortterm treatment duration. Though comorbidities have not been clearly defined, epidemiologic findings lead to the consideration that antipsychotics used by schizophrenia patients contribute to the risk of OCS [4].
10. Menzies L, Chamberlain SR, Laird AR, et al. Integrating evidence from neuroimaging and neuropsychological studies of obsessive-compulsive disorder: the orbitofronto-striatal model revisited. Neurosci Biobehav Rev. 2008;32:525-49. 11. Cai J, Zhang W, Yi Z, et al. Influence of polymorphisms in genes SLC1A1, GRIN2B, and GRIK2 on clozapine induced obsessive compulsive symptoms. Psychopharmacology. 2013;230:49-55. 12. Zink M, Englisch S, Knopf U, Kuwilsky A, Dressing H. Augmentation of clozapine with valproic acid for clozapine-induced obsessive-compulsive symptoms. Pharmacopsychiatry. 2007;40:202–3. 13. Canan F, Aydinoglu U, Sinani G. Valproic acid augmentation in clozapineassociated hand-washing compulsion. Psychiatry Clin Neurosci. 2012;66:4634. 14. Biondi M, Fedele L, Arcangeli T, et al. Development of obsessive-compulsive symptoms during clozapine treatment in schizophrenia and its positive response to clomipramine. Psychother Psychosom. 1999;68:111-2. 15. Leung JG, Palmer BA. Psychosis or Obsessions? Clozapine Associated with Worsening Obsessive-Compulsive Symptoms. Case Rep Psychiatry. 2016. 16. Coskun M, Zoroglu S. Clozapine induced obsessions treated with sertraline in an adolescent with schizophrenia. Klinik Psikofarmakol Bulteni. 2009;19:155-8.
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CASE REPORT
Medicine Science International Medical Journal
Medicine Science 2019;8(2):451-3
A case with pyoderma gangrenosum, after an abdominal surgery Gulbahar Sarac1, Irem Mantar1, Hulya Cenk2, Mehmet Sarac3 1 Inonu University, Faculty of Medicine, Department of Dermatology, Malatya, Turkey 2Malatya Training and Research Hospital, Department of Dermatology, Malatya, Turkey 3Malatya Training and Research Hospital, Department of General Surgery, Malatya, Turkey
Received 27 August 2018; Accepted 04 October 2018 Available online 28.10.2018 with doi:10.5455/medscience.2018.07.8919 Copyright Š 2019 by authors and Medicine Science Publishing Inc. Abstract Pyoderma gangrenosum (PG) is a pathergy positive, ulcerative neutrophilic dermatosis. Pathergy phenomenon is described as a sterile pustule and an ulcer development after minor skin traumas like a bump or bruise, or needlestick injury. In the literature, there are PG cases associated with the pathergy phenomenon on the post-surgical scar tissue. It presents as a necrotic and an ulcerative lesion clinically and, debridement is performed mostly with wrong pre-diagnoses. Debridement makes the lesion get wider and the morbidity increase. There are some PG case reports in the literature which were ended up with amputation due to debridement of a lesion which was an overlooked PG. Herein, we present a case with a giant abdominal pyoderma gangrenosum developed after a surgery in the abdominal drainage site and has reached to 30 cm size after debridement. Keywords: Pyoderma gangrenosum, post-surgical pyoderma gangrenosum, debridement
Introduction Pyoderma gangrenosum (PG) is a noninfectious, rare dermatological disease which causes ulcerative lesions. PG appears as papule and pustules, then it leads to exudative, deep, painful and violaceous ulcers with a sharp and irregular border [1]. Half of the cases are idiopathic although 50-70 % of them has inflammatory bowel disease, hematologic malignancy or rheumatic diseases among underlying reasons [2]. PG is a neutrophilic dermatosis and pathergy phenomenon is observed. Pathergy phenomenon is characterized by a sterile inflammation and ulcer development after some minor skin traumas such as a bump or venipuncture [3]. This phenomenon is observed also in Sweet syndrome, which is another neutrophilic disease, and in Behçetâ&#x20AC;&#x2122;s disease. Neutrophil dysfunction and enhanced neutrophil activation are the possible reasons for migration of neutrophils to the epidermis and dermis which leads to pathergy positivity [4].
*Coresponding Author: Hulya Cenk, Malatya Training and Research Hospital, Department of Dermatology, Malatya, Turkey E-mail: hullya86@msn.com
There are PG cases developed after surgery in the literature. These cases must be differentiated from the diseases requiring debridement like necrotizing fasciitis due to the similar necrotic and ulcerated appearance because debridement in PG may activate the lesion and makes the risk of permanent damage higher [5]. Case Presentation A 66 year-old male patient has been consulted to dermatology clinic because of his ulcerated wound in the abdominal region on 7th. day of his hospitalization in the surgery service due to an abdominal surgery. At the dermatological examination, there was a painful ulcer with an erythematous, sharp and irregular border. The lesion was 30x20 cm in size in the right lower quadrant of the abdomen and it had a necrotic and yellowish exudative appearance in some parts (Picture 1). The patient had undergone a segmental ileal resection surgery 19 days ago because of acute abdomen findings. The current complaints have started after 4 days of the surgery as a small wound around the surgical drain. During the follow-up, on the 12th. postoperative day, he has been hospitalized in the surgery service with the prediagnosis of wound infection and has debridement treatment. Afterward, the wound became an ulcer which was wider and deeper. Laboratory test results were 451
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as following: WBC: 4,6x109/L, HGB:6,7 gr/dl, CRP: 17,2 mg/ dL, creatinine: 1,51 mg/dl and albümin: 1,9 g/dl. Microbiological wound and blood culture result were negative. Thereafter, prophylactic ceftriaxone and ornidazole treatment have been started but the patient had still fever, so he has been consulted to the department of infectious diseases and the antibiotherapy was substituted by piperacillin and tazobactam treatment. Four days later the treatment was changed again because of ineffectiveness to meropenem and linezolid treatment and the patient was consulted to the dermatology clinic. A skin biopsy performed and also we learned that he had myelodysplastic syndrome in his past medical history and he has been followed up without treatment. In brief, the patient didn’t answer to multiple antibiotherapy, his culture results were negative, he had a suspicion of malignity in his medical history and his lesion was compatible with PG. By this way, 60 mg systemic steroid and topical betamethasone and gentamycin combination treatment has been started, after 1 week, a dramatic improvement was observed in the lesion (Picture 2). The biopsy resulted later and it revealed abscess formation and densely mixed inflammation extending along the subcutaneous fat tissue. A topical epithelializing agent was added to treatment and the steroid treatment was tapered to zero ensuing 3 weeks. After the treatment, full remission has been reached with only a cribriform scar in the lesions place (Picture 3). An informed consent has been taken from the patient to be allowed to share his pictures and medical data in any of medical journals and meetings.
Figure 1. Ulcerated wound after surgery
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Figure 3. Full epithelisation at the 3rd. week of the treatment
Discussion PG is correlated with inflammatory bowel diseases, hematologic malignities, rheumatic diseases and liver diseases such as chronic active hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis in the rate of 50-70% [6]. This case had also the myelodysplastic syndrome. It’s very important to have a detailed medical history of the patients with recalcitrant, ulcerated lesions in terms of pathergy positivity and a past history of PG and the history of the diseases which could be related to PG so that a correct and timely diagnosis can be made [5]. The rate of pathergy positivity in PG is 30%. Pathergy positivity may be caused by debridement and surgery procedures besides any minor trauma. Surgery-associated PG cases are seen mostly after abdominal and breast surgeries [6]. There are some PG lesions reported on the chest wall after by-pass surgery, on the scar of episiotomy, around the gastrostomy tube and on the hand after the surgery for carpal tunnel syndrome [1,3,5,6]. PG development duration is approximately 7 days after a surgery [2], but the duration for an exact diagnosis might be as long as 28 months [7]. There are 220 cases of surgery-associated PG cases in the literature, but, it’s considered that this number is not reflecting the true number of cases because of difficulties in making the correct diagnosis and lots of patients who have been followed up with wrong diagnoses [5]. The lesion had been noticed on the 4th. postoperative day in our case. The lack of objective diagnostic criteria makes PG a diagnosis of exclusion and the diagnosis is made based on histoclinicopathologic findings [1]. Histopathologically, epidermal necrosis, dense neutrophilic inflammation and abscess formation may be seen [7]. Presence of actively inflamed violaceous borders, exudative discharge, and necrotizing ulcerative lesion makes the differential diagnosis wider including necrotizing soft tissue infections. Actively inflamed violaceous border, negative culture results and neutrophil accumulation in the histopathologic evaluation are important supportive features for the diagnosis of PG [2].
Figure 2. Clinical improvement at the first week of the treatment
The most important step of the treatment includes making the correct diagnosis which enables avoiding unnecessary debridement and protecting the tissue from minor traumas. Topical and systemic 452
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steroids, cyclosporine and dapsone are the treatment options. Also, PG cases who were successfully treated with intravenous immunoglobulin and anti-TNF agents have been reported in the literature [8].
Irem Mantar ORCID: 0000-0002-4772-5397 Hulya Cenk ORCID: 0000-0003-4871-6342 Mehmet Sarac ORCID: 0000-0003-2221-4141
The exact cause of pyoderma gangrenosum is not known; however, there are cases with PG which has been developed after by-pass, splenectomy, episiotomy, thoracostomy and gastrostomy. In our case, the wound with surgical sutures had been closed without any problem and apart from that, a small PG lesion had been developed around the surgical drainage tube. There arenâ&#x20AC;&#x2122;t enough studies which could clarify the good wound healing on the sutured skin but a PG development around the drainage tube in this patient.
1.
Bryan CS. Fatal pyoderma gangrenosum with pathergy after coronary artery bypass grafting. Tex Heart Inst J. 2012;39:894-7.
2.
Vaysse-Vic M, Mathieu P-A, Charissoux A, et al. Pyoderma gangrenosum or necrotising fasciitis? Diagnostic and therapeutic wanderings. Orthop Traumatol Surg Res. 2017;103:615-7.
3.
Davis C, Wright B. Healing of a pyoderma gangrenosum at the site of a percutaneous endoscopically sited gastrostomy tube without tube removal. BMJ Case Rep. 2014;2014:1-3.
Conclusion
4.
Xia FD, Liu K, Lockwood S, et al. Risk of developing pyoderma gangrenosum after procedures in patients with a known history of pyoderma gangrenosum-A retrospective analysis. J Am Acad Dermatol. 2018;78:310-4.e1.
5.
Ruebhausen MR, Mendenhall SD, Neumeister MW, et al. Postsurgical Pyoderma Gangrenosum Following Carpal Tunnel Release: A Rare Disease Following a Common Surgery. Eplasty. 2017;17:e10.
6.
Alani A, Sadlier M, Ramsay B, et al. Pyoderma gangrenosum induced by episiotomy. BMJ Case Rep 2016;2016:1-3.
7.
Gulyas K, Kimble FW. Atypical pyoderma gangrenosum after breast reduction. Aesthetic Plast Surg. 2003;278:328-31.
8.
Taguchi M, Inoue T, Nishida T, et al. A Case of Pyoderma Gangrenosum of the Penis Difficult to Distinguish from Fournier Gangrene. Acta Urologica Japonica. 2015;61:459-63.
PG should also be kept in mind in necrotic and ulcerative lesions developing after surgeries, besides infectious reasons. Especially, the history of the patient about unhealing wounds or concomitant diseases is important. An early dermatologic consultation is required in ulcerated lesions which are unresponsive to antibiotherapy in terms of avoiding unnecessary debridement and permanent damage. Competing interests The authors declare that they have no competing interest Financial Disclosure The financial support for this study was provided by the investigators themselves. Gulbahar Sarac ORCID: 0000-0002-7246-6382
References
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CASE REPORT
Medicine Science International Medical Journal
Medicine Science 2019;8(2):454-6
Cause of rare acute abdomen: Primary omental torsion Guleser Akpinar1, Bedia Gulen2, Ali Duman3, Afsin Ipekci4, Hilal Hocagil5 1
SBU Istanbul Sisli Hamidiye Etfal Training and Research Hospital, Clinic of Emergency Medicine, Istanbul, Turkey 2 Bezmialem Vakif University Faculty of Medicinel, Department of Emergency Medicine, Istanbul, Turkey 3 Adnan Menderes University Faculty of Medicine, Department of Emergency Medicine, Aydin, Turkey 4 Cerrahpasa University Faculty of Medicine, Department of Emergency Medicine Istanbul, Turkey 5 Bulent Ecevit University Faculty of Medicine, Department of Emergency Medicine, Zonguldak, Turkey Received 20 August2018; Accepted 04 October2018 Available online 30.01.2019 with doi:10.5455/medscience.2018.07.8936 Copyright Š 2019 by authors and Medicine Science Publishing Inc.
Abstract Omental infarction is a rare pathology which develops as a result of impairment of perfusion of the omentum magus, which can imitate almost all acute abdomen symptoms with its clinical findings. The patient who applied to our emergency department with the complaint of abdominal pain that has started three days ago was taken under operation with the prediagnosis of omental infarction as a result of the analyses conducted. In laparotomy, omentum torsioned along normal appendix and long axis and undergone necrosis was observed. Torsioned necrotic omentum tissue has been excised. Our conclusion from the case and literature is that omental torsion and idiopathic omental necrosis should be also considered in patients with abdominal pain complaint. Keywords: Omental infarction, omental torsion, acute abdomen
Introduction Omental infarction is a rare pathology defined almost a century ago. With start of the use of cross-sectional diagnostic methods developed in the recent years, it was understood to be a pathology that is more common than as known. Omental infarction is seen most frequently in the fourth and fifth decades. Its male-female ratio is 2:1. Only 15% of the cases are in the pediatric age group [1]. Omental infarction can occur as a result of torsion of the omentum or without torsion. Omental torsion may be of primary of secondary type. As primary, it can occur especially in obese patients with the effect of the predisposant factors, in association with omentum anomaly, excessive exercise, sudden movements,
*Coresponding Author: Guleser Akpinar, SBU Istanbul Sisli Hamidiye Etfal Training and Research Hospital, Clinic of Emergency Medicine, Istanbul, Turkey E-mail: guleserakpinarduman@gmail.com
hyperperistaltism. Secondary omental torsion most frequently occurs due to the causes such as hernia, tumor, adhesion force [2]. Both cases result in torsion and infarction. The infarctions developing without torsion may be observed as secondary omental infarction or idiopathic segments omental infarction coexisting with systemic conditions such as vasculitis, pancreatitis, hypercoagulability [3]. In this study, we evaluated the case we administered follow-up and treatment of due to the cause of acute abdomen in the light of literature data. Case Report 28-year-old female patient applied to our emergency department with complaint of abdominal pain that has started 3 days ago. It was expresses that the pain had started instantly and become acute thereafter. Nausea, vomiting, fever, lack of appetite and urinary symptoms were absent. She did not have surgery, illness and continued drug use in her history. In physical examination of the patient, TA:110/60 mmHg, KTA:74/dk, fever:36.7°, in abdominal examination, sensitivity with palpation especially in both lower 454
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quadrants were present, she did not have distension. She described stools discharge as recent diarrhea, she did not describe dysuria and vaginal secretion. Patient’s body mass index was within the normal limits. Results of laboratory analysis were glucose: 142 mg/dl (74 - 106 mg/dl), urea: 17.5 mg/dl (0 - 50 mg/dl), creatinine: 0.57 mg/dl (0 - 0.95mg/dl), SGOT: 11.8 u/l (0 - 32 u/l), SGPT: 5.9 u/l (0 - 33 u/l), LDH: 124 u/l (135 - 214 u/l ), total bilirubin: 0.31 mg/dl ( 0 - 1.2 mg/dl ), direct bilirubin: 0.16 mg/dl (0 - 0.3 mg/dl), amylase: 52 u/l (28 – 100 u/l), lipase: 14 u/l (21 – 67 u/l), CRP: 57.12 mg/l (0 – 5 mg/l), WBC: 11,29 K / uL (4-11 K / uL), Hemoglobin:10 g / dL (13-17.5 g / dL), Platelet:160 K / uL (150 – 400 K / uL) Electrocardiography was in normal sinus rhythm. The patient first underwent whole abdominal ultrasonography, and no feature was observed. Radiology commented that appendix was normal, density increases that could be consistent with inflammation in omentum were observed in abdominal lower quadrants in iv-contrast abdominal tomography of the patient. The patient for whom consultation was made with general surgery was taken under urgent operation with the pre-diagnosis of omentum infarction. In laparotomy, omentum torsioned along normal appendix and long axis and undergone necrosis was observed. Torsioned necrotic omentum tissue was excised. She was discharged without problem on post-operative day three. Discussion Omental torsion is rare clinical condition progressing with hemorrhagic exudates and acute abdomen findings in association with development of necrosis in distal of the torsion due impairment of arterial supply and venous drainage in consequence of rotation of the omental structure and appendices around the long axis It is more commonly seen in the 3rd and 5th decades. Omental torsion was first defined by Eitel in 1899, and primary omental torsion was encountered at the rate of 01% in laparotomies of the children with the pre-diagnosis of acute abdomen [2]. It is very difficult to diagnose omental torsion preoperatively. Diagnosis can be usually made intraoperatively. In the studies conducted, it is reported that 0.2% to 4.8% of all cases can be diagnosed correctly preoperatively [4]. Diagnosis was made preoperatively in our case, too. In the clinic, subfebrile fever and moderate leucocytosis may be seen in 50% of the patients. Our cases had moderate leucocytosis . In the literature, omental torsion and pain in infarct is seen to be characterized as starting instantly, continuous, non-spreading, and having intensity increasing with time and motion. In physical examination, sensitivity and rebound may be frequently preset in the right lower quadrant, this may be accompanied by nausea and vomiting [2,3]. In our case, pain onset was instant before 3 days and continued constantly. In physical examination, she had common sensitivity, she did not complain of nausea and vomiting. Patient’s body mass index was within the normal limits and she was young. Findings usually imitated acute appendicitis, cholecystitis, or over cyst torsion, and if left-sided, misdiagnosis of diverticulitis or renal colic might be made, albeit rarely. In physical examination, palpable mass and localized peritonitis findings were identified in the right lower quadrant in half of the patients [5]. It differs from acute appendicitis with absence or insignificance of gastrointestinal
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symptoms such as nausea, vomiting, lack of appetite, absence or subfebrile course of fever, duration of the symptoms, and lower significance of the peritoneal findings [6]. Mostly radiological imaging techniques such as ultrasonography and computerized tomography may be utilized in diagnosis tests. However, precision of ultrasonography may vary depending on the intestinal gas and experience of the performer. With computerized tomography, preoperative diagnosis rates increased, cases approached conservatively and recovered without complications were reported. Computerized tomography is accepted as the golden standard in tomography. Typical ultrasonogaphic appearance is in the form of mass lesion showing moderate hyperchogenicity, uncompressible, oval, peritoneal adhesion, and peritoneal fluid may also be observed [7]. Ultrasonographically, there was no feature in our case. In the evaluation performed with computerized tomography, inflammation was detected in the abdominal lower quadrant. While etiologies and physiopathologies of omental torsion and necroses are different, similar clinical pictures emerge in all cases. Natural pathological course of omental infarction is termination of the inflammation process as retraction, fibrosis and finally, as complete or autoamputation. Sepsis, abscess formation and adhesion development are among late complications [8]. Publications stating that conservative therapy may be tried in a selected part of the patients diagnosed preoperatively. With the increasingly common use of CT, number patients on whom conservative therapy may be tried increased. Analgesics, antiinflammatory drugs and prophylactic antibiotics are used in conservative therapy. Potential complications (abscess, adhesions, sepsis, etc.) should be kept in mind while administering conservative therapy. In the cases with necrosis, treatment option is resection of the necrotic segment. First option in surgical treatment should be laparoscopic approach [9,10]. Conclusion In conclusion, while omental torsions are usually conditions which start instantly and present acute abdominal findings, they may sometimes be among the causes of chronic pain, i.e. nonspecific abdominal pain. Often intraoperative diagnosis is made, nevertheless, with the increased use of CT, there was increase in the number of patients diagnosed preoperatively. Competing interests The authors declare that they have no competing interest Financial Disclosure The financial support for this study was provided by the investigators themselves. Guleser Akpinar ORCID: 0000-0001-8559-5098 Bedia Gulen ORCID: 0000-0002-7675-0014 Ali Duman ORCID: 0000-0001-9461-5812 Afsin Ipekci ORCID: 0000-0001-6125-4061 Hilal Hocagil ORCID: 0000-0001-7314-752X
References 1.
Schwartzman GJ, Jacobs JE, Birnbaum BA. Omental infarction as a delayed complication of abdominal surgery. Clin Imaging. 2001;25:341-3.
2.
Nina Breunung, Paul Strauss. A diagnostic challenge. primary omental
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torsion and literature review - a case report. World J Emerg Surg. 2009;4:40.
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Parr NJ, Crosbie RB. Intermittent omental torsionâ&#x20AC;&#x201D;an unusual cause of recurrent abdominal pain? Postgrad Med J. 1989;65:114-5.
Al-Bader I, Said Ali AA, Al-Sharraf K, et al. Primary omental torsion: two case reports. Med Princ Pract. 2007;16:158-60.
8.
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Efthimiou M, Kouritas VK, FafoulakÄąs F, et al. Primary Omental Torsion. Report of Two Case. Surg Today. 2009;39:64-7.
Stella DL, Schelleman TG. Segmental infarction of the omentum secondary to torsion: ultrasound and computed tomography diagnosis. Australas Radiol. 2000;44:212-5.
5.
Tsironis A, Zikos N, Bali C, et al. Primary torsion of the greater omentum: report of two cases and review of the literature. J Emerg Med. 2013;44:45-8.
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Coulier B. Segmental omental infarction in childhood: a typical case diagnosed by CT allowing successful conservative treatment. Pediatr Radiol. 2006;36:141-3.
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Saber A, LaRaja R. Omental torsion. EMedicine, article 191817;2007. [http:// emedicine.medscape.com].
10. Occhionorelli S, Zese M, Cappellari L, et al. Acute abdomen due to primary omental torsion and infarction. Case Rep Surg. 2014;2014:2082-3.
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CASE REPORT
Medicine Science International Medical Journal
Medicine Science 2019;8(2):457-9
Tuberculosis of fifth metatarsal bone- a rare case report Apoorva HC, Amit Kumar C Jain, Suresh Kumar Amit Jain’s Institute of Diabetic Foot and Wound Care, Brindhavvan Areion Hospital, Bangalore, India Received 04 August 2018; Accepted 12 Octaber 2018 Available online 24.12.2018 with doi:10.5455/medscience.2018.07.8948 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract Abscess and ulcers of foot are common in adult, especially if they are diabetic and are commonly caused due to pyogenic infection. However, occasionally atypical organism gives us surgical surprises. Rarely,do we encounter tuberculosis of foot.We report rare case of tuberculosis of fifth metatarsal in a middle aged non diabetic female patient. Keywords: Foot, abscess, tuberculosis, metatarsal, India
Introduction Tuberculosis remains to be a challenge to the health in a country like India and other developing/under developed countries [1].The osteoarticular tuberculosis accounts for less than 3% of the cases of the extra pulmonary tuberculosis [2]. The overall incidence of tubercular osteomyelitis is considered to be rare [3]. It can affect any bone of the human body. The involvement of short long bones is an uncommon entity in clinical practice and further, the involvement of foot and ankle is considered rare [2,3]. This case reports aims to highlight the fact that tuberculosis can occur at unusual location and one should be vigilant to identify it especially in countries where tuberculosis is common.
Physical examination showed presence of swelling over left side dorsum of forefoot and midfoot [Figure 1]. There was no local rise of temperature .Tenderness was present.Patient had oedema till lower leg.The swelling had variable consistency.
Case report A 36 year old female patient presented to us with history of swelling and pain over left foot from past 2 weeks of duration. There was no history of any trauma. She had fever for first 2 days which subsided after taking oral medication from the local general practitioner. Her pain and swelling did not subside in spite of oral medications. Patient had history of loss of weight and appetite from 2 weeks. Patient was not a diabetic. *Coresponding Author: Amit Kumar C Jain, Amit Jain’s Institute of Diabetic Foot and Wound Care, Brindhavvan Areion Hospital, Bangalore, India E-mail: dramitkumarcj@yahoo.in
Figure 1. showing swelling over the dorsum of the left foot A clinical diagnosis of abscess of foot was considered. Her haemoglobin was 9.4g%, total WBC counts was 5500, random 457
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blood sugar of 108mg% , serum creatinine of 0.4mg%. Her ESR was 50. Serology for HIV and HBsAg was negative X ray foot showed a well defined expansile lytic lesion in the distal end of fifth metatarsal bone [Figure 2].There was thinning of cortex. Rest of the visualized bones and joints appeared normal.
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Patient was referred to primary health care centre where she was started on antitubercular drugs for 1 year based on DOTS regimen followed at our place. Patients used to come for weekly dressing at our centre. At end of 3 weeks, her wound granulated well. She underwent secondary suturing. Her 3 month follow up showed a good healthy scar [Figure 4]. She was on antitubercular drug of 1 year duration.
With a suspicion of abscess with osteomyelitis, patient underwent a 5th toe amputation with debridement. Intraoperative finding showed presence of beads of pus with unhealthy subcutaneous tissue and bone.The pus and tissue was sent for culture and bone for biopsy.
Figure 3. showing presence of epithelioid granuloma, Langhans giant cell and central necrosis in the bone
Figure 2. is x ray of the foot showing a well-defined expansile lytic lesion in the distal end of fifth metatarsal bone Post operative period was uneventful and she was discharged. Her culture and sensitivity on day 3 showed Methicillin sensitive Staphylococcus aureus. She was given oral Clindamycin tablets in view of sensitivity. Her wound appeared healthy with no pus discharge. On day 5 of follow up, her histopathology report of bone gave us a surprise. It showed bone tuberculosis with interspersed area of granulation tissue with epithelial granulomas and multinucleated Langhanâ&#x20AC;&#x2122;s giant cells. There were areas of caseation [Figure3]. Features were suggestive of tuberculosis osteomyelitis of 5th metatarsal bone.
Figure 4. shows well healed wound during follow-up period 458
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Discussion
enchondromata, etc [5].
Musculoskeletal tuberculosis accounts for around 1-2% of all cases of tuberculosis seen in the western world and they are often difficult to diagnose [4].Tuberculosis osteomyelitis are known to have unusual course and often the diagnosis is delayed due to unusual presentation and absence of clinical features [3].
In view of paucibacillary infection, mycobacterium can rarely be isolated from tissue [2,5]. Diagnosis is often made on histopathology [4]. In our case too, we were able to obtain final diagnosis only after histopathology of the metatarsal bone. Antitubercular drugs are recommended at least for 12 months [2, 5]. It comprises of four drugs for 2 months (isoniazid, rifampicin, pyrazinamide and ethambutol) followed by two drugs for 10 months or more(isoniazid and rifampicin) [5]. Prognosis is usually good unless other adjacent bones or joints are involved [5].
The osteoarticular tubercular infection accounts for 1-3% of cases wherein it affects commonly the spine and major joints like hips and knees [1,3,5].Around 10% of osteoarticular tuberculosis are known to affect the foot and ankle [5]. Among the foot bones, calcaneum is the most commonly affected bone followed by metatarsal and phalanges [3,5]. The possible explanation for involvement of calcaneum is that it is the largest foot bone making it possible to detect lesions early and also due to its vulnerability to trauma [2]. It has been observed that there have been 35 cases of tuberculosis of metatarsal being documented in literature [5]. Literature suggests that metatarsal TB osteomyelitis is less than 0.5% [5]. The fifth metatarsal bone is rarely affected by pyogenic or tubercular infection [3]. Patientâ&#x20AC;&#x2122;s common foot symptoms are pain, swelling, stiffness, redness and sometimes formation of abscess [1,6]. Often patient has either with a sinus or non healing ulcer with secondary infection [1]. The classical symptoms of fever and weight loss is rarely seen [4]. The tuberculosis of the foot and ankle are classified into 4 basic forms namely periarticular granuloma, central granuloma, primary haematogenous synovitis and bursal tuberculosis [2,6]. Although tuberculosis osteomyelitis of metatarsal bones are secondary to lymphohaematogenous spread from a pulmonary lesion, up to 50% of patients do not show pulmonary manifestation [1,3]. The X ray of foot in tuberculosis of foot are non specific and includes bone marrow oedema,osteoporosis or lytic lesions [3, 4].Mittal et al have classified tuberculosis of foot into 5 radiological types namely cystic, subperiosteal, rheumatoid,kissing and spina ventosa [2,5]. However, these features are not exclusive for tuberculosis and are also seen in chronic pyogenic osteomyelitis, sarcoidosis,
Conclusion Tuberculosis is a common problem in India. It can affect any part of the body. However, it rarely involves the foot. Involvement of 5th metatarsal is very rare just like our case. Most of the time the diagnosis at presentation is not taught and we can face with histopathological surprises in view of non specific clinical and radiological presentations. Competing interests The authors declare that they have no competing interest. Financial Disclosure The authors declared that this study has received no financial support. Apoorva HC ORCID: 0000-0002-4637-3801 Amit Kumar C Jain ORCID: 0000-0002-4070-6855 Suresh Kumar ORCID: 0000-0002-2103-1186
References 1.
Nayak B, Dash RR, MohapatraKC, et al. Ankle and foot tuberculosis: a diagnostic dilemma. J Fam Med Primary Care. 2014;3:129-31.
2.
Dhillon MS, Aggrawal S, Prabhakar S, et al. Tuberculosis of the foot: an osteolytic variety. Indian J Orthop. 2012;46:206-11.
3.
Ganda V, Kadu V, Gadghate N, et al. Unusual site of tubercular osteomyelitis of fifth metatarsal. Int J Health Sci Res. 2015;2:479-82.
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Flint JD, Saravana S. Tuberculosis osteomyelitis of midfoot: a case report. Cases J. 2009;2:6859.
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Madi S, Naik M, Vijayan S, et al. An isolated case of first metatarsal tuberculosis. Oxf Med Case Reports. 2015;3:241-3.
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Agarwal A, Qureshi NA, Khan SA et al. Tuberculosis of foot and ankle in children. J Ortho Surg. 2011:19:213-7.
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CASE REPORT
Medicine Science International Medical Journal
Medicine Science 2019;8(2):460-1
A case of myasthenia gravis accompanied with hasimato thyroiditis and familial mediterranean fever Fatma Ebru Algul ORCID:0000-0003-0318-7571 Malatya Education and Researh Hospital, Clinic of Neurology, Malatya, Turkey Received 21 September 2018; Accepted 16 Octaber 2018 Available online 26.12.2018 with doi:10.5455/medscience.2018.07.8945 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract Familial mediterranean fever (FMF), Hasimato’s thyroiditis (HT) ve Myastenia gravis (MG) are chronical diseases that show autoimmunity. Literature reviews indicate several cases of coexisting MG and HT and only one case coexistence of MG and FMF. We present a clinical table of a 21-year-old male patient with all three diseases. The patient admitted to the hospital with limited eye movements, difficulty in swallowing which became evident towards the end of a meal. The patient had a history of FMF. The anti-TPO and anti-TG levels of the patient had increased. The ACh Receptor antibody was in the normal range (0.01), and the anti-MuSK value was high (>12). Single fiber EMG results of the patient were compatible with myasthenia gravis. The methylprednisolone and pyridostigmine treatment led to an almost complete improvement of the symptoms. As the patient had three different autoimmune disorders at once, it was thought to be a notable case worth presenting. Keywords: Myasthenia gravis, hashimoto thyroiditis, familial mediterranean fever
Introduction Myasthenia gravis (MG) is a chronic neuromuscular disease with a reported annual incidence of 0.25-2.00 per 100,000 population. Autoinflammation is considered to play a role in the etiology of MG [1]. Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by recurrent attacks of fever and polyserositis (peritonitis, pleuritis, arthritis) [2]. Hashimoto’s thyroiditis (HT) is a thyroid disease of autoimmune origin resulting from autoimmune destruction of the thyroid gland by cellular and humoral immune mechanisms [3]. Coexistence of MG with other autoimmune diseases has been shown in the literature [4]. Moreover, the autoimmune nature of FMF, HT, and MG implicates that coexistence of these diseases is highly likely. In this report we present a case of coexisting FMF, HT, and MG. Case Report The 21-year-old male patient presented with a 6-month history of bilateral ptosis that became prominent within a short time after wake-up in the morning and was accompanied by diplopia. Patient history revealed that the patient received a diagnosis of FMF 6 *Coresponding Author: Fatma Ebru Algul, Malatya Education and Researh Hospital, Clinic of Neurology, Malatya, Turkey, E-mail: ebruycl86@yahoo.com
years earlier, suffered from dysphagia that became prominent particularly at the end of meals for the last 5 months, and noticed eye-movement restriction about 2.5 months earlier. Family history revealed that the father of the patient was an FMF carrier. The patient was on regular treatment with colchicine 2x0,5 mg/day. Physical examination was normal. Neurological examination showed marked bilateral ptosis that was more prominent in the right and also revealed that the left eye could partially move down and was restricted in all other directions while the right eye could partially move inward and down and was restricted in all other directions. The neurological examination was otherwise normal. Hormone tests indicated high levels of anti-thyroid peroxidase (anti-TPO) (582.4) and anti tiroglobulin (anti-TG) (1420.5) antibodies, thyroid function test results were normal, and antiacetylcholine receptor antibody (AChR-Ab) (0.01) was detected. Cranial magnetic resonance imaging (MRI) was normal except for extra-axial arachnoid cyst in size 25 mm in the left temporal lobe. A chest computed tomography (CT) showed a nodular thymic lesion approximately 8 mm in the anterior mediastinum. Single-fiber electromyography (SFEMG) was consistent with MG. After the initiation of pyridostigmine and prednol, a significant improvement was achieved in the eye symptoms and functions. The patient had a high level of anti-muscle specific kinase antibody (anti-MuSK-Ab) (<12). 460
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Discussion Myasthenia gravis (MG) typically occurs as a result of the disruption of neuromuscular transmission caused by the antibodies developing against the acetylcholine receptors, characterized by muscle weakness that worsens on exertion. A high level of antiAChR-Ab is evident in 85% and the anti-MuSK-Ab is positive in 4-6% of the patients with generalized MG. However, no elevation of antibodies may be seen in 10-15% of the patients [5]. Familial Mediterranean fever (FMF) is a genetic multisystem disease characterized by recurrent attacks of fever accompanied by symptoms of abdominal pain, chest pain, joint pain and/or skin rashes [6]. FMF is also an autosomal recessive disorder caused by the heterozygous mutation in the MEFV gene localized on the short arm of chromosome 16. The MEFV gene encodes a protein known as pyrin, which is an inhibitor of the chemotactic factor, interleukin (IL)-8 and suppressor T cells. Numerous studies have shown that FMF can be accompanied by autoimmune diseases such as multiple sclerosis, Behçet’s disease, and polyarteritis nodosa [6]. Hashimoto’s thyroiditis (HT) is the most common form of autoimmune thyroid disease. Literature indicates that the levels of T cells that produce interferon gamma (IFNγ) and tumor necrosis factor (TNF)-alpha (TNF-α) tend to be higher in individuals with high levels of anti-TPO antibody [7]. Moreover, the possibility of the coexistence of MG with thyroid autoimmunity has been reported to be 10-20% [4]. Clinical manifestations of MG often emerge within 2 years of the onset of autoimmune diseases, mostly in the form of ocular or generalized MG [8]. Literature reviews indicate that the first cases of coexisting MG and HT were reported by Daly, Jackson and Simpson in 1964 [9]. In 1966, Singer et al. presented a case of coexisting HT, MG, and pernicious anemia [10]. Kanawaza et al. showed that the incidence of autoimmune diseases such as Grave’s disease and HT was higher in patients with MG compared to the general population [11]. A similar finding was also presented by a population-based study in Poland that was conducted with 343 patients with MG [12]. Another study that was conducted in Japan reported that the incidence of autoimmune diseases was higher in patients with AChR-Ab-positive patients compared to anti-MuSK-Ab-positive patients [13]. However, Toth et al. found no significant difference between the patients with seropositive MG and those with seronegative MG with regard to the incidence of autoimmune thyroid diseases [14]. As consistent with the finding reported by Toth et al., our patient was a case of coexisting seronegative MG and HT. Kubiszewska et al. showed that the presence of thymoma in MG is related to higher risk of non-autoimmune thyroid diseases [12]. In our patient, however, thymoma was coexisting with HT. To our knowledge, coexistence of MG and FMF has been reported in only one case in the literature, who was also accompanied by Morvan’s syndrome [15]. The case presented in this study is worth
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noting since he had coexistence of FMF with autoimmune diseases, i.e. MG and HT. Moreover, although there have been several cases of coexisting HT and MG in the literature, this is the first case to be reported with HT and MG coexisting with FMF. Conclusion In conclusion, coexistence of FMF, HT, and MG in the present case implicates a possible link between auto-inflammation- and auto-antibody-mediated diseases. Financial Disclosure The authors declared that this study has received no financial support Fatma Ebru Algul ORCID: 0000-0003-0318-7571
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Verschuuren J, Palace J, Gilhus NE. Clinical aspects of myasthenia explained. Autoimmunity. 2010;43:344-352).
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Kiss MH, Magalhaes CS. Autoinflammatory diseases: mimics of autoimmunity or part of its spectrum? Case presentation. J Clin Immunol. 2008;28:84-9.
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Stassi G, DeMaria R. Autoimmune thyroid disease: new models of cell death in autoimmunity. Nat Rev Immunol. 2002;2:195-204.
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Christensen PB, Jensen TS, Tsiropoulos I, et al. Associated autoimmune diseases in Myasthenia gravis. A population-based study. Acta Neurologica Scandinavica. 1995;91:192-5.
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Evoli A, Padua L. Diagnosis and therapy of Myasthenia gravis with antibodies to muscle-spesific kinase. Autoimmun Rev. 2013:12:931-5.
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Granel B, Seratrice J, Dode C, et al. Overlap syndrome between FMF and TRAPS in patient carrying MEFV and TNFRSF1A mutations. Clin Exp Rheumatol. 2007;25:45:93-5.
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Karanikas G, Schuetz M, Wahl K, et al. Relation of anti-TPO autoantibody titre and T-lymphocyte cytokine production patterns in hashimoto’s thyroiditis. Clin Endocrinol. 2005;63:191-6.
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Ohno M, Hamada N, Yamakawa J et al. Myasthenia gravis associated Graves’ disease in japan. Jpn J Med. 1987;26;2-6.
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Simpson JA . Scot Med. 1960;7:419.
10. Singer W, Sahay BM. Myasthenia gravis, hashimoto’s thyroiditis and pernicious anaemia. Brit Med. 1966;1:904. 11. Kanawaza M, Shimohata T, Tanaka K, et al. Clinical features of patients with Myasthenia gravis associated with autoimmune diseases. Eur J Neurol. 2007;14:1403-4. 12. Kubiszewska J, Szyluk B, Szczudlik P, Bartoszewick Z et al. Prevalence and impact of autoimmune thyroid disease on Myasthenia gravis course. Brain Behavior. 2016;6:e00537. 13. Nakata R, Motomura M, Masuda T et al. Thymus histology and concomitant autoimmune diseases in Japanese patients with muscle-specific receptor tyrosine-antibody-positive Myasthenia gravis. Eur J Neurol. 2013;20:1272-6. 14. Toth C, McDonald D, Oger J, et al. Acetylcholine receptor antibodies in Myasthenia gravis are associated with greater risk of diabetes and thyroid disease. Acta Neurol Scandinavica. 2006;114:124-32. 15. Koge J, Hayashi S, Murai H et al. Morvan’s syndrome and Myasthenia gravis related to familial Mediterranean fever gene mutations. J Neuroinflmamation. 2016;13:68.
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CASE REPORT
Medicine Science International Medical Journal
Medicine Science 2019;8(2):462-3
Olanzapine-induced bilateral pedal and pretibial edema: A case report Behice Han Almis1, Mehmet Hamdi Orum2 2
1 Adiyaman University Training and Research Hospital, Psychiatry, Adiyaman, Turkey Adiyaman University Faculty of Medicine, Department of Psychiatry, Adiyaman, Turkey
Received 18 Octaber 2018; Accepted 26 November 2018 Available online 10.01.2019 with doi:10.5455/medscience.2018.07.8962 Copyright Š 2019 by authors and Medicine Science Publishing Inc. Abstract Olanzapine is a second generation antipsychotic which has antagonistic action on serotonergic, histaminergic, dopaminergic, and muscarinic receptors. The most common seen side effects of olanzapine are weight gain, dry mouth, dizziness, and constipation. There are case reports with olanzapine especially as peripheral edema. Herein, we present a female patient who developed bilateral pedal and pretibial edema after treatment with olanzapine added to sertraline. In this case, the systemic causes of edema were ruled out. The edema resolved completely one week after cessation of the treatment. The patient was managed by aripiprazole and sertraline and the same side effect was not seen with this medication. Keywords: Olanzapine, edema, side effect, antipsychotic
Introduction Olanzapine is a second generation antipsychotic with affinity for D1-D4 (dopaminergic), 5-HT2,3,6 (serotonergic), M1-5 (muscarinic), alpha-1 (adrenergic) and H1 (histaminergic) receptors [1]. Although it is generally used in the treatment of psychiatric disorders such as schizophrenia, bipolar disorder, low dose is used in depression, anxiety disorders and obsessivecompulsive disorder. Extrapyramidal symptoms are less important than first-generation antipsychotic drugs, while they cause significant weight gain such as some other second-generation antipsychotics and impair glucose metabolism. It is a significant advantage that extrapyramidal symptoms are caused more rarely than first-generation antipsychotic drugs [2,3]. However, as some other second-generation antipsychotics cause significant weight gain and impair glucose metabolism, they are the disadvantages of patientsâ&#x20AC;&#x2122; poor compliance to treatment. Common side effects include weight gain, constipation, postural hypotension, akathisia, sedation, weakness, headache, abdominal and limb pain, fatigue, dry mouth, tremors [2]. Peripheral edema is frequently associated
*Coresponding Author: Mehmet Hamdi Orum, Adiyaman University Faculty of Medicine, Department of Psychiatry, Adiyaman, Turkey, E-mail: mhorum@hotmail.com
with the use of beta blockers, calcium channel blockers, nonsteroidal anti-inflammatory drugs and some hormones [3]. It has been shown that 1% of the placebos are caused by peripheral edema, whereas 3% of those using olanzapine experience this side effect and are therefore considered to be a rare side effect [4]. In this case report, we discussed a female patient who developed peripheral edema after olanzapine use and resolved edema after switching from olanzapine to aripiprazole. Case Presentation Our case, a 38-year-old, single, female patient was undergoing psychiatric treatment for 10 years with the diagnosis of major depressive disorder with psychotic features. The patient was admitted to the psychiatric outpatient unit with the complaints of reference delusions. In the past, there was a history of use of risperidone and sertraline perioral (PO) and was still using sertraline 50 mg/day PO for three years. She was diagnosed with major depressive disorder with mood-congruent psychotic features according to Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) [5] and was treated with olanzapine 10 mg/day PO in addition to sertraline 50 mg/day PO. One week addition of olanzapine to the sertraline, the patient developed significant edema in both lower extremities, especially in the pedal and pretibial region. She had no family history. She had no history of alcohol, smoking or substance abuse. The patient stated that 462
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there was no change in dietary and fluid intake in recent days. The patient had no drug use other than sertraline and olanzapine. She had no systemic disease such as hypertension or diabetes mellitus. Physical examination was unremarkable. Urea and electrolyte, hemogram, creatinine, urine analysis, liver function tests, fasting blood glucose, protein level and lipid profile were within normal limits. Chest X-ray, electrocardiogram, renal ultrasonography, and lower extremity doppler ultrasonography gave normal results. There was no diurnal variation of edema and thyroid function tests showed normal results. Edema was attributed to olanzapine use; therefore olanzapine was stopped, sertraline 50 mg/day was continued and aripiprazole 5 mg/day PO was added to the sertraline. Three days after, edema began to decrease and aripiprazole dose was increased to 10 mg/day. 5 days after cessation of olanzapine, edema disappeared. No additional treatment was applied for the reduction of edema. No similar side effects were reported during the follow-up of the patient. Psychiatric complaints decreased significantly. The patient and his relatives were warned of edema due to olanzapine use and informed consent was obtained from them for their knowledges. Naranjo Adverse Dug Reaction Probability Scale (NADRPS) score of the patient was 5 [6]. Discussion This case report was evaluated as a case of peripheral edema due to olanzapine. Because there was a temporal relationship between them, the side effect began with the addition of the drug and completely cured after discontinuation of the drug. In addition, other examinations were normal. The NADRPS score indicates a probable association between drug use and side effect [6]. The exact mechanism of edema associated with olanzapine is not known, but this is thought to be associated with the receptor profile. Some hypotheses are proposed to explain this relationship [7]. First, olanzapine causes alpha-1 adrenergic blockade, resulting in peripheral vasodilatation and decreased vascular resistance. Secondly, the post receptor mechanisms for muscarinic1, histaminic1 and serotonergic 5-HT2. These olanzapine-induced receptor blockages inhibit the physiological increase of inositol triphosphate (IP3), down regulate adenosine triphosphate-dependent calcium pump and reduce smooth muscle contractility resulting in vasodilatation and edema. Third, olanzapine-induced 5-HT2 receptor blockade increases cyclic adenosine monophosphate, relaxing vascular smooth muscles through myosin light chain kinase phosphorylation. Fourth, the use of olanzapine-induced dopaminergic blockade is thought to result in edema by disrupting renal regulation of fluid and electrolytes. Yalug et al. [7] suggested that the side effect of creating olanzapine edema was dose-dependent. However, we found it appropriate to change the drug, which is thought to cause side effects in our study. On the other hand, edema cases related to aripiprazole use have been found in the literature, but this side effect was not seen in our case [8]. This was attributed to the fact that both drugs had different receptor profiles. Ng et al. [9], in their study examining olanzapine-induced edema cases, they suggested that the condition
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was independent of sex but that the severity of edema and age were positively correlated. Our case was in the middle age group. When edema occurs, the patient’s general medical condition should be reassessed and other organic conditions that may cause edema should be excluded. Dose can be reduced or the drug can be changed. Leg elevation, varicose vein stockings, diuretics can be used in the management of edema [10]. In our patient, there was no need for them, and when the drug was stopped, the edema disappeared. Conclusion As a result; olanzapine is an antipsychotic commonly used in psychiatric clinical practice. In addition to the important advantages, some side effects may impair the compliance of the patients. We think that this case report will be useful for clinicians to be careful about the edematous side effects of olanzapine and to question the patients in this respect. Competing interests The authors declare that they have no competing interest. Financial Disclosure The financial support for this study was provided by the investigators themselves. Behice Han Almis ORCID: 0000-0002-9440-2451 Mehmet Hamdi Orum ORCID: 0000-0002-4154-0738
References 1.
Sadock BJ, Sadock VA. Kaplan and Sadock’s synopsis of psychiatry. 10th ed. Philadelphia: Lippincott Williams and Wilkins; 2007. p. 1094.
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Han-Almis B, Celik M. Facial edema after olanzapine addition to sertraline: a case report. Anatol J Psychiatry. 2017;18:46-7.
3.
Orum MH, Han-Almis B, Karaca HT. Rapid onset of pedal edema associated with risperidone in two male patients: Simultaneous clinical cases. JMOOD. 2017;7:237-40.
4.
Toz HI, Tasdemir DM, Ozer U, et al. Bilateral pedal edema associated with olanzapine treatment: A case report. J Neurobehavioral Sci. 2015;2:1-3.
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American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed.; Author: Washington, DC, 2013.
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Kose S, Akin E, Cetin M. Adverse drug reactions and causality: The Turkish version of Naranjo Adverse Drug Reactions Probability Scale. Psychiatry Clin Psychopharmacol. 2017;27:205-6.
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Yaluğ I, Ozten E, Evren Tufan A, et al. Bilateral pedal edema associated with olanzapine use in manic episode of bipolar disorder: report of two cases. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:1541-2.
8.
Cetin M, Celik M, Cakıcı M, et al. Aripiprazole induced non-cardiogenic pulmonary edema: a case report. Turk Psikiyatri Derg. 2014;25:287-9.
9.
Ng B, Postlethwaite A, Rollnik J. Peripheral oedema in patients taking olanzapine. International Clin Psychopharmacol. 2003;18:57-9.
10. Badtieva VA, Truckhacheva NV, Savin EA. The modern trends in the treatment and prevention of lymphedema of the lower extremities. Vopr Kurortol Fizioter Lech Fiz Kult. 2018;95:54-61.
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Pemphigus vulgaris and koebner phenomenon Hulya Nazik, Perihan Ozturk, Mehmet Kamil Mulayim, Esra Aslan Koyuncu Kahramanmaras Sutcu Imam University, Department of Dermatology, Kahramanmaras, Turkey Received 13 November 2018; Accepted 29 November 2018 Available online 10.01.2019 with doi:10.5455/medscience.2018.07.8963 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract Pemphigus vulgaris is a rare disease characterized by loose bullae and erosions in the skin and mucous membranes. Koebner phenomenon is defined as the occurrence of new lesions that are characteristic of the disease at the site of trauma in normal-looking skin in other aspects. We report a 53-year-old woman who was followed for pemphigus. The patient’s first complaints started 10 years ago, after tonsillectomy. The patient was operated 2 months ago for the application of spacer to infected hip prosthesis. One month after the operation, especially around the incision scar and in the mounth, common lesions emerged. Because the lesions around the incision scar appeared one month after the operation, it was interpreted as the Koebner phenomenon in this patient. In conclusion, it was aimed to draw attention to the fact that trauma may be a disease initiator factor or disease-triggering factor in remission, in patients with pemphigus vulgaris. Keywords: Pemphigus vulgaris, Koebner phenomenon, trauma
Introduction Pemphigus vulgaris is a rare autoimmune bullous disease characterized by loose bullae and erosions in the skin and mucous membranes [1]. The annual incidence of pemphigus in the world shows geographic differences and ranges from 0.5 to 16.1 per million[2]. Pemphigus has been reported to be triggered by various factors such as drugs, stressful events, radiation, burns, electrical damage and surgical intervention [1]. The isomorphic response or Koebner phenomenon is defined as the occurrence of new lesions that are characteristic of the disease at the site of trauma in healthy and normal-looking skin in other aspects [3]. The presentation of the case was found appropriate because of rare presence of the Koebner phenomenon in pemphigus disease. Case A 53-year-old female patient was followed with the diagnosis of pemphigus vulgaris. The patient’s complaints started 10 years ago *Coresponding Author: Hulya Nazik, Kahramanmaras Sutcu Imam University, Department of Dermatology, Kahramanmaras, Turkey, E-mail: dr.hulyagul@hotmail.com
as wounds that did not improve in the mouth after tonsillectomy operation. Approximately 4-5 months later, she had a diagnosis ofpemphigus vulgaris after performing biopsy and direct immune fluorescence from the lesions on the skin and scalp. She had been on methylprednisolone and azothiopurine treatments for the first 5 years of her disease. Six years ago, she had a prosthetic replacement of the left hip joint due to aseptic necrosis of the femoral head. She had been receiving methylprednisolone and azothiopurine treatments at the time of the prosthesis application and she had no recent lesions. She received intravenous immunoglobulin (IVIG) treatment lasting 2 years. After IVIG treatment, remission was achieved for approximately 2.5 years. The patient was operated 2 months ago for the application of spacer to the infected hip prosthesis. One month after the operation, especially around the incision scar and in the mounth, common lesions emerged. The distribution of the lesions of the patient with pemphigus vulgaris is given in Figure 1. She was admitted to our clinic 1 month after the onset of her symptoms and she was started on IVIG 2 g/kg/day and azathiopurine 2x50 mg / day. No biopsy was performed because the lesions were typical. The Nikolsky’s sign was positive. Her laboratory values were within normal ranges. The patient’s anti-desmoglein 3 value was 1000 U / mL and the anti-desmoglein 1 value was 36 U / mL, both above the cut-off value (> 20 U / mL). 464
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be high during the active period in which the lesions recurred. After ionized radiation, surgical interventions, burns, chemical peeling, periodontal surgery, tuberculin test and hair transplantation, new pemphigus lesions have been reported in the literature [1,5,8]. In a study evaluating 36 pemphigus patients induced by trauma in Iran, the hijama (cupping therapy) and laser treatment were highlighted as triggering factors [1]. In this case, pemphigus disease started with non-healing wounds after tonsillectomy. In a case report, it was reported that the lesions were not limited to the trauma area in the newly diagnosed pemphigus patient and then became generalized [4].
Figure 1. Distribution of lesions of the patient with pemphigus vulgaris A. Erosions on tongue and right buccal mucosa B. Placed erode plaques scattered on the back C. Loose bullae and erode plaque in the right inguinal area D. Wide plaque surrounding the incision scar on the outer face of the left thigh
Discussion Although the pathogenesis of the Koebner phenomenon in pemphigus vulgaris is not known exactly, genetic factors, environmental triggers, local and systemic factors affecting the immune response and wound healing are blamed [4]. Dermatological diseases such as psoriasis, vitiligo and lichen planus are known to be Koebner positive, but the condition in pemphigus is controversial. In this disease, the Koebner phenomenon must be distinguished from Nikolsky’s sign. In Nikolsky’s sign, blisters appear in normalappearing skin immediately after lateral pressure is applied to the skin. In order to be able to say ‘Koebner phenomenon’, there should be a period of time between trauma and bulla formation [5]. Because the lesions around the incision scar appeared one month after the operation, it was interpreted as the Koebner phenomenon in this patient. In a study, the time between trauma and the onset of pemphigus was ranged from 7 days to 3 years and it was reported to be about 2 months [1]. Pemphigus is characterized by intraepithelial acantholysis caused by immunoglobulin G (IgG) autoantibodies against desmoglein 1 and 3, which are desmosomal transmembrane glycoproteins in keratinocytes. Increased expression of epidermal antigens and increased antigen presentation in genetically predisposed patients due to injuries that disrupt the dermoepidermal composition of the skin or oral mucosa is one of the theories that explain the Koebner phenomenon [6]. Anti-desmoglein antibody levels are associated with disease severity and disease activity [7]. Similar to the literature, desmoglein 3 and 1 levels were found to
In a study by Daneshpazhooh et al. [1], some of the patients had lesions in the limited area of the trauma area. In another part, new lesions have been reported outside the trauma area. In this case, in a period when the patient was in remission without treatment, she had new lesions around the scar, around the body and in the mouth after the surgical intervention. The patient did not have a history of a new lesion after surgery in the period of using azothiopurine and methylprednisolone. This condition has been associated with the preservation of medical treatment. In conclusion, it was aimed to draw attention to the fact that trauma may be a disease initiator factor or disease-triggering factor in remission, in patients with pemphigus vulgaris. Competing interests The authors declare that they have no competing interest Financial Disclosure The financial support for this study was provided by the investigators themselves. Hulya Nazik ORCID: 0000-0003-4004-3964 Perihan Ozturk ORCID: 0000-0002-9303-6808 Mehmet Kamil Mulayim ORCID: 0000-0002-4373-5678 Esra Aslan Koyuncu ORCID: 0000-0003-1061-2695
References 1.
Daneshpazhooh M, Fatehnejad M, Rahbar Z, et al. Trauma-induced pemphigus: a case series of 36 patients. JDtsch Dermatol Ges. 2016;14:16671.
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Alpsoy E. Epidemiology of autoimmune bullous diseases. Turkderm. 2011;45:3-7.
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Sagi L, Trau H. The Koebner phenomenon. Clin Dermatol. 2011;29:231-6.
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Mehregan DR, Roenigk RK, Gibson LE. Postsurgical pemphi¬gus. Arch Dermatol. 1992;128:414-5.
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Balighi K, Daneshpazhooh M, Azizpour A, Lajevardi V, Mohammadi F, Chams-Davatchi C. Koebner phenomenon in pemphigus vulgaris patients. JAAD Case Rep. 2016;2:419-21.
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Aguado L, Marquina M, Pretel M, et al. Lesions of pemphigus vulgaris on irradiated skin. Clin Exp Dermatol. 2009;34:148-50.
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Yılmaz M, Bülbül Başkan E, Budak F, Sarıcaoğlu H, Tunalı Ş. Relationship of serum levels of anti-desmoglein antibodies and direct immunofluorescence findings with clinical activity of pemphigus. Turkderm. 2011;45:77-82.
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Vinay K, Kanwar AJ, Saikia UN. Pemphigus occurring at tuber¬culin injection site: role of cytokines in acantholysis. Indian J Dermatol Venereol Leprol. 2013;79:539-41.
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Lichenoid hypersensitivity reaction against to dental amalgam: Case report Merve Nur Guvenc1, Emine Turkmen Samdanci1, Ayse Nur Akatli1, Eren Erdogan2, Umit Yolcu2 1 Inonu University, Faculty of Medicine, Department of Medical Pathology, Malatya, Turkey Inonu University, Faculty of Dentistry, Department of Oral and Maxillofacial Surgery, Malatya, Turkey
2
Received 24 November 2018; Accepted 23 December2018 Available online 30.01.2019 with doi:10.5455/medscience.2018.07.8973 Copyright Š 2019 by authors and Medicine Science Publishing Inc.
Abstract Amalgam or its components may cause delayed hypersensitivity reactions and constitute lesions compatible with lichenoid mucositis in relation to localization. A white colored lesion was detected in the buccal mucosa of a 37-year-old male patient with amalgam filling in the tooth number 46. The lesion was histopathologically reported as lichenoid mucositis. This rare lesion with a specific morphology is presented with the literature. Keywords: Lichenoid mucositis, amalgam, contact hypersensitivity reaction
Introduction Amalgam or its components may cause delayed hypersensitivity reactions representing type IV hypersensitivity reaction and constitute lesions compatible with lichenoid mucositis in relation to localization. However, there are very few reported cases of oral lichenoid reaction associated with amalgam fillings in the literature [1-3]. Oral lichenoid reaction is histopathologically similar to oral lichen planus, a chronic inflammatory lesion of the oral cavity, but oral lichen planus generally has not a defined etiological factor [4]. The clinical presentation is similar either but lichenoid reaction associated with amalgam fillings has a definite etiology[1]. The diagnosis of an oral lichenoid reaction associated with amalgam restorations should only be made by combining the medical information, clinical examination and histopathological findings together.
*Coresponding Author: Merve Nur Guvenc , Inonu University, Faculty of Medicine, Department of Medical Pathology, Malatya, Turkey E-mail: mervenur.guvenc@inonu.edu.tr
Because of its rarity the case of contact allergic reaction to amalgam leading to lichenoid mucositis is presented herein. Case Report A 37-year-old man presented to dental clinic with a white lesion on the mandibular right cheek mucosa. The lesion was unrelated to teeth and bone structures. The patient had not any systemic, autoimmune or dermatologic disease in his medical history. He has not used any medication. On the oral examination of the patient, there was an amalgam filling made five years ago in the tooth number 46 adjacent to the present lesion (Figure 1). The lesion was excised and sent to the pathology department. Microscopic examination of the biopsy revealed necrotic keratinocytes, lymphocyte exocytosis and basal vacuolar degeneration in the keratotic and focally ulcerative hyperplastic squamous epithelium on Hematoxylin&Eosin (H&E) stained sections. (Figure 2). There was band-like lymphoplasmacytic inflammation in the subepithelial area, and the inflammation had a perivascular and paravascular nodular pattern in the deeper areas (Figure 3). The case was reported to be a lichenoid hypersensitivity reaction that has a rare histomorphologic appearance in which dental amalgam can take place in its etiology. 466
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long-time period, from months to years [5,6]. The dental amalgam in the present case was placed five years ago, and the patientâ&#x20AC;&#x2122;s complaints started in the last three months. There are also human and animal studies evaluating the relation between oral lichenoid reaction against to amalgam and patch testing [7,8]. In cases of positive patch test reaction to mercury/ amalgam components, partial or complete replacement of the amalgam fillings is adviced [8].
Figure 1. Amalgam filling in tooth 46 in panoramic image
Histopathologically, although band-like lymphocyte infiltration as well as epithelial changes is seen in classical lichenoid mucositis, lymphocytes are accompanied by increased plasma cells in our case. Furthermore, as different from classical lichenoid mucositis, lymphoplasmositer inflammation at perivascular, paravascular region and nodular pattern was seen [4]. In the differential diagnosis, other lesions in the oral mucosa were considered. In clinical examination, the patient does not have any systemic disease or any lesions in the skin and oral mucosa consistent with oral lichen planus. Therefore, it was thought to be associated with amalgam adjacent to the lesion with the support of histopathological evaluation. Conclusion
Figure 2. Lymphoplasmacytic inflammation which is band type at subepithelial area, and perivascular and paravascular nodular pattern at the deeper areas. H&E x10
The present case is rare, and in the diagnosis of these lesions clinical information is very important for excluding other possibilities. Therefore, the differential diagnosis of lichenoid mucositis was evaluated in terms of relation with amalgam and contact time with amalgam in the context of the literature. Competing interests The authors declare that they have no competing interest. Financial Disclosure All authors declare no financial support. Merve Nur Guvenc ORCID: 0000-0001-7717-2132 Emine Turkmen Samdanci ORCID: 0000-0002-0034-5186 Ayse Nur Akatli ORCID: 0000-0002-9677-2456 Eren Erdogan ORCID: 0000-0001-8368-9429 Umit Yolcu ORCID: 0000-0001-7312-2867
References
Figure 3. Necrotic keratinocytes, lymphocyte exocytosis and basal vacuolar degeneration were seen in the keratotic and hyperplastic squamous epithelium. H&E x50
Discussion Although the target antigen has not been identified yet, lichenoid mucositis is considered to be an autoimmune reaction by some investigators. It can be seen in many clinical situations, such as idiopathic, drug-induced, contact, infectious agents, stress, chronic diseases (such as diabetes, hypertension), chronic graft versus host disease[4,8]. Lichenoid lesions have also been associated with dental amalgam, representing type IV hypersensitivity reaction. This reaction occurs in response to some components of metal alloys, particularly mercury. It generally develops after a relatively
1.
Aggarwal V, Jain A, Kabi D. Oral lichenoid reaction associated with tin component of amalgam restorations: A case report. Am J Dermatopathol. 2010;32:46-8.
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Thanyavuthi A, Boonchai W, Kasemsarn P. Amalgam contact allergy in oral lichenoid lesions. Dermatitis. 2016;27:215-21.
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McCullough MJ, Tyas MJ. Local adverse effects of amalgam restorations. Intern Dental J. 2008;58:3-9.
4.
Sook-Bin Woo. Oral Pathology: A Comprehensive atlas and text. 2nd edition. Elsevier, Philadelphia, 2017. p. 170-8.
5.
Lopes de Oliveira LM, Batista LHC, Neto APDS, et al. Oral Lichenoid Lesion Manifesting as Desquamative Gingivitis: Unlikely Association? Case Report. Open Dent J. 2018;12:679-86.
6.
Athavale PN, Shum KW, Yeoman CM, et al. Oral lichenoid lesions and contact allergy to dental mercury and gold. Contact Dermatitis. 2003;49:264-5.
7.
Ronald L, Sybren K. Dekker, et al. Oral lichen planus and allergy to dental amalgam restorations. Arch Dermatol. 2004;140:1434-8.Dunsche A, Frank MP, LĂźttges J, et al. Lichenoid reactions of murine mucosa associated with amalgam. British J Dermatol. 2003;148:741-8.
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Medicine Science 2019;8(2):468-9
Actinomyces abscess mimicking mandibular bone cyst Nasuhi Engin Aydin Katip Celebi University, Department of Pathology, Izmir, Turkey Received 10 November 2018; Accepted 29 December 2018 Available online 08.02.2019 with doi:10.5455/medscience.2018.07.8972 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract A radiolucent, well demarcated right mandibular bone lesion with a clinical presumptive diagnosis of solitary bone cyst was surgically excised in a 60 year old woman. The histopathologic examination revealed Actinomyces colonies surrounded by chronic granulation tissue. This presentation is unique due to its completely encapsulated abscess formation rather than the more common fistula formation seen in Actinomyces lesions. Keywords: Actinomyces, histopathology, mandibular abscess
Introduction Actinomycosis is an infection with the anaerobic gram-positive filamentous bacterium Actinomyces, which may cause cervicofacial infection, and occasionally pulmonary, gastrointestinal, or disseminated infections [1,2]. It is uncommon, but is still an important cause of morbidity. Its clinical presentation is usually indolent and chronic as slow growing masses that may evolve into fistulae, and for that reason are frequently underdiagnosed. Actinomyces spp is often disregarded clinically and is classified as a colonizing microorganisms since they are commensal in human body.
paraffin embedding all the tissues received revealed a chronic inflammatory granulation tissue and huge, prominent colonies of a filamentous microorganism within small bone fragments (Figures 1 and 2). The filamentous microorganism granules were Gram’s stain and Grocott’s methenamine silver (GMS) positive (Figure 3) besides yielding a periodic acid Schiff positive reaction following diastase digestion (Figures 4). A diagnosis of Actinomyces abscess was made. The aerobic microbiological cultures of the lesion was negative for any bacteria. The clumps of Actinomyces microorganisms were surrounded by fragments of bone showing chronic osteomyelitis. There were no signs of another pathological process.
Case Report A 60 year old woman complaining of intermittent pain in the right jaw region for a few months was seen at the outpatient department. The patient’s medical history was unremarkable without any health problem. Physical examination and CBC was unremarkable but a plain radiograph of the jaw region showed a 2 cm well delineated lucency suggestive of a simple bone cyst. A diagnostic and therapeutic surgical excision was made by curettage of the lesion. There was no cyst fluid, but soft friable tissue fragments with yellowish foci were noticed in the mandibular bone during the procedure. Specimens received at the pathology laboratory measured soft, light brown tissue fragments 1.5x1x1 cm in aggregate with yellowish areas. Histopathologic examination after *Coresponding Author: Nasuhi Engin Aydin, Ataturk Hospital, Pathology Department, Yesilyurt, Izmir, Turkey E-mail: nasuhiengin@gmail.com
Figure 1. Large colonies of Actinomyces microrganisms among necrotic bone fragments and chronic
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Figures 2. Higher power view of the Actinomyces colonies showing a dense structure nearby the necrotic bone fragments, ((Hematoxylin eosin, x400)
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Discussion Due to its prominent filamentous morphology, this anaerobe microorganism was previously classified as a fungus but presently it is considered as a bacterium of the genus Actinomyces is a part of the oral, gastrointestinal and urogenital commensal flora belong to the Actinobacteria phylum and Actinomycetales order and are related to other genera such as Corynebacterium, Mycobacterium, Nocardia, and Propionibacterium [1,2]. Physicians must be aware of typical clinical presentations (such as cervicofacial actinomycosis following dental focus of infection, pelvic actinomycosis in women with an intrauterine device, and pulmonary actinomycosis in smokers with poor dental hygiene), but also that actinomycosis may mimic neoplastic processes in various anatomical sites [1-3]. In the human oropharynx, Actinomyces species are particularly prevalent within gingival crevices, tonsillar crypts, periodontal pockets and dental plaques, as well as on carious teeth. Consequently, actinomycosis is mainly considered an endogenous infection that is triggered by a mucosal lesion [4,5]. In this completely excised case since there was no other accompanying pathological process in the surrounding bone fragments it was regarded as a primary lesion. However, the pathogenesis of invasive disease following oral mucosal breach is not clear. Cervicofacial actinomycosis is the most frequent clinical form that may be associated with large abscesses and/or mandibular osteomyelitis with or without sinus tract. Conclusion Cervicofacial actinomycosis may lead to distant organ dissemination, including brain, lungs, and digestive tract so early diagnosis and treatment with penicillin group of antibiotics essential in which high-dose penicillin is the cornerstone of therapy. The risk of developing penicillin resistance appears to be minimal.
Figure 3. Histochemical reaction with silver impregnation of the sections show the filamentous structure of the Actinomyces colonies (GMSx400)
Financial Disclosure The financial support for this study was provided by the investigators themselves. Nasuhi Engin Aydin ORCID:0000-0003-3145-2432
References
Figure 4. Reddish-purple (magenta) coloured positive periodic acid Schiff reaction of the Actinomyces colony following diastase digestion, (D-PAS, x400)
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Mahadevia P, Brandwein-Gensler M. Infectious diseases of the head and neck in surgical pathology of head and neck, volume 3, Editor: Leon Barnes, 3rd edition, Informa Healthcare. 2009. p.1620-1.
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Valour F, SĂŠnĂŠchal A, Dupieux C, et al. Actinomycosis: etiology, clinical features, diagnosis, treatment, and management. Infection Drug Resistance. 2014;7:183-97.
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Isik B, Aydin E, Sogutlu G, et al. Abdominal actinomycosis simulating malignancy of the right colon. Dig Dis Sci. 2005;50:1312-4.
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Valour F, Chidiac C, Ferry T. A 22-year-old woman with right lumpy jaw syndrome and fistula. BMJ Case Rep Nov. 2015.
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Gannepalli A, Ayinampudi BK, Baghirath PV, et al. Actinomycotic osteomyelitis of maxilla presenting as oroantral fistula. Case Rep Dent. 2015:689240.
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Medicine Science 2019;8(2):470-2
Early treatment with esophageal stenting in trauma-induced esophageal perforation- a case report and literature review Yasir Furkan Cagin Inonu University, Faculty of Medicine, Department of Gastroenterology, Malatya, Turkey Received 30 December2018; Accepted 06 January 2019 Available online 08.02.2019 with doi:10.5455/medscience.2018.07.8977 Copyright Š 2019 by authors and Medicine Science Publishing Inc. Abstract Esophageal perforation is a life-threatening clinical condition that was usually treated with surgical intervention in the past. There is no definite consensus on the ideal treatment that is controversial. Early diagnosis and treatment are very important. So, this condition improves treatment success. Nowadays, with the use of clips and selfexpandable removable stents, it becomes an entity that facilitates conservative treatment. Here, we present 37-year-old male patient who was admitted to the emergency department after being assaulted with a knife in his right upper chest. He Healed in a short time after esophageal stent placement in early esophageal perforation. Keywords: Esophageal perforation, esophageal stenting, trauma
Introduction Esophageal perforation due to any cause such as iatrogenic, trauma spontaneous and foreign bodies is a clinical condition that requiring urgent surgical treatment that is difficult to treat [1,2]. If early diagnosis and treatment are performed within the first 24 hours after perforation, the success rate of treatment increases [2]. Radiologic imaging and endoscopy are the most basic approach for the diagnosis and treatment of esophageal perforation and its complications[3]. Although not a definite consensus in treatment, both surgical and conservative treatments have significant morbidity and mortality [1-3]. Especially in patients with risk for surgical treatment, self-expandable covered metallic stents are offered as alternative treatment. Major disadvantage of metallic stents is complications that occur during removal [1]. This report describes a case of a short-term recovery with a covered metallic stent used in the treatment of esophageal perforation caused by trauma and includes a review of the relevant literature. Case The patient was a 37-year-old male who was admitted to the emergency department after being assaulted with a knife in his right
*Coresponding Author: Yasir Furkan Cagin, Inonu University, Faculty of Medicine, Department of Gastroenterology, Malatya, Turkey E-mail: yafur@hotmail.com
upper chest. In the examination, an entrance wound of 3 x 3 cm in size was detected in the second intercostal space, 3 cm lateral to the right side of the sternum, about 5 cm above the right nipple. WBC was 16100/Îźl (neutrophils 82%), Hb 13,1 g/dl, PLT 237000/ Îźl, serum glucose 146 mg/dl, serum amylase 127 U/L and LDH 311 IU/L. The patient is being operated the pericardial injury with primary repair by the cardiovascular surgeon. At the same time a chest tube is inserted for hemopneumothorax. A gastroenterology consultation was requested after the bloody material appeared in the nasogastric (NG) tube inserted postoperatively. On the upper GIS endoscopy, two 2 cm esophageal perforation areas with crossover, 36 cm from the incisor teeth (figure 1A) were recognized at the lower part of the esophagus, covering one in eight of the esophageal circumference. Gastroesophageal junction was at 40 cm from the incisor teeth. The perforation was treated with placement of a 10 cm long full-covered metal stent (Neotech, Healt Microport Medical Device Co,Ltd., Jiangsu, Chine) 20 hours after its the estimated creation period (figure 1B,C). The patient was treated conservatively with Intravenous (IV) Fluid, IV antibiotics (imipenem, teicoplanin and metronidazole for 15 days), appropriate wound care and nutrition. Then, the patient who was intubated due to respiratory insufficiency was transferred to the reanimation unit. The patient who was extubated was observed to have a stent in place (figure 1D) in the control chest X-ray at 2 weeks later. On the control upper GIS endoscopy performed to start orally feeding 2 days later and was observed, the stent that migrated 470
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to the stomach was not in the esophagus, and perforation areas were closed (figure 1E). Despite pressure contrast with the ERCP catheter, there was no leakage in the fluoroscopy (figure 1F). It was removed (figure 2) and oral intake started. The patient was discharged with suggestions after clinical and laboratory improvement in very good condition. There was no problem in control the outpatient clinic.
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common cause of esophageal perforations as well as it also may occur spontaneously and trauma [5]. In the present case, the esophageal perforation was formed as a result of injury due to knife injury. It is often seen symptoms and signs such as pain, fever, swallowing difficulty, shortness of breath and subcutaneous emphysema in the esophageal perforation. Also tachycardia, hydropneumothorax, mediastinal emphysema and shock signs can also be seen [6]. Rarely can manifest themselves with other GIS bleeding findings, such as hematemesis and melana[7]. In present case, it had fever, sweating, chest pain, and swallowing difficulties. It also had mediastinitis and pleural effusion. However, main reason of the gastroenterological consultation is blood material from the nasogastric tube. The presence of symptoms and signs depends entirely to the location and size of the perforation and whether the patient is hungry. Early diagnosis of esophageal perforation is very important and emergency treatment should be planned. Even if, chest X-ray, chest CT, radiopaque the passage graphy helps in diagnosis. The last two technics can also show whether there is a leak [8]. Although endoscopy is controversial, definite diagnosis put on endoscopy[9]. In the present case, definite diagnosis was established with endoscopy.
Figure 1. (A) Endoscopic appearance of perforation seen at two different sites distal to esophagus (circled) (B) Full-covered metallic esophagus stent placed in the esophagus, (C) The fluoroscopic appearance of the placed esophagus stent(dashed lines), (D) Appearance of the esophagus stent in the control chest X-ray taken 2 weeks later(dashed lines), (E) Esophageal perforation areas appear to be closed in the endoscopic control(circled), (F) Fluoroscopic view of the esophagus without leakage after pressure contrast with catheter
In the treatment of esophageal perforation, there is no a standard approach. The treatment option is depending the reason, localization of perforation, presence of esophageal disease, time of diagnosis, environmental injury, general condition of the patient and age[3]. The main treatment is surgery, but recently trend has been shifted towards non-operative treatment options[10]. Conservative treatment can be selected in the some situations including not taken orally, early diagnosis. In addition, the use of transient endoscopic esophageal stents as a less invasive procedure is increasing[11]. In present case, it is placed endoscopic covered metallic esophagus stent. We did not choose surgical procedure due to the general condition of the patient was very bad. On the contrary, we chose faster and less invasive endoscopic procedure. Endoscopic closure with metallic clips wasnâ&#x20AC;&#x2122;t chosen. Because it is suitable only for selected patients with small (â&#x2030;¤ 1.5 cm) clean perforation and minimal infection[12]. Whereas the perforation size of our patient was bigger than 1.5 centimeters. There are many different studies on the duration of stenting. In a study conducted, the mean duration of stent was 39 days[13] whereas in another study was 4â&#x20AC;&#x201C;6 weeks[14]. In the present case, stent explantation was the 15th day. However, this stent explantation was caused by a necessity arising from migration. The migration is a very significant problem in the esophagus stents.
Figure 2. Removed esophagus stent
Discussion Esophageal perforations are one of the rare but most serious clinical problems of GIS and are an increasingly common problem due to developing invasive procedures and a high mortality rate if not diagnosed early[4]. Iatrogenic injuries are the most
The most important problem of metallic stents is complications that arise when they are removed[14]. But, in the presented case, there were no complications when removing the stent. Conclusion As a result, early diagnosis and treatment in esophageal perforations is life saving especially in selected cases. Use of esophageal stent 471
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in the treatment reduces morbidity and mortality and decrease need for surgery. Esophageal stent placement is a safe and effective endoscopic procedure in the thumping majority of esophageal perforation. It should be kept in mind that the duration of stenting may varies according to patients. And patients may recover earlier.
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Kapetanos D, Kokozidis G, Maris T, et al. Three cases of esophageal perforation treated successfully with plastic stents and clips. Ann Gastroenterol. 2008:194-196.
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Kaman L, Iqbal J, Kundil B, et al. Management of esophageal perforation in adults. Gastroenterol Res. 2010;3:235.
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Kroepil F, Schauer M, Raffel A, et al. Treatment of early and delayed esophageal perforation. Indian J Surg. 2013;75:469-72.
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Chirica M, Champault A, Dray X, et al. Esophageal perforations. J Visceral Surg. 2010;147:117-28.
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Hermansson M, Johansson J, Gudbjartsson T, et al. Esophageal perforation in south of sweden: Results of surgical treatment in 125 consecutive patients. BMC Surg. 2010;10:31.
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Mackler S: Spontaneous rupture of the esophagus; an experimental and
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clinical study. Surg Gynecol Obstet. 1952;95:345-56. 7.
Søreide JA, Viste A: Esophageal perforation: Diagnostic work-up and clinical decision-making in the first 24 hours. Scand J Trauma Resusc Emerg Med. 2011;19:66.
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Sajith A, Oâ&#x20AC;&#x2122;Donohue B, Roth R, et al. Ct scan findings in oesophagogastric perforation after out of hospital cardiopulmonary resuscitation. Emerg Med J. 2008;25:115-6.
9.
Arantes V, Campolina C, Valerio SH, et al. Flexible esophagoscopy as a diagnostic tool for traumatic esophageal injuries. J Trauma.2009;66:1677-82.
Financial Disclosure All authors declare no financial support. Yasir Furkan Cagin ORCID:0000-0002-2538-857X
10. Brinster CJ, Singhal S, Lee L, et al. Evolving options in the management of esophageal perforation. Ann Thorac Surg. 2004;77:1475-83. 11. Zhou J-H, Gong T-Q, Jiang Y-G, et al. Management of delayed intrathoracic esophageal perforation with modified intraluminal esophageal stent. Dis Esophagus. 2009;22:434-8. 12. Raymer GS, Sadana A, Campbell DB, et al. Endoscopic clip application as an adjunct to closure of mature esophageal perforation with fistulae. Clin Gastroenterol Hepatol. 2003;1:44-50. 13. van Boeckel PG, Dua KS, Weusten BL, et al Fully covered self-expandable metal stents (sems), partially covered sems and self-expandable plastic stents for the treatment of benign esophageal ruptures and anastomotic leaks. BMC Gastroenterol. 2012;12:19. 14. van Heel NC, Haringsma J, Spaander MC, et al. Short-term esophageal stenting in the management of benign perforations. Am J Gastroenterol. 2010;105:1515-20.
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CASE REPORT
Medicine Science International Medical Journal
Medicine Science 2019;8(2):473-5
Ultrasound-guided supracondylar radial nerve block in pain management of distal radius fractures Sami Eksert1, Sinan Akay2 Gulhane Traning and Research Hospital, Department of Anesthesia and Reanimation, Ankara, Turkey 2 Gulhane Traning and Research Hospital, Department of Radiology, Ankara, Turkey
1
Received 02 April 2019; Accepted 30 April 2019 Available online 14.06.2019 with doi:10.5455/medscience.2019.08.9047 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract Radius fracture causes severe pain and requires extensive pain management. We aimed to present the efficacy of ultrasound (US)-guided supracondylar radial nerve block (SCRNB) in pain relief of two distal radius fracture cases. Two patients with distal radius fracture presented to emergency department. Both patients received US-guided SCRNB to provide analgesia during and after the closed reduction procedure. Reduction of displaced distal radial fractures is extremely painful and requires adequate analgesia. US-guided SCRNB is easy to administer, and comfortable with low complication risk. In previous studies, the preferred local anesthetic was lidocaine. Using bupivacaine in addition to lidocaine can provide long term analgesia. US-guided SCRNB is a safe and simple technique to perform with a minimal risk of complication and may replace commonly used sedo-analgesia in distal radius fracture at emergency department. Keywords: Ultrasound, radial nerve, radius fractures, emergency department
Introduction Distal radius fracture is one of the most common injuries encountered in emergency department (ED) [1]. These fractures are generally caused by falling on an outstretched arm or by direct trauma. For distal radius fractures, there are various treatment modalities. Nature of the fracture, patient’s age, surgeon’s preference, and physical facilities of the admitted medical centre are considered in determining the treatment [2]. Open or closed reduction can be applied. Bone corrections without surgical incision are called closed reduction. Closed reduction is the most commonly used treatment but is extremely painful. In pain management of this procedure, sedation, analgesic medications, and nerve blocks are commonly used [3]. However, ultrasound (US) guidance in peripheral nerve blocks has recently gained popularity [4-7]. US-guided, peripheral nerve blocks that can be used in distal radius fractures are interscalene, supraclavicular, infraclavicular brachial plexus, and axillary nerve blocks [8]. Along these proximal brachial plexus blocks, US-guided selective radial, ulnar, median, and musculocutaneous nerve blocks can be administered as well [9]. In this paper, we presented our findings
*Coresponding Author: Sami Eksert, Gulhane Traning and Research Hospital, Department of Anesthesia and Reanimation, Ankara, Turkey E-mail: exert79@yahoo.com
on feasibility and efficacy of US-guided supracondylar radial nerve block (SCRNB) in closed reduction of distal radius fracture. Case Report Case 1 A 21-year-old, male, ASA I was admitted to our ED. The patient complained of swelling and severe pain in his forearm that developed after falling. On plain radiographs, a Colles fracture in that the broken radius fragment tilted upward was detected (Figure 1a). Although diclofenac sodium 75 mg intra muscular was administered at the time of initial admission, the patient’s visual analog scale (VAS) score was 8, which was unbearable when the arm was moved. VAS score defined by the patient was 8 and this pain was unbearable when the arm was moved. Preanesthetic evaluations of the patient was done, and there was no contraindications. After written consent obtained from the patient, we performed US-guided lateral SCRNB to reduce pain and provide adequate analgesia for closed reduction standard motorization (ECG, pulse oximetry, NIBP). Ten minutes after the block, we applied reduction successfully without need to sedoanalgesia. When the patient was inquired about his pain 10 minutes after the block, he declared that his pain was almost completely relieved and decreased to VAS: 0. We applied reduction without a need for sedo-analgesia, and we didn’t observe any complication. First 9 hours after the block procedure, patient didn’t feel pain, and 473
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no rescue analgesic was needed. After then, tramadol 100 mg per oral was administered.
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visualized continuously. Ten minutes after the injection, pinprick test was used to confirm the block level and the pain levels of the patients were inquired as VAS score. Thereafter, closed reduction of the fracture was performed with adequate analgesia. We confirmed appropriate reduction of the fractures with radiographs and discharged patient with a forearm splint.
Figure 1. Case 1, Lateral forearm radiograph demonstrating distal radial fracture 1b. Case 2, Oblique radiograph of distal ulna–radius fracture
Case 2 A 35-year-old, male, ASA I presented to the ED with severe pain, malposition and edema on the right forearm after falling. We observed a distal radius fracture with associated ulnar head fracture on the patient’s wrist radiographs (Figure 1b). The patient was administered 75 mg diclofenac sodium intra muscular at the time of first admission to the ED but still had intolerable pain of VAS:9. Pre-anesthetic evaluations of the patient was done, and there was no contraindications. After written consent obtained from the patient, we performed US-guided lateral SCRNB under standard motorization. Ten minutes after the US-guided SCRNB, the patient stated that the pain level decreased to VAS:1. Closed reduction could be performed without a need for analgesics and no complication was observed during the block process. The patient did not have pain during the first 11 hours after the block, tramadol 100 mg per oral was then administered as a rescue analgesic. Technique The procedures were performed in outpatient service of ED under local anesthesia. US scanning and blocks were performed by an anesthesiologist experienced in US-guided procedures. The patient was placed in supine position. The elbow of the fractured forearm was brought to flexion with a 90° angle and the hand was placed on the abdomen. After aseptic preparation of the skin with chlorhexidine, a high-frequency (12-5 MHz) linear transducer of an US machine (Philips HD6, Philips Ultrasound Systems, Bothell, WA, USA) was transversely positioned 3–4 cm above the lateral elbow, where the superficial and deep radial nerves are not separated yet (Figure 2A). The radial nerve was observed hyper-echoic between biceps and triceps muscles (Figure 2B). The skin was infiltrated with 2 ml of 2 % prilocaine using a 25G needle. In plane approach, a 21G, 5 cm echogenic needle (Pajunk, SonoPlex Stim, USA) was advanced to radial nerve under US guidance. Neurostimulation was applied at 2 Hz, with 1 ms pulse width. Patient described paresthesia in the distribution of radial nerve and a motor response was observed at 0.5 V. The needletip placement and spread of local anesthetic solution (5 ml, 2 % lidocaine and 5 ml 0.5 % bupivacaine) around radial nerve was
Figure 2a. Placement of the ultrasound probe in the supracondylar radial nerve block. The elbow was placed at a 90° flexion and the linear probe was transversely placed 3–4 cm above the lateral elbow, 2b. The transverse image shows the ultrasonographic anatomy of the target area for the supracondylar radial nerve block and the distribution of the local anesthetic drug (R: Radial nerve, LA: Local anesthetic drug).
Discussion Our report presented that the selective US-guided SCRNB with a volume of 10 ml bupivacaine and lidocaine solution provided rapid pain relief during closed reduction of two distal radius fracture cases. US-guided SCRNB preserves the motor function at the elbow while the brachial plexus and axillary blocks do not. Recently, interest in ambulatory surgery has increased due to longterm hospital stay complications and economic factors [9]. In our cases, US-guided SCRNB provided immediate and satisfactory pain relief with prompt recovery due to improved retention of motor function at the elbow. Equipments required for US-guided SCRNB block treatment are only an ultrasound machine, echogenic nerve block needle, and local anesthetic. On the other hand, an operation room environment is required for reduction under general anesthesia or sedo-analgesia. Also, after the procedure, patients need close follow-up in the recovery period. However, patients who undergo ultrasound-guided nerve block do not require intensive follow-up, thus reducing cost for both equipment and staff [10]. Eventhough, SCRNB is an easy to administer block under US guidance because of superficial localization of the nerve, there is very limited studies in the literature. In these studies, the preferred 474
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local anesthetic during the block was lidocaine, and the studies focused only on pain relief during the closed reduction procedure [11,12]. In our study, we provided long-term analgesia with bupivacaine rather than giving only lidocaine. Since, bupivacaine has longer duration of action considerably longer than lidocaine, in our study, we provided long-term analgesia with bupivacaine rather than administering only lidocaine. Addition of lidocaine to bupivacaine provided more rapid onset of block as well. Brachial plexus block can be performed at different anatomical sites such as interscalene, supraclavicular, infraclavicular, and axillary region [13]. However, at these levels, brachial plexus is adjacent to important anatomical structures and has risk of catastrophic complications related to needle puncture such as pneumothorax, nerve palsy, and hematoma [14,15]. SCRNB, has very low risk profile when compared to these brachial plexus blocks. At supracondylar level, radial nerve can be recognized quite easily. US guidance makes the technique, SCRNB safer by preventing misplacement of the needle tip and undesirable spread of local anesthetic. Hereby, we applied the US-guided SCRNB rapidly, comfortably, safely, and confidently under US guidance. Thus, US-guided SCRNB can be administered easily as a bedside procedure, with low risk of adverse events and complications in closed reduction of radius fractures.
Competing interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Financial Disclosure The author(s) received no financial support for the research, authorship, and/or publication of this article. Sami Eksert ORCID: 0000-0001-5566-286X Sinan Akay ORCID: 0000-0001-7201-475X
References 1.
Walenkamp MM, Aydin S, Mulders MA, et al. Predictors of unstable distal radius fractures: a systematic review and meta-analysis. J Hand Surg Eur.
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2016;41:501-5. 2.
Putnam K, Kaye B, Timmons Z, et al. Success rates for reduction of pediatric distal radius and ulna fractures by emergency physicians. Pediatr Emerg Care. Published Online: Jan 29, 2019.
3.
Bear DM, Friel NA, Lupo CL et al. Hematoma block versus sedation for the reduction of distal radius fractures in children. J Hand Surg Am Jan. 2015;40:57- 61.
4.
Sir E, Eksert S, Emin Ince M, et al. A novel technique: ultrasound-guided serratus anterior plane block for the treatment of post-traumatic intercostal neuralgia. a case report. Am J Phys Med Rehabil. Published Online: Dec 28, 2018.
5.
Kaya M, Eksert S, Akay S, et al. Interscalene or suprascapular block in a patient with shoulder dislocation. Am J Emerg Med. 2017;35:191-5.
6.
Erdem Y, Sir E. The efficacy of ultrasound-guided pulsed radiofrequency of genicular nerves in the treatment of chronic knee pain due to severe degenerative disease or previous total knee arthroplasty. Med Sci Monit. 2019;25:1857-63.
7.
Amini R, Kartchner JZ, Nagdev A, et al. Ultrasound-Guided Nerve Blocks in emergency medicine practice. J Ultrasound Med. 2016;35:731-6.
8.
E Sir, ME Orhan, S Eksert, et al. A Prospective Randomized Comparison of Ultrasound Guidance Versus Neurostimulation for Interscalene Brachial Plexus Blockade For Shoulder Arthroscopy. Proceedings of the 8th World Congress of the World Institute of Pain, 20-23 May 2016. New York, USA, 132.
9.
Zhu W, Zhou R, Chen L, et al. The ultrasound-guided selective nerve block in the upper arm: an approach of retaining the motor function in elbow. BMC. Anesthesiol. 2018;18:143.
Conclusions Distal radius fractures are orthopedic urgent cases those can be encountered in ED frequently. Since, analgesia for closed reduction and postoperative pain management of these cases are challenging, US-guided SCNRB is a promising approach. According to our experience, US-guided SCRNB is an easy–to–perform and fast– acting peripheral nerve block technique that can be effectively used in ED. In order to generalize the effects of SCRNB on distal radius fractures, there is a need for larger patients series.
10. Gonano C, Kettner SC, Ernstbrunner M, et al. Comparison of economical aspects of interscalene brachial plexus blockade and general anaesthesia for arthroscopic shoulder surgery. Br J Anaesth. 2009;103:428-33. 11. Aydin AA, Bilge S, Kaya M, et al. Novel technique in ED: supracondylar ultrasound-guided nerve block for reduction of distal radius fractures. Am J Emerg Med. 2016;34:912-3. 12. Unluer EE, Karagoz A, Unluer S, et al. Ultrasound-guided supracondylar radial nerve block for Colles Fractures in the ED. Am J Emerg Med. 2016;34:1718-20. 13. Maurer K, Ekatodramis G, Rentsch K, et al. Interscalene and infraclavicular block for bilateral distal radius fracture. Anesth. Analg. 2002;94:450-2. 14. Bhatia A, Lai J, Chan VW, et al. Case report: pneumothorax as a complication of the ultrasound-guided supraclavicular approach for brachial plexus block. Anesth Analg. 2010;111:817-9. 15. Buise MP, Bouwman RA, van der Gaag A, et al. Phrenic nerve palsy following interscalene brachial plexus block; a long lasting serious complication. Acta Anaesthesiol Belg. 2015;66:91-4.
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REVIEW ARTICLE
Medicine Science International Medical Journal
Medicine Science 2019;8(2):476-9
An updated overview of periodontal health in chronic diseases Selale Sahin Malatya Provincial Directorate of Health, Directorate of Public Health, Malatya, Turkey Received 14 March 2019; Accepted 28 May 2019 Available online 14.06.2019 with doi:10.5455/medscience.2019.08.9041 Copyright Š 2019 by authors and Medicine Science Publishing Inc. Abstract Periodontal diseases are chronic inflammatory diseases characterized by periodontal ligament loss and destruction of the alveolar bone, affecting the periodontium. Chronic diseases are complex diseases that vary regarding their causes and effects on society, some of which cause death, while others are long-term and unable to recover without treatment, which results with loss of function. There is much evidence showing the relationship between periodontal diseases and chronic diseases. Periodontitis is an independent risk factor for coronary artery disease. Poor oral hygiene, especially periodontal disease, increases the risk of CVD. The relationship between periodontal infection and DM has been reported in many studies. In particular, there are studies showing that periodontal disease increases insulin resistance, which plays a role in the pathogenesis of DM. It has been demonstrated that dramatically increasing obesity worldwide is a risk factor for periodontal disease. Oxidative stress can be an intersection point for obesity and periodontal disease. Rheumatoid arthritis is a chronic disease that causes many serious complications and requires many physical and psychological problems to be solved. Similar to periodontal diseases, the level of proinflammatory cytokines is increased in RA patients. Similarly, studies have shown that there is a close and complex link between periodontal disease and chronic kidney disease. The patients with periodontitis have an increased risk of chronic renal failure, and there is evidence that periodontal treatment has positive results in these patients. Periodontal diseases have been associated with increased cancer risk and region-specific cancers, but the mechanism is not precise yet. In this review, the relationship between periodontal diseases and chronic diseases and the effects of oral health on chronic diseases will be evaluated. Keywords: Periodontal diseases, chronic diseases, cardiovascular diseases, diabetes, cancer
Introduction The extension of life expectancy at birth leads to increase the incidence of many chronic diseases. Periodontal disease is the 6th most common disease in the world. Periodontal diseases may associated with most of chronicle diseases including CVD, DM, Obesity, Cancer, HT, PCOS, ED, AD and hypothyroidism etc. This review aims to evaluate the periodontal problems in chronic diseases. Periodontal diseases are chronic inflammatory diseases characterized by periodontal ligament loss and destruction of the alveolar bone, affecting the periodontium. It is characterized by periodontal ligament loss and destruction of alveolar bone [1]. These diseases are diseases that are initiated by dental plaque microorganisms, progressing in a mixed host-microorganism relationship and are ultimately characterized by hard and soft tissue destruction [2].
*Coresponding Author: Selale Sahin, Malatya Provincial Directorate of Health, Directorate of Public Health, Malatya, Turkey, E-mail: selaleseda@hotmail.com
Periodontal destruction can occur at any time during a personâ&#x20AC;&#x2122;s life. Usually, the first symptoms manifest themselves in the adult period. It occurs clinically in the age of 30 and the 40s and 50s, the progression of the disease is observed if the patient is not treated or treated insufficiently. Therefore, it is essential to determine the diagnosis and treatment for the disease depending on the amount of periodontal destruction and the rate of progression [3]. Chronic diseases are long-term, non-self-healing, complex diseases that vary regarding their causes and effects on society, some of which cause death, while others cause loss of function. Chronic diseases constitute an important part of the deaths and are increasing in countries all over the world [4]. In the literature, periodontal diseases are frequently encountered in patients with chronic disease. Periodontal diseases are often neglected during chronic diseases. Periodontal diseases can be the first symptom of many systemic diseases and/or affect the factors involved in the etiopathogenesis of the disease and may lead to the development and/or progression of the disease [5]. The infectious and chronic characteristics of the periodontal diseases may lead to the local and systemic response. It has been suggested that this condition may affect the general health and the 476
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course of some systemic diseases. Study evaluating the economic burden of periodontitis showed that cost to society found to be substantial and comparable with that of other chronic diseases. And this high economic burden may mainly be due to the high prevalence of the disease and resulting need for specialist periodontal care. In addition, patients with periodontitis also suffer from many chronic diseases mentioned above [6]. This study aims to evaluate the relationship between periodontal diseases and chronic diseases with in the light literature and to emphasize the importance of oral health in individuals with chronic diseases. The Risk Factors in Periodontal Diseases Various factors may increase the risk of periodontal disease. These factors are classified as modifiable (smoking, oral hygiene, nutrition, stress and drugs) and non-modifiable risk factors ( age and genetics) [7]. The Relationship Between Periodontal Diseases and Chronic Diseases Cardiovascular Diseases (CVD) Nowadays cardiovascular diseases are one of the most important causes of mortality and morbidity. Periodontitis is an independent risk factor for coronary artery disease [7]. It has been suggested that oral hygiene, especially the presence of periodontal diseases increases the risk of CVD. Studies in different populations suggest that atherosclerosis and acute thromboembolic diseases are associated with chronic oral infections and especially periodontal disease. In these studies, gram-negative periodontal pathogens were detected in atheroma plaques [8]. It has been shown that periodontitis is associated with an increased risk of CVD. Cardio vascular risk factors like smoking, stress, older age, and socioeconomic status are also risk factor for periodontitis The chronic inflammation of periodontitis and the immune response to the inflammation is supposed underlying mechanism for this association [ 9,10]. Hypertension It has been shown that hypertension and periodontitis share common risk factors. Oxidative stress and endothelial dysfunction have been shown to be playing a role in the pathogenesis of both diseases. Furthermore, observational studies support an association between periodontal disease and hypertension [11]. Diabetes Mellitus (DM) Although bacterial plaque is the main factor in periodontal diseases, it is known that some systemic and metabolic factors affect disease severity and prognosis. DM is a widespread disease in society. The relationship between periodontal infection and DM has been reported in numerous studies. There may be many reasons for the increased likelihood of periodontal disease in people with diabetes. The changes in immune response, the change in polymorphonuclear leukocyte functions, and the increase of oxidation may cause periodontal disease development in DM [12]. In these two diseases, the level of proinflammatory cytokine is high and may affect the pathological effects of each other negatively
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[13]. According to a meta-analysis report in the literature, periodontal treatment has been observed to provide glycemic control in patients with type 2 DM for at least three months [14]. Also, the literature supports the relationship between periodontitis and insulin resistance. Periodontal disease has been suggested to exacerbate insulin resistance that plays a role in the pathogenesis of DM. It was also reported that periodontal intervention might reduce insulin resistance in diabetic patients [15]. Obesity Obesity is a significant public health problem affecting both developed and developing countries. Studies have shown that overweight and obesity are associated with many chronic diseases, including periodontal diseases. Inflammatory and hyper-oxidative changes in obesity may cause hypersensitivity to bacterial infections and may facilitate the initiation or progression of periodontal infection. Oxidative stress may constitute an intersection point for obesity and periodontal disease [16]. Persistent systemic inflammation in obese individuals may support the microcirculation of periodontal tissue and the increase of pathogenic species in periodontal diseases [17]. The relationship between obesity and periodontitis is a topic to be evaluated in terms of public health [18]. Rheumatoid Arthritis (RA) Rheumatoid arthritis is a chronic disease that causes many serious complications and has many physical and psychological problems. In epidemiological studies, the prevalence of RA ranged from 0.5% to 1%, with an annual incidence of 12-1200 per 100,000 populations. The risk of gastrointestinal, respiratory, cardiovascular, infectious and hematological diseases increases in patients with RA [19]. However, the level of proinflammatory cytokines was high in the samples taken from the joints of patients with RA, and this was shown to be similar to periodontal diseases [20]. Chronic renal failure Chronic kidney disease affects 8% to 16% of the global population and causes increased morbidity and mortality [21]. In the literature, there are studies showing that periodontal diseases are a potential risk factor for non-communicable diseases (such as diabetes mellitus, cardiovascular diseases, pulmonary diseases, and chronic kidney diseases) [22]. Periodontal pathogen gram-negative bacteria and their products, such as lipopolysaccharides, significantly activate host immunity, and this effect is not limited to periodontal tissues. In the literature, several studies, which provided evidence of the increase in the prevalence of periodontal disease in patients with kidney disease, especially in patients who underwent dialysis and kidney transplantation, have been published [23]. In a systematic review, the risk of chronic renal failure increased in patients with periodontitis; and there is evidence that periodontal treatment has positive results in these patients [24]. Numerous studies have shown a close and complex relationship between periodontal disease and chronic kidney disease [25]. Cancer Cancer is an important health problem increasing around the world, alongside it is also a disease that can cause both financial and moral losses for individuals [26]. Oral cancers include lip, oral cavity, and cancers in the pharyngeal 477
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region; it is a major threat for adults and elderly in both high- and low-income countries and is known as the eighth most common type of cancer worldwide [27]. Periodontal diseases have been associated with increased cancer risk and region-specific cancers, but the mechanism is not precise yet. Periodontal pathogens can be transferred to the esophageal and colon tissues via saliva; to the lung tissue via aspiration. There are many studies in the literature showing periodontal pathogens isolated from lymph nodes, arteries, lungs, precancerous stomach, and colon lesions and esophageal, colorectal cancers. Periodontal pathogens may promote cancer formation when they find the appropriate environment [28]. Stress Chronic stress has been shown to be negative effect on the occurrence, development, and response to the treatment of periodontal disease by means of indirect actions on the periodontium [29]. Stress may be considered as an important risk factor for periodontal disease. Human studies evaluating role of psychological stress showed hyperactivation of the hypothalamuspituitary-adrenal axis in patients with chronic periodontitis [30]. Psychological factors have an adverse effect over the plaque levels and gingival status among the students [31]. Chronic obstructive Pulmonary Disease (COPD) Many studies suggest that COPD and periodontitis could be causally linked each other. Thus, treatment of one could decrease the severity and progression of the other. There are similarities in the pathogenesis like dysfunctional neutrophil, chronic neutrophilic inflammation, and connective tissue loss that support epidemiological evidence of relations in both diseases [32]. Alzheimer’s Disease (AD) and Dementia Poor oral health and periodontal diseases could possibly contribute to the risk of AD onset or progression. Additional cohort studies are needed to evaluate whether any cause-and-effect association exist or not [33]. Likewise recent studies suggest that older patients with dementia have high levels of plaque and poor oral health disorder related to oral soft tissues, such as gingival bleeding, periodontal pockets, stomatitis, mucosal lesions, and decreased salivary flow [34]. Multiple sclerosis Multiple sclerosis is a inflammatory neurodegenerative disease and its prevalence around the 69.1 per 100,000 subjects. Since both diseases have an inflammatory origin, link between multiple sclerosis and periodontitis is not surprising. Thus, multiple sclerosis patients needs special support by dentist and treatment could be provided to these patients to improve their dental health [35]. Erectile Dysfunctions (ED) A few of studies have investigated possible relation between ED and dental health. Oral and dental examination of 300 adult men demonstrated that statistically significant relationship between score of periodontal disease and presence of ED. And the prevalence of PD in adult men with ED was shown to be 26.9% aged less than 30 years. PD is play a crucial role in the etiology of ED by increasing reactive oxygen species in the tissues which reduces the bioavailability of nitric oxide, which increase endothelial
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dysfunction and impairs the muscular contractions [36]. Polycystic ovary syndrome (PCOS) Many studies investigated passible the association between periodontal diseases and PCOS. In these studies, proinflammatory cytokines were evaluated from gingival and saliva specimen. Likewise, salivary microbes were investigated. All studies indicated that a strong association exists between periodontal disease and PCOS. Patients with PCOS should also be referred to the dentist for oral examination and treatment those need it [37]. Vitamin D deficiency Vitamin D plays important functional roles in many organ systems; but prevalence of deficiency is very high and constitutes 30-50% of the population. Its effects on bone density/osteoporosis are very well known, but it has been shown that Vitamin D deficiency may be associated with the periodontal diseases. Recent studies showed that there are significant relations between dental health and periodontal diseases and intake of vitamin D and calcium, more importantly vitamin D therapy can improve periodontal status, decrease severity of periodontal disease, and increase bone mineral decrease alveolar bone resorption. It must be kept in mind that vitamin D beside the role in bone and calcium homeostasis, acts as an anti-inflammatory molecule since it decreases immune cell cytokine expression. This finding indicate that vitamin D may play beneficial role in the treatment of periodontitis improve dental health [38]. Hypothyroidism Decreased serum levels of thyroid hormones may increase periodontitis- related bone loss, as a function of an increased number of resorbing cells, but the tooth- supporting alveolar bone seems to be less sensitive to changes in hormone levels [39]. Conclusion and Suggestions Community-based screening is needed to detect periodontal diseases at an early stage. Since periodontitis can be the first symptom of many systemic diseases. It is necessary to raise awareness about the problems that may be caused by inadequate oral hygiene (dental caries, gingivitis, periodontitis, etc.). All the society should be informed for the possible chronic diseases and their interaction with the inadequate oral hygiene. As a consequence, both the permanent damage of the disease and the cost to society will be reduced. Financial Disclosure All authors declare no financial support. Selale Sahin ORCID: 0000-0001-7394-0800
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10. M Zamirian, S Raoofi, H Khosropanah, et al. Relationship between periodontal disease and acute myocardial infection. Iranian Cardiovas Res J. 2008;1:216-21. 11. PB Lockhart, AF Bolger, PN Papapanou, et al. Periodontal disease and atherosclerotic vascular disease: does the evidence support an independent association? A scientific statement from the American heart association. Circulation. 2012;125:2520-44, 12. Tunalı M, Ersahan S, Aydınbelge M. The two way relationship between periodontal diseases and diabetes. J of Health Sci. 2014;23:28-38. 13. Anwar A, Quasar AM, Akbar S. Association of C-reactive protein levels with periodontitis and type II diabetes mellitus. PJMHS . 2016;10:608-10. 14. Teeuw WJ, GerdesVE, Loos BG. Effect of periodontal treatment on glycemic control of diabetic patients: A systematic review and meta-analysis. Diabetes Care. 2010;33:421-27. 15. Lim SG, Han K, Kim HA, et al. Association between insulin resistance and periodontitis in Korean adults. J Clin Periodontol. 2014;41:121-30. 16. Dursun E, Akalin FA, Genc T, et al. Oxidative stress and periodontal disease in obesity. Medicine (Baltimore) 2016;95:1-7. 17. Silva-Boghossian CM, Cesário PC, Leão ATT, et al Subgingival microbial profile of obese women with periodontal disease. J Periodontol. 2018;89:186– 94 . 18. WHO. Global Health Observatory (GHO) Data. Obesity. http://www.who.int/ gho/ncd/risk_factors/obesity_text/en. access date 21.01.2019. 19.
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20. Pers JO, Saraux A, Pierre R, et al.. Anti TNF-a immunotherapy is associated with increased gingival inflammation without clinical attachment loss in subjects with rheumatoid arthritis. J Periodontol. 2008;79:1645-51. 21. Jha V, Garcia-Garcia G, Iseki K, et al. Chronic kidney disease: global dimension and perspectives. Lancet. 2013;382:260-72. 22. Soroye MO, Ayanbadejo PO. Oral conditions, periodontal status and periodontal treatment need of chronic kidney disease patients. J Oral Res
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Rev. 2016;8:53-8. 23. Joseph R, Krishnan R, Narayan V. Higher prevalence of periodontal disease among patients with predialytic renal disease. Braz J Oral Sci 2009;8:14-8. 24. Chambrone L, Foz AM, Guglielmetti MR, et al. Periodontitis and chronic kidney disease: A systematic review of the association of diseases and the effect of periodontal treatment on estimated glomerular filtration rate. J Clin Periodontol. 2013;40:443-56. 25. Hou Y, Wang X, Zhang CX, et al. Risk factors of periodontal disease in maintenance hemodialysis patients. Medicine (Baltimore) 2017;96:1-5. 26. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in globocan 2012. Int J Cancer. 2015;136:359-86. 27. Gil-Montaya J, Ferreira de Mello AL, Barrios R, et al. Oral health in the elderly patient and its impact on general well-being: a non systematic review. Clin Interv Aging. 2015;10:461-67. 28. Ngozi N, Nwizu, James R. et al. Periodontal disease and incident cancer risk among postmenopausal women: Results from the women’s health initiative observational cohort cancer. Epidemiol Biomarkers Prev. 2017;26:1255-65. 29. Gunepin M, et al. Impact of chronic stress on periodontal health J Oral Med Oral Surg 2018;24:44-50. 30. Mannem S, Chava VK. The effect of stress on periodontitis: A clinicobiochemical study J Indian Periodontol. 2012 Jul-Sep; 16:365-9. 31. Penmetsa GS, Seethalakshm P. Effect of stress, depression and anxiety over periodontal health indicators among health professional students. J Indian Assoc Public Health Dent. 2019;17:36-40. 32. Hobbins S, Chapple LC, Sapey E, et al. Is periodontitis a comorbidity of COPD or can associations be explained by shared risk factors/behaviors? Int J Chron Obstruct Pulmon Dis. 2017;12:1339-49. 33. Olsen I, Singhrao SK. Can oral infection be a risk factor for Alzheimer’s disease? J Oral Microbiol. 2015;7:29143. 34. Delwel S, Binnekade TT, Perez RSGM, et al. Oral hygiene and oral health in older people with dementia: a comprehensive review with focus on oral soft tissues Clin Oral Investig. 2018; 22:93-108. 35. Elemek E, Almas K. Multiple sclerosis and oral health-an update. J Mich Dent Assoc. 2013;95:28-31. 36. Kellesarian SV, Kellesarian TV, Melignaggi VR et al . Association Between Periodontal Disease and Erectile Dysfunction: A Systematic Review. Am J Men Health’s. 2018; 12:338–46. 37. Kellesarian SV, Maligning VR, Kellesarian TV et al. Association between periodontal disease and polycystic ovary syndrome: a systematic review. Int J Impot Res. 2017;29:89-95. 38. Anand N, Chandrasekaran SC, Raiput NS .Vitamin D and periodontal health: Current concepts J Indian Soc Periodontol. 2013;17:302-8. 39. Feiltosa DS, Marguez MR, Casati MZ et al. The influence of thyroid hormones on periodontitis- related bone loss and tooth- supporting alveolar bone: a histological study in rats J of Periodont Res 2009;44:472-8.
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REVIEW ARTICLE
Medicine Science International Medical Journal
Medicine Science 2019;8(2):480-1
The history and current status of forensic pathology Mumine Gormez1, Emine Samdanci2 Tokat Gaziosmanpasa University, Faculty of Medicine, Department of Medical Pathology, Tokat, Turkey. 2 Inonu University, Faculty of Medicine, Department of Medical Pathology, Malatya, Turkey
1
Received 30 May 2019; Accepted 31 May 2019 Available online 14.06.2019 with doi:10.5455/medscience.2019.08.9046 Copyright Š 2019 by authors and Medicine Science Publishing Inc. Abstract Forensic pathology is currently one of the basic touchstones of forensic science in criminal investigations. Together with developing technology and science, the importance of forensic pathology in resolving judicial events is increasing. The aim of this paper was to review the historical development of forensic pathology and the current status. Since ancient times, determining the cause of death has been of the greatest importance for the determination of the punishment to be given for crimes committed. There is known to have been an autopsy to determine the cause of death following the assassination of Roman Emperor Julius Caesar (44 BC). Developments over time in medicine also led to developments in autopsies. Pathology became a separate science with developments in the knowledge of anatomy starting in the 16th century and the invention of the microscope in the 17th century, and thus the normal anatomy, histology and pathology of human tissue came to be better understood. The first pathological anatomy autopsy is known to have been performed in 1286. The importance of forensic medicine and pathology in the process of explaining the cause of death and resolving judicial events has been well understood for hundred of years and has rendered the existence of forensic pathology imperative. Thus, in current international autopsy protocols, pathological examinations have become an indispensable part of autopsies. Despite the different nomenclature in different countries, such as forensic medicine specialist or forensic pathologist, a multidisciplinary approach is necessary in all forensic autopsies. Autopsy procedures are performed by forensic medicine specialists in Europe, by forensic pathologists in the USA and some other countries, and by forensic medicine specialists and forensic pathologists together in Turkey.. Keywords: Forensic pathology, historical review, current status, otopsy, death
Introduction Forensic pathology is currently one of the basic touchstones of forensic science in criminal investigations. Together with developing technology and science, the importance of forensic pathology in resolving judicial events is increasing. The aim of this paper was to review the historical development of forensic pathology and the current status. Historical Development According to the humoral theory in the medicine of Ancient Greece, the body is composed of black bile, yellow bile, phlegm andblood. Therefore, it was believed that diseases originated from an imbalance in rate of these 4 components. Throughout later centuries, this theory was accepted in Europe and developments in the subject of anatomy slowed down [1]. The majority of developments in anatomy in ancient times progressed with the anatomy of common animals. The history of autopsies is based *Coresponding Author: Mumine Gormez, Tokat Gaziosmanpasa University, Faculty of Medicine, Department of Medical Pathology, Tokat, Turkey E-mail: muminegormez@hotmail.com
on the beginnings of anatomy and medicine [2]. The first autopsy was in Ancient Egypt in 3000 BC and when limited to animal autopsies, the history goes back to Babylon in 4000 BC [2,3]. The Egyptian PharaohPtolemy I Soter (367-282 BC), which supported pathological anatomy, established the university and great library at Alexandria. The ancient Greek doctor, Herophilos of Chalcedon (335-280 BC), who is considered the first anatomist, performed autopsies in Alexandria, and wrote a work on human anatomy [4]. Since ancient times, determining the cause of death has been of the greatest importance for the determination of the punishment to be given for crimes committed. There is known to have been an autopsy to determine the cause of death following the assassination of Roman Emperor Julius Caesar (44 BC).As autopsies were forbidden in the Middle Ages in Europe, there were no significant developments in pathology, and medicolegal autopsies were performed for the first time in 1302. Muslim doctors investigating infectious diseases in Asia have contributed to the development of pathology, and Ibn-I-ZĂźhr (1091-1161) was one of the physicians performing postmortem autopsies. In the 1500s, autopsy was accepted by the Catholic Church and written records of the developments in forensic pathology started in the 16th century [2]. Giovanni Bathista Morgagni (1682-1771), who is accepted as the 480
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founder of autopsies, considered the relationship between clinical and pathological findings on the subject of understanding diseases. William Hunter (1718-1783) and John Hunter (1728-1793) founded the first English museum to providebeing learnedof pathology. Matthew Baillie (1761-1823) published the first pathology atlas in 1793 [1]. Jean Lobstein (1777-1835) became a Professor at Strasbourg University in 1819, and thus for the first time pathology started to be accepted as a separate branch. At the end of the 19th century, pathology was accepted as a field of medicine. With the first use of microscopes by pathologists in the mid-19th century, and with the understanding of the value of the microscope in pathology by the German pathologist, Rudolf Virchow (1812-1902), who is known as the â&#x20AC;&#x153;father of pathologistsâ&#x20AC;? [2], the microscope became more important in pathology examinations. By further developing forensic pathology with better teaching of anatomy and general pathology, the applicability of medical science to legal events increased, and the development in forensic pathology accelerated especially at the end of the 20th century and beginning of the 21 st. However, just as there has been macroscopic interpretation of wounds since before the birth of forensic pathology, pathologists and other doctors who are relatively lacking in basic knowledge of the area of forensic medicine compared to forensic medicine specialists, performed examinations of the dead [5]. This created problems from a legal aspect and led to the formation of forensic pathology from the intersection of forensic medicine and pathology. Forensic pathology is a sub-branch of the more extensive field of forensic medicine, andis the combined application of forensic sciences and pathology in the resolution of judicial events such as death [2,6]. The basic duty of a forensic pathologist is to perform autopsies in addition to postmortem examination. The word autopsy has the meaning of seeing with oneâ&#x20AC;&#x2122;s own eyes. Cause of death is determined in an autopsy from a detailed medical examination of the body and internal organs of the deceased person. There are 2 types of autopsy; medical and forensic. A medical autopsy clarifies a natural death and a forensic autopsy provides clarification of a suspicious death [7]. Conclusion and Current Status The importance of forensic medicine and pathology in the process of explaining the cause of death and resolving judicial events has been well understood for hundred of years and has rendered the existence of forensic pathology imperative. Thus, in current international autopsy protocols, pathological examinations have become an indispensable part of autopsies. Despite the different nomenclature in different countries, such as forensic medicine specialist or forensic pathologist, a multidisciplinary approach is necessary in all forensic autopsies. In 1999, recommended guidelines were published related to the necessary rules to be followed in forensic autopsies in member states and candidate members of the European Union. These state the minimum procedures to be performed in a forensic autopsy. The minimum requirement in all forensic autopsies is that macroscopic and microscopic pathological examinations are made of the basic
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organs [8]. Thus, pathology applications have become routine in forensic autopsy procedures in the countries of continental Europe. The Minnesota Autopsy Protocol was published as the rules to be followed in autopsies where the death is claimed to be related to a breach of human rights [9]. In addition to the routine histopathological examinations, this protocol makes it necessary to take samples of suspicious lesions in all cases of claims requiring investigation of suspicious death as a result of torture or similar events, such as lesions that could form associated with electricity applied to the body. Although there are differences between countries, autopsy procedures are performed by forensic medicine specialists in Europe, by forensic pathologists in the USA and some other countries, and by forensic medicine specialists and forensic pathologists together in Turkey. Histopathological examination is a component of current forensic autopsies just as much as describing the lesions, defining the medical identity and performing toxicology examinations in all autopsies. A forensic autopsy in which histopathological examinations have not been made should be considered an insufficient autopsy. Competing interests The author confirms that this article content has no conflict of interest. Financial Disclosure This study was presented as an oral presentation in 2. Turkish Forensic Sciences Congress, 11-14 April 2019, Kas, Antalya, Turkey. Ethical approval As it is a compilation study, we do not have an ethics committee approval. Mumine Gormez ORCID: 0000-0003-4579-3393 Emine Samdanci ORCID: 0000-0002-0034-5186
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LETTER TO THE EDITOR
Medicine Science International Medical Journal
Medicine Science 2019;8(2):482-3
The use of prophylactic heparin in cancer Yasemin Benderli Cihan Kayseri Education and Research Hospital, Department of Radiation Oncology, Kayseri, Turkey Received 05 November 2018; Accepted 13 February 2019 Available online 16.04.2019 with doi:10.5455/medscience.2018.07.9001 Copyright Š 2019 by authors and Medicine Science Publishing Inc.E-mail: mkececi83@hotmail.com
It is known that tendency to coagulation increases in many of cancer patients. The incidence of venous thrombo embolic (VT) events is approximately 10-20%. Besides myeloproliferative disorders, VTs are most commonly seen with gastrointestinal system, lung, prostate, ovarian, and brain tumors. Several mechanisms have been proposed to explain this association; among these are release of procoagulant factors from the tumor, necrosis and hemodynamic disorders as well as decreased fibrinolytic activity and treatments such as surgery and chemotherapy [1]. The role of radiotherapy in the ethio pathogenesis of venous thromboembolism is not fully known. Unlike chemotherapy, data about the epidemiology and clinical features of VT and during radiotherapy are limited. To our current knowledge, 13% of patients receiving radiotherapy have been reported to receive anticoagulant therapy, although there is no evidence about the effects of radiation [2]. In cancer patients, a number of risk factors such as chemotherapy, radiotherapy, surgical treatment, presence of concomitant diseases (previously, deep vein thrombosis, DM, HT, etc.) have been determined in the development of VT. VT development was found to be higher in patients with high risk factors [1-3]. Venous thromboembolism is usually common in cancer patients with metastasis and affects the prognosis negatively. In population-based studies conducted with cases of all cancers, 1-year survival has been reported as 12% in patients with thromboembolic events and 36% in those without such events [1,3]. The main basis in preventation and treatment of acute venous thromboembolic events is anticoagulant therapy. Low-molecular weight heparins are successfully used in treatment and prophylaxis of cancer patients. Heparin has been proven to prevent fatal thromboembolism and inhibit tumoral cell growth, adhesion and metastasis in cancer patients directly or through the inhibition of
*Coresponding Author: Yasemin Benderli Cihan, Kayseri Education and Research Hospital, Department of Radiation Oncology, Sanayi District, Ataturk Boulevard, Hastane Street, No 78, 38010 Kocasinan, Kayseri, Turkey Email: cihany@erciyes.edu.tr
coagulant proteases or P-selectin [3-5]. In the FAMOUS (Fragmin Advanced Malignancy Outcome Study) randomized, placebo- controlled, double-blind study, they looked at the effect on survival with DMAH in patients with advanced malignant disease. There was no significant difference in survival between the groups in the 1st, 2nd and third year results. However, in subgroup analysis, it was observed that the patients who lived more than 17 months and who had good prognosis had a mean 24 months in the placebo group and 43 months in the DMHA group (p: 0.03) [3]. Another important study is the CLOT study. In this study, oral anti-coagulant therapy was compared with DMHA treatment for the prevention of thromboembolic event in patients with acute thromboembolic disease. While there was no significant difference between the two groups in the one-year results, it was reported that there was a one-year survival benefit in favor of the DMHA-treated group in the non-distant metastasis group in the subgroup analysis (p: 0.03) [6]. In the animal model studies performed by Borsig, DMHA treatment has been reported to show antimetastatic activity. It was reported that Pand L-selectin were inhibited by blocking, inhibiting angiogenesis and inhibiting extracellular matrix protease heparanase [7]. These results, however, have brought about discussions. Therefore, new studies are needed to better clarify this issue. As a result, the risk of venous thromboembolism is high in cancer patients, especially during cancer. Heparin has an important role in the treatment of both anticoagulant and cancer. It can be seen that heparin can provide significant contribution to both anticoagulant treatment and cancer prevention, growth and prevention of metastases. However, there is no clarity in the literature. A randomized prospective study or meta-analysis results are needed. Financial Disclosure The authors declared that this study had received no financial support. Yasemin Benderli Cihan ORCID: 0000-0001-9295-4917
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