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Volume 27, Number 8
January 2017, Pages 701–800
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IJCP Group of Publications Dr Sanjiv Chopra Prof. of Medicine & Faculty Dean Harvard Medical School Group Consultant Editor Dr Deepak Chopra Chief Editorial Advisor
Dr KK Aggarwal Group Editor-in-Chief IJCP Group, eMedinewS and eMediNexus Dr Veena Aggarwal MD, Group Executive Editor
IJCP Editorial Board Obstetrics and Gynaecology Dr Alka Kriplani, Dr Thankam Verma, Dr Kamala Selvaraj Cardiology Dr Praveen Chandra, Dr SK Parashar Paediatrics Dr Swati Y Bhave Diabetology Dr CR Anand Moses, Dr Sidhartha Das, Dr A Ramachandran, Dr Samith A Shetty, Dr Vijay Viswanathan, Dr V Mohan, Dr V Seshiah, Dr Vijayakumar ENT Dr Jasveer Singh, Dr Chanchal Pal Dentistry Dr KMK Masthan, Dr Rajesh Chandna Gastroenterology Dr Ajay Kumar, Dr Rajiv Khosla, Dr JS Rajkumar Dermatology Dr Hasmukh J Shroff, Dr Pasricha, Dr Koushik Lahiri, Dr Jayakar Thomas Nephrology Dr Georgi Abraham Neurology Dr V Nagarajan, Dr Vineet Suri, Dr AV Srinivasan Oncology Dr V Shanta Orthopedics Dr J Maheshwari
Anand Gopal Bhatnagar Editorial Anchor Advisory Bodies Heart Care Foundation of India Non-Resident Indians Chamber of Commerce & Industry World Fellowship of Religions
This journal is indexed in IndMED (http://indmed.nic.in) and full-text of articles are included in medIND databases (http://mednic.in) hosted by National Informatics Centre, New Delhi.
Volume 27, Number 8, January 2017 FROM THE DESK OF THE GROUP EDITOR-IN-CHIEF
705 Top 10 Advances in Cardiology (AHA)
KK Aggarwal
AMERICAN FAMILY PHYSICIAN
709 Complementary/Integrative Therapies That Work: A Review of the Evidence
Benjamin Kligler, Raymond Teets, Melissa Quick
715 Practice Guidelines 717 Photo Quiz CARDIOLOGY
720 An Autopsy and Echocardiographic Study of Left Ventricular Trabeculations
Deep C Pant, Hema Pant, Ajay Bahl, Uma Saikia
DRUGS
727 A Pharmacokinetics Study of Docetaxel New Formulation by 1-hour Intravenous Infusion in Patients with Advanced Malignant Solid Tumors
S Aloorkar, C Harita, BB Teja
736 Current Perspectives and Prescribing Patterns in the Use of Phenytoin Sodium for Seizure Control in Adult Epilepsy Patients in India: A Physician-based Survey
Jasbir Singh Kathpal, Samir Adsule, Kartik Peethambaran
HEMATOLOGY
748 The Innocent Bystanders: Endocrine Complications of Thalassemia Major with Iron Overload
Surekha B Shetty, Lalitha Shivaprakash
INTERNAL MEDICINE
752 A Clinical Study of Febrile Thrombocytopenia: A Hospital-based Retrospective Study
Praveen Kumar, Kalpana Chandra
NUTRACEUTICALS
759 Promising Role of Vitamin D3 in Improving Overall Health
G Vijayakumar
OBSTETRICS AND GYNECOLOGY
Published, Printed and Edited by Dr KK Aggarwal, on behalf of IJCP Publications Ltd. and Published at E - 219, Greater Kailash Part - 1 New Delhi - 110 048 E-mail: editorial@ijcp.com
766 Obstructed Labor: Scenario in a Tertiary Care Hospital
Surya Malik, Khushpreet Kaur, Parneet Kaur
PEDIATRICS
Printed at New Edge Communications Pvt. Ltd., New Delhi E-mail: edgecommunication@gmail.com
774 Changing Trends in Childhood Obesity
Copyright 2017 IJCP Publications Ltd. All rights reserved.
Sidhant Kapila, Sneh Prabha Goel, Ashish Prakash, Ajay Punj
MEDILAW
The copyright for all the editorial material contained in this journal, in the form of layout, content including images and design, is held by IJCP Publications Ltd. No part of this publication may be published in any form whatsoever without the prior written permission of the publisher.
780 Maintaining Correct and Updated Medical Records of the Patient CONFERENCE PROCEEDINGS
Editorial Policies
782 46th Annual Conference of Endocrine Society of India (ESICON 2016)
The purpose of IJCP Academy of CME is to serve the medical profession and provide print continuing medical education as a part of their social commitment. The information and opinions presented in IJCP group publications reflect the views of the authors, not those of the journal, unless so stated. Advertising is accepted only if judged to be in harmony with the purpose of the journal; however, IJCP group reserves the right to reject any advertising at its sole discretion. Neither acceptance nor rejection constitutes an endorsement by IJCP group of a particular policy, product or procedure. We believe that readers need to be aware of any affiliation or financial relationship (employment, consultancies, stock ownership, honoraria, etc.) between an author and any organization or entity that has a direct financial interest in the subject matter or materials the author is writing about. We inform the reader of any pertinent relationships disclosed. A disclosure statement, where appropriate, is published at the end of the relevant article.
787 10th World Stroke Congress 2016 AROUND THE GLOBE
791 News and Views LIGHTER READING
796 Lighter Side of Medicine
Note: Indian Journal of Clinical Practice does not guarantee, directly or indirectly, the quality or efficacy of any product or service described in the advertisements or other material which is commercial in nature in this issue.
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FROM THE DESK OF THE GROUP EDITOR-IN-CHIEF
Dr KK Aggarwal
Group Editor-in-Chief IJCP Group, eMedinewS and eMediNexus
Top 10 Advances in Cardiology (AHA) 1. In selective high-risk groups, additional therapies help prevent a second stroke: Previous research has shown that to prevent a second stroke, “aggressive medical management”—treating and controlling high cholesterol, high blood pressure (BP) and blood sugar, as well as lifestyle behaviors such as smoking cessation and exercise—is better than stenting. But a study, Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS), published in JAMA identified a subgroup of patients at higher risk for a recurrent stroke despite medical management—and who need stenting. Investigators found that high-risk patients included those who had an old stroke in the area of the blockage, a new stroke or were not on a statin at the time they joined the study. 2. New possibilities for treating women with heart attacks: The study, in the American Heart Association’s journal, Circulation: Cardiovascular Imaging, found that women had a type of plaque thought to be vulnerable throughout the blood vessels, while in men, they were mostly found in the earliest part of the artery. The way plaques “broke” often was different as well. Men had larger size plaques even though the women in the study had more cardiovascular risk factors. 3. More options for valve replacements in the elderly: In high-risk patients with aortic valve stenosis, treatment means either open-heart surgery or transcatheter aortic valve replacement. This study, which focused on older patients, compared surgery and transcatheter aortic valve replacement (TAVR) by looking at the survival and stroke rates of intermediate-risk patients. The research, published in the NEJM, showed the rates were similar and that use of either procedure would produce similar outcomes. 4. Long-term study validates less-selective invasive treatment for narrowed neck arteries: In the past, the typical treatment for carotid arteries narrowing was carotid endarterectomy. And now, research, Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) study published in the NEJM and based on a 10-year follow-up, gives stenting more validation as an accepted alternative. 5. Better together: Managing BP and cholesterol at same time helps lower heart risk: This research, called the Heart Outcomes Prevention Evaluation (HOPE)-3, is a combination of three articles published simultaneously in the NEJM that, taken together, conclude that reducing both BP and cholesterol is better than doing either alone. It also provide further evidence supporting the benefits of statins in Asian and Hispanic populations. 6. Evidence we might be able to outsmart our genes: A study in NEJM found that among participants at high genetic risk for cardiovascular disease, a favorable lifestyle was associated with a nearly 50% lower relative risk than those with an unfavorable lifestyle that included smoking, obesity, lack of exercise and poor diet. 7. Disparity in counseling women and minorities with heart failure: Implantable cardioverter defibrillator(ICD) can be lifesaving by preventing sudden death in people with severe heart failure. But, according to this
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FROM THE DESK OF THE GROUP EDITOR-IN-CHIEF study of 21,000 patients published in Circulation, women and ethnic minority patients eligible for the device far too often aren’t counseled about it. The findings show as many as four out of five hospitalized patients with heart failure eligible for ICD counseling did not receive it, particularly women and ethnic minority patients. 8. Fainting could be a sign of pulmonary embolism in some patients: NEJM: In the past, fainting had not been considered high on the list of signs and symptoms pointing to pulmonary embolism. But researchers in the Pulmonary Embolism in Syncope Italian Trial (PESIT) study used a diagnostic work-up to assess the presence of the embolism and found it was present in about one out of six, or 18%, of the patients. 9. Advancing the treatment of severe strokes: This meta-analysis of patient data from five landmark trials shows the benefits of stent retrievers that snare large clots from the brain. The research published in The Lancet consolidates work that means providing timely treatment for these patients could have a global impact. 10. Two studies move the needle toward better prevention of heart disease: ÂÂ
Lowering BP to below 120/90 mmHg, compared with 140/90 mmHg, led to significantly lower rates of death and “cardiovascular events” among adults age 75 and older. The study, published in the JAMA, extends the results of the recent, the Systolic Blood Pressure Intervention Trial (SPRINT) trial and could help clear up inconsistencies in how doctors set BP targets for geriatric populations.
ÂÂ
Also this year, investigators in a separate project identified a gene variant that determines whether a carrier may have a lower risk of coronary heart disease than those without the gene variation (NEJM). This gene, called ANGPTL4, governs the action of lipoprotein lipase, or LPL, which plays a critical role in breaking down a type of fat in the blood produced by the liver, called triglycerides. High triglyceride levels are a contributor to heart disease risk. In this study, people with a specific genetic variation in the ANGPTL4 gene had lower triglyceride levels, higher “good” high-density lipoprotein cholesterol levels and lower coronary artery disease risk than those who did not have the mutation. ■■■■
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2017
2017
AMERICAN FAMILY PHYSICIAN
Complementary/Integrative Therapies That Work: A Review of the Evidence BENJAMIN KLIGLER, RAYMOND TEETS, MELISSA QUICK
ABSTRACT Significant evidence supports the effectiveness and safety of several complementary or integrative treatment approaches to common primary care problems. Acupuncture is effective in the management of chronic low back pain. Mind-body interventions such as cognitive behavior therapy, yoga, tai chi, qi gong, and music therapy may be helpful for treating insomnia. Exercise can reduce anxiety symptoms. Herbal preparations and nutritional supplements can be useful as first-line therapy for certain conditions, such as fish oil for hypertriglyceridemia, St. John’s wort for depression, and Ginkgo biloba extract for dementia, or as adjunctive therapy, such as coenzyme Q10 for heart failure. Probiotic supplementation can significantly reduce the likelihood of antibiotic-associated diarrhea. Physicians should caution patients about interactions, and counsel them about the quality and safety of herbal and nutritional supplements.
Keywords: Complementary or integrative treatment, acupuncture, mind-body interventions, herbal preparations, nutritional supplements, probiotic supplementation
A
bout one-third of U.S. adults in 2012 reported that they used complementary therapies in the previous year, according to data from the Centers for Disease Control and Prevention.1 Studies have shown that 12% to 64% of patients do not disclose this use to their physician.2 The American Academy of Family Physicians advocates for evidencebased evaluations of integrative medicine to facilitate education, treatment, and counseling of patients.3 This article will discuss the evidence for eight of the beststudied integrative interventions, which primary care physicians should consider incorporating into their practices (Table 1). The lack of adequate regulation of herbs and supplements by the U.S. Food and Drug Administration makes it difficult for consumers and physicians to be assured of the quality and safety of a specific supplement. When possible, this article recommends specific brands of herbal medicines and nutritional supplements known to be of high quality. Reputable information about the
BENJAMIN KLIGLER, MD, MPH, is an associate professor in the Department of Family and Community Medicine at Icahn School of Medicine at Mount Sinai, New York, NY. RAYMOND TEETS, MD, is an associate professor in the Department of Family and Community Medicine at Icahn School of Medicine at Mount Sinai. MELISSA QUICK, DO, is a family physician at Group Health Cooperative, Seattle, Wash. Source: Adapted from Am Fam Physician. 2016;94(5):369-374.
quality of specific herb and supplement brands can be found at Consumer Lab.com (http://www.consumer lab.com/) and the U.S. Pharmacopeial Convention (http:// www.usp.org/dietary-supplements/overview). ACUPUNCTURE FOR CHRONIC LOW BACK PAIN Acupuncture is a component of traditional East Asian medicine that involves the insertion of needles at specific points on the body to facilitate the recovery of health. A 2012 meta-analysis of pooled data from 29 studies involving 17,922 patients found that acupuncture was effective for treating chronic low back pain compared with sham acupuncture and no treatment, with a moderate effect size of 0.55.1,4 Acupuncture also provided significant pain relief compared with sham acupuncture and no treatment in a 2015 systematic review and meta-analysis,5 and in a 2015 overview of 16 systematic reviews.6 In general, acupuncture is extremely safe, with the most common risk being transient mild discomfort. The Joint Commission recently recommended acupuncture as a treatment option for pain management.7 Acupuncture is most often provided individually by licensed acupuncturists; the practice of community or group acupuncture may reduce costs and improve access. Medical acupuncture courses offer family physicians training in this treatment option.
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AMERICAN FAMILY PHYSICIAN Table 1. Summary of Indications for Complementary Therapies Treatment
Indication
First-line vs. adjunctive
Comments
Acupuncture
Chronic low back pain
First-line
Should be performed by a licensed practitioner
Coenzyme Q10
Heart failure
Adjunctive
Dosage is 100 mg three times per day
Exercise
Anxiety
First-line
May be helpful in patients with diagnosed anxiety disorders, those with chronic illness without diagnosed anxiety, and those with depression; aerobic exercise is best studied; 30 minutes three to five times per week seems to be most effective
Fish oil
Hypertriglyceridemia
First-line
Lowers triglyceride levels, but unclear if it reduces cardiovascular events; dosage is 4 g of combined eicosapentaenoic acid/ docosahexaenoic acid per day; may have minor gastrointestinal adverse effects; no significant medication interactions
Ginkgo biloba
Dementia
First-line
Use extract standardized to 22% to 27% ginkgo flavonoids; typical dosage is 240 mg per day
Mind-body interventions
Insomnia
First-line
Cognitive behavior therapy is most effective; alternatives include meditation, hypnosis, yoga, and tai chi
Probiotics
Prevention of antibiotic-associated diarrhea
First-line
Start within one to three days of starting antibiotics, and continue for one week after stopping; dosage is 5 to 10 billion colony-forming units per day for children, 10 to 20 billion colony-forming units per day for adults; multiple strains available; not clear which are most effective
St. John’s wort
Depression
First-line
Use in mild to moderate depression rather than severe depression; do not use in combination with selective serotonin reuptake inhibitors; significant potential for interactions; occasional gastrointestinal adverse effects
CoQ10 AS ADJUNCTIVE TREATMENT FOR HEART FAILURE Coenzyme Q10 (CoQ10), also called ubiquinone, is an antioxidant found in high concentrations in the heart. It has a role in mitochondrial electron transport and in supplying myocardial energy. CoQ10 concentrations have been inversely related to the severity of systolic and diastolic heart failure,8 and low plasma CoQ10 levels may independently predict mortality in patients with heart failure.9 A 2013 meta-analysis of 13 randomized controlled trials (RCTs) found that CoQ10 increased net ejection fraction by 3.7%.10 A 2014 multicenter RCT showed that CoQ10 added to standard therapy was safe and well tolerated, improved symptoms, and reduced major car diovascular events in patients with heart failure.11 There are multiple formulations of CoQ10, and bioavailability depends on the type or preparation, although clinical outcomes have not been assessed in head-to-head trials.12 The Q-SYMBIO trial used the brand Kaneka Q10 at a dosage of 100 mg three times per day.11 It was well tolerated with similar or fewer adverse effects vs. placebo. The Kaneka Q10 formulation is available under various brand names, including Jarrow and NatureWise. CoQ10 is an adjunctive therapy and should not be used alone to treat heart failure.
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EXERCISE FOR ANXIETY A recent review of 37 meta-analyses of RCTs and observational studies with a total of 42,264 participants reported that exercise had a small but meaningful average anxiolytic effect size of 0.34 in patients with diagnosed anxiety disorders,13 similar to the average effect size of 0.37 reported in published antidepressant trials.14 This effect size increased when only RCTs were included. Most studies evaluated the effect of aerobic exercise, although strength training may be effective as well.15 Another meta-analysis including only RCTs found an effect size of 0.48 for exercise in reducing anxiety symptoms.16 A third recent analysis examining a pooled sample of 2,914 sedentary adults with chronic illness but no specific anxiety diagnosis found a smaller but still meaningful mean effect size of 0.29.15 Although the dose, type, and frequency of exercise most effective for specific anxiety conditions are unclear, 30 minutes of aerobic exercise three to five times per week seems reasonable, given current physical activity guidelines. Exercise may also have a modest benefit in treating depression, with an effect size ranging from 0.31 to 0.56 in recent reviews.17 For patients who are unable to perform vigorous aer obic exercise, qi gong—a gentle form of exercise that
AMERICAN FAMILY PHYSICIAN originated in China and has recently become popular in the West18—and yoga15 also show promise in reducing anxiety symptoms. FISH OIL FOR HYPERTRIGLYCERIDEMIA The omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), found in fish oil, have been shown in multiple studies to lower high triglyceride levels.19-21 EPA/DHA at a dosage of 4 g per day decreases triglyceride levels by 25% to 30%.19 Adverse effects are rare, with some patients reporting mild gastrointestinal effects, such as reflux with a fishy taste. Fish oil does not have any known interactions, and dosages up to 5 g per day do not increase bleeding risk.19 Although elevated triglyceride levels are associated with increased cardiovascular mortality22 and fish consumption two to four times per week is associated with lower cardiovascular mortality in cohort studies,23 it is not known if the triglyceride-lowering effect of fish oil decreases cardiovascular events.24 Given the safety of fish oil, it seems reasonable to consider it as a means to lower triglyceride levels, while recognizing that its effect on patient-centered outcomes must still be determined. Fish oil capsules are available as the prescription drug Lovaza and as generic equivalents, as well as less expensive over-the-counter brands such as Nordic Naturals and Carlson. GINKGO BILOBA FOR DEMENTIA Ginkgo biloba is an herb whose leaves have been studied extensively for the treatment of Alzheimerand vascular-type dementias. Its proposed mechanisms of action include preservation and improvement of mitochondrial function, promotion of hippocampal neurogenesis and neuroplasticity, and enhancement of cerebral blood flow.25,26 The extract EGb 761, a dry extract of the leaves standardized to 22% to 27% ginkgo flavonoids, has been most extensively studied.27 A meta-analysis of seven RCTs including 2,684 patients with Alzheimer- or vascular-type dementia showed that standard measures of overall cognition and activities of daily living improved in those who received ginkgo extract at 240 mg per day, whereas a daily dosage of 120 mg had no effect.26 Effect sizes were similar to those of anticholinesterase medications currently approved for the treatment of Alzheimer-type dementia.25 Adverse effects were infrequent and included headache and dizziness; discontinuation rates were the same between the ginkgo and placebo groups.27 Many of the
clinical trials of ginkgo, as well as the meta-analyses, have been industry-funded or included an author with industry affiliation. Although there have been some case reports suggesting an association between ginkgo and increased bleeding risk, a 2011 meta-analysis did not find increased bleeding events or changes in coagulation parameters with standardized ginkgo extract EGb 761.28 Given the specificity of the Ginkgo biloba extract studied in the meta-analyses, it is important to recommend a supplement that matches EGb 761, such as Nature’s Way Ginkgold. An RCT of ginkgo for prevention of dementia showed no benefit.29 Because of its apparent effectiveness compared with prescription medications and its favorable adverse effect profile, it is reasonable to recommend ginkgo as an alternative first-line treatment for dementia. MIND-BODY INTERVENTIONS FOR INSOMNIA Mind-body interventions such as hypnosis, meditation, guided imagery, mindfulness-based stress reduction, cognitive behavior therapy (CBT), biofeedback, yoga, traditional Chinese practices (e.g., qi gong, tai chi), and music therapy represent safe and cost-effective treatment options for insomnia and other sleep-quality disturbances. A 2015 systematic review found that CBT was the most effective mind-body intervention for insomnia.30 A previous article in American Family Physician reviewed CBT for insomnia and various psychiatric disorders (http://www.aafp.org/ afp/2015/1101/p807.html). CBT can be costly, however, so group-based versions of mindful awareness practices may offer an economical alternative and have been shown to benefit older patients with sleep disturbances.31 A recent meta-analysis in patients with cancer and insomnia showed that yoga, meditation, hypnosis, mindfulness-based stress reduction, and qi gong have a moderate effect on the improvement of sleep quality for up to three months.32 A Cochrane review found that listening to music improves sleep quality and is safe and easy to administer.33 A 2015 systematic review suggested that specific movementoriented mind-body approaches such as yoga, tai chi, and qi gong may be beneficial for sleep, especially in older adults and cancer survivors.34 Familiarity with one or more mind-body interventions will provide physicians with nonpharmacologic treatment options as first-line therapies to improve sleep quality in all patients. However, there are very few data
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AMERICAN FAMILY PHYSICIAN comparing the effectiveness of different interventions for insomnia in specific patient populations; as such, the choice of intervention should be based on physicianpatient dialogue and negotiation, as well as cost and availability. PROBIOTICS FOR PREVENTION OF ANTIBIOTICASSOCIATED DIARRHEA A large variety of probiotics are now being used in clinical practice; the most widely used and thoroughly researched are Lactobacillus species, Bifidobacterium species, and Saccharomyces boulardii, a nonpathogenic yeast. A recent systematic review pooling data from 63 RCTs including 11,811 participants found a 0.58 relative risk of antibiotic-associated diarrhea among participants who supplemented with probiotics, with a number needed to treat of 13.35 Most studies used Lactobacillus species alone or in combination with other species. A second meta-analysis of 34 studies with 4,138 participants found a similar relative risk of 0.53 and a number needed to treat of 8.36 This preventive effect persisted regardless of probiotic species used, age group, or duration of treatment. For the prevention of Clostridium difficile–associated diarrhea, a meta-analysis including 23 trials and 4,213 participants recently found a relative risk of 0.36 in the probiotic group.37 The typical recommended dosage of probiotics is 5 to 10 billion colony-forming units per day for children and 10 to 20 billion per day for adults. Additional research is needed to determine which strains are most effective for specific indications; brands include Culturelle, Jarrow, and Nature’s Way Primadophilus. Patients should be advised to start probiotic treatment within one to three days of starting antibiotics and continue for one week after stopping. A recent safety review by the Agency for Healthcare Research and Quality that included more than 24,000 participants reported no adverse effects significant enough to require hospitalization.38 ST. JOHN’S WORT FOR DEPRESSION Extracts of St. John’s wort, or Hypericum perforatum, have been evaluated for treatment of depressive symptoms and major depressive disorder in adults. In a 2008 Cochrane review, St. John’s wort was found to be more effective than placebo for the treatment of major depression, although most of the studies focused on mild to moderate rather than severe depression.39 The St. John’s wort group had lower dropout rates than other antidepressants and had a good adverse effect
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profile, similar to that of placebo.40 The number needed to treat for St. John’s wort is 3.5, which is similar to that of prescription antidepressants.39 There appear to be minimal differences in effectiveness between various St. John’s wort extracts. Patients should be counseled to use extracts that match those studied, such as extracts standardized to 0.3% hypericin. Two examples available in the United States include Perika St. John’s wort by Nature’s Way and Kira St. John’s wort by Enzymatic Therapy. Therapeutic dosages range from 500 to 1,200 mg per day; a commonly recommended dosage is 300 mg three times per day. The mechanism of action is not entirely clear.41 Although St. John’s wort is generally safe, it is known to cause induction of several cytochrome P450 enzymes, which can lead to significant interactions. Some examples include the increased metabolism of oral contraceptives, some antibiotics, protease inhibitors, and certain immunosuppressive medications, as well as decreased levels of digoxin.42 Because of a possible risk of serotonin syndrome due to additive serotonergic effects, concomitant use with selective serotonin reuptake inhibitors should be avoided. A careful medication history is important, as is the use of an interaction checker database that includes herbs and supplements. For patients with mild to moderate depression who prefer not to use conventional antidepressants, St. John’s wort is a reasonable first-line treatment. REFERENCES 1. Clarke TC, Black LI, Stussman BJ, Barnes PM, Nahin RL. Trends in the use of complementary health approaches among adults: United States, 2002–2012. National Health Statistics Reports. February 10, 2015. http:// www.cdc. gov/nchs/data/nhsr/nhsr079.pdf. Accessed March 8, 2016. 2. Robinson A, McGrail MR. Disclosure of CAM use to medical practitioners: a review of qualitative and quantitative studies. Complement Ther Med. 2004; 12(2-3):90-98. 3. American Academy of Family Physicians. Integrative medicine. http:// www.aafp.org/about/policies/all/ integrative-medicine1.html. Accessed January 16, 2016. 4. Vickers AJ, Cronin AM, Maschino AC, et al.; Acupuncture Trialists’ Collaboration. Acupuncture for chronic pain: individual patient data meta-analysis. Arch Intern Med. 2012;172(19):1444-1453. 5. Yuan QL, Guo TM, Liu L, Sun F, Zhang YG. Traditional Chinese medicine for neck pain and low back pain: a systematic review and meta-analysis. PLoS One. 2015;10(2):e0117146.
AMERICAN FAMILY PHYSICIAN 6. Liu L, Skinner M, McDonough S, Mabire L, Baxter GD. Acupuncture for low back pain: an overview of systematic reviews. Evid Based Complement Alternat Med. 2015;2015:328196. 7. The Joint Commission. Clarification of the pain management standard. http://www.jointcommission. org/clarification_of_the_pain_management__standard/. Accessed September 27, 2015. 8. Molyneux SL, Florkowski CM, George PM, et al. Coenzyme Q10: an independent predictor of mortality in chronic heart failure. J Am Coll Cardiol. 2008;52(18): 1435-1441. 9. Folkers K, Vadhanavikit S, Mortensen SA. Biochemical rationale and myocardial tissue data on the effective therapy of cardiomyopathy with coenzyme Q10. Proc Natl Acad Sci U S A. 1985;82(3):901-904. 10. Fotino AD, Thompson-Paul AM, Bazzano LA. Effect of coenzyme Q10 supplementation on heart failure: a metaanalysis. Am J Clin Nutr. 2013;97(2):268-275. 11. Mortensen SA, Rosenfeldt F, Kumar A, et al.; Q-SYMBIO Study Investigators. The effect of coenzyme Q10 on morbidity and mortality in chronic heart failure: results from Q-SYMBIO: a randomized double-blind trial. JACC Heart Fail. 2014;2(6):641-649. 12. DiNicolantonio JJ, Bhutani J, McCarty MF, O’Keefe JH. Coenzyme Q10 for the treatment of heart failure: a review of the literature. Open Heart. 2015;2(1):e000326. 13. Wegner M, Helmich I, Machado S, Nardi AE, AriasCarrion O, Budde H. Effects of exercise on anxiety and depression disorders: review of meta-analyses and neurobiological mechanisms. CNS Neurol Disord Drug Targets. 2014;13(6):1002-1014. 14. Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med. 2008;358(3):252-260. 15. Herring MP, O’Connor PJ, Dishman RK. The effect of exercise training on anxiety symptoms among patients: a systematic review. Arch Intern Med. 2010;170(4):321-331. 16. Wipfli BM, Rethorst CD, Landers DM. The anxiolytic effects of exercise: a meta-analysis of randomized trials and dose-response analysis [published correction appears in J Sport Exerc Psychol. 2009;31(1):128-129]. J Sport Exerc Psychol. 2008;30(4):392-410. 17. Rimer J, Dwan K, Lawlor DA, et al. Exercise for depression. Cochrane Database Syst Rev. 2012;(7):CD004366. 18. Wang CW, Chan CH, Ho RT, Chan JS, Ng SM, Chan CL. Managing stress and anxiety through qigong exercise in healthy adults: a systematic review and meta-analysis of randomized controlled trials. BMC Complement Altern Med. 2014;14:8. 19. Roth EM. ω-3 carboxylic acids for hypertriglyceridemia. Expert Opin Pharmacother. 2015;16(1):123-133.
20. Weitz D, Weintraub H, Fisher E, Schwartzbard AZ. Fish oil for the treatment of cardiovascular disease. Cardiol Rev. 2010;18(5):258-263. 21. Nestel P, Clifton P, Colquhoun D, et al. Indications for omega-3 long chain polyunsaturated fatty acid in the prevention and treatment of cardiovascular disease. Heart Lung Circ. 2015;24(8):769-779. 22. Liu J, Zeng FF, Liu ZM, Zhang CX, Ling WH, Chen YM. Effects of blood triglycerides on cardiovascular and allcause mortality: a systematic review and meta-analysis of 61 prospective studies. Lipids Health Dis. 2013;12:159. 23. Zheng J, Huang T, Yu Y, Hu X, Yang B, Li D. Fish consumption and CHD mortality: an updated metaanalysis of seventeen cohort studies. Public Health Nutr. 2012;15(4):725-737. 24. Weintraub H. Update on marine omega-3 fatty acids: management of dyslipidemia and current omega-3 treatment options. Atherosclerosis. 2013;230(2):381-389. 25. von Gunten A, Schlaefke S, Überla K. Efficacy of Ginkgo biloba extract EGb 761 in dementia with behavioural and psychological symptoms: a systematic review. World J Biol Psychiatry. Published online ahead of print July 30, 2015. http://www.tandfonline.com/doi/pdf/10.3109/156 22975.2015.1066513. Accessed March 8, 2016. 26. Gauthier S, Schlaefke S. Efficacy and tolerability of Ginkgo biloba extract EGb 761 in dementia: a systematic review and meta-analysis of randomized placebo-controlled trials. Clin Interv Aging. 2014;9:2065-2077. 27. Weinmann S, Roll S, Schwarzbach C, Vauth C, Willich SN. Effects of Ginkgo biloba in dementia: systematic review and meta-analysis. BMC Geriatr. 2010;10:14. 28. Kellermann AJ, Kloft C. Is there a risk of bleeding associated with standardized Ginkgo biloba extract therapy? A systematic review and meta-analysis. Pharmacotherapy. 2011;31(5):490-502. 29. Vellas B, Coley N, Ousset PJ, et al.; GuidAge Study Group. Long-term use of standardised Ginkgo biloba extract for the prevention of Alzheimer’s disease (GuidAge): a randomised placebo-controlled trial. Lancet Neurol. 2012;11(10):851-859. 30. Trauer JM, Qian MY, Doyle JS, Rajaratnam SM, Cunnington D. Cognitive behavioral therapy for chronic insomnia: a systematic review and meta-analysis. Ann Intern Med. 2015;163(3):191-204. 31. Black DS, O’Reilly GA, Olmstead R, Breen EC, Irwin MR. Mindfulness meditation and improvement in sleep quality and daytime impairment among older adults with sleep disturbances: a randomized clinical trial. JAMA Intern Med. 2015;175(4):494-501. 32. Chiu HY, Chiang PC, Miao NF, Lin EY, Tsai PS. The effects of mind-body interventions on sleep in cancer patients: a meta-analysis of randomized controlled trials. J Clin Psychiatry. 2014;75(11):1215-1223.
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AMERICAN FAMILY PHYSICIAN 33. Jespersen KV, Koenig J, Jennum P, Vuust P. Music for insomnia in adults. Cochrane Database Syst Rev. 2015;(8):CD010459. 34. Neuendorf R, Wahbeh H, Chamine I, Yu J, Hutchison K, Oken BS. The effects of mind-body interventions on sleep quality: a systematic review. Evid Based Complement Alternat Med. 2015;2015:902708. 35. Hempel H, Newberry SJ, Maher AR, et al. Probiotics for the prevention and treatment of antibiotic-associated diarrhea: a systematic review and meta-analysis. JAMA. 2012;307(18):1959-1969. 36. Videlock EJ, Cremonini F. Meta-analysis: probiotics in antibiotic-associated diarrhoea. Aliment Pharmacol Ther. 2012;35(12):1355-1369.
38. Hempel S, Newberry S, Ruelaz A, et al. Safety of probiotics to reduce risk and prevent or treat disease. Evidence reports/technology assessments no. 200. Rockville, Md.: Agency for Healthcare Research and Quality; 2011. 39. Linde K, Berner MM, Kriston L. St John’s wort for major depression. Cochrane Database Syst Rev. 2008;(4):CD000448. 40. Kasper S, Gastpar M, Müller WE, et al. Efficacy of St. John’s wort extract WS 5570 in acute treatment of mild depression: a reanalysis of data from controlled clinical trials. Eur Arch Psychiatry Clin Neurosci. 2008;258(1): 59-63. 41. Farahani MS, Bahramsoltani R, Farzaei MH, Abdollahi M, Rahimi R. Plant-derived natural medicines for the management of depression: an overview of mechanisms of action. Rev Neurosci. 2015;26(3):305-321.
37. Goldenberg JZ, Ma SS, Saxton JD, et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev. 42. Shi S, Klotz U. Drug interactions with herbal medicines. 2013;(5):CD006095. Clin Pharmacokinet. 2012;51(2):77-104. ■■■■
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Practice Guidelines CDC RELEASES UPDATED GUIDELINES FOR POSTEXPOSURE PROPHYLAXIS AFTER SEXUAL, INJECTION DRUG, OR OTHER NONOCCUPATIONAL EXPOSURES TO HIV
be made without delay, based on the assumption that the exposed person is not infected with HIV. nPEP can be discontinued if the patient is later determined to have HIV infection.
Postexposure prophylaxis (PEP) with antiretroviral drugs to prevent transmission of human immunodeficiency virus (HIV) following sexual or injection drug use exposures (nonoccupational PEP or nPEP) is an essential intervention requiring a timely response. Updated guidelines from the Centers for Disease Control and Prevention (CDC) provide clinicians with guidance on assessing and managing exposures, new nPEP regimens, schedules for baseline and follow-up testing for HIV and associated infections, and longer-term prevention measures including preexposure prophylaxis (PrEP).
Source person testing should also be obtained, if possible. A fourth-generation HIV antigen-antibody test is recommended because it can detect recent infection a few weeks earlier than standard antibody tests. If this test is negative, the source person is presumed to be uninfected, and nPEP is not indicated. If there are signs or symptoms of acute HIV infection, additional evaluation is required. For many exposures, the source person’s HIV status will not be known, so risk will be estimated based on known or suspected risk factors.
Indications for nPEP Indications for nPEP remain unchanged. The patient must be exposed to a potentially infectious fluid, including semen, vaginal or rectal secretions, and blood or any body fluid contaminated with blood. Non-bloody saliva, urine, feces, vomitus, sputum, nasal secretions, sweat, and tears are not infectious for HIV. There should be knowledge or rea sonable suspicion that the source person is infected with HIV. With sex partners and injection drug use, it might not be possible to obtain accurate information on the source person’s HIV status. The patient needs to come into contact with a mucous membrane (e.g., vagina, rectum, mouth) for sexual exposures or through the skin for injection drug exposures. And finally, exposure needs to have occurred within the previous 72 hours.
Baseline Testing Exposed persons should have HIV testing, preferably using a rapid antibody or rapid antigen-antibody test, to rule out infection from a previous exposure. Exposed persons with HIV infection are not candidates for nPEP and need further evaluation for treatment. If HIV test results will not be available during the initial evaluation, a decision whether nPEP is indicated should
The guideline provides schedules for baseline laboratory testing, including hepatitis B and C and sexually transmitted infections, for source and exposed persons initiating nPEP. Pregnancy testing is recommended when appropriate.
Initiating nPEP as Soon as Possible After Exposure Postexposure prophylaxis is a time-sensitive intervention because effectiveness appears to wane over time. Prompt evaluation and initiation of nPEP (when clinically indicated) as soon as possible after exposure are essential. Initiating nPEP should not be delayed pending HIV test results or additional source person risk factor assessment. nPEP is unlikely to be effective when initiated more than 72 hours after exposure. Therefore, the guidelines do not recommend nPEP after that time-frame.
Treatment Recommended nPEP Regimens Three-drug nPEP regimens are now standard treatment, based on the effectiveness of combination antiviral drug regimens in HIV disease. Most patients tolerate the current medication regimens without serious adverse effects or drug interactions. The preferred regimen includes: Tenofovir disoproxil, 300 mg/emtricitabine, 200 mg once daily
Source: Adapted from Am Fam Physician. 2016;94(5):392-393.
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AMERICAN FAMILY PHYSICIAN Raltegravir, 400 mg twice daily or dolutegravir, 50 mg daily The alternative regimen is: Tenofovir disoproxil, 300 mg/emtricitabine, 200 mg once daily plus Darunavir, 800 mg and ritonavir, 100 mg once daily An important adverse effect of tenofovir nPEP regimens is renal toxicity among those with preexisting kidney disease. Baseline creatinine measurement is mandatory. Raltegravir and dolutegravir need to be given two hours before or six hours after administration of sucralfate and products containing calcium, magnesium, aluminum, iron, zinc and other buffered products, although raltegravir (but not dolutegravir) can be administered with calcium carbonate–containing antacids. Duration nPEP should be given for 28 days regardless of the severity of exposure.
Follow-up Testing HIV antibody testing at four to six weeks and three months is recommended. Schedules for follow-up laboratory testing for HIV, hepatitis, sexually transmitted infections, and pregnancy are also provided.
Acute HIV The signs and symptoms associated with acute (pri mary) HIV infection, most commonly fever and rash, are described. Acute HIV infection requires immediate referral to a physician experienced in treating patients with HIV infection.
Special Considerations The guidelines address special considerations, such as: nPEP in pregnancy; approaches in sexual assault
cases; prophylaxis for sexually transmitted infections and hepatitis; use of antiretroviral drugs in children; antiretroviral use in renal and hepatic disease; drug resistance; repeated use of nPEP; safer sex and injection drug use practices; adherence, behavioral change, prevention counseling, and risk reduction; legal, regulatory, and reporting concerns; and financial assistance for nPEP medications.
PrEP Many persons who are evaluated for nPEP following sexual and injection drug use exposures have ongoing risk factors and remain at markedly increased risk for future HIV infection. These persons, and persons who have received nPEP in the past year, should be provided risk reduction counseling and intervention services, including consideration of preexposure prophylaxis with tenofovir disoproxil/emtricitabine. When used regularly with good adherence, PrEP can decrease transmissions substantially. HIV infection must be ruled out before initiating PrEP.
Found-Needle Injuries No HIV infections caused by injuries from needles discarded in public settings (e.g., parks) have been documented. These injuries typically involve smallbore needles that have been exposed to drying and contain only limited amounts of blood with viruses of low infectiousness.
Consultation For challenging cases or when the guidelines do not provide the guidance needed on indications and implementation of PEP and PrEP, local experts, the national PEPline (888-448-4911), or the national PrEPline (855- 448-7737) may be consulted.
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Photo Quiz NONTENDER ELBOW NODULES A 77-year-old woman presented with a long-standing history of daily pain and stiffness in multiple joints. She reported morning stiffness in her shoulders, knees, dorsal feet, and metacarpophalangeal joints that improved with hot showers. She did not have acute attacks of pain or constitutional symptoms such as fever, chills, or weight changes. On physical examination, she had symmetric swelling, warmth, and tenderness of the second, third, and fourth metacarpophalangeal joints. She also had bilateral irregularly shaped, nontender, firm, fixed nodules over the extensor surfaces of her elbows (Figure 1).
Figure 1.
Question Based on the patient’s history and physical examination findings, which one of the following is the most likely diagnosis? A. Epidermoid cysts. B. Olecranon bursitis. C. Rheumatoid nodules. D. Tophaceous gout.
SEE THE FOLLOWING PAGE FOR DISCUSSION.
Source: Adapted from Am Fam Physician. 2016;94(5):375-376.
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AMERICAN FAMILY PHYSICIAN Discussion
Summary Table
The answer is C: rheumatoid nodules. Rheumatoid arthritis is a symmetric polyarthritis that typically involves the small joints of the hands and feet, although any joint with a synovial lining may be affected. Classically, it begins with the gradual onset of pain and stiffness that is worse in the morning. The joints are usually affected for an hour or more, and there is improvement with activity.1 The nodules are usually found on areas exposed to chronic pressure but may occur within other organ systems, including the lung, heart, and rarely the central nervous system.
Condition
Characteristics
Epidermoid cyst
Benign, mobile dermal growths that often contain a central punctum; filled with keratinaceous debris
Olecranon bursitis
Fluctuant collection of fluid in the olecranon bursa due to trauma, chronic pressure, overuse, or other rheumatic conditions
Rheumatoid nodule
Rheumatoid nodules are the most common cutaneous finding in rheumatoid arthritis, occurring in 30% to 40% of patients with the disease.2 The exact etiology is unknown. They are composed of inflammatory cells, fibrin, and necrotic proteinaceous debris.3 Most patients with rheumatoid nodules are seropositive for rheumatoid factor and anticyclic citrullinated peptide antibodies.4 Patients with rheumatoid nodules typically have a more severe course and more rapid progression of rheumatoid arthritis than patients without nodules.5 Nodules range from 2 mm to 5 cm and are firm, usually nontender, and mobile, although they may become fixed to the underlying periosteum.6 Occasionally, nodules may be painful or large enough to limit range of motion or compress nearby nerves, necessitating treatment. Treatments include glucocorticoid injections,7 and occasionally surgical excision for recalcitrant cases.8
Firm, nontender, mobile or fixed nodule that develops over pressure points as an extra-articular manifestation of rheumatoid arthritis
Tophaceous gout
Firm, nontender nodule caused by the repeated deposition of monosodium urate crystals in soft tissues
Epidermoid cysts are benign, mobile dermal growths that often contain a central punctum. They are filled with keratinaceous debris. Intact cysts may be removed by simple excision, whereas inflamed cysts may be injected with corticosteroids and excised when asymptomatic.9 Olecranon bursitis is characterized by the fluctuant collection of fluid in the olecranon bursa due to trauma, chronic pressure, overuse, or other rheumatic conditions. Signs of inflammation and tenderness depend on the acuity of the etiologic process. Unless a secondary infection is suspected, treatment consists of joint protection and compression with or without aspiration. Tophaceous gout is considered the end-stage of monosodium urate crystal deposition. Tophi are firm, nontender nodules often with associated chronic inflammation and destructive changes in nearby tissues. Although the tophi are usually not painful,
gout is typically characterized by the onset of discrete attacks of monoarticular arthritis interspersed with asymptomatic periods. REFERENCES 1. Rindfleisch JA, Muller D. Diagnosis and management of rheumatoid arthritis. Am Fam Physician. 2005;72(6): 1037-1047. 2. Turesson C, Jacobsson LT. Epidemiology of extraarticular manifestations in rheumatoid arthritis. Scand J Rheumatol. 2004;33(2):65-72. 3. Athanasou NA, Quinn J, Woods CG, Mcgee JO. Immunohistology of rheumatoid nodules and rheumatoid synovium. Ann Rheum Dis. 1988;47(5):398-403. 4. Kim SK, Park SH, Shin IH, Choe JY. Anti-cyclic citrullinated peptide antibody, smoking, alcohol consumption, and disease duration as risk factors for extraarticular manifestations in Korean patients with rheumatoid arthritis. J Rheumatol. 2008;35(6):995-1001. 5. Nyhäll-Wåhlin BM, Turesson C, Jacobsson LT, et al. The presence of rheumatoid nodules at early rheumatoid arthritis diagnosis is a sign of extra-articular disease and predicts radiographic progression of joint destruction over 5 years. Scand J Rheumatol. 2011;40(2):81-87. 6. García-Patos V. Rheumatoid nodule. Semin Cutan Med Surg. 2007;26(2):100-107. 7. Baan H, Haagsma CJ, van de Laar MA. Corticosteroid injections reduce size of rheumatoid nodules. Clin Rheumatol. 2006;25(1):21-23. 8. McGrath MH, Fleischer A. The subcutaneous rheumatoid nodule. Hand Clin. 1989;5(2):127-135.
9. Higgins JC, Maher MH, Douglas MS. Diagnosing com mon benign skin tumors. Am Fam Physician. 2015;92(7): 601-607. ■■■■
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2017
CARDIOLOGY
An Autopsy and Echocardiographic Study of Left Ventricular Trabeculations DEEP C PANT*, HEMA PANT†, AJAY BAHL‡, UMA SAIKIA#
ABSTRACT Background: Left ventricular (LV) trabeculations are normal anatomic variants, which can be confused with pathologic entities like mural thrombi. This was a pilot study to know the incidence and morphology of normal LV trabeculations in normal hearts both by autopsy and echocardiography. Objectives: To study the incidence of prominent LV trabeculations by autopsy and echocardiography. Material and methods: Prominent LV trabeculations, defined as trabeculations with thickness at least 50% of underlying myocardium were studied in 50 patients both by echocardiography and autopsy. Results: Prominent LV trabeculations were found in 16% of normal heart on autopsy and 14% hearts on echocardiography and incidence by two modalities was comparable. Conclusion: Prominent LV trabeculations, which are normal anatomic variants can be found in minority of hearts and can be reliably detected by echocardiography.
Keywords: Left ventricle trabeculation, incidence, autopsy, echocardiography
A
dvancement in transducers and introduction of high-resolution second harmonic technology has improved the evaluation of heart anatomy and in particular, left ventricular anatomy. Left ventricle false tendons and trabeculations are present is about half the human hearts in pathologic conditions, whereas their echocardiographic incidence in adults has been demonstrated to be very low in comparison with the prevalence on morphologic examination. Even though the echocardiographic recognition of these cavitary structures may have little clinical significance per se, these anatomic variants may be very important because of their potential to be mistaken for more important pathologic entities like mural thrombi. This was a pilot study to see the morphology of left ventricular (LV) trabeculations by 2D echocardiography, (2D echo) and at autopsy to define the incidence and normal variations in the (LV) trabeculations.
*Associate Professor, Dept. of Cardiology †Associate Professor, Dept. of Pathology SRMS-IMS, Bareilly, Uttar Pradesh ‡Associate Professor, Dept. of Cardiology #Associate Professor, Dept. of Pathology PGIMER, Chandigarh Address for correspondence Dr Deep C Pant Dept. of Cardiology SRMSIMS, Bareilly, Uttar Pradesh E-mail: pantpgimer@yahoo.co.in
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AIM To characterize the variations in LV trabeculations in normal heart on echocardiography and at autopsy. OBJECTIVES ÂÂ
To study LV trabeculations in normal hearts on 2D echo.
ÂÂ
To study the variations, number and morphology of LV trabeculations at autopsy in patients without cardiac disease.
ÂÂ
To compare the echocardiographic and autopsy findings of variations in LV trabeculations in normal hearts.
MATERIAL AND METHODS
2D Echocardiography Fifty consecutive individuals were included in the study with age <50 years with no apparent cardiac sign or symptoms. Inclusion Criterion ÂÂ
Age <50 years.
ÂÂ
Patients attending Cardiology OPD with a negative treadmill test and no evidence of heart disease.
ÂÂ
Healthy attendants accompanying patients coming for 2D echo study of their patients who were
CARDIOLOGY willing to undergo screening 2D echo for LV trabeculations. Exclusion Criterion
short-axis at 0.5 cm thickness from base to apex and total number of trabeculi were counted. Ratio of thickness of trabeculi to underlying myocardium was noted.
ÂÂ
ÂÂ
Presence of heart disease including coronary heart disease, congenital heart disease, cardiomyopathies of various types, rheumatic heart diseases.
ÂÂ
Systemic hypertension
ÂÂ
Diabetes mellitus
7
ÂÂ
Chronic renal failure
6
ÂÂ
Long-standing anemia
ÂÂ
Other medical causes, which have direct effect on cardiac functions i.e., diabetes mellitus (type 1 and type 2), chronic glomerulonephritis, chronic pyleonephritis.
No. of trabeculations
The above exclusion criteria were strictly followed both for echocardiography and autopsy study.
8
5 4 3 2 1
2D Echo Study
0
Left ventricle trabeculi were studied at following three levels (Fig. 1, Table 1 and 2): ÂÂ
Parasternal short-axis at mitral level
ÂÂ
Parasternal short-axis at papillary muscle level
ÂÂ
Short axis at apex
ÂÂ
Prominent LV trabeculation was defined as trabeculation with thickness at least 50% of underlying myocardium in end-systole. Figure 2 shows percentage for the number of LV trabeculations.
ÂÂ
Echocardiography of the patients was done on Acuson Sequoia C512 machine.
Autopsy Study All the cases dying of noncardiac causes including exclusion criterion mentioned for 2D echo were included for the study. A total of 50 consecutive autopsy cases performed as standard medical autopsy with prior informed consent of the patients relatives were studied. The heart specimens were dissected along the flow of blood and fixed in 10% buffered formalin for preservation. LV and RV trabeculations were assessed for their number, coarseness, gross morphology, dimensions and any other abnormality. All the cases were photographed digitally, stored and the data was saved.
Papillary muscle level
Short-axis level
Mitral value
Figure 1. Showing the number of trabeculations at different short-axis levels on 2D echo.
Table 1. Percentage-wise Distribution of Number of Trabeculations on 2D-Echo Number of trabeculations No. of hearts
Percentage (%)
1
4
57
2
3
43
Table 2. Percentage-wise Distribution of Site of LV Trabeculations on 2D Echo Level of short-axis
Number of heart
Percentage (%)
Mitral valve level
1
14
Papillary muscle level
3
43
Apical short-axis
3
43
1 Trabeculation 2 Trabeculations
11% 11%
67% 11%
3 Trabeculations 5 Trabeculations
Gross Features Heart weight was taken in relation to expected heart weight for body weight. Cut section of heart in
Figure 2. Showing percentage for the number of LV trabeculations.
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CARDIOLOGY ÂÂ
Measurement of trabeculi was done by vernier callipers.
ÂÂ
All trabeculi were photographed digitally and stored for future comparison.
ÂÂ
Prominent LV trabeculation was defined as trabeculation thickness at least 50% of underlying myocardium.
Table 4. Distribution of LV Trabeculations on Gross Morphology
ÂÂ
Prominent LV trabeculations were studied and counted at short-axis at apex.
ÂÂ
Cases were studied with routine sectioning of right and left ventricle, with Masson's trichrome and elastic Verhoeff-Van Gieson stains performed for collagen and elastic tissue, respectively. Any associated incidental cardiac anomaly was also noted.
ÂÂ
seven heart had ratio of trabeculation to underlying myocardium between 0.5 and 1. One heart had ratio of trabeculation to underlying myocardium between
No. of trabeculation
No. of hearts
Percentage (%)
1
4
50
2
3
37
3
1
13
OBSERVATION AND RESULTS Fifty consecutive heart specimen were studied at autopsy and the heart specimens were dissected along the flow of blood. The age of the patients varied from 18 years to 50 years. The mean age of the patients studied was 32.7 ± 7.6 years. Out of the 50 hearts selected for study, 33 hearts belonged to male subjects and 17 hearts belonged to female subjects (Table 3). The weight of the heart specimens varied from 194 g to 430 g and mean weight was 274 ± 96 g.
Left Ventricle Trabeculations Left ventricle was studied for presence of significant trabeculations. The cases in which trabeculation thickness was least 50% of underlying myocardium in short-axis at the apex was considered as significant trabeculation. Of the total of 50 hearts studied, eight hearts (16%) had significant LV trabeculations. Of these eight hearts with prominent trabeculations, four hearts had single trabeculation, three hearts had two trabeculations and one heart had three trabeculations (Table 4 and Figs. 3-8). Of the eight heart with prominent trabeculations,
Figure 3. Showing single prominent LV trabeculation at apex.
Table 3. Age and Sex Distribution of Subjects at Autopsy Sex Male
Female
18-30 years
24 (48%)
16
8
31-40 years
15 (30%)
11
6
41-50 years
11 (22%)
6
3
Mean age of the subjects antemortem was 32.7 ± 7.6 years.
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Figure 4. Showing two prominent LV trabeculations at apex.
CARDIOLOGY
Figure 5. Showing single prominent LV trabeculations at apex.
Figure 6. Showing three prominent LV trabeculation with dilated LV cavity.
Figure 7. Showing two prominent LV trabeculations at apex.
Figure 8. Showing two prominent LV trabeculations at apex.
1 and 1.5. None of the heart had ratio of measured trabeculation to underlying myocardium >1.5.
Left Ventricle Trabeculations
ECHOCARDIOGRAPHIC STUDY
Age and Sex Distribution of Patients The number of male subjects in echocardiographic study was 29. The number of female subjects was 21. The age of subjects ranged from 19 years to 48 years and the mean age was 32 Âą 6.4 years. The mean age of the subjects examined was 32 Âą 6.4 years.
Fifty hearts of healthy subjects were examined for prominent LV trabeculations. Prominent trabeculation in present study was defined as trabeculations with thickness at least 50% of underlying myocardium. Prominent LV trabeculations were detected in seven hearts out of 50 hearts of healthy subjects examined (14%). Four hearts had single LV trabeculation. Three hearts had two prominent trabeculations (Figs. 9-12). Of the hearts with prominent trabeculations the ratio of measured trabeculation to underlying myocardium
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CARDIOLOGY
Figure 9. Showing two prominent LV trabeculations at papillary muscle level in short-axis of heart.
Figure 10. Showing single prominent LV trabeculation at apex.
Figure 11. Showing single prominent LV trabeculation at papillary muscle level.
Figure 12. Showing single prominent LV trabeculation at apex.
thickness was between 0.5 and 1 in all the seven hearts. In none of the hearts this observed ratio was >1.
examined (16%) while echocardiographically LV trabeculations were observed in seven hearts of the 50 hearts examined (14%).
Comparison of Echocardiographic and Autopsy Study ÂÂ
Mean age of the subjects in autopsy study was 32.7 ± 7.6 years and for echocardiographic subjects was 32 ± 6.1 years (p < 0.001) for equivalence in age two groups.
ÂÂ
At autopsy studies 34% cases were females while in echocardiographic study 42% of the subjects were female.
ÂÂ
Observations at autopsy revealed prominent LV trabeculations in eight of the total of 50 heart specimens
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Indian Journal of Clinical Practice, Vol. 27, No. 8, January 2017
ÂÂ
The difference in incidence of LV trabeculations examined by two modalities was not statistically significant.
DISCUSSION The LV is typically less trabeculated than the right ventricle, and other than the papillary muscles it is infrequent to note coarse muscle trabeculations in the left ventricle. Occasionally trabeculated left ventricle apex is encountered, the degree of which rarely approaches
CARDIOLOGY that seen in right ventricle. According to Stollberger et al, in human hearts the LV has up to three prominent trabeculations and is thus less traebeculated than the right ventricle. No study has till now simultaneously studied autopsy and echocardiography to detect the incidence of LV trabeculations in normal hearts and compared the two diagnostic modalities. In the present study, a detailed search was made for LV trabeculations in normal human hearts. The morphology, variations and incidence of LV trabeculations was studied both by echocardiography and at autopsy in 50 subjects and cases, respectively. In the 2D echo study, LV trabeculations were studied in short-axis view at mitral level, papillary muscle level and at apical short-axis. All trabeculations, which had thickness ≥50% of underlying myocardium were considered prominent trabeculations and were considered for analysis for calculating the incidence and morphology of LV trabeculation. On 2D echo study, prominent LV trabeculations were detected in seven patients (14%) of the 50 healthy hearts examined. Four (57%) of these hearts had single LV trabeculation only, while 3 (43%) hearts had two trabeculations. In male subjects, four hearts had prominent LV trabeculation out of 29 hearts examined (28%). In female subjects, three hearts had significant LV trabeculations out of 21 hearts examined (24%). Hence, incidence of LV trabeculations was slightly more in male subjects on 2D echo. At autopsy, LV trabeculations were seen in eight hearts (16%) out of total 50 hearts examined. All trabeculations were studied at apical short-axis in heart specimen and measured with a scale. Of all hearts having LV trabeculation, four heart had single LV trabeculations, while two trabeculations were seen in two hearts. One heart had three LV trabeculation. The overall incidence of LV trabeculation was found to be 16% at autopsy and 14% on echocardiography. The incidence of LV trabeculation in males subjects was 15% (5/33) and female subjects was 17.6% (3/17). The mean age of the patient having LV trabeculation was 36.11 ± 8. 4 years. The mean weight of the heart specimen examined was 274 ± 96 g. On comparison of echocardiographic incidence of LV trabeculations in our study to study done by Tamborini et al, the incidence of prominent LV trabeculation in our study is slightly lower, 14% versus 26%, respectively. Tamborini et al, sought to review echocardiographic incidence of AI (anamolous images) such as false tendons and apical trabeculations and to define the normal echocardiographic appearance of LV
endocardial surface. In 1580, patients the presence of false tendons, trabeculations or thrombi were evaluated with transthoracic echocardiography and correlated to clinical characteristics and echocardiographic parameters. The incidence of AI was 46.2 (75% false tendons, 23% trabeculations, 2% thrombi) slightly higher in pathologic (48.9%) then in normal hearts (40.8%). In AI was more frequent in male patient (52%) then female patients (39.7%) and associated with LV dilatation, hypertrophy and systolic dysfunction. False tendons and LV trabeculations were not related to age. Male sex was the most significant independent predictor of anamolous image. There is need of correct technical approach for a complete examination of the LV apex for detection of LV trabeculations. All studies included not only the standard views from all the echocardiographic windows, but also off axis views obtained by angulating the probe to better visualize the apex and insertion points and orientation of the suggested trabeculation. In the present study, we also used one additional echocardiographic view of apical short-axis to visualize the LV trabeculations. Trabeculations also were observed between two points on the ventricular septum in 37 (6%) of the hearts and between two points along the free wall in 36 (6%). Less common patterns included trabeculations between the ventricular septum and the posteromedial papillary muscle in 10 hearts (2%), the ventricular septum and the anterolateral papillary muscles in two, the two papillary muscles in one and the apex and the ventricular septum in one heart. In our study, solated right ventricular hypertrabeculation was found in one heart at autopsy. In this heart, non-compacted portion of right ventricular myocardium was more than three times the underlying compacted right ventricular myocardium at apex with dilated RV cavity. In the above heart left ventricular apex was relatively spared but however both the papillary muscles of left ventricle were poorly developed. Poorly developed papillary muscle on left side of heart is one of the criteria at autopsy for diagnosis of left ventricular noncompaction. However, the significance of isolated noncompaction of right ventricle with poorly formed papillary muscle on left side is not known. STUDY LIMITATIONS The sample size was small in our study both in echocardiography and at autopsy, which could have resulted in lower incidence of LV trabeculations in our
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CARDIOLOGY study when compared to other similar large studies. Another limitation of our study was that success of patients for echocardiography and autopsy study were different, so a comparison cannot be made between the diagnostic accuracy of echocardiography against the bench mark of autopsy study for detection of LV trabeculations. SUMMARY AND CONCLUSIONS ÂÂ
Incidence and morphologic variations in prominent LV trabeculations in 50 normal hearts on 2D echo and at autopsy were studied.
ÂÂ
Prominent LV trabeculations were seen in eight hearts (16%) out of the 50 normal hearts examined at autopsy.
ÂÂ
On 2D echo, prominent LV trabeculation were found in seven hearts (14%) of 50 heart examined.
ÂÂ
The echocardiographic and autopsy incidence of prominent LV trabeculations is comparable i.e., 14% versus 16% (p = 0.16).
ÂÂ
No of prominent trabeculations detected by autopsy varied between one to three (mean 1 ± 0.56).
ÂÂ
No of prominent trabeculations detected by echocardiography varied between one and two (mean 1 ± 0.49)
ÂÂ
In the autopsy study, the ratio of prominent LV trabeculations to underlying myocardium thickness was between 0.5 and 1 in seven hearts, while in one heart this ratio was between 1 and 1.5. None of the examined hearts had this ratio >1.5.
ÂÂ
In the echocardiography study, all prominent LV trabeculations had ratio of trabeculation to underlying myocardium thickness between 0.5 and 1. None of the measured trabeculation had this ratio >1.
CONCLUSION ÂÂ
Prominent LV trabeculations are seen in 14-16% of normal hearts.
ÂÂ
Only 1-3 prominent LV trabeculation were seen in studied normal hearts.
ÂÂ
None of the hearts had ratio of trabeculation to underlying myocardium thickness >1.5 by autopsy and 1 by echocardiography study.
SUGGESTED READING 1. Tamborini G, Pepi M, Celeste F, Muratori M, Susini F, Maltagliati A, et al. Incidence and characteristics of left ventricular false tendons and trabeculations in the normal and pathologic heart by second harmonic echocardiography. J Am Soc Echocardiographic 2004;17(4):367-74. 2. Stöllberger C, Finsterer J, ValentinA, Blazek G, Tscholakoff D. Isolated left ventricular abnormal trabeculation in adults is associated with neuromuscular disorders. Clin Cardiol. 1999;22(2):119-23. 3. Burke A, Mont E, Kutys R, Virmani R. Left ventricular noncompaction: a pathological study of 14 cases. Hum Pathol. 2005;36(4):403-11. 4. Ritter M, Oechslin E, Sütsch G, Attenhofer C, Schneider J, Jenni R. Isolated noncompaction of the myocardium in adults. Mayo Clin Proc. 1997;72(1):26-31. 5. Pignatelli RH, McMahon CJ, Dreyer WJ, Denfield SW, Price J, Belmont JW, et al. Clinical characterization of left ventricular noncompaction in children: a relatively common form of cardiomyopathy. Circulation. 2003;108(21):2672-8. 6. Ichida F, Hamamichi Y, Miyawaki T, Ono Y, Kamiya T, Akagi T, et al. Clinical features of isolated noncompaction of the ventricular myocardium: long-term clinical course, hemodynamic properties, and genetic background. J Am Coll Cardiol. 1999;34(1):233-40.
7. Agmon Y, Connolly HM, Olson LJ, Khandheria BK, Seward JB. Noncompaction of the ventricular myocardium. J Am Soc Echocardiogr. 1999;12(10):859-63. ■■■■
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DRUGS
A Pharmacokinetics Study of Docetaxel New Formulation by 1-hour Intravenous Infusion in Patients with Advanced Malignant Solid Tumors S ALOORKAR, C HARITA, BB TEJA
ABSTRACT Docetaxel is a semi-synthetic analog of paclitaxel. It exhibits potential antitumor activity in humans. Docetaxel is used either as monotherapy or in combination with other drugs for treatment of breast and non-small cell lung cancer, and in combination with other drugs for treatment of squamous head and neck, gastric and prostate cancer. Docetaxel formulation in the nonionic surfactant polysorbate 80 (D-PS80) is associated with acute infusion-related reactions (previously known as hypersensitivity reactions). Therefore, an injection concentrate formulated without polysorbate 80 (docetaxel injection) is being assessed for use without steroid premedication. It is expected to have the same pharmacokinetic and pharmacodynamic profile as D-PS80. The present study had the following objectives: To identify one or more doses of docetaxel injection that would yield pharmacokinetic profiles (Cmax and AUC) that are comparable to 75 mg/m2 of D-PS80, by 1-hour intravenous infusion in patients with advanced malignant solid tumors; to evaluate the qualitative and quantitative toxicity and reversibility of toxicity of the docetaxel injection formulation; to explore the clinical pharmacology of docetaxel injection formulation when administered this way; to archive any antitumor activity observed with the docetaxel injection formulation. This Phase I, multicenter, openlabel, dose-escalating study evaluated the pharmacokinetics and pharmacodynamics of docetaxel test formulation (docetaxel injection) in comparison with the published data of reference docetaxel (D-PS80) at comparable doses in patients with advanced malignant solid tumors. According to the statistical results of previous 12 patients, a hypothesis was suggested that “test/ reference” ratio of geometric means for AUC(0-t), AUC(0-∞) and Cmax for those patients having data for both the treatments were lesser than the expectations, for docetaxel. Therefore, this study tested the hypothesis in additional 6 patients, at dose level 75 mg/m2. An increase was observed in the “test/reference” ratio for Cmax that was much higher than 95%. During Cycles 1 and 2, the safety profile of the patients after administration of docetaxel injection and D-PS80 was comparable. At the end of the study, 11 patients exhibited overall response as progressive disease, 5 achieved stable disease and 2 achieved partial response. Out of total 22 patients who underwent tumor measurement, best overall response was stable disease for 7 patients and partial response for 2 patients. It was concluded that the safety of the new docetaxel formulation (docetaxel injection) was similar to the marketed formulation D-PS80.
Keywords: Docetaxel, docetaxel formulation in nonionic surfactant polysorbate 80, docetaxel formulated without polysorbate 80, advanced malignant solid tumors
D
ocetaxel is a semi-synthetic analog of paclitaxel. Paclitaxel is a taxane and is one of the most effective and extensively-used anticancer drugs. Docetaxel also exhibits potential antitumor activity in humans. Both the drugs are known to stabilize microtubules inhibiting dividing cells.
Dept. of Cancer Krishna Cancer Hospital, Gokal Nagar, Karamsad, Anand, Gujarat Address for correspondence Dr BB Teja Therdose Pharma Plot No.: 118-120, ALEAP IE, Kukatpally, Hyderabad, Andhra Pradesh
Docetaxel is used either as monotherapy or in combination with other drugs for treatment of breast and non-small cell lung cancer (NSCLC), and in combination with other drugs for treatment of squamous head and neck, gastric and prostate cancer. Docetaxel formulation in the nonionic surfactant polysorbate 80 (D-PS80) has been found to be associated with acute infusion-related reactions (previously known as hypersensitivity reactions). Cumulative fluid retention is also common. A 3-day course of steroid prophylaxis starting 1 day before D-PS80 administration is associated with a delay in the development of fluid retention and reduced severity. These side effects have been partly attributed
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DRUGS to polysorbate 80 in the formulation. Corticosteroid prophylaxis does not seem to have any impact on the incidence or severity of infusion-related reactions. An injection concentrate formulated without polysorbate 80 (docetaxel injection) is being assessed for use without steroid premedication. It is expected to have the same pharmacokinetic and pharmacodynamic profile as D-PS80.
malignancy, which could not be treated with any conventional therapy other than docetaxel. ÂÂ
Patients must have recovered from the adverse effects of previous therapies.
ÂÂ
Patients having a life expectancy of at least 12 weeks and the Eastern Cooperative Oncology Group (ECOG) performance status of <2.
ÂÂ
Patients having adequate bone marrow function, characterized by a granulocyte count >1,500/mm3 and platelet count of >1,00,000/mm3.
ÂÂ
Patients with adequate liver and renal function, defined by serum creatinine and total bilirubin levels no greater than 1.5 times the Institution’s upper normal limits and transaminase levels no greater than 2.5 times the Institution’s upper normal limits.
ÂÂ
Patients with no disease markers of human immunodeficiency virus (HIV) I & II, hepatitis B surface antigen (HBsAg) and hepatitis C virus antibodies (HCVAb).
ÂÂ
Patients with a normal 12-lead ECG or one with abnormality that is clinically insignificant.
OBJECTIVES The study was based on the following objectives: ÂÂ
To identify one or more doses of docetaxel injection that would yield pharmacokinetic profiles (Cmax and AUC) that are comparable to 75 mg/m2 of D-PS80, by 1-hour intravenous (IV) infusion in patients with advanced malignant solid tumors.
ÂÂ
To evaluate the qualitative and quantitative toxicity and reversibility of toxicity of the docetaxel injection formulation.
ÂÂ
To explore the clinical pharmacology of docetaxel injection formulation when administered this way.
ÂÂ
To archive any antitumor activity observed with the docetaxel injection formulation.
Considering the statistical results of previous 12 patients, the hypothesis was suggested that “test/reference” ratio of geometric means for AUC(0-t), AUC(0-∞) and Cmax for those patients having data for both the treatments were lesser than the expectations, for docetaxel. Therefore, the hypothesis was tested in additional 6 patients, at dose level 75 mg/m2 in the study. METHODOLOGY This was a Phase I, multicenter, open-label, doseescalating study that evaluated the pharmacokinetics and pharmacodynamics of docetaxel test formulation (docetaxel injection) in comparison with the published data of reference docetaxel (D-PS80) at comparable doses in patients with advanced malignant solid tumors. The protocol was approved by the Institutional Ethics Committee.
Exclusion Criteria ÂÂ
Patients with known or clinical evidence of central nervous system metastasis.
ÂÂ
Patients undergoing corticosteroid therapy for their cancer (for example, those with prostate cancer).
ÂÂ
Patients nonresponsive to previous docetaxel treatment.
ÂÂ
Patients with simultaneous serious infections (i.e., requiring an IV antibiotic).
ÂÂ
Patients with current peripheral neuropathy that is greater than Grade 1.
ÂÂ
Pregnant women or women of childbearing potential, not using methods to avoid pregnancy.
ÂÂ
Patients with an unstable or serious concurrent medical condition - uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, spinal cord compression, superior vena cava syndrome or any psychiatric disorder that prohibits obtaining informed consent.
ÂÂ
Patients who have recently had a major surgery (within the past 14 days) or large field radiation therapy or chemotherapy in the last 28 days and 6 weeks for previous chemotherapy with nitrosoureas or mitomycin C.
Inclusion Criteria ÂÂ
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Adult patients >18 years of age, with histologically confirmed advanced malignant solid tumors of lung (SCLC, NSCLC BAC, SCC, etc.), breast, mesothelioma, gastric, colon, esophageal, intestinal, pancreatic, head and neck sarcoma (soft tissue and osteo-), ovarian, testicular, melanoma, thyroid who had failed conventional therapy or had a
Indian Journal of Clinical Practice, Vol. 27, No. 8, January 2017
DRUGS ÂÂ
Patients who have had one-third or more of their marrow-bearing bone irradiated.
ÂÂ
History of drug abuse (benzodiazepines, opioids, cocaine, tetrahydrocannabinol and amphetamine, etc.) within 3 months.
ÂÂ
History of alcoholism (more than 2 years), moderate drinkers (more than 3 drinks/day) or having consumed alcohol within 48 hours prior to dosing.
ÂÂ
High caffeine (more than 5 cups of coffee or tea/ day) or tobacco (5 or more packets of gutka/day) consumption.
Dose level 1, i.e., 30 mg/m2 (docetaxel injection), by 1-hour infusion on Day 1 of every 21-day cycle; 3 patients
ÂÂ
Dose level 2, i.e., 60 mg/m2 (docetaxel injection), by 1-hour infusion on Day 1 of every 21-day cycle; next 3 patients.
ÂÂ
Dose level 3, i.e., 75 mg/m2 (docetaxel injection) was given by 1-hour infusion to previously enrolled 13 patients and by 40 minutes infusion to additional 6 patients.
ÂÂ
ÂÂ
Having participated in any clinical study in last 3 months.
ÂÂ
Donation of blood (1 unit or 350 mL) within 3 months prior to receiving the first dose of study medication.
ÂÂ
Pregnant and breastfeeding women.
Before being recruited in the study, all patients provided a pre-study medical and treatment history. Patients underwent physical examination at the time of screening. This included evaluation of blood pressure (BP), pulse rate, respiration rate, temperature and 12-lead ECG (electrocardiogram). Patient’s demographic data, including age, height, weight as well as body mass index (BMI), body surface area (BSA) was collected. Routine laboratory tests performed at the time of screening included complete and differential blood count, platelet count, electrolytes, SMA-12 and urinalysis. Computed tomography (CT) scan was also done at the time of screening. Cardiac function was assessed with the help of chest X-ray and ECG. At every week of each cycle, complete and differential blood count, platelet count, electrolytes, SMA-12 and urinalysis were assessed. Tumor measurement, using CT scan, was done at the end of every third cycle. At dose level 1 (30 mg/m2), 3 patients aged 45-61 years were enrolled. At dose level 2 (60 mg/m2), 3 patients aged 20-55 years were enrolled. Going by the protocol, approximately 18 patients, more than 18 years of age, with advanced malignant solid tumors were to be enrolled in the study and additional patients could be added at any of the dose levels in order to have a comprehensive assessment of the pharmacokinetic and safety profile. Hence, one additional patient was enrolled in order to replace one patient who was withdrawn after Cycle 1 at dose level 3 (75 mg/m2). Ten patients were enrolled at one center and 9 patients at another center. As per amendment 03 (dated April 26, 2010), additional 6 patients with advanced malignant solid tumors were recruited at dose level 75 mg/m2, at one center.
Thus, 3 patients were enrolled at each of the first two dose levels of 30 mg/m2 and 60 mg/m2. Thirteen and additional 6 patients were enrolled at 3rd dose level of 75 mg/m2. Written informed consent was obtained from all the patients. The 25 enrolled patients received either of the three dose levels:
Based on the comparable safety profile of docetaxel injection to that of D-PS80, at dose level 1, the next dose level was initiated. Three patients were enrolled at dose level 2, 60 mg/m2. Based on the comparable safety data of docetaxel injection at dose level 2nd, 3rd dose level was initiated. Thus, dose escalation was done on the basis of comparable safety data of docetaxel injection versus D-PS80. With the initiation of the 75 mg/m2 dose level, the study design followed a crossover design. There were 2 cohorts of 6 patients each at the 75 mg/m2 dose level: Patients received docetaxel injection 75 mg/m2 or D-PS80 75 mg/m2 on Day 1 Cycle 1. They were given the alternate study product in the subsequent cycle following randomization. At 3rd cycle and onwards, all 12 patients received docetaxel injection. Additional 6 patients received docetaxel injection 75 mg/m2 or D-PS80 75 mg/m2 on Day 1 Cycle 1. They received the alternate study product in the subsequent cycle following the randomization. At 3rd cycle and onwards, all 6 patients were given docetaxel injection. Following patients were included in the pharmacokinetic analysis: ÂÂ
Three patients for 1st cycle of dose level 1, i.e., 30 mg/m2
ÂÂ
Two patients for 2nd cycle of dose level 1, i.e., 30 mg/m2
ÂÂ
Three patients for 1st cycle of dose level 2, i.e., 60 mg/m2
ÂÂ
One patient for 2nd cycle of dose level 2, i.e., 60 mg/m2
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DRUGS ÂÂ
Eighteen patients for 1st and 2nd cycle of dose level 3, i.e., 75 mg/m2.
All 25 patients (19 + 6 patients) who were enrolled in the study underwent safety assessment. Both the formulations of docetaxel were given as an IV infusion lasting 1 hour for 19 patients. Additional 6 patients received docetaxel injection as 40 minutes infusion and D-PS80 as 1 hour infusion. At first dose level, maximum three cycles of treatment was given to the patients. At second dose level too, a maximum of three cycles of treatment was given to the patients. At third dose level, maximum six cycles of treatment was given. Six additional patients were enrolled in the 2 cohorts of 3 patients, each at 3rd dose level. Patients received docetaxel injection 75 mg/m2 by 40 minutes infusion or D-PS80 75 mg/m2 by 1 hour infusion on Day 1 Cycle 1, followed by the alternate study product in the subsequent cycle. At 3rd cycle and onwards (till six cycles), all 18 patients received docetaxel injection. The previously enrolled 19 patients received one tablet each of 10 mg loratadine and 150 mg of ranitidine, about 60 minutes before each docetaxel injection infusion. Nearly 30 minutes before each docetaxel injection infusion, additional 6 patients were given injection pheniramine 2 cc IV (1 cc = 22.75 mg) and ranitidine 50 mg IV as premedication. In the D-PS80 group (in the later crossover portion of the study), all patients received premedication with oral dexamethasone 8 mg b.i.d. (i.e., 16 mg/day) 1 day prior to infusion on the day of infusion, and the day following infusion.
Mode of Administration The test product, docetaxel injection, was administered intravenously by 1-hour infusion to previously enrolled 12 patients and by 40 minutes infusion to additional 6 enrolled patients on Day 1, every 21-day cycle, at three different dose levels (30 mg/m2, 60 mg/m2 and 75 mg/m2). The reference product, D-PS80, was given intravenously by 1-hour infusion in Cycle 1 or 2 at dose level 75 mg/m2.
Efficacy Evaluation Tumor measurements were assessed at the end of every three 21-day courses, i.e., after every 3rd cycle, by RECIST criteria version 1.1. Any observed antitumor activity or progression of disease was evaluated and patients exhibiting progressive disease did not proceed with docetaxel injection therapy.
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Pharmacokinetics The following pharmacokinetic parameters were calculated by standard IV infusion noncompartmental methods for all three dose levels: AUC(0-t), AUC(0-∞), Cmax, Tmax, λz (Kel), t½, Vz, Vss, Tlast, clearance, R2 and MRTinf.
Safety Adverse events were assessed to monitor safety. Additionally, vital signs were monitored and all the concomitant treatments and laboratory parameters were documented after every week of each cycle at all three dose levels. RESULTS
Pharmacokinetics At dose level 1 (30 mg/m2), for Cycle 1, one patient (Patient No. 101) had %AUCextra >20%. There was increase in the AUC(0-∞) in approximate proportion to dose from 3891.61 ng•h/mL (30 mg/m2) to 6055.99 ng•h/mL (60 mg/m2) during Cycle 1. At dose level 3 (for 12 patients), 2 patients (Patient No. 310 and 311) for docetaxel injection had %AUCextra >20%. For the pharmacokinetic parameters, lnAUC(0-t), lnAUC(0-∞) and lnCmax, lsmean (docetaxel injection, D-PS80) were (8.61918418, 8.65980989), (8.75239671, 8.60692514) and (7.96526670, 8.23968249), respectively. The 90% confidence intervals of the ratio “test/reference” for patients having data for both the treatments, for AUC(0-t), AUC(0-∞) and Cmax were 70.15% to 131.43%, 83.90% to 159.45% and 57.94% to 99.69%, respectively. Among the additional 6 patients, no patient had %AUCextra >20% and all the patients showed clear terminal phase. For the pharmacokinetic parameters, lnAUC(0-t), lnAUC(0-∞) and lnCmax, lsmean (docetaxel injection, D-PS80) were (8.44042021, 8.29468965), (8.55659972, 8.36033573) and (8.49561457, 8.12099814), respectively. The 90% confidence intervals of the ratio “test/ reference” for those having data for both the treatments, for AUC(0-t), AUC(0-∞) and Cmax were 84.33% to 158.71%, 84.89% to 174.43% and 99.17% to 213.30%, respectively. Statistically significant differences were observed between two treatments for the parameter Kel (λz).
Efficacy Table 1 summarizes the treatment response shown by the patients at dose level 1 (30 mg/m2). Of the 3 patients
DRUGS Table 1. Treatment Response at Dose Level 1 Patient number
Target Non-target lesions lesions
New lesions
Overall response
101 (Cycle 3)
SD
-
No
SD
103 (Cycle 3)
PD
IR/SD
No
PD
IR/SD = Incomplete response/Stable disease; PD = Progressive disease; SD = Stable disease.
Table 2. Treatment Response at Dose Level 2 Patient number
Target Non-target lesions lesions
New lesions
Overall response
201 (Cycle 3)
SD
PD
Yes
PD
203 (Cycle 1)
SD
IR/SD
No
PD
enrolled at dose level 1, two patients completed at least three cycles. Table 2 summarizes the treatment response shown by the patients at dose level 2 (60 mg/m2). Of the 3 patients enrolled at dose level 2, tumor assessment was done for 2 patients; 1 patient was withdrawn during Cycle 1 due to adverse event. Table 3 summarizes the treatment response shown by the patients at dose level 3 (75 mg/m2). Of the 19 patients dosed at this dose level, 1 patient with carcinoma of the oropharynx and hypopharynx was withdrawn during Cycle 1 due to adverse event. Eighteen patients completed at least three cycles. CONCLUSIONS
Table 3. Treatment Response at Dose Level 3
Pharmacokinetics
Patient number
Target lesions
Non-target lesions
New lesions
Overall response
302 (Cycle 3)
SD
-
Yes
PD
303 (Cycle 3)
PD
IR/SD
No
PD
304 (Cycle 3)
SD
-
No
SD
Dose level 1 and 2: There was increase in the AUC(0-∞) in approximate proportion to dose from 3891.61 ng•h/mL (30 mg/m2) to 6055.99 ng•h/mL (60 mg/m2) during Cycle 1. However, the number of patients at each dose level was too small to conclude precisely.
304 (Cycle 6)
SD
IR/SD
No
SD
Dose level 3 - For 12 patients:
305 (Cycle 3)
PD
-
Yes
PD
306 (Cycle 3)
PR
IR/SD
No
PR
309 (Cycle 6)
PR
IR/SD
No
PR
310 (Cycle 3)
SD
IR/SD
Yes
PD
The 90% confidence intervals of the ratio “test/reference” for patients having data for both the treatments, for AUC(0-t), AUC(0-∞) and Cmax were 70.15% to 131.43%, 83.90% to 159.45% and 57.94% to 99.69%, respectively. It was hypothesized that decreasing the infusion time of docetaxel injection to 40 minutes would increase the “test/reference” ratio for Cmax to approximately 95%. The hypothesis was investigated in 6 additional patients.
311 (Cycle 3)
SD
IR/SD
No
SD
For 6 additional patients: The 90% confidence intervals of the ratio “test/ reference” for 6 additional patients for AUC(0-t), AUC(0-∞) and Cmax were 84.33% to 158.71%, 84.89% to 174.43% and 99.17% to 213.30%, respectively.
306 (Cycle 6)
PR
IR/SD
No
PR
307 (Cycle 3)
PD
-
Yes
PD
308 (Cycle 3)
SD
IR/SD
Yes
PD
309 (Cycle 3)
SD
CR
No
SD
312 (Cycle 3)
SD
IR/SD
No
SD
312 (Cycle 6)
SD
PD
No
PD
313 (Cycle 3)
SD
-
No
SD
313 (Cycle 6)
SD
-
Yes
PD
314 (Cycle 3)
SD
-
No
SD
314 (Cycle 6)
SD
-
No
SD
315 (Cycle 3)
SD
-
No
SD
315 (Cycle 6)
SD
-
No
SD
316 (Cycle 3)
PD
-
Yes
PD
317 (Cycle 3)
SD
IR/SD
No
SD
318 (Cycle 3)
PR
PD
Yes
PD
319 (Cycle 3)
SD
-
No
SD
319 (Cycle 6)
PD
-
Yes
PS
CR = Complete response; PR: Partial response.
The hypothesis suggested by the data for previous 12 patients was tested by enrolling additional 6 patients. As per the hypothesis, an increase was observed in the “test/reference” ratio for Cmax. However, the increase was much higher than 95%.
Safety All the patients dosed at the three dose levels experienced adverse events. All patients experienced adverse events of Grade 3 severity or more at dose levels 1 and 2. At dose level 3, after administration of docetaxel injection during the crossover phase, 78%
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DRUGS patients experienced adverse events of Grade 3 or greater severity, while after administration of D-PS80, 74% patients experienced adverse events of Grade 3 severity or greater during Cycle 1 and 2. At dose level 3, 42% patients reported serious adverse events after administration of D-PS80, compared with 39% patients after administration of docetaxel injection. Greater number of patients experienced serious adverse events at dose level 3 after administration of D-PS80 during Cycle 1 and 2.44% patients experienced serious adverse events after administration of docetaxel injection, over the entire study period. Dose level 1 and 2: At dose level 1, Grade 4 anemia, leukopenia and lymphopenia were recorded in 1 patient each. No Grade 4 severity hematological adverse events related to the study medication were recorded at dose level 2. No patient experienced nonhematological adverse events related to the study medication of Grade 3 or 4 at dose level 1 and 2. Dose level 3: A higher number of patients experienced Grade 4 neutropenia and leukopenia related to the study medication during Cycle 1 and 2 after administration of D-PS80, compared with the administration of docetaxel injection. Similar number of patients reported Grade 3 febrile neutropenia during Cycle 1 and Cycle 2 after administration of docetaxel injection and D-PS80. Two patients each experienced Grade 4 anemia and lymphopenia, after administration of docetaxel injection during Cycle 1 and 2. No patient experienced Grade 4 anemia and lymphopenia after administration of D-PS80 during Cycle 1 and 2. One patient each reported with Grade 4 stomatitis and hyponatremia following docetaxel injection, while no patient experienced the same effects after D-PS80 administration during Cycle 1 and 2. There appeared to be no significant difference in the number of patients experiencing nonhematological adverse events after administration of docetaxel injection and D-PS80 during Cycle 1 and 2. Cycle 3 onwards, where all the patients were given docetaxel injection, no significant elevation was found in the number of patients having adverse events in comparison with number of patients having adverse events during Cycle 1 and 2 after administration of docetaxel injection and D-PS80. Therefore, the overall safety results suggest that during Cycles 1 and 2, the safety profile of the patients after administration of docetaxel injection and D-PS80 was comparable.
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Indian Journal of Clinical Practice, Vol. 27, No. 8, January 2017
Efficacy At dose level 1, overall response of 1 patient was progressive disease while the second patient’s response was stable disease after three cycles of the treatment. Best overall response was stable disease for 1 patient. At dose level 2, two patients exhibited progressive disease, 1 patient after one cycle of treatment and another after three cycles of treatment. Best overall response could not be assessed at this dose level. At dose level 3, out of total 19 patients, 18 completed at least three cycles. Of these 18 patients, 8 completed six cycles and 10 patients completed three cycles of the treatment. Of the 10 patients completing three cycles, 8 exhibited an overall response of progressive disease and 2 patients achieved stable disease. Out of the 8 patients completing six cycles, 3 patients achieved stable disease after 3rd and 6th cycle of treatment; 1 patient achieved partial response after the 3rd and 6th cycle of treatment 1 patient achieved stable disease after the 3rd cycle and partial response after 6th cycle of treatment; and 3 patients achieved stable disease after 3rd cycle and showed overall response progressive disease after 6th cycle. At the end of the study, 11 patients exhibited overall response as progressive disease, 5 achieved stable disease and 2 achieved partial response. Two patients exhibited best overall response as partial response and 6 exhibited best overall response as stable disease.
Overall Efficacy Conclusion In all, 22 patients were subjected to tumor measurement. Of these, 13 patients completed at least three cycles of treatment, 8 patients completed six cycles of treatment and for 1 patient tumor measurement was carried out after Cycle 1 at the investigator’s discretion. ÂÂ
Of the 13 patients completing at least three cycles of treatment, 10 patients showed an overall response as progressive disease and 3 achieved stable disease.
ÂÂ
Of 8 patients completing six cycles, 3 patients achieved stable disease after 3rd and 6th cycle of treatment. One patient achieved partial response after the 3rd and 6th cycle of treatment. One patient achieved stable disease after the 3rd cycle and partial response after 6th cycle of treatment. Three patients achieved stable disease after 3rd cycle and exhibited overall response as progressive disease after 6th cycle.
DRUGS Disease progression could be attributed to the fact that all patients included in the study had advanced malignant solid tumors. Besides, among patients who exhibited progressive disease, 6 patients had tumor metastasis at enrollment. Three patients achieved stable disease after the 3rd and 6th cycle of treatment and 1 patient achieved stable disease after 3rd cycle of treatment at 3rd dose level despite having metastatic tumor at the time of enrollment. Out of total 22 patients who underwent tumor measurement, best overall response was stable disease for 7 patients and partial response for 2 patients. It can be concluded from the available data that the safety of the new docetaxel formulation (docetaxel injection) is similar to the marketed formulation D-PS80.
experience. Part I: Preclinical experience. Anticancer Drugs. 1995;6(3):339-55, 363-8. 2. Van Oosterom AT, Schrijvers D, Schrijvers D. Docetaxel (Taxotere), a review of preclinical and clinical experience. Part II: Clinical experience. Anticancer Drugs. 1995;6(3):356-68. 3. Bissery MC. Preclinical pharmacology of docetaxel. Eur J Cancer. 1995;31A Suppl 4:S1-6. 4. Extra JM, Rousseau F, Bruno R, Clavel M, Le Bail N, Marty M. Phase I and pharmacokinetic study of Taxotere (RP 56976; NSC 628503) given as a short intravenous infusion. Cancer Res. 1993;53(5):1037-42. 5. Rosing H, Lustig V, van Warmerdam LJ, Huizing MT, ten Bokkel Huinink WW, Schellens JH, et al. Pharmacokinetics and metabolism of docetaxel administered as a 1-h intravenous infusion. Cancer Chemother Pharmacol. 2000;45(3):213-8.
6. Ten Tije AJ, Verweij J, Carducci MA, Graveland W, Rogers T, Pronk T, et al. Prospective evaluation of the pharmacokinetics and toxicity profile of docetaxel in the 1. Bissery MC, Nohynek G, Sanderink GJ, Lavelle F. elderly. J Clin Oncol. 2005;23(6):1070-7. Docetaxel (Taxotere): a review of preclinical and clinical ■■■■
SUGGESTED READING
Indian Journal of Clinical Practice, Vol. 27, No. 8, January 2017
733
Every citizen of India should have the right to accessible, affordable, quality and safe heart care irrespective of his/her economical background
Sameer Malik Heart Care Foundation Fund An Initiative of Heart Care Foundation of India
E-219, Greater Kailash, Part I, New Delhi - 110048 E-mail: heartcarefoundationfund@gmail.com Helpline Number: +91 - 9958771177
“No one should die of heart disease just because he/she cannot afford it” About Sameer Malik Heart Care Foundation Fund
Who is Eligible?
“Sameer Malik Heart Care Foundation Fund” it is an initiative of the Heart Care Foundation of India created with an objective to cater to the heart care needs of people.
Objectives Assist heart patients belonging to economically weaker sections of the society in getting affordable and quality treatment. Raise awareness about the fundamental right of individuals to medical treatment irrespective of their religion or economical background. Sensitize the central and state government about the need for a National Cardiovascular Disease Control Program. Encourage and involve key stakeholders such as other NGOs, private institutions and individual to help reduce the number of deaths due to heart disease in the country. To promote heart care research in India.
All heart patients who need pacemakers, valve replacement, bypass surgery, surgery for congenital heart diseases, etc. are eligible to apply for assistance from the Fund. The Application form can be downloaded from the website of the Fund. http://heartcarefoundationfund.heartcarefoundation. org and submitted in the HCFI Fund office.
Important Notes The patient must be a citizen of India with valid Voter ID Card/ Aadhaar Card/Driving License. The patient must be needy and underprivileged, to be assessed by Fund Committee. The HCFI Fund reserves the right to accept/reject any application for financial assistance without assigning any reasons thereof. The review of applications may take 4-6 weeks. All applications are judged on merit by a Medical Advisory Board who meet every Tuesday and decide on the acceptance/rejection of applications. The HCFI Fund is not responsible for failure of treatment/death of patient during or after the treatment has been rendered to the patient at designated hospitals.
To promote and train hands-only CPR.
Activities of the Fund Financial Assistance
The HCFI Fund reserves the right to advise/direct the beneficiary to the designated hospital for the treatment.
Financial assistance is given to eligible non emergent heart patients. Apart from its own resources, the fund raises money through donations, aid from individuals, organizations, professional bodies, associations and other philanthropic organizations, etc.
The financial assistance granted will be given directly to the treating hospital/medical center.
After the sanction of grant, the fund members facilitate the patient in getting his/her heart intervention done at state of art heart hospitals in Delhi NCR like Medanta – The Medicity, National Heart Institute, All India Institute of Medical Sciences (AIIMS), RML Hospital, GB Pant Hospital, Jaipur Golden Hospital, etc. The money is transferred directly to the concerned hospital where surgery is to be done.
Drug Subsidy
The HCFI Fund has the right to print/publish/webcast/web post details of the patient including photos, and other details. (Under taking needs to be given to the HCFI Fund to publish the medical details so that more people can be benefitted). The HCFI Fund does not provide assistance for any emergent heart interventions.
Check List of Documents to be Submitted with Application Form Passport size photo of the patient and the family A copy of medical records Identity proof with proof of residence Income proof (preferably given by SDM)
The HCFI Fund has tied up with Helpline Pharmacy in Delhi to facilitate
BPL Card (If Card holder)
patients with medicines at highly discounted rates (up to 50%) post surgery.
Details of financial assistance taken/applied from other sources (Prime Minister’s Relief Fund, National Illness Assistance Fund Ministry of Health Govt of India, Rotary Relief Fund, Delhi Arogya Kosh, Delhi Arogya Nidhi), etc., if anyone.
The HCFI Fund has also tied up for providing up to 50% discount on imaging (CT, MR, CT angiography, etc.)
Free Diagnostic Facility
Free Education and Employment Facility
The Fund has installed the latest State-of-the-Art 3 D Color Doppler EPIQ 7C Philips at E – 219, Greater Kailash, Part 1, New Delhi.
HCFI has tied up with a leading educational institution and an export house in Delhi NCR to adopt and to provide free education and employment opportunities to needy heart patients post surgery. Girls and women will be preferred.
This machine is used to screen children and adult patients for any heart disease.
Laboratory Subsidy HCFI has also tied up with leading laboratories in Delhi to give up to 50% discounts on all pathological lab tests.
About Heart Care Foundation of India
Help Us to Save Lives The Foundation seeks support, donations and contributions from individuals, organizations and establishments both private and governmental in its endeavor to reduce the number of deaths due to heart disease in the country. All donations made towards the Heart Care Foundation Fund are exempted from tax under Section 80 G of the IT Act (1961) within India. The Fund is also eligible for overseas donations under FCRA Registration (Reg. No 231650979). The objectives and activities of the trust are charitable within the meaning of 2 (15) of the IT Act 1961.
Heart Care Foundation of India was founded in 1986 as a National Charitable Trust with the basic objective of creating awareness about all aspects of health for people from all walks of life incorporating all pathies using low-cost infotainment modules under one roof. HCFI is the only NGO in the country on whose community-based health awareness events, the Government of India has released two commemorative national stamps (Rs 1 in 1991 on Run For The Heart and Rs 6.50 in 1993 on Heart Care Festival- First Perfect Health Mela). In February 2012, Government of Rajasthan also released one Cancellation stamp for organizing the first mega health camp at Ajmer.
Objectives Preventive Health Care Education Perfect Health Mela Providing Financial Support for Heart Care Interventions Reversal of Sudden Cardiac Death Through CPR-10 Training Workshops Research in Heart Care
Donate Now... Heart Care Foundation Blood Donation Camps The Heart Care Foundation organizes regular blood donation camps. The blood collected is used for patients undergoing heart surgeries in various institutions across Delhi.
Committee Members
Chief Patron
President
Raghu Kataria
Dr KK Aggarwal
Entrepreneur
Padma Shri, Dr BC Roy National & DST National Science Communication Awardee
Governing Council Members Sumi Malik Vivek Kumar Karna Chopra Dr Veena Aggarwal Veena Jaju Naina Aggarwal Nilesh Aggarwal H M Bangur
Advisors Mukul Rohtagi Ashok Chakradhar
Executive Council Members Deep Malik Geeta Anand Dr Uday Kakroo Harish Malik Aarti Upadhyay Raj Kumar Daga Shalin Kataria Anisha Kataria Vishnu Sureka
This Fund is dedicated to the memory of Sameer Malik who was an unfortunate victim of sudden cardiac death at a young age.
Rishab Soni
HCFI has associated with Shree Cement Ltd. for newspaper and outdoor publicity campaign HCFI also provides Free ambulance services for adopted heart patients HCFI has also tied up with Manav Ashray to provide free/highly subsidized accommodation to heart patients & their families visiting Delhi for treatment.
http://heartcarefoundationfund.heartcarefoundation.org
DRUGS
Current Perspectives and Prescribing Patterns in the Use of Phenytoin Sodium for Seizure Control in Adult Epilepsy Patients in India: A Physician-based Survey JASBIR SINGH KATHPAL*, SAMIR ADSULE†, KARTIK PEETHAMBARAN‡
ABSTRACT Objectives: To understand the perspectives, current practices and prescribing patterns of phenytoin sodium as a first-line treatment option for epilepsy by Indian physicians. Material and methods: In this cross-sectional survey, 300 physicians were interviewed regarding preferences and perspectives towards epilepsy management. Responses were captured and descriptively analyzed. Results: Phenytoin was preferred as the first-line treatment for newly diagnosed cases (76%). Physicians preferred phenytoin as a first choice in generalized tonic-clonic (72.7%) and partial seizures (53.7%). It was observed that 45.7% and 49% of the physicians preferred adding a second antiepileptic drug (AED) in partial and generalized epilepsy respectively, if the seizure was not adequately controlled with phenytoin. Less than 25% of the physicians preferred to switch on another AED (levetiracetam was the second preferred) in partial (20%) and generalized (18.7%) epilepsy. Physicians rated patient satisfaction was very good/good with both monotherapy (76%) and adjuvant therapy (78.6%). Also, 67.6% and 73.7% of the physicians rated patient’s tolerability and compliance as very good and good, respectively. While only 56.7% of the physicians rated the availability of phenytoin as excellent, 98.3% considered phenytoin to be more cost-effective against the second- and thirdgeneration AEDs. Conclusion: Phenytoin, as a monotherapy or in combination, has been the most preferred drug of choice by Indian physicians in epilepsy management.
Keywords: Antiepileptic drugs, epilepsy, partial seizures, phenytoin
E
pilepsy is one of the most common neurological disorder that is characterized by its neurobiological, cognitive, psychological and social consequences. It is a chronic condition characterized by unprovoked recurrent (≥2) epileptic seizures. Around 70 million epilepsy cases have been reported globally with a median prevalence of active epilepsy as 4.9 per 1,000 population for developed countries and more than 12.7 per 1,000 and 5.9 per 1,000 in rural and urban studies in developing countries.1,2 Approximately 90% of epileptic cases have been
*Honorary Associate Professor and Head Dept. of Neurology Choitaram Hospital and Research Centre, Indore, Madhya Pradesh †Head Medical Affairs ‡Senior Medical Advisor Abbott India Limited, Chembur, Mumbai, Maharashtra Address for correspondence Dr Samir Adsule Head Medical Affairs Abbott India Limited 3-4 Corporate Park, Sion-Trombay Road, Chembur - 400 071, Mumbai, Maharashtra
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Indian Journal of Clinical Practice, Vol. 27, No. 8, January 2017
reported from the developing countries.3 More than 10 million epilepsy cases have been reported in India with an overall prevalence rate of 3-11.9 per 1,000 population and incidence rate of 0.2-0.6 per 1,000 population per year; these rates were comparable to the rates of high-income countries and contribute to nearly one-sixth of the global burden.2 Cases of epilepsy have been predominantly reported in males, rural population, older age and in population of poor socioeconomic status.2 Since, epilepsy cases impose a huge burden on the healthcare systems, it should be treated by a suitable antiepileptic drug (AED), which should not cause any significant side effect(s) and have higher benefits than risks. Usage of AED differs considerably among physicians and across different countries, depending on their economic conditions and drug availability. Phenytoin, a first-line AED, has been the predominant medication for the treatment of epilepsy for over several decades. It was first synthesized in 1908 at the University of Kiel, Germany. Its anticonvulsant properties were first described by Merritt and Putnam in 1938 and since 1940, it became the most important and
DRUGS frequently used drug to treat epilepsy. Phenytoin works by slowing down impulses in the brain that cause seizures, promotes sodium efflux from neurons and stabilizes the threshold against hyperexcitability. Over the last two decades, second-generation AEDs, including drugs such as gabapentin, lamotrigine, vigabatrin and topiramate are available with an improved tolerability and safety than first-line AEDs.4 There have been mixed reviews about the use of phenytoin in epilepsy. Several studies have reported phenytoin to be the most common AED prescribed for seizures, primarily due to its lower procurement costs, high affordability and high efficacy and less adverse drug reactions.5-7 However, few studies have undermined the use of phenytoin in epilepsy.3,8
who had an expertise in epilepsy management, were well-versed with prescription of phenytoin, had an academic degree of DM/DNB/MD and were willing to sign the physician authorization form were included in the survey. These physicians were asked questions regarding the management of epilepsy and their responses were captured in the paper-based questionnaire survey form. The data was descriptively analyzed; continuous variables by mean ± SD, median, range and 95% CI and categorical variables by number and percentages. Given that it was a survey-based study with no direct participation of any patient, ethics committee approval was not required.
In India, many people with epilepsy do not receive appropriate treatment for their condition, leading to a large treatment gap; the reason for this treatment gap may be due to lack of identified cases, failure to deliver right treatment to the identified cases, nonavailability of drugs, poverty, social stigma and cultural beliefs, poor health education and healthcare facilities, unavailability of expert practitioners and high treatment cost.9 Even though data regarding prescribing patterns for treatment of adult patients with epilepsy is available, the information regarding physicians’ perspectives in the usage of phenytoin for epilepsy in the Indian clinical setting is still limited. Although physicians may be managing the seizures, they may not be meeting all of the patient’s needs because of differences between their and patient’s perception of concerns.10
Three hundred physicians (150 each were consultants [with MD degree] and neurologists [with DM/DNB degree]) were interviewed in the study; of these 114 (38%) physicians were from cities with population ≥1,00,000 (city Tier 1) and 186 (62%) were from cities with population ranging from 50,000 to 99,999 (city Tier 2) (Fig. 1). Ninety-nine percent (n = 296) of these physicians either worked in hospitals or private clinics and 91% (n = 274) physicians had >5 years of practicing experience (Fig. 2). Higher proportion of neurologists, in comparison to consultants, treated ≥21 epileptic patients per week (53.3% vs. 15.9%) and ≥6 new epileptic (62% vs. 33.6%) and follow-up patients per week (84.6% vs. 45.3%). Also, 44.7% of the neurologists reported that ≥11% of their follow-up patients were already on phenytoin as compared to 33.9% of the consultants (Table 1).
Hence, the present study was planned with an aim to understand the perspectives, current practices and prescribing patterns of Indian neurologists and consultant physicians on the use of phenytoin sodium as a first-line treatment option in the management of epilepsy and its seizure types (partial seizures, generalized tonic-clonic [GTC] seizures and status epilepticus); their preference for other AEDs when seizures were not adequately controlled by phenytoin; the most common adjuvant AED prescribed along with phenytoin and the availability and cost-effectiveness of phenytoin against second- and third-generation AEDs.
RESULTS
MATERIAL AND METHODS
A statistically significant higher proportion (75.7%; n = 227) of physicians preferred phenytoin as the firstline of treatment for newly diagnosed cases of epilepsy (p < 0.0001). Of these physicians, significantly higher proportion of consultants preferred phenytoin as the first-line of treatment for new cases of epilepsy than neurologists (84.7% vs. 66.7; p = 0.0003). Also, 30.3% (n = 91) of the physicians reported that 76-100% of their patients continued their treatment with phenytoin for 6 months followed by 118 (39.3%) and 108 (36%) physicians who reported that 51-75% of their patients continued treatment on phenytoin for 1 years and >2 years, respectively (Fig. 3).
This was a cross-sectional survey where 300 physicians (both neurologists and consultant physicians) were interviewed regarding their preferences and perspectives towards epilepsy treatment, effectiveness, tolerability, availability, cost-effectiveness and compliance with phenytoin sodium. Those physicians
A statistically significant higher proportion of physicians preferred phenytoin as the first-line of treatment in case of GTC seizures (218 [72.7%] physicians) and status epilepticus after benzodiazepine treatment (277 [92.3%] physicians). A total of 161 (53.7%) physicians preferred phenytoin as the first-
Indian Journal of Clinical Practice, Vol. 27, No. 8, January 2017
737
DRUGS
A. City Tier 1
1.1%
B. City Tier 2 10.8%
11.4%
17.5%
17.2%
5.4%
16.7%
5.9%
0.5%
8.8% 26.3%
1.6%
City 2-Chennai
City 4-Hyderabad
3.2% 3.8% 3.2% 3.2%
9.7%
19.3%
City 1-Bangalore
9.1%
8.1%
City 5-Kolkata
3.8%
3.2% 5.4%
0.5% 3.2%
1.1%
City 1-Ahmedabad
City 2-Bhopal
City 3-Chandigarh
City 4-Delhi NCR
City 5-Gorakhpur
City 6-Guwahati
City 7-Hubli
City 8-Indore
City 9-Jaipur
City 3-Delhi
City 10-Jalandhar
City 11-Kanpur
City 12-Kochi
City 6-Mumbai
City 13-Lucknow
City 14-Ludhiana
City 15-Madhubani
City 16-Nagpur
City 17-Patna
City 18-Pune
City 19-Trivandrum
City 20-Varanasi
Figure 1. Geographical distribution of physicians as per city tiers.
A. Practice setting
B. Years of practicing experience 1% 0% 9% 23%
44% 40% 59% 24%
Hospital
Private clinic
Hospital + Private clinic
0-5 years
Tertiary care private hospital
5-10 years
10-15 years
>15 years
Figure 2. Physician characteristics.
Table 1. Physicianâ&#x20AC;&#x2122;s Response of Epileptic Patients Treated per Week Number of patients/week
Epilepsy patients Consultant (n = 150)
Neurologist (n = 150)
New epilepsy patients Consultant (n = 150)
Follow-up patients
Follow-up patients already on phenytoin
Neurologist Consultant Neurologist Consultant (n = 150) (n = 150) (n = 150) (n = 150)
Neurologist (n = 150)
Number (%) of physicians 1-5
45 (30.0)
8 (8.5)
98 (65.3)
57 (38.0)
82 (54.7)
27 (18.0)
50 (33.3)
45 (30.0)
6-10
45 (30.0)
27 (18.0)
34 (22.7)
40 (26.7)
38 (25.3)
41 (27.3)
49 (32.7)
38 (25.3)
11-20
36 (24.0)
35 (23.3)
12 (8.0)
29 (19.3)
20 (13.3)
46 (30.7)
21 (14.0)
28 (18.7)
21-30
14 (9.3)
38 (25.3)
4 (2.7)
16 (10.7)
7 (4.7)
20 (13.3)
13 (8.6)
14 (9.3)
31-40
5 (3.3)
15 (10.0)
1 (1.1)
5 (3.3)
3 (2.0)
7 (4.7)
2 (1.3)
7 (4.7)
41-50
-
7 (4.7)
1 (1.1)
3 (2.0)
-
4 (4.3)
4 (2.7)
3 (2.0)
5 (3.3)
20 (13.3)
-
-
-
5 (3.3)
11 (7.3)
15 (10.0)
>50
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Indian Journal of Clinical Practice, Vol. 27, No. 8, January 2017
DRUGS
Duration
At least 6 months
At least 1 year
>2 years
76-100%
51.1
18.1
51-75%
72.4
26-50%
52.1
1-25% None 76-100%
17 41.6
26.6 87.1
51-75% 26-50%
28.7 33
52.6 15.4
None 3.3
Neurologist (DM/DNB)
31.9
24.3 0
1-25%
Consultant MD
33
10.6
1.1
76-100%
55.6
51-75%
31.9
47.8
26-50%
57.8 37.7
1-25%
28.7 20.2 18.1
None1.1 1.1 0
20
40
60
80
100
120
140
Percentage of patients
Figure 3. Percentage of patients who continued treatment with phenytoin.
line of treatment for partial seizures. Of all physicians, a statistical significant higher proportion (84%) of consultants preferred phenytoin as the first-line of treatment for GTC seizures than neurologists (61.3%) (p < 0.0001); however, a comparable proportion of consultants and neurologists preferred phenytoin for partial seizures and status epilepticus after benzodiazepine treatment (Table 2). Approximately 59.3% (n = 178) and 30% (n = 90) of the physicians reported that they had used phenytoin as an adjuvant AED in <25% and 25-50% of their epileptic patients, respectively (Table 3). A total of 45.7% (n = 137; consultants: 84 [56%]; neurologists: 53 [35.3%]) and 49% (n = 147; consultants: 82 [54.7%]; neurologists: 65 [43.3%]) of the physicians preferred to add a second AED to phenytoin in cases of partial and generalized epilepsy, which were not adequately controlled by phenytoin, respectively. Levetiracetam was the most preferred second AED to phenytoin in patients with partial epilepsy (93 [31.0%] physicians) and generalized epilepsy (126 [42.0%]). Approximately 39.3% (n = 118) of the physicians also preferred sodium valproate as the second AED to phenytoin in generalized epilepsy cases not adequately controlled by phenytoin. A comparable proportion of consultants and neurologists preferred to add levetiracetam to phenytoin in partial and generalized epilepsy cases and sodium valproate to phenytoin in generalized epilepsy cases not adequately controlled by phenytoin. Less than 25% of the physicians preferred to stop phenytoin and start a new AED in partial (20%, n = 60) and generalized epilepsy (18.7%, n = 56) cases, which were not adequately controlled by phenytoin.
Levetiracetam was preferred as a new AED in partial epilepsy (113 [37.7%] physicians) and sodium valproate (144 [48%] physicians) and levetiracetam (127 [42.3%] physicians) were the preferred new AEDs in cases of generalized epilepsy not adequately controlled when on phenytoin. A comparable proportion of consultants and neurologists preferred to stop phenytoin and start levetiracetam in partial and generalized epilepsy cases and sodium valproate in generalized epilepsy cases not adequately controlled by phenytoin (Table 4). A higher proportion of physicians rated patient satisfaction with seizure control as ‘very good’ or ‘good’ when phenytoin was used as monotherapy (76% physicians) or as an adjuvant AED in the treatment of epilepsy (78.6% physicians). In addition, a higher proportion of physicians rated patient’s tolerability (67.6% physicians) and compliance with phenytoin therapy (73.7% physicians) as ‘very good’ or ‘good’ in comparison to second- and third-generation AEDs. Eighty percent (n = 240) of the physicians believed that extended-release formulation of phenytoin improves patient compliance (p < 0.0001); the proportion of consultants believing that extended-release formulation of phenytoin improves patient compliance was significantly higher than neurologists (85.3% vs. 74.7%; p = 0.0209). About 56.7% (n = 170) of the physicians rated the availability of phenytoin against second- and thirdgeneration AEDs as ‘excellent’. While 98.3% (n = 295) of the physicians reported that phenytoin was significantly more cost-effective as compared to newer AEDs in the management of epilepsy (p < 0.0001); however, no statistical significant difference was reported between consultants and neurologists (p = 0.1761) (Table 5).
Indian Journal of Clinical Practice, Vol. 27, No. 8, January 2017
739
DRUGS Table 2. Preference of Phenytoin as a First-line of Treatment Response
Tier 1 (n = 114) Consultant (n = 58)
Tier 2 (n = 186)
Neurologist (n = 56)
Consultant (n = 92)
Neurologist (n = 94)
Overall (N = 300)
P value*
Number (%) of physicians [95% CI] Phenytoin is preferred as a first-line of treatment in case of new patients of epilepsy Yes
46 (79.3) [0.66:0.88]
36 (64.3) [0.50:0.76]
81 (88.0) [0.79:0.93]
64 (68.1) [0.57:0.77]
227 (75.67) [0.70:0.80]
No
12 (20.7) [0.11:0.33]
20 (35.7) [0.23:0.49]
11 (12.0) [0.06:0.20]
30 (31.9) [0.22:0.42]
73 (24.33) [0.19:0.29]
Overall consultants
Overall neurologists
Yes
127 (84.7)
100 (66.7)
227 (75.67)
No
23 (15.3)
50 (33.3)
73 (24.33)
P value**
0.0003
<0.0001
Phenytoin is preferred as a first-line of treatment in case of partial seizures Yes
31 (53.4) [0.39:0.66]
24 (42.9) [0.29:0.56]
53 (57.6) [0.46:0.67]
53 (56.4) [0.45:0.66]
161 (53.67) [0.47:0.59]
No
27 (46.6) [0.33:0.60]
32 (57.1) [0.43:0.70]
39 (42.4) [0.32:0.53]
41 (43.6) [0.33:0.54]
139 (46.33) [0.40:0.52]
Overall consultants
Overall neurologists
Yes
84 (56.0)
77 (51.3)
161 (53.67)
No
66 (44.0)
73 (48.7)
139 (46.33)
P value**
0.4177
0.2040
Phenytoin is preferred as a first-line of treatment in case of GTC seizures Yes
44 (75.9) [0.62:0.86]
33 (58.9) [0.44:0.71]
82 (89.1) [0.80:0.94]
59 (62.8) [0.52:0.72]
218 (72.67) [0.67:0.77]
No
14 (24.1) [0.13:0.37]
23 (41.1) [0.28:0.55]
10 (10.9) [0.05:0.19]
35 (37.2) [0.27:0.47]
82 (27.33) [0.22:0.32]
Overall consultants
Overall neurologists
Yes
126 (84.0)
92 (61.3)
218 (72.67)
No
24 (16.0)
58 (38.7)
82 (27.33)
P value**
<0.0001
<0.0001
If physician prefer injection phenytoin after benzodiazepine treatment for status epilepticus Yes
53 (91.4) [0.81:0.97]
53 (94.6) [0.85:0.98]
87 (94.6) [0.87:0.98]
84 (89.4) [0.81:0.94]
277 (92.33) [0.88:0.95]
No
5 (8.6) [0.02:0.18]
3 (5.4) [0.01:0.14]
5 (5.4) [0.01:0.12]
10 (10.6) [0.05:0.18]
23 (7.67) [0.04:0.11]
Overall consultants
Overall neurologists
Yes
140 (93.3)
137 (91.3)
277 (92.33)
No
10 (6.7)
13 (8.7)
23 (7.67)
P value**
0.515
<0.0001
*P value was calculated for the comparison of response of ‘overall MD’ versus ‘overall DM’ using Chi-square test. **P value was calculated by using One-Sample Z-test for proportion considering null hypothesis as no significant difference between “Yes” count and “No” count against the alternative that there was significant difference between “Yes” count and “No” count.
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Indian Journal of Clinical Practice, Vol. 27, No. 8, January 2017
DRUGS Table 3. Percentage of Responses Where Phenytoin Used as an Adjuvant Percentage of patients
Tier 1 (n = 114) Consultant (n = 58)
Tier 2 (n = 186)
Neurologist (n = 56)
Consultant (n = 92)
Overall (N = 300)
Neurologist (n = 94)
Number (%) of physicians 0-25
37 (63.8)
46 (82.1)
42 (45.7)
53 (56.4)
178 (59.33)
25-50
12 (20.7)
9 (16.1)
39 (42.4)
30 (31.9)
90 (30.00)
50-75
8 (13.8)
1 (1.8)
8 (8.7)
8 (8.5)
25 (8.33)
75-100
1 (1.7)
3 (3.3)
3 (3.2)
7 (2.33)
Table 4. Physicianâ&#x20AC;&#x2122;s Response When Partial and GTC Seizures were not Adequately Controlled by Phenytoin Drugs
Consultant (n = 114)
Neurologist (n = 186)
Overall (N = 300)
Number (%) of physicians In case of patients with partial epilepsy, who were not adequately controlled on phenytoin, Most preferred choice Stop phenytoin and start a new AED Add a second AED to phenytoin
32 (21.3)
28 (18.7)
60 (20.00)
84 (56)
53 (35.3)
137 (45.7)
32 (21.3)
37 (24.7)
69 (23.0)
1 (1.1)
5 (5.3)
6 (2.0)
Preferred AED in case of stopping phenytoin sodium and start a new AED Carbamazepine Lacosamide Lamotrigine Levetiracetam
5 (3.3)
3 (2.0)
8 (2.7)
56 (37.3)
57 (38.0)
113 (37.7)
Phenobarbitone
7 (4.7)
10 (6.7)
17 (5.7)
Oxcarbazepine
14 (9.3)
30 (20.0)
44 (14.7)
Sodium valproate
35 (23.3)
6 (4.0)
41 (13.7)
Clobazam
-
1 (1.8)
1 (0.3)
Others (Depends on the epilepsy syndrome lorazepam)
-
1 (1.1)
1 (0.3)
Preferred AED in case a second AED is to be added to phenytoin Carbamazepine
18 (12.0)
10 (6.7)
28 (9.3)
Clobazam
14 (9.3)
43 (28.7)
57 (19.0)
Gabapentin
8 (8.7)
6 (6.4)
14 (4.7)
Lamotrigine
4 (4.3)
4 (2.7)
8 (2.7)
Levetiracetam
52 (34.7)
41 (27.3)
93 (31.0)
Oxcarbazepine
10 (6.7)
13 (8.7)
23 (7.7)
Sodium valproate
42 (28.0)
23 (15.3)
65 (21.7)
Topiramate
-
2 (1.3)
2 (0.7)
Lacosamide
2 (2.2)
7 (4.7)
9 (3.0)
-
1 (1.1)
1 (0.3)
Others (Stop phenytoin and start oxcarbazepine)
In case of patients with generalized epilepsy, who were not adequately controlled on phenytoin, Most preferred choice Stop phenytoin and start a new AED Add a second AED to phenytoin
21 (14)
35 (23.3)
56 (18.7)
82 (54.7)
65 (43.3)
147 (49)
Preferred AED in case of stopping phenytoin sodium and start a new AED Clobazam
1 (1.1)
-
1 (0.3)
Phenobarbitone
11 (7.3)
8 (8.5)
19 (6.3) Cont'd...
Indian Journal of Clinical Practice, Vol. 27, No. 8, January 2017
741
DRUGS ...Cont'd
Table 4. Physician’s Response When Partial and GTC Seizures were not Adequately Controlled by Phenytoin Drugs
Consultant (n = 114)
Neurologist (n = 186)
Overall (N = 300)
Number (%) of physicians Felbamate Levetiracetam
1 (1.1)
1 (1.1)
2 (0.7)
77 (51.3)
50 (33.3)
127 (42.3)
Zonisamide
-
-
-
Topiramate
-
2 (2.1)
2 (0.7)
56 (37.3)
88 (58.7)
144 (48.0)
4 (6.9)
1 (1.8)
5 (1.7)
Valproate Lamotrigine Preferred AED in case a second AED is to be added to phenytoin Lamotrigine
4 (2.7)
3 (2.0)
7 (2.3)
Levetiracetam
71 (47.3)
55 (36.7)
126 (42.0)
Sodium valproate
52 (34.7)
66 (44.0)
118 (39.3)
Topiramate
2 (1.3)
-
2 (0.7)
Phenobarbital
4 (2.7)
10 (6.7)
14 (4.7)
15 (10.0)
11 (7.3)
26 (8.7)
Carbamazepine Felbamate
-
-
-
Lacosamide
-
3 (2.0)
3 (1.0)
2 (1.3)
2 (2.1)
4 (1.3)
Others (Clobazam)
DISCUSSION India, being a developing country, is a home to large numbers of epilepsy cases where 90% of the patients do not receive appropriate treatment due to cultural misbeliefs, inadequate healthcare facilities, lack of awareness, etc.11 There is always a difference in the opinion among physicians regarding the choice of prescribed AEDs to the patients; this choice varies due to severity of the symptoms, availability, accessibility, efficacy, cost and side effects of the drug, patient’s specific needs and compliance rate, place of practice of prescribing physicians, etc. In a study, Lim and Tan reported that general practitioners or doctors at government polyclinics usually see the patients with less severe epilepsy and often prescribes the older and conventional AEDs and rarely use new AEDs. However, the neurologists who are well-trained in neurology and epilepsy prefer to see cases, which are not well-controlled and prefer a combination of AEDs or newer AEDs rather than using the old conventional medication.12 In our physician-based survey, 59% of the physicians worked in private clinics and 40% worked in hospitals. Both neurologists and consultants participated in the study; the higher number of new and follow-up epileptic patients visited the neurologist’s outpatient department in comparison to consultants.
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Indian Journal of Clinical Practice, Vol. 27, No. 8, January 2017
Over several decades, phenytoin (sodium 5,5-diphenyl-2, 4-imidazolidinedione) has been the most preferred AED recommended for the treatment of newly diagnosed cases of epilepsy.13,14 In our study as well, over 75% of the physicians preferred phenytoin, as a monotherapy, as the first-line of treatment for newly diagnosed cases of epilepsy. Of these physicians, 84.7% of the consultants preferred to use phenytoin as the first-line of treatment than neurologists (67%). Our results were in parallel with an earlier published study where non-neurologists generally preferred to use monotherapy as they believed that polytherapy was meant for difficult to control seizures but again the choice of drug varied upon the physician’s individual preference.12 Approximately, 40% of the physicians in the study reported that ≥11% of their followup patients were already on phenytoin; indicating higher patient satisfaction after the use of phenytoin. In addition, a higher proportion of physicians preferred to use phenytoin in cases of partial (53%) and GTC seizures (73%) and in 92% of cases of status epilepticus after benzodiazepine treatment. Similar results were reported in a previous study wherein phenytoin was considered as one of the most effective drugs for treating status epilepticus, partial and secondary generalized seizures.15 In 2013, Sebastian et al reported phenytoin to be the highly preferred AED for treatment
DRUGS Table 5. Physicianâ&#x20AC;&#x2122;s View on Patient Satisfaction in Context of Phenytoin Response
Consultant (MD) (n = 114)
Neurologist (DM/DNB) (n = 186)
Overall (N = 300)
Number (%) of physicians Patient satisfaction with seizure control when phenytoin sodium was used as monotherapy for new onset epilepsy Excellent
34 (22.7)
28 (18.7)
62 (20.7)
Very Good
70 (46.7)
62 (41.4)
131 (43.7)
Good
42 (28.0)
55 (36.7)
97 (32.3)
Fair
4 (2.7)
6 (6.4)
10 (3.3)
Poor
-
-
-
Patient satisfaction with seizure control when phenytoin sodium was used as adjuvant in treatment of epilepsy Excellent
21 (14.0)
4 (4.3)
25 (8.3)
Very Good
73 (48.7)
40 (26.7)
133 (44.3)
Good
48 (32.0)
55 (36.7)
103 (34.3)
Fair
12 (8.0)
28 (18.7)
36 (12.0)
Poor
-
3 (3.2)
3 (1.0)
Tolerability of phenytoin as compared to the other conventional AEDs Excellent
26 (17.3)
10 (6.7)
36 (12.0)
Very Good
59 (39.3)
44 (29.3)
103 (34.3)
Good
49 (32.7)
51 (34)
100 (33.3)
Fair
18 (12)
42 (28)
58 (19.3)
Poor
-
3 (2)
3 (1.0)
Patient compliance with phenytoin therapy as compared to second- and third-generation AEDs Excellent
25 (16.7)
13 (8.7)
38 (12.7)
Very Good
69 (46)
53 (35.3)
122 (40.7)
Good
42 (28)
57 (38)
99 (33.0)
Fair
11 (7.3)
25 (16.7)
36 (12.0)
Poor
3 (2.0)
2 (1.3)
5 (1.7)
Ease of availability of phenytoin sodium as compared to second- and third-generation AEDs Excellent
89 (59.4)
81 (54.0)
170 (56.7)
Very Good
35 (23.3)
36 (24.0)
71 (23.7)
Good
23 (15.3)
17 (11.3)
40 (13.3)
Fair
2 (3.4)
15 (10.0)
17 (5.7)
Poor
1 (1.1)
1 (1.1)
2 (0.7)
Phenytoin sodium was more cost-effective as compared to newer AEDs in the management of epilepsy Yes
149 (99.3)
146 (97.3)
295 (98.33)
of generalized seizures and valproic acid for the partial seizures.6 In another study, carbamazepine was considered as the preferred AED in case of partial seizures.5 Combination of drugs have been reported to be beneficial in patients with multiple seizure types or refractory disease due to their complementary or additive action.16 In our study, more than 45% of the physicians preferred to add a second AED to phenytoin in cases of partial and generalized seizures; levetiracetam was reported as the most preferred second AED to phenytoin in patients with partial and GTC seizures. Few studies supported substitution of another monotherapy when one monotherapy either failed to control seizures or had led to unacceptable side effects, before opting for combination therapy as the latter therapy enhance the healthcare cost burden, drug-drug interactions and may lead to higher incidence of adverse effects.17 Less than 25% of the physicians preferred to stop phenytoin and start a new AED in epileptic cases not controlled by phenytoin. A higher proportion of physicians recommended levetiracetam for partial and generalized seizures. Hence, levetiracetam was the preferred drug of choice when partial and generalized epilepsy were either not adequately controlled by phenytoin or physicians decided to start a new AED and stop phenytoin. Levetiracetam is a novel, second-generation AED with a broad safety profile with no interactions with other antiepileptics. It binds to synaptic vesicle protein 2A and affects neural excitability. Due to its pharmacological benefits, it has been reported as the first-line or adjunctive therapy for epileptic seizures.18 It has been approved by European Medicine Agency and Food and Drug Administration for use as a monotherapy and adjunctive therapy in the treatment of partial onset and GTC seizures in adults.19-21 Various studies have shown levetiracetam to be efficacious and safe in adjunctive therapy and as a monotherapy in partial22-24 and GTC seizures.25 Sodium valproate, as a monotherapy, was the most common AED used in treatment of GTC seizures, which were not adequately controlled by phenytoin. Valproate was approved by the Food and Drug Administration in 1978 for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures and was also effective for GTC seizures.26,27 National Institute for Health and Care Excellence guidelines 2012 on AEDs also suggested sodium valproate as an adjunctive treatment.28
Indian Journal of Clinical Practice, Vol. 27, No. 8, January 2017
743
DRUGS The cost of the drug plays an important consideration in the choice of treatment of epilepsy. The physicians also weigh the clinical benefit of the treatment against the cost before preferring any drug to the patient. Phenytoin has been the most preferred choice of physicians due to its: 1) Low cost and 2) comparable efficacy to other first-line AEDs (carbamazepine and valproic acid).29 In other studies as well, phenytoin was the most preferred AED in epileptic patients attending the secondary hospital7 and after carbamazepine in university hospitals.3,30 The mean drug cost/patient in a year varied between USD 27.5 at secondary hospital to USD 47.7 to 53.7 in university hospitals; this difference in cost was due to the choice of AED as phenytoin was most commonly used in secondary hospitals while in universities, newer AEDs were used. In 2008, Beghi et al reported that newer AEDs had similar effectiveness to first-generation AEDs but had significantly higher acquisition costs.31 All these studies support high use of phenytoin in the treatment of epileptic patients due to its cost-effectiveness and similar efficacy to other AEDs. In our study as well, ~75% of our physicians reported that 51-75% of their patients continued their treatment with phenytoin for more than 1 year and this may be due to cost-effectiveness of the drug, patientâ&#x20AC;&#x2122;s high satisfaction rate with seizure control, high tolerability, high compliance rate and easy availability. Our results further strengthen the role of physicians in the management of epilepsy cases. CONCLUSIONS As per our survey phenytoin, as a monotherapy or in combination, has been the most preferred drug of choice by Indian physicians in epilepsy management.
Acknowledgment We thank JSS Medical Research India Ltd. (formerly Max Neeman International) for assisting in overall study conduct, data analysis and medical writing.
REFERENCES 1. Ngugi AK, Bottomley C, Kleinschmidt I, Sander JW, Newton CR. Estimation of the burden of active and life-time epilepsy: a meta-analytic approach. Epilepsia. 2010;51(5):883-90.
4. Foletti GB. Clinical utilization of new anti-epileptic agents. Rev Med Suisse Romande. 2000;120(9):703-7. 5. Mathur S, Sen S, Ramesh L, Kumar SM. Utilization pattern of antiepileptic drugs and their adverse effects, in a teaching hospital. Asian J Pharm Clin Res. 2010;3(1):55-9. 6. Sebastian J, Adepu R, Keshava BS, Harsha S. Assessment of antiepileptic drugs usage in a South Indian tertiary care teaching hospital. Neurology Asia. 2013;18(2):159-65. 7. Krishnan A, Sahariah SU, Kapoor SK. Cost of epilepsy in patients attending a secondary-level hospital in India. Epilepsia. 2004;45(3):289-91. 8. Das RR, Griesemer DA, Kothare SV. The role of phenytoin in the treatment of localization related epilepsy: an international internet-based survey of neurologists and epileptologists. ISRN Neurol. 2013;2013:613456. 9. Sridharan R. Epidemiology of Epilepsy. Curr Sci. 2002;82(6):664-70. 10. Devinsky O, Penry JK. Quality of life in epilepsy: the clinician's view. Epilepsia. 1993;34 Suppl 4:S4-7. 11. Krishnan A, Ritvik, Chowdhury D. Cost of antiepileptic drugs in India. Neurology Asia. 2007;12(Suppl 1):42-3. 12. Lim SH, Tan EK, Chen C. Pattern of antiepileptic drug usage in a tertiary referral hospital in Singapore. Neurol J Southeast Asia. 1997;2:77-85. 13. Vettikkadan AR, Jith A, Krishnaveni K, Kumar SR. Study of utilization pattern and drug interactions of antiepileptic drugs in a private hospital. Asian J Pharm Clin Res. 2014;7(4):164-6. 14. Naithani N, Kshitiz KK. The conventional antiepileptic drug use when compared to a combination therapy regime in a teaching hospital in India. Int J Pharma Bio Sci. 2012;3(1):191-7. 15. Sirven JI, Waterhouse E. Management of status epilepticus. Am Fam Physician. 2003;68(3):469-76. 16. Deckers CL, Czuczwar SJ, Hekster YA, Keyser A, Kubova H, Meinardi H, et al. Selection of antiepileptic drug polytherapy based on mechanisms of action: the evidence reviewed. Epilepsia. 2000;41(11):1364-74. 17. Guberman A. Monotherapy or polytherapy for epilepsy? Can J Neurol Sci. 1998;25(4):S3-8. 18. Patsalos PN. The pharmacokinetic characteristics of levetiracetam. Methods Find Exp Clin Pharmacol. 2003;25(2):123-9. 19. Uges JWF, Vecht CJ. Levetiracetam. In: Panayiotopoulos CP (Ed.). Atlas of Epilepsies. UK: Springer Verlag, London Limited 2010;271:1775-85.
2. Amudhan S, Gururaj G, Satishchandra P. Epilepsy in India I: Epidemiology and public health. Ann Indian Acad Neurol. 2015;18(3):263-77.
20. Patsalos PN, Bourgeois BFD. Levetiracetam. In: The Epilepsy Prescriberâ&#x20AC;&#x2122;s Guide to Antiepileptic Drugs. UK: Cambridge University Press; 2010. pp. 124-33.
3. Radhakrishnan K, Nayak SD, Kumar SP, Sarma PS. Profile of antiepileptic pharmacotherapy in a tertiary referral center in South India: a pharmacoepidemiologic and pharmacoeconomic study. Epilepsia. 1999;40(2):179-85.
21. Snoeck E, Jacqmin P, Sargentini-Maier ML, Stockis A. Modeling and simulation of intravenous levetiracetam pharmacokinetic profiles in children to evaluate dose adaptation rules. Epilepsy Res. 2007;76(2-3):140-7.
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DRUGS 22. Lambrechts DA, Sadzot B, van Paesschen W, van Leusden JA, Carpay J, Bourgeois P, et al. Efficacy and safety of levetiracetam in clinical practice: results of the SKATE trial from Belgium and The Netherlands. Seizure. 2006;15(6):434-42. 23. Morrell MJ, Leppik I, French J, Ferrendelli J, Han J, Magnus L. The KEEPER trial: levetiracetam adjunctive treatment of partial-onset seizures in an open-label community-based study. Epilepsy Res. 2003;54(2-3): 153-61. 24. Ben-Menachem E, Falter U. Efficacy and tolerability of levetiracetam 3000 mg/d in patients with refractory partial seizures: a multicenter, double-blind, responder-selected study evaluating monotherapy. European Levetiracetam Study Group. Epilepsia. 2000;41(10):1276-83.
26. Bourgeois B, Beaumanoir A, Blajev B, de la Cruz N, Despland PA, Egli M, et al. Monotherapy with valproate in primary generalized epilepsies. Epilepsia. 1987;28 Suppl 2:S8-11. 27. Mattson RH. Selection of antiepileptic drug therapy. In: Levy RH, Dreifuss FE, Mattson RH, Meldrum BS, Penry JK (Eds.). Antiepileptic Drugs. 3rd Edition, New York: Raven Press; 1989. pp. 103-15. 28. NICE clinical guideline 137, NICE, 2012. Available at: https://www.epilepsysociety.org.uk/nice-guidelinesanti-epileptic-drugs#.WBxSay197IU. 29. Chisholm D; WHO-CHOICE. Cost-effectiveness of firstline antiepileptic drug treatments in the developing world: a population-level analysis. Epilepsia. 2005;46(5):751-9.
30. 25. Berkovic SF, Knowlton RC, Leroy RF, Schiemann J, Falter U; Levetiracetam N01057 Study Group. Placebo-controlled study of levetiracetam in idiopathic generalized epilepsy. 31. Neurology. 2007;69(18):1751-60. ■■■■
Thomas SV, Sarma PS, Alexander M, Pandit L, Shekhar L, Trivedi C, et al. Economic burden of epilepsy in India. Epilepsia. 2001;42(8):1052-60. Beghi E, Atzeni L, Garattini L. Economic analysis of newer antiepileptic drugs. CNS Drugs. 2008;22(10):861-75.
Indian Journal of Clinical Practice, Vol. 27, No. 8, January 2017
745
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HEMATOLOGY
The Innocent Bystanders: Endocrine Complications of Thalassemia Major with Iron Overload SUREKHA B SHETTY*, LALITHA SHIVAPRAKASH*
ABSTRACT Thalassemia represents a group of recessively inherited hemoglobin disorders, characterized by decreased or absent synthesis of a globin chain, leading to hemolytic anemia. It is important for treating physicians to be aware that multiple endocrine abnormalities can develop in patients with thalassemia major having significant iron overload, particularly after the age of 10 years. We report the case of a 19-year-old boy with beta-thalassemia major who had hemolytic anemia and was on recurrent blood transfusions for the same. He was diagnosed to have thalassemia major at the age of 6 months and he now presented with the history of increased thirst and urination for the last few days. He was investigated and found to have endocrine complications due to iron overload and managed accordingly.
Keywords: Thalassemia major, iron overload, endocrine complications, diabetes mellitus
CASE REPORT
ÂÂ
Fasting C-peptide - 0.402 ng/mL.
A 19-year-old boy was diagnosed to have betathalassemia major at the age of 6 months when he was evaluated for failure to thrive, pallor and hepatosplenomegaly. He was found to have hemolytic anemia and is on recurrent blood transfusions for the same. Now, he presented with the history of increased thirst and urination for the last few days.
ÂÂ
Total bilirubin - 3 mg/dL, direct bilirubin 0.6 mg/dL. Serum glutamic oxaloacetic transaminase/serum glutamic pyruvic transaminase (SGOT/SGPT) - 99/48 U/L.
ÂÂ
Thyroid-stimulating hormone (TSH) 2.25 μIU/mL.
ÂÂ
Serum creatinine - 0.7 mg/dL.
ÂÂ
Serum ferritin - 1,500 ng/mL.
ÂÂ
Serum calcium - 9.4 mg/dL.
ÂÂ
Echo - Dilated chambers. EF - 45%.
On Examination His height was 138 cm and the body weight was 28 kg. He had moderate pallor and mild icterus. Systemic examination showed moderate hepatomegaly. Secondary sexual characters were absent. Genital examination showed stretched penile length of 7 cm, testicular volume of 3 mL as measured by orchidometer and stage 2 pubic hairs.
Investigations ÂÂ
ÂÂ
Fasting blood sugar (FBS) - 219 mg/dL, postprandial blood sugar (PPBS) - 257 mg/dL and glycosylated hemoglobin (HbA1c) - 10.3%. Hemoglobin - 8.1 g/dL.
*Consultant Diabetologist Dept. of Internal Medicine Karnataka Institute of Diabetology, Bangalore, Karnataka
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Indian Journal of Clinical Practice, Vol. 27, No. 8, January 2017
Diagnosis ÂÂ Beta-thalassemia major with iron overload. ÂÂ Short stature. ÂÂ Hypogonadism. ÂÂ Insulin-dependent diabetes mellitus. ÂÂ Dilated cardiomyopathy. Treatment Further hormonal evaluation for short stature and hypogonadism could not be done due to financial restraints. Since, he had proven insulin deficiency, he was started on insulin therapy for achieving glycemic control. He was also started on ramipril for management of dilated cardiomyopathy. Since, the ferritin level was above 1,000 ng/mL, he was advised to be started on deferoxamine too.
HEMATOLOGY DISCUSSION
ÂÂ
Impaired glucose tolerance (6.5%)
Thalassemia represents a group of recessively inherited hemoglobin disorders, characterized by decreased or absent synthesis of a globin chain, leading to hemolytic anemia.1 It is classified as alpha-thalassemia and betathalassemia. Alpha-thalassemia is caused by deficient or absent synthesis of alpha globin chains, leading to excess beta-globin chains. Beta-thalassemia is caused by deficient or absent synthesis of beta-globin chains, leading to excess alpha chains. Depending on the severity of gene defect, thalassemia can present in one of the 3 forms: thalassemia major, thalassemia intermedia or thalassemia minor. The heterozygous state results in beta-thalassemia trait or minor and is asymptomatic. It is characterized by microcytosis and mild anemia. The homozygous state results in betathalassemia major, also known as Cooley anemia. It is characterized by severe anemia, needing regular blood transfusion.1
ÂÂ
Insulin-dependent diabetes mellitus (3.2%)
ÂÂ
Primary hypothyroidism (3.2%).
Beta-thalassemia major presents in the age group of 6 and 24 months. Affected infants fail to thrive and become progressively pale. Diarrhea, recurrent bouts of fever and abdominal distension due to splenic and liver enlargement are commonly seen. Fortunately, the combination of transfusion and chelation therapy has improved the life expectancy of thalassemic patients. But, in untreated or inadequately transfused children, growth retardation, poor musculature and skeletal changes are seen. On the other hand, transfused patients develop complications related to iron overload including growth retardation and delayed sexual maturation. Delayed complications include dilated myocardiopathy, liver cirrhosis and endocrinopathies (diabetes mellitus, hypogonadism, hypoparathyroidism, hypothyroidism, hypopituitarism and, hypoadrenalism).2 Several authors have reported a high incidence of endocrine complications in children, adolescents and young adults suffering from thalassemia major. However, the incidence of the various endocrinopathies changes among different series of the patients due to a combination of causes other than iron overload. Thalassemia International Federation Study Group on Growth and Endocrine Complications in Thalassemia3 reported that the most common endocrine complications include: ÂÂ
Lack of pubertal changes (40.5%)
ÂÂ
Short stature (31.1% of males and 30.5% of females)
ÂÂ
Growth hormone deficiency (7.9% in males and 8.8% in females)
ÂÂ
Hypoparathyroidism (6.9%)
A study from the Dept. of Pediatric Hematology, Ege University Turkey, done on 37 patients with thalassemia major4 found: ÂÂ
Growth retardation in 40% of patients, growth hormone deficiency being the most prominent cause of growth retardation
ÂÂ
Gonadal dysfunction in 47% of patients
ÂÂ
Hypothyroidism in 16% of patients
ÂÂ
Impaired glucose metabolism in 10.8% of patients.
DIABETES IN THALASSEMIA Diabetes occurs very frequently in thalassemia with transfusional hemosiderosis and has a reported prevalence of 2.3-24%. Studies have observed that diabetes could vary from asymptomatic glucose intolerance to insulin-dependent diabetes. This is due to the wide variation in pancreatic β-cell function in different patients. Pretransfusion hemoglobin concentration, serum ferritin concentration, incidence of liver disease and the presence of a family history of diabetes have been identified as independent risk factors for abnormal glucose tolerance. The onset of diabetes mellitus seemed to be followed by the appearance of other endocrine or cardiac complications.5 The mechanism of abnormal glucose homeostasis in patients with beta-thalassemia major is still unclear, but is attributed to insulin deficiency caused by pancreatic iron deposition and insulin resistance caused by hepatic and myocytic iron deposition.6 Iron chelation therapy with desferrioxamine, deferiprone or deferasirox has been found to be effective in normalizing β-cell function by improving insulin secretion and insulin resistance. This has been shown to normalize the impaired glucose tolerance in initial stages. In established diabetes, the medical treatment depends on the severity of insulin deficiency. In the early stages, oral hypoglycemia may be effective. Since, metformin reduces insulin resistance, it is effective in early stages. But, there is limited data on its use in thalassemia. Glibenclamide has been reported to produce long-lasting glycemic control in few studies. Acarbose also has been used effectively in these patients. But, insulin remains the mainstay of treatment in thalassemic patients, particularly in presence of severe hyperglycemia or proven insulin deficiency.7
Indian Journal of Clinical Practice, Vol. 27, No. 8, January 2017
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HEMATOLOGY CONCLUSION It is important for treating physicians to be aware that multiple endocrine abnormalities can develop in patients with thalassemia major having significant iron overload, particularly after the age of 10 years. Hence, periodic monitoring of growth, pubertal development and endocrine functions should be done in thalassemic patients after 10 years of age. Since, iron overload and liver infection seem to be the most important factors responsible for endocrine complications, attention should be paid to adequate chelation therapy and precautions against liver infections particularly hepatitis C. Once diagnosed, management of diabetes and other endocrine complications needs special attention in these patients. REFERENCES
2. Galanello R, Origa R. Beta-thalassemia. Orphanet J Rare Dis. 2010;5:11. 3. De Sanctis V, Eleftheriou A, Malaventura C; Thalassaemia International Federation Study Group on Growth and Endocrine Complications in Thalassaemia. Prevalence of endocrine complications and short stature in patients with thalassaemia major: a multicenter study by the Thalassaemia International Federation (TIF). Pediatr Endocrinol Rev. 2004;2 Suppl 2:249-55. 4. Aydinok Y, Darcan S, Polat A, Kavakli K, Nigli G, Coker M, et al. Endocrine complications in patients with betathalassemia major. J Trop Pediatr. 2002;48(1):50-4. 5. De Sanctis V, Zurlo MG, Senesi E, Boffa C, Cavallo L, Di Gregorio F. Insulin dependent diabetes in thalassaemia. Arch Dis Child. 1988;63(1):58-62. 6. Chern JP, Lin KH, Lu MY, Lin DT, Lin KS, Chen JD, et al. Abnormal glucose tolerance in transfusion-dependent beta-thalassemic patients. Diabetes Care. 2001;24(5):850-4.
7. Chatterjee R, Bajoria R. New concept in natural history 1. Rund D, Rachmilewitz E. Beta-thalassemia. N Engl J Med. and management of diabetes mellitus in thalassemia 2005;353(11):1135-46. major. Hemoglobin. 2009;33 Suppl 1:S127-30. ■■■■
Link Between Genetic Variation and Resistance to Chemotherapy for Acute Lymphocytic Leukemia Mutations in IKZF1 gene increases the likelihood of developing inheritable acute lymphocytic leukemia in pediatric population, suggests a study presented at the 58th American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego. The results also suggest that this genetic variation might be the plausible cause of increased resistance to chemotherapy in some patients. The study demonstrated increased cellular aggregation and "stickiness" of cells in the bone marrow and reduced sensitivity of the cancer cells towards the chemotherapeutic drug dasatinib. Researchers demanded for further research to calculate the rate at which these mutations increase the risk of acute lymphocytic leukaemia in families.
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2017
INTERNAL MEDICINE
A Clinical Study of Febrile Thrombocytopenia: A Hospital-based Retrospective Study PRAVEEN KUMAR*, KALPANA CHANDRA†
ABSTRACT Introduction: Febrile thrombocytopenia is a usually condition commonly caused by infections. The present study is intended to know the underlying etiology of febrile thrombocytopenia in our community, the various presentations and relationship between platelet count and severity of disease and prognosis. Material and methods: The study was conducted on 190 patients who presented with fever and thrombocytopenia and were admitted in Sri Ram Murti Smarak Institute of Medical Sciences (SRMS-IMS), Bhojipura, Bareilly, Uttar Pradesh from January 2011 to December 2011. Results and observations: Febrile thrombocytopenia affected all age group rangings from 18 to 88 years of age but was common in 18-40 years age group (52%) with male-to-female ratio 66.3:38.9%. It was common during the months of July to September. Fifty percent patients were having platelet >50,001/mm3. Malaria was the commonest cause constituting 32.6%, which was closely followed by septicemia forming 31.2%. About 76.8% patients had good recovery. In 18 mortality cases, 83.33% were due to septicemia with multiorgan dysfunction and 16.67% were due to complicated malaria. Conclusion: Febrile thrombocytopenia is an important clinical condition commonly caused by malaria and septicemia.
Keywords: Febrile thrombocytopenia, malaria, septicemia, multiorgan dysfunction
T
hrombocytopenia may be defined as a subnormal number of platelets in the circulating blood. A normal human platelet count ranges from 1,50,000 to 4,50,000 platelets/µL of blood. Often patients with thrombocytopenia are asymptomatic and are diagnosed by routine complete blood count. Occasionally, there may be bruising, purpura, petechiae, nose bleeding and gum bleeding. Rarely, platelet count may be as low as 5,000/mm3 predisposing the patients to life-threatening bleeding in the central nervous system (CNS) or from the gastrointestinal and genitourinary tracts.1 Thrombocytopenia occurs due to decreased platelet production, which occurs in conditions such as
*Associate
Professor Dept. of General Medicine †Associate Professor Dept. of Pathology Sri Ram Murti Smarak Institute of Medical Sciences, Bhojipura Bareilly, Uttar Pradesh Address for correspondence Dr Praveen Kumar Associate Professor Dept. of General Medicine Sri Ram Murti Smarak Institute of Medical Sciences, Bhojipura Bareilly, Uttar Pradesh
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vitamin B12 and folate deficiency, leukemia, sepsis (bacterial or viral infection) and hereditary disease. Thrombocytopenia may also occur due to increased destruction such as idiopathic thrombocytopenic purpura (ITP), thrombotic thrombocytopenia purpura (TTP), hemolytic uremic syndrome (HUS), disseminated intravascular coagulation (DIC), paroxysmal nocturnal hemoglobinuria (PNH), systemic lupus erythematosus (SLE), antiphospholipid syndrome, post-transfusion purpura and hypersplenism. Drugs, which can cause thrombocytopenia are quinine, valproic acid, methotrexate, carboplatin, interferon, isotretinoin and heparin.1-6 Febrile thrombocytopenia is the thrombocytopenia associated with fever. Diseases which commonly present with fever and thrombocytopenia are malaria, leptospirosis, rickettsial infections, septicemia, typhoid, borreliosis, arbovirus such as dengue or yellow fever, rodent-borne viruses such as Hanta and Lassa fever, human immunodeficiency virus (HIV), visceral leishmaniasis and TTP-HUS.1,7 The study was intended to know the underlying etiology of febrile thrombocytopenia in our community, the various presentations and relationship between platelet level and severity of disease and prognosis.
INTERNAL MEDICINE OBJECTIVE
RESULTS AND OBSERVATIONS
The aim of the study was to know the underlying etiology of febrile thrombocytopenia in our community, the various presentations and relationship between platelet level and severity of disease and prognosis.
A total of 190 patients admitted over a period of 1 year in our hospital were studied. The study subjects were in the age group of 18-88 years. Out of 190 patients suffering from fever with thrombocytopenia, 126 were male and 74 were females.
MATERIAL AND METHODS The study was conducted on 190 patients admitted in Sri Ram Murti Smarak Institute of Medical Sciences (SRMS-IMS), Bhojipura, Bareilly, Uttar Pradesh from January 2011 to December 2011. The patients were selected as per protocol based on inclusion and exclusion criteria.
Inclusion Criteria ÂÂ All new patients above 18 years with fever (temperature >99.9°F). ÂÂ Thrombocytopenia (platelet count <1,00,000 cells/mm3). Exclusion Criteria ÂÂ Patient presenting with thrombocytopenia without fever. ÂÂ Diagnosed case of immune thrombocytopenic purpura. ÂÂ Patient with thrombocytopenia already diagnosed to have hematological disorder/malignancy or on treatment with chemotherapy and other immunosuppressive agent. ÂÂ Diagnosed cases of platelet disorder and dysfunction. ÂÂ Patients on treatment with antiplatelet drugs and other drugs causing thrombocytopenia. ÂÂ Patients with cirrhosis and chronic liver disease. Outcome Variables ÂÂ Primary outcome variable ÂÂ Platelet count ÂÂ Secondary outcome variable ÂÂ Mortality This was a retrospective analysis of charts of patients admitted to a tertiary care hospital, between January 2011 to December 2011. Patients for this study were selected from hospital records based on inclusion and exclusion criteria. Data of the selected patients were collected from medical record from record room. Complete history and clinical findings and investigations as noted in the medical record were noted down.
Febrile thrombocytopenia was common in young to middle age group affecting 115 patients below 40 years. Fifty-eight patients were in the age group of 41-65 years and 17 patients were above 66 years of age. Febrile thrombocytopenia was common in between July to September affecting 84 patients. Fifty-six patients were affected between October to December, 27 from January to March and 23 from April to June. Out of 190 patients under study, 62 patients had definite diagnosis of malaria, which turned out to be the commonest cause of febrile thrombocytopenia in our institution in study year, which was closely followed by septicemia in 60 patients, dengue in 30, viral infection in 12, enteric fever in 7, pulmonary tuberculosis in 2 and one case of Kala-azar. The number of newly diagnosed cases of acute leukemia was significant, which constituted 16 patients. Commonest symptom after fever was vomiting (36) followed by abdominal pain (31), loose motion (9), gastrointestinal bleed (10) and respiratory symptoms like cough and dyspnea in 15. Abnormal renal function was in 62 patients and abnormal liver function test in 47. In our study, 20 patients had platelet count <20,000/µL, followed by 75 patients in the range of 20,001-50,000/µL and 95 patients had >50,001/µL. Clinical manifestations of thrombocytopenia were noted in 21 patients. Out of 21, gastrointestinal (GI) bleed was found in 10 patients, seven presented with petechial rash and four had hematuria. Out of 190 patients, 146 of them had good recovery, 18 patients expired, 10 left against medical advice and 16 cases of hematological malignancies were referred to higher centers (Table 1 and Figs. 1-6). Out of 18 cases of mortality, 15 were due to septicemia with multiorgan dysfunctions and three were due to complicated malaria. The expired patients were having hypotension in seven cases, abnormal renal function in 14 cases and abnormal liver function test in 7. Eleven patients were having platelet count >50,001/mm3, five had platelet count between 20,001-50,000/mm3 and two had <20,000/mm3 (Table 2 and Fig. 7).
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INTERNAL MEDICINE Table 1. Preliminary Data of the Study Total number of cases Male:Female Age range Age-wise prevalence 18-40 41-65 >66 Month-wise prevalence January to March April to June July to September October to December Platelet count distribution < 20,000/mm3 20,001-50,000/mm3 >50,001/mm3 Outcome Discharged Expired LAMA Referral to higher center Etiological diagnosis Malaria Septicemia Dengue Viral infection Enteric fever Pulmonary tuberculosis Kala-azar Acute leukemia Clinical feature Fever Headache Body ache Joint pain Petechial rashes Abdominal pain Vomiting Loose motion GI bleed Cough and dyspnea CNS Hematuria Abnormal RFT Abnormal LFT Hypotension Tachycardia
190 126:74 18-88
115 (60.52%) 58 (30.52%) 17 (8.94%) 27 (14.21%) 23 (12.10%) 84 (44.21%) 56 (29.47%) 20 (10.52%) 75 (39.47%) 95 (50.00%) 146 (76.84%) 18 (9.47%) 10 (5.26%) 16 (8.42%) 62 (32.63%) 60 (31.57%) 30 (15.78%) 12 (6.31%) 7 (3.68%) 2 (1.05%) 1 (00.52%) 16 (8.42%) 190 (100%) 16 (8.42%) 8 (4.21%) 5 (2.63%) 7 (3.68%) 31 (16.31%) 36 (18.94%) 9 (4.73%) 10 (5.26%) 15 (7.89%) 13 (6.84%) 4 (2.10%) 62 (32.63%) 47 (24.73%) 24 (12.63%) 66 (34.73%)
LAMA = Left against medical advice; GI = Gastrointestinal; CNS = Central nervous system; RFT = Renal function test; LET = Liver function test.
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Table 2. Data of Expired Patients Total death
18 (9.47%)
Causes of death Septicemia
15 (83.33%)
Malaria
3 (16.66%)
Male:Female
14:4
Clinical and Lab features Fever
18 (100%)
Abdominal pain
3 (16.60%)
Vomiting
4 (22.22%)
GI bleed
1 (5.55%)
Respiratory symptoms
3 (16.66%)
H/o DM
1 (5.55%)
H/o CRF
1 (5.55%)
Tachycardia
8 (44.44%)
Hypotension
7 (38.88%)
Anemia
3 (16.60%)
Leukopenia
1 (5.55%)
Leukocytosis
17 (94.44%)
Platelet count â&#x2030;¤20,000/mm3
2 (11.11%)
Platelet count 20,001-50,000/mm3
5 (27.11%)
Platelet count > 50,000/mm3
11 (61.11%)
Abnormal RFT
14 (77.77%)
Abnormal LFT
7 (38.88%)
Pneumonia
1 (5.55%)
H/o DM = History of diabetes mellitus; H/o CRF = History of chronic renal failure; RFT = Renal function test; LFT = Liver function test.
Female (33.7%) Male (66.3%)
Figure 1. Sex-wise prevalence in %.
DISCUSSION Febrile thrombocytopenia is a common clinical condition and is caused by infectious and noninfectious etiology. A total of 190 patients admitted over a period of 1 year in our hospital were studied. The affected
INTERNAL MEDICINE
50 40 30.52
30
76.84
30 20
20 8.94
10
9.47
10 Discharge
18-40
41-65
35 30
40
32.63 31.57
15.78
za
m
-a
ke
TB y ar
on lm
ia
r
1.05 00.52
r ve
n
fe
ng
tio
ric
te
Pu
Figure 3. Month-wise prevalence in %.
Se
En
Oct-Dec
ec
July-Sep
ia
em
ic pt
nf
April-June
ia
ar
al
M
ue
0
5 0 Jan-March
3.68
la
5
12.10
De
14.21
8.42
6.31
eu
10
.l
15
Ac
25
20
Ka
29.47
30
15 10
Referral to higher center
25
35
20
LAMA
Figure 5. Outcome in %.
44.21
45
Expired
>66
Figure 2. Age-wise prevalence %.
50
8.42
5.26
0
0
li
60
90 80 70 60 50 40
60.52
Vi ra
70
Figure 6. Etiology in %.
60 50
50 39.47
40
Malaria (16.66%)
30 20 10 0
10.52
<20,000
Septicemia (83.33%) 20,001-50,000
>50,001
Figure 4. Platelet count in %.
populations were in the age group of 18-88 years with prevalence common in males (66.31%) and in age group of <40 years (61.15%). The disease was most commonly prevalent in the month of July to September (44.21%). This high incidence in July to September was due to large number of cases of malaria and dengue in this region during that period. Malaria was the commonest cause accounting 32.63%, which was followed by septicemia (31.57%), dengue (15.78%), acute leukemia (8.42%), viral infection (6.31%),
Figure 7. Etiology of death in %.
enteric fever (3.6%), pulmonary tuberculosis (1.055%) and Kala-azar (0.52%). In a study by Lohitashwa et al on 100 patients from March 2004 to September had similar observation (i.e., malaria being the commonest cause).8 Another prospective study, which was conducted on 228 patients with fever and thrombocytopenia in Medical Unit of Hayat Abad Medical Complex during 20082010 was showing malaria as a commonest cause (53%) out of which 68% were having falciparum malaria.9
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INTERNAL MEDICINE Malaria is commonly accompanied by mild-tomoderate thrombocytopenia in 40.53-85% (78.4% by Jadhav et al, 80.6% by Medical Unit 3, JPMC, Karachi, 85.5% by Shaikh et al).10-12 In an observational study conducted by Malik et al at Karachi on endemicity of malaria and hematological finding in Gadap region on 392 patients observed malarial prevalence in 11.72%, out of which thrombocytopenia was observed in 70% cases.13 Thrombocytopenia in malaria is probably due to increased splenic sequestration, immune-mediated destruction and a shortened platelet survival and consumption by DIC. Along with quantitative defects, qualitative defects have also been documented, which are platelet hyperactivity, due to aggregating agent like immune complexes and damage of endothelial cells followed by platelet hypoactivity, which returns to normal in 1-2 weeks. Thrombocytopenia along with acute febrile syndrome is having 100% sensitivity, 70% specificity, 100% negative predictive value and 86% positive predictive value in malarial diagnosis.14 Another study had reported 60% sensitivity and 88% specificity of thrombocytopenia for malaria diagnosis in acute febrile patients.15 Thrombocytopenia is the very common finding in septicemia and is an independent prognostic marker. In a study conducted by Lee et al on 53 patients with septicemia thrombocytopenia was observed in 57% patients and DIC in 35% patients.16 The etiology of thrombocytopenia in sepsis is multifactorial. It is commonly associated with DIC and is caused by splenic destruction of immune complex coated platelets, platelet adherence to damaged vascular surfaces and by direct platelet toxicity caused by microorganisms.7 It is also probably related to impaired production of platelets from within the bone marrow, active phagocytosis of megakaryocytes and other hematopoietic cells by monocytes and macrophages hypothetically due to stimulation with high levels of macrophage colony-stimulating factor (M-CSF) in sepsis and platelet consumption due to ongoing generation of thrombin. Dengue is the most common arbovirus disease worldwide and occurs in tropical countries. Thrombocytopenia is an important finding and has got predictive as well recovery parameter of dengue fever/dengue hemorrhagic fever/dengue shock syndrome (DF/DHF/DSS). Thrombocytopenia in DF is caused by bone marrow suppression (i.e., decreased platelet synthesis and increased immune-mediated destruction of platelets).17 Commonest symptom after fever was vomiting in 18.94%, abdominal pain in 16.31%, loose motion in
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4.73% cases, GI bleed in 5.26% cases and respiratory symptom like cough and dyspnea in 7.89%. Abnormal renal function was detected in 32.63% and abnormal liver function test in 24.73%. So, GI symptoms were the most common symptoms associated with febrile thrombocytopenia. In our study, platelet count was commonly > 50,001/mm3 (50%) followed by 20,001/-50,000/mm3 (39.47%) and <20,000/mm3 in 10.52% cases. So, we observed in the study, thrombocytopenia is commonly mild in febrile thrombocytopenia. Clinical manifestations of thrombocytopenia were noted in 11.05% patients (GI bleed - 5.26% patients, petechial rashes - 3.67% and hematuria - 2.10%). But, the study conducted by Lohitashwa et al observed bleeding manifestation in 49% cases and petechiae was the commonest bleeding manifestation.8 Out of 190 patients, 76.84% of them had good recovery, 9.47% patients expired, 5.26% left against medical advice and 8.42% were referred to higher centers. Study conducted by Lohitashwa et al observed similar outcome of recovery in 82% cases and mortality in 18% cases.8 Out of 18 cases of mortality, 83.33% were due to septicemia with multiorgan dysfunction and 16.67% were due to complicated malaria. The expired patients were having hypotension (38.88%), abnormal renal function (77.77%) and abnormal liver function test (48.88%). About 61.11% patients were having platelet >50,000/mm3. This indicates deaths were not related to degree of thrombocytopenia but were related to underlying etiology and concomitant involvement of other organs leading to multiorgan dysfunction. Renal failure was the commonest organ dysfunction, which was related to compromised systemic perfusion and direct effect of underlying etiology. Study conducted by Lohitashwa et al observed that septicemia was the most cause of death (78%) followed by dengue.8 CONCLUSION Febrile thrombocytopenia is an important clinical condition commonly caused by infections, particularly malaria and septicemia. It commonly manifests as symptom/signs of underlying condition and sometime with bleeding manifestation. Treatment of underlying condition will lead to rapid improvement in platelet count with complete clinical recovery. Mortality in febrile thrombocytopenia is not directly associated with degree of thrombocytopenia but with concomitant involvement of other organs leading to multiorgan dysfunction.
INTERNAL MEDICINE 7. Lee GR, Foerster J, Lukens J, Paraskevas F, Greer JP, Rodgers GM. Shirley Parker Levine - Miscellaneous causes I take this opportunity to extend my gratitude and sincere of thrombocytopenia. In: Wintrobe’s Clinical Haematology. thanks to all those who helped me to complete this study. Vol. 2, 10th Edition, Philadelphia: Lipincott Williams; 1999. I am highly thankful to Dept. of Medicine, Surgery, pp. 1623-9. Pulmonology, Gynecology, Pathology, Microbiology and 8. Lohitashwa SB, Vishwanath BM, Srinivas G. Clinical and Lab Critical Care department for providing me adequate facility, Profile of Fever with Thrombocytopenia. Abstract Free which helped me to carry out this study. I owe great sense Paper Oral Presentation - APICON, 2008. Available at: of indebtedness to dean SRMS-IMS, Bhojipura, Bareilly, Uttar http://www.japi.org/march_2009/oral_presentation Pradesh for permitting me to carry out this study. 9. Khan SJ, Abbass Y, Marwat MA. Thrombocytopenia as an indicator of malaria in adult population. Malar Res Treat. REFERENCES 2012;2012:405981. 1. Konkle BA. Disorders of platelets and vessel wall. In: 10. Jadhav UM, Patkar VS, Kadam NN. Thrombocytopenia Fauci AS, Braunwald E, Kasper DL, et al. (Eds.). Harrison’s in malaria - correlation with type and severity of malaria. Principles of Internal Medicine. Vol. 1, 17th Edition, New J Assoc Physicians India. 2004;52:615-8. York, NY: McGraw-Hill; 2008. pp. 718-23. 11. Shaikh QH, Ahmad SM, Abbasi A, Malik SA, Sahito AA, 2. Craig JIO, McClelland DBL, Watson HG. Munir SM. Thrombocytopenia in malaria. J Coll Physicians Thrombocytopenia. In: Colledge NR, Walker BR, Ralston Surg Pak. 2009;19(11):708-10. SH (Eds.). Davidson’s Principles and Practice of Medicine. 12. Shaikh MA, Ahmed S, Diju IU, Dur-E-Yakta. Platelet 21st Edition, Edinburgh: Churchill Livingstone Elsevier; count in malaria patients. J Ayub Med Coll Abbottabad. 2010. pp. 1003-4. 2011;23(1):143-5. 3. Bichile SK. Platelet disorder. In: Munjal YP (Ed.). API 13. Malik AM, Zaffar N, Ali N, Malik AM, Khan R. Textbook of Medicine. Vol. 1, 9th Edition, New Delhi: Haematological findings and endemicity of malaria in Jaypee Brothers; 2012. pp. 987-8. Gadap region. J Coll Physicians Surg Pak. 2010;20(2):112-6. 4. Firkin F, Penington D, Chesterman C, Rush B. The 14. Patel U, Gandhi G, Friedman S, Niranjan S. hemorrhagic disorders. In: deGruchy’s Clinical Thrombocytopenia in malaria. J Natl Med Assoc. Hematology in Medical Practice. 5th Edition, Bombay: 2004;96(9):1212-4. Oxford University Press; 1989. pp. 375-92. 15. Lathia TB, Joshi R. Can hematological parameters 5. Lee GR, Foerster J, Lukens J, Paraskevas F, Greer JP, discriminate malaria from nonmalarious acute febrile Rodgers GM. Shirley Parker Levine - Thrombocytopenia: illness in the tropics? Indian J Med Sci. 2004;58(6):239-44. Pathophysiology and Classification. In: Wintrobe’s Clinical 16. Lee KH, Hui KP, Tan WC. Thrombocytopenia in sepsis: a Haematology. Vol. 2, 10th Edition, Philadelphia: Lipincott predictor of mortality in the intensive care unit. Singapore Wlliams & Wilkins; 1999. pp. 1579-82. Med J. 1993;34(3):245-6. 6. Diz-Kucukkaya R, Chen J, Geddis A, Lopez JA. 17. Jayashree K, Manasa GC, Pallavi P, Manjunath GV. Thrombocytopenia. In: Kaushansky K, Lichtman MA, Evaluation of platelets as predictive parameters in dengue Beutler E, Kipps TJ, Selisohn U, Prchal JT, (Eds.). William’s Hematolgy. 8th Edition, New York; 2011. pp. 1891-918. Fever. Indian J Hematol Blood Transfus. 2011;27(3):127-30. ■■■■
Acknowledgment
Anticholinergic Cognitive Burden Score Linked to Cognitive Impairment in Elderly Population A study published online in the journal Pharmacotherapy, assesses the relationship between Anticholinergic Cognitive Burden (ACB) score and cognitive impairment and healthcare utilization both, in elderly population and found that elevated risk for cognitive impairment and recurrent healthcare utilization was associated with ACB score. Results demonstrated that with every unit increase in mean total daily ACB score there was significant increase in cognitive impairment, inpatient admission and number of outpatient visits.
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NUTRACEUTICALS
Promising Role of Vitamin D3 in Improving Overall Health G VIJAYAKUMAR
ABSTRACT The role of vitamin D in the regulation of bone metabolism has been well-established. However, in recent years, many studies have demonstrated that its role extends far beyond bone health. Growing evidence has shown a strong association between vitamin D deficiency and hypertension, metabolic syndrome, diabetes mellitus and atherosclerosis. Moreover, the deficiency of this essential vitamin may even contribute to the development of 17 different types of cancers, especially breast, colon and prostate cancers. Despite this fact, nearly 25-50% or greater proportion of patients have been reported to have low levels of vitamin D. Vitamin D deficiency has now been identified as a pandemic that can be ascribed to various factors, including lifestyle and environmental, that decrease the exposure to sunlight required for the production of vitamin D in the skin. Thus, it is important to maintain its optimal concentration. In context to this, mounting evidence emphasizes on the benefits of administering vitamin D3 as a supplement. It not only helps in improving skeletal health but also displays favorable extraskeletal outcomes. Additionally, it is likely to be superior to the other form of vitamin D, vitamin D2. A considerable base of evidence has indicated the efficacy of 60,000 IU of cholecalciferol along with calcium for maintaining optimal vitamin D levels.
Keywords: Vitamin D, ergocalciferol, cholecalciferol, calcium absorption, calcium homeostasis
V
itamin D, recognized not only as a fatsoluble vitamin but also a prohormone, has garnered significant attention over the past few decades.1-4 A unique property of this nutrient is that it can be synthesized by the human body via action of sunlight.2 In addition, it can also be obtained through diet and supplements.5 Studies conducted in the early 20th century showed its importance in maintaining calcium homeostasis and skeletal health which could be attributed to the endogenous serum metabolite of vitamin D (calcitriol, 1,25[OH]2D3), which is considered a true steroid hormone. Moreover, latter years of the 20th century highlighted that this metabolite exerts several biological activities apart from its skeletal actions.4 Thus, vitamin D has been suggested to play a vital role in multiple spheres.1 Despite this fact, nearly 25-50% or greater proportion of patients have been reported to have low levels of vitamin D.6 Statistics indicate the figure to be around 1 billion across the world including individuals of all age groups and ethnicities.1 Vitamin D deficiency has now been identified as a pandemic that can be ascribed to various factors including lifestyle
Senior Consultant Diabetologist Apollo Specialty Hospital and Diabetes Medicare Center, Chennai, Tamil Nadu
(such as reduced outdoor activities) and environmental factors (like air pollution) that decrease the exposure to sunlight required for the production of vitamin D in the skin.1,7 Besides these, a wide range of factors have been determined that enhance the risk of vitamin D deficiency. As this condition exerts a considerable burden and is presumed to worsen in the near future, its prevention and appropriate treatment are of utmost importance.1 The current review intends to provide an insight into the metabolism and physiological actions of vitamin D. This is followed by a note on the epidemiology and consequences of vitamin D deficiency. Subsequently, a section has been devoted to the benefits of vitamin D3 supplementation. METABOLISM AND PHYSIOLOGICAL ACTIONS OF VITAMIN D: AN OVERVIEW
Metabolism Vitamin D consists of a group of fat-soluble secosterols.2 It has been documented that 50-90% of vitamin D is synthesized by sunlight and the remaining is obtained from the diet via food items like egg yolk, fatty fish, fortified dairy products and beef liver.1,8 This vitamin exists in 2 forms, vitamin D2 (ergocalciferol) and
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NUTRACEUTICALS vitamin D3 (cholecalciferol). Both of these forms can be synthesized commercially and are also found in diet supplements or fortified foods. Vitamin D2 can be obtained from the ultraviolet radiation of the yeast sterol ergosterol and is found naturally in sun-exposed mushrooms. On the other hand, vitamin D3 is produced in the skin by the action of the ultraviolet-B light from the sun and can also be obtained by consuming animalbased foods such as oil-rich fish including salmon, mackerel and herring.1,2 These 2 forms of vitamin D obtained from the skin or diet are biologically inert and undergo two enzymatic hydroxylation reactions in the liver and kidneys. The ingested vitamin D is incorporated into chylomicrons, which are absorbed into the lymphatic system and enter the venous blood. The first hydroxylation occurs in the liver. It is mediated by vitamin D-25-hydroxylase (most likely cytochrome P450 2R1) leading to the formation of 25-hydroxyvitamin D (25[OH]D), the major circulating form of vitamin D which is bound to a specific plasma carrier protein, vitamin D-binding protein. This is followed by a second reaction that takes place in the kidneys and is mediated by 1-alphahydroxylase (CYP27B1). This results in the formation of the biologically active form of vitamin D, calcitriol (1,25-dihydroxyvitamin D or 1,25[OH]2D). The metabolism of vitamin D has been comprehensively depicted in Figure 1.1,2,4,9,10 Furthermore, it has been suggested that other cells and tissues of the body, including macrophages, brain, breast, colon, prostate and others, possess the enzymatic machinery to locally produce 1,25(OH)2D. This form 7-dehydrocholesterol (vitamin D precursor of skin) UVB rays from the sun Previtamin D3
Cholecalciferol (D3)
Foods and supplements
25-hydroxylase in liver 25-hydroxyvitamin D3
Ergocalciferol
1-alpha-hydroxylase in kidneys 1,25-dihydroxyvitamin D3 (activated form) Binding to vitamin D receptors Biologic actions
Figure 1. Metabolism of vitamin D.
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is known to activate its cellular receptor, vitamin D receptor that activates target genes for performing its biological actions.7
Physiological Actions The most dominant function of vitamin D is regulation of calcium absorption and homeostasis. It stimulates calcium absorption from the gut and enables mineralization of newly formed osteoid tissue in bone.7,11 It acts by increasing the concentrations of plasma calcium and phosphate, required for bone mineralization. It has been observed that without vitamin D, only 10-15% of dietary calcium and around 60% of phosphorus are absorbed.7 The researchers have proposed 3 different mechanisms by which calcitriol elevates plasma ionized calcium levels to the normal range. In the first mechanism, parathyroid hormone is not required; calcitriol promotes intestinal calcium absorption throughout the entire length of the intestine, displaying greatest activity in the duodenum and jejunum. In the second mechanism, parathyroid hormone is required; calcitriol is involved in the mobilization of calcium from bone. In the third mechanism, calcitriol along with parathyroid hormone stimulates the renal distal tubule reabsorption of calcium, thereby ensuring retention of calcium by the kidneys when calcium is required. Overall, it can be suggested that calcitriol acts on the intestine, bone and kidneys to increase serum calcium concentrations, closing the calcium loop. An inverse relation between serum calcium levels and parathyroid hormone has been seen; a rise in calcium levels is associated with a decrease in parathyroid hormone. If there is a significant increase in serum calcium levels, the parafollicular cells of the thyroid secrete calcitonin. This, in turn, causes the blockade of calcium resorption from bone and thus helps in keeping calcium levels within the normal range. Normalization of plasma calcium levels is important for the functioning of the neuromuscular junction, nerve transmission, vasodilatation and hormonal secretion.2 Furthermore, as vitamin D receptor is present in several tissues and cells of the body, it is involved in various biological actions, such as hindering the formation of renin and inhibiting angiogenesis, inducing insulin synthesis and stimulating macrophage cathelicidin production. In addition, it also exerts an immunomodulatory activity on monocytes and activated T and B lymphocytes. The local production of 1,25(OH)2D has been reported to be responsible
NUTRACEUTICALS for regulating around 200 genes, thereby providing many pleiotropic health benefits. For instance, its local production in noncalcium-regulating tissues such as the breast, colon and prostate is believed to be helpful for controlling cell growth and differentiation. This may, in turn, prevent the possibility of transformation of the cells into a malignant state.1,7,12 Thus, it can be stated that vitamin D not only influences the bones and muscles but is also of significance in the brain, intestines, pancreas, immune and cardiovascular systems and for the control of cell cycles.1 Therefore, its deficiency can affect in multiple ways and may lead to the occurrence of several disorders. VITAMIN D DEFICIENCY: A CONSIDERABLE CAUSE OF CONCERN The status of vitamin D primarily depends on the synthesis of vitamin D3 in the skin by ultraviolet radiation received from the sun and vitamin D consumption through diet or supplements.8 Although extensive research has been done on vitamin D, the range of optimal concentration remains a controversial topic. According to the Institute of Medicine, the levels of 25(OH)D should be maintained between 20-40 ng/mL, while data from other experts, including some UpToDate editors recommend maintaining these levels between 30-50 ng/mL. The National Osteoporosis Foundation, the International Osteoporosis Foundation, the Endocrine Society and the American Geriatric Society have propounded the minimum value to be 30 ng/mL in the elderly for reducing the risk of falls and fractures. However, levels below 20 ng/mL have been advised to be harmful to the skeletal health.13
Epidemiology of Vitamin D Deficiency Wide prevalence of vitamin D deficiency has been witnessed across the globe, affecting both developed and developing nations. It is not only common in countries with low latitude where ultraviolet B radiation was presumed to be adequate for preventing the deficiency but also in industrialized nations where implementation of vitamin D fortification has been carried out for many years, but substantial fortification is yet to be achieved in a large proportion of countries.8,14,15 The highest cases of vitamin D deficiency have been reported in Australia, Africa, South America, the Middle East and India.1 It has been observed that it is a common problem all over the Indian subcontinent, with a prevalence around 70-100% in the general population.14 Moreover, it affects both adults and children. According to a study16 conducted in Indian
children, the highest prevalence was seen in Northern, Western and Southern states. The results showed that median 25(OH)D was 19 ng/mL. Severe deficiency was seen in 19.2% of the population with serum 25(OH)D levels <10 ng/mL. Around 52.9% candidates had <20 ng/mL (deficiency), 24.5% had 20-29 ng/mL (insufficiency) and 22.6% had >30 ng/mL (optimum). Highest deficiency was found in adolescents, followed by school children and pre-school children (86.1%, 61% and 41.6%). It was noteworthy that the concentrations of vitamin D were lowest in winters and spring in contrast to that in summers.16 Apart from the seasons that lead to inadequate exposure to sunlight, multiple factors have been identified that enhance the risk of vitamin D deficiency. The most common ones include topical application of a sunscreen, especially with a sun protection factor of 30; naturally dark skin tone; obesity; fat malabsorption syndromes; nephritic syndrome; chronic granulomaforming disorders such as sarcoidosis, tuberculosis and chronic fungal infections; some of the lymphomas; primary hyperparathyroidism and medications like anticonvulsants and those used to treat acquired immunodeficiency syndrome and aging. These risk factors have been summarized in Box 1.1,6,17
Consequences of Vitamin D Deficiency Skeletal Effects As aforementioned, vitamin D is involved in the regulation of calcium and phosphorus balance for bone mineralization and remodeling; thus, its deficiency can be detrimental to skeletal health.11,14 It can result in several abnormalities related to calcium, phosphorus and Box 1. Risk Factors for Vitamin D Deficiency yy Limited sun exposure yy Inadequate oral intake yy Malnutrition yy Malabsorption (short bowel syndrome, pancreatitis, inflammatory bowel disease, amyloidosis, celiac sprue and malabsorptive bariatric surgical procedures) yy Chronic granuloma-forming disorders such as sarcoidosis, tuberculosis and chronic fungal infections yy Primary hyperparathyroidism yy Obesity yy Severe liver disease or failure yy Medications such as glucocorticoids, antiepileptic drugs, drugs used to treat acquired immunodeficiency syndrome yy Renal insufficiency, glomerular filtration rate <60% yy Nephrotic syndrome yy Aging
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NUTRACEUTICALS bone metabolism.1 During vitamin D deficiency, there is a reduction in the absorption of dietary calcium and phosphorus, which, in turn, increases parathyroid hormone levels and renal reabsorption of calcium. Subsequently, there is an increase in osteoclastic activity which creates local foci of bone weakness and leads to a generalized decrease in bone mineral density, resulting in osteopenia and osteoporosis.1,5,14 Moreover, an inadequate calcium-phosphorus product causes a mineralization defect in the skeleton, resulting in rickets in young children and osteomalacia in adults.1,5,11 In rickets, the cartilage fails to mature and mineralize normally. It is marked by skeletal deformities including craniotabes and deformations of the lower limbs, known as knocked knees and bowed legs; widening at the end of the long bones and rachitic rosary. Moreover, associated biochemical abnormalities are hypophosphatemia, high alkaline phosphatase levels and serum 25(OH)D levels <5 ng/mL. Rickets can further be classified into vitamin D-dependent rickets type 1 and type 2. Type 1 disorder is an autosomal recessive trait and manifests in the first year after birth. It is associated with abnormally low calcitriol concentrations but normal serum 25(OH)D levels. Moreover, intestinal calcium absorption is impaired due to mutations in vitamin D-dependent rickets type 1 that, in turn, affects the 1-alpha-hydroxylase enzyme. Type 2 disorder is also an autosomal recessive trait. It occurs as a result of a mutation in the Vdr gene. It usually appears in the second year after birth or remains unrecognized until adulthood. It results in hypocalcemia, convulsions, tetany, alopecia and rickets. On the other hand, in osteomalacia, the newly deposited bone matrix fails to mineralize adequately and there is presence of wide unmineralized bone matrix seams. The unmineralized osteoid provides less structural support for the periosteal covering, which causes isolated or generalized bone discomfort along with pain in joints and muscles.2,7,11,12,14 Furthermore, less severe vitamin D deficiency, also often known as vitamin D insufficiency, may lead to secondary hyperparathyroidism, bone loss, muscle weakness and may be responsible for falls and fragility fractures in elderly individuals.11,14 Muscle weakness in children may pose difficulty in standing and walking, whereas, in older people, it is characterized by more sway and frequent falls, thereby enhancing the risk of fractures.1,7
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Extraskeletal Effects Besides the well-established role of vitamin D in musculoskeletal health, its deficiency has been associated with several nonskeletal disorders.11 The most common ones are hypertension; cardiovascular disorders; infectious diseases; type 1 and type 2 diabetes mellitus; autoimmune diseases such as Parkinson's disease, multiple sclerosis, rheumatoid arthritis; depression; dementia; age-related cognitive decline; obesity; fibromyalgia; chronic fatigue syndrome; neurodegenerative diseases including Alzheimer’s disease; birth defects and periodontal disease.7,8,11,12,18 Moreover, the deficiency of this essential vitamin may even contribute to the development of 17 different types of cancers, especially breast, colon and prostate cancers.7 Various skeletal and extraskeletal effects of vitamin D deficiency are illustrated in Figure 2.1,2,5,7,8,11,12,14,18 CLINICAL BENEFITS OF VITAMIN D SUPPLEMENTATION A large proportion of individuals assume that the amount of vitamin D obtained via diet is adequate. However, it is unfortunate that only few food items naturally contain vitamin D and only some are fortified with vitamin D.12 This necessitates the need for using vitamin D supplements to attain optimal levels which can, in turn, prevent and treat several diseases.18 A wealth of data are available to support the skeletal
Effects of Vitamin D Deficiency
Skeletal effects
yyOsteopenia yyOsteoporosis yyRickets (vitamin D-dependent rickets type 1 and type 2) yyOsteomalacia yySecondary hyperparathyroidism yyMuscle weakness yyFalls and fractures, especially in the elderly
Extraskeletal effects
yyHypertension yyCardiovascular disorders yyInfectious diseases yyType 1 and type 2 diabetes mellitus yyAutoimmune diseases yyDepression yyDementia yyAge-related cognitive decline yyObesity yyFibromyalgia yyChronic fatigue syndrome yyAlzheimer’s disease yyBirth defects yyPeriodontal disease yyCancers
Figure 2. Effects of vitamin D deficiency.
NUTRACEUTICALS benefits of vitamin D.14 The European nutrition and health claim regulations have indicated the importance of vitamin D in multiple domains including normal absorption and utilization of calcium and phosphorus, normal calcium concentrations, maintenance of normal bones and teeth, normal growth and development of bones in children. In addition, it helps in maintaining normal muscle function and enhancing muscle strength, thereby preventing falls. This action can be ascribed to vitamin D receptors that are present on the fast-twitch muscle fibers, and are the first ones to respond in a fall. Evidence in favor of this has been provided by several studies, one of which showed that supplementation with around 800 IU of vitamin D per day led to reduction in hip and nonspinal fractures by about 20%.1,6,11 Furthermore, a considerable base of evidence suggests the potential of vitamin D against various illnesses apart from musculoskeletal disorders. The most common ones are diabetes, heart disease, autoimmune diseases, cancers, influenza and depression.1Â It has been presumed that vitamin D3 plays a role in controlling the immune system that raises the possibility of reducing the risk of cancers and autoimmune diseases. Moreover, it also increases neuromuscular function, thereby improving mood, protecting the brain against toxic chemicals and potentially decreasing pain.8 As discussed above, vitamin D contributes to prevention of diabetes. The findings of a study demonstrated that administration of 2,000 IU/day of vitamin D from 1 year of age in children decreased their risk of developing type 1 diabetes mellitus by 80% throughout the next 20 years. On the contrary, those with vitamin D deficiency at 1 year of age had a 4-fold increased risk of developing type 1 diabetes. Another study revealed the benefit of vitamin D in decreasing the risk of developing rheumatoid arthritis.12 According to a meta-analysis, an association has also been found between vitamin D supplementation and significantly reduced mortality.1
Evidence-based Efficacy of Vitamin D3 Although supplementation of vitamin D is important, selection between its 2 forms, ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3) remains a debatable issue. Some researchers suggest vitamin D3 to be the most potent form of vitamin D. This can be attributed to the diminished binding of vitamin D2 metabolites to vitamin D-binding protein in plasma. The presence of a methyl group at carbon-24 position on the D2 molecule underlines this difference
in the binding capacity. It is evident that the different hydroxylation sites of 2 forms of vitamin D result in the synthesis of unique biologically active metabolites. The 24-hydroxylation after the 25-hydroxylation leads to the production of 1,24,25(OH)3D2 and deactivation of vitamin D2 molecule. On the other hand, the vitamin D3 metabolite 1,24,25(OH)3D3 undergoes an additional side chain oxidation to be biologically deactivated. Moreover, it is noteworthy that 1,24,25(OH)3D3 possesses approximately 40% greater capacity to bind with vitamin D receptor than with 1,25(OH)2D3. Moreover, it has been reported that a large, single dose of vitamin D3 lasts relatively longer than a large dose of D2. According to a study in which participants were given one dose of 50,000 IU of either vitamin D2 or vitamin D3, although both forms were absorbed well, blood levels of 25(OH)D started to decline rapidly after 3 days in patients who were administered vitamin D2 while those on vitamin D3 sustained high levels for 2 weeks before gradual dropping. Another study also showed superiority of vitamin D3 over D2 by displaying that a daily dose of 4,000 IU of vitamin D3 for 2 weeks was 1.7 times more effective in elevating 25(OH)D levels than the similar dose of vitamin D2. Moreover, vitamin D3 has also shown better outcomes than vitamin D2 in patients with vitamin D insufficiency with subsequent hip fractures. In a study, 1,000 IU of vitamin D3 therapy for 3 months resulted in 31-52% increase in 25(OH)D levels in contrast to that achieved with vitamin D2 therapy.17 Harinarayan and coworkers performed a study19 to evaluate the efficacy and safety of vitamin D supplementation according to the Endocrine Society Clinical Practice Guidelines (it recommends the tolerable upper intake level of cholecalciferol to be 10,000 IU/day for adults who are vitamin D deficient for a duration of 8 weeks) in individuals with vitamin D deficiency. These candidates were supplemented with cholecalciferol 9,572 IU/day and elemental calcium 1 g/day. At the end of the 2nd month, cholecalciferol 3,000 IU/day were given to those who attained vitamin D sufficiency, while those who still had vitamin D deficiency were given cholecalciferol 5,286 IU/day along with 1 g elemental calcium. All patients were administered oral cholecalciferol 60,000 IU/week (Calcirol) (equivalent to cholecalciferol 8,572 IU/day) along with calcium tablets twice-daily (each tablet contained 1,250 mg of calcium carbonate equivalent to elemental calcium of 500 mg along with cholecalciferol 500 IU) for 8 weeks. In total, these patients received cholecalciferol of 9,572 IU/day (8,572 from the
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NUTRACEUTICALS
Malhotra and colleagues20 also assessed the efficacy and safety of oral vitamin D (cholecalciferol) supplementation in 100 healthy women of reproductive age. The study cohort was randomized into 2 groups; control and supplement. The supplement group was given 60,000 IU of cholecalciferol/month for 3 months and then control group was administered 60,000 IU and supplement group 1,20,000 IU/month for 6 months. In supplement group, 25(OH)D levels increased from 4.8 ± 3.5 to 31.6 ± 15.5 ng/mL in 3 months. A slight increase was also seen in the control group, from 4.5 ± 3.4 ng/mL (in spring) to 10.8 ± 7.2 ng/mL (in summer). In control group (60,000 IU/month), mean 25(OH)D level had increased to 22.3 ± 12.4 ng/mL at 9 months (winter) while in supplement group (1,20,000 IU/month), the levels were maintained at 30.7 ± 12.8 ng/mL at 9 months (winter). These findings indicate that administration of 60,000 IU/month cholecalciferol may be adequate in healthy individuals with vitamin D deficiency in the months of summer, however, higher doses may be required during winters.20 Furthermore, since vitamin D deficiency is widely prevalent among the Indian population, attaining the optimal levels by administering the regimen for a short duration is not sufficient, thereby warranting the need for maintenance of these levels. This notion has been supported by a study that was conducted by Goswami and coworkers21 among 28 healthy Asian Indians. These candidates had low serum 25(OH)D levels (mean 13.5 nmol/L) at baseline. Moreover, the level of serum parathyroid hormone was above the normal range in 30% of them. They were supplemented with 60,000 IU cholecalciferol/week along with 1 g elemental calcium daily for 8 weeks.
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90 Mean serum 25(OH)D levels (nmol/L)
sachets and 1,000 IU/day through the calcium tablets along with 1 g of elemental calcium) as supplementation therapy. The mean ± standard deviation of serum calcium, phosphorous and alkaline phosphatase were in the normal range at baseline, 2nd and 5th months of supplementation. The baseline median (interquartile range) of 25(OH)D and parathyroid hormone was 6 (4-11) ng/mL and 19.6 (33-62) pg/mL, respectively. At 2nd month, there was a 3-fold rise in 25(OH)D levels: 19.6 (14.6-28.75) ng/mL and further 50% increase at 5th month of supplementation. Parathyroid hormone levels were suppressed by 38% at 2nd month and remained stable at 5th month. At the end of 5th month, vitamin D sufficiency was attained by 46% participants. Thus, it can be suggested that vitamin D3 supplementation along with elemental calcium 1 g/day is an effective and safe approach for managing vitamin D deficiency.19
82.4
80 70 60 50 40 30
24.7
20
13.5
10 0 At baseline
After 8 weeks
After 1 year
Figure 3. Mean serum 25(OH)D levels in Indians with vitamin D deficiency after administration of 60,000 IU cholecalciferol/week with 1 g elemental Ca daily for 8 weeks.
Of the total study participants, 23 were reassessed for serum 25(OH)D, total calcium, inorganic phosphate and intact parathyroid hormone at 8 weeks as well as after 1 year. The results showed that the mean 25(OH)D levels increased to 82.4 nmol/L at 8 weeks; with the levels >49.9 nmol/L in 22 of 23 candidates. The serum parathyroid hormone also normalized in all of them. At 1 year, although the mean 25(OH)D level was 24.7 nmol/L (remarkably higher than the baseline), all participants were reported to be 25(OH)D deficient; Figure 3. In addition, recurrence of biochemical hyperparathyroidism was noticed in 5 individuals with supranormal intact parathyroid hormone level at baseline. Thus, this study indicates that quick supplementation with cholecalciferol for 8 weeks may be efficient for improving vitamin D and parathyroid hormone levels only for a short duration. However, for maintaining sustained levels, it has been suggested that vitamin D supplementation should be continued even after the initial 8 weeks of cholecalciferol loading regimen.21 CONCLUSION On the basis of the above-mentioned data, it can be suggested that vitamin D is a valuable nutrient. Its deficiency can contribute to the occurrence of several adverse events. Thus, it is important to maintain its optimal concentration. In context to this, mounting evidence emphasizes on the benefits of administering vitamin D3 as a supplement. It not only helps in improving skeletal health but also displays favorable extraskeletal outcomes. Moreover, it is likely to be superior to the other form of vitamin D, vitamin D2.
NUTRACEUTICALS Therefore, its supplementation for normalizing the levels appears to be prudent. A considerable base of evidence has indicated the efficacy of 60,000 IU of cholecalciferol along with calcium for maintaining optimal vitamin D levels. In addition, some researchers have proposed that the initial loading regimen should be followed by the maintenance phase for achieving sustained vitamin D levels. REFERENCES 1. Nair R, Maseeh A. Vitamin D: The "sunshine" vitamin. J Pharmacol Pharmacother. 2012;3(2):118-26. 2. Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium; Ross AC, Taylor CL, Yaktine AL, et al., editors. Dietary Reference Intakes for Calcium and Vitamin D. Washington (DC): National Academies Press (US); 2011. 3, Overview of Vitamin D. Available at: https://www.ncbi.nlm.nih.gov/ books/NBK56061/ 3. Adams JS, Hewison M. Update in vitamin D. J Clin Endocrinol Metab. 2010;95(2):471-8. 4. Anderson PH, May BK, Morris HA. Vitamin D metabolism: new concepts and clinical implications. Clin Biochem Rev. 2003;24(1):13-26. 5. Sunyecz JA. The use of calcium and vitamin D in the management of osteoporosis. Ther Clin Risk Manag. 2008;4(4):827-36. 6. Kennel KA, Drake MT, Hurley DL. Vitamin D deficiency in adults: when to test and how to treat. Mayo Clin Proc. 2010;85(8):752-7; quiz 757-8. 7. Holick MF, Chen TC. Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr. 2008;87(4):1080S-6S. 8. Naeem Z. Vitamin D deficiency - an ignored epidemic. Int J Health Sci (Qassim). 2010;4(1):V-VI.
10. Kochupillai N. The physiology of vitamin D: current concepts. Indian J Med Res. 2008;127(3):256-62. 11. Spiro A, Buttriss JL. Vitamin D: An overview of vitamin D status and intake in Europe. Nutr Bull. 2014;39(4):322-50. 12. Holick MF. Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr. 2004;80(6 Suppl):1678S-88S. 13. Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment. Available at: http:// www.uptodate.com/contents/vitamin-d-deficiencyin-adults-definition-clinical-manifestations-andtreatment. Accessed on 21 Dec, 2016. 14. G R, Gupta A. Vitamin D deficiency in India: prevalence, causalities and interventions. Nutrients. 2014;6(2):729-75. 15. Palacios C, Gonzalez L. Is vitamin D deficiency a major global public health problem? J Steroid Biochem Mol Biol. 2014;144 Pt A:138-45. 16. Basu S, Gupta R, Mitra M, Ghosh A. Prevalence of vitamin D deficiency in a pediatric hospital of Eastern India. Indian J Clin Biochem. 2015;30(2):167-73. 17. Alshahrani F, Aljohani N. Vitamin D: deficiency, sufficiency and toxicity. Nutrients. 2013;5(9):3605-16. 18. Haines ST, Park SK. Vitamin D supplementation: what's known, what to do, and what's needed. Pharmacotherapy. 2012;32(4):354-82. 19. Harinarayan CV, Appicatlaa L, Nalini A, Joshi S. Efficacy and safety of cholecalciferol supplementation in vitamin D deficient subjects based on Endocrine Society Clinical Practice Guidelines. Endocr Metab Syndr. 2012;S4:004. 20. Malhotra N, Mithal A, Gupta S, Shukla M, Godbole M. Effect of vitamin D supplementation on bone health parameters of healthy young Indian women. Arch Osteoporos. 2009;4(1-2):47-53.
21. Goswami R, Gupta N, Ray D, Singh N, Tomar N. Pattern of 25-hydroxy vitamin D response at short (2 month) and long (1 year) interval after 8 weeks of oral supplementation 9. Cuppari L, Garcia Lopes MG, Kamimura MA. Vitamin D with cholecalciferol in Asian Indians with chronic biology: from the discovery to its significance in chronic hypovitaminosis D. Br J Nutr. 2008;100(3):526-9. kidney disease. J Ren Nutr. 2011;21(1):113-6. ■■■■
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OBSTETRICS AND GYNECOLOGY
Obstructed Labor: Scenario in a Tertiary Care Hospital SURYA MALIK*, KHUSHPREET KAUR†, PARNEET KAUR‡
ABSTRACT Background: Obstructed labor is an important cause of maternal and fetal morbidity and mortality. Objective: To study the incidence, causes, maternal outcome including morbidity, mortality and fetal outcome in cases of obstructed labor. Material and methods: The present study was conducted on a prospective basis for 1 year, from 1st February 2011 to 31st January 2012, in the Dept. of Obstetrics and Gynecology, Govt. Medical College and Rajindra Hospital, Patiala, Punjab. All cases who presented with features of obstructed labor were included in this study. Detailed history and thorough general physical examination, local examination, including per abdomen and per vaginum examination was done in every case. A written informed consent was taken in each and every case. Results: During this study period, total number of deliveries were 2223, out of which 33 cases were diagnosed to have obstructed labor, hence the incidence came out to be 1.48%; of these 69.7% were primigravida. Maximum patients (94%) belonged to rural background and were unbooked (84.84%) and uneducated (75.75%). Most common cause of obstructed labor was cephalopelvic disproportion, which was responsible in 69.7% of cases. Lower segment cesarean section (LSCS) was done in 94% of the patients, while 6% of patients underwent laparotomy with subtotal hysterectomy due to rupture uterus. Various complications that were encountered included wound sepsis 21.2%, puerperal sepsis 27.27%, postpartum hemorrhage (PPH) 6%, vesicovaginal fistula (VVF) 3% and ICU stay in 6% of cases. There was no maternal mortality. There were 81.8% live births and 18.18% stillbirths. Conclusion: Obstructed labor has a major contribution in maternal morbidity and mortality. Proper antenatal care, skilled birth attendants, emergency obstetric care and postnatal care are needed for bridging the gaps to attain safe motherhood.
Keywords: Obstructed labor, cephalopelvic disproportion, postpartum hemorrhage, vesicovaginal fistula
O
bstructed labor is an important cause of maternal and perinatal morbidity and mortality.1 In advanced countries, modern obstetrics care and rarity of severely contracted pelvis have led to virtual disappearance of obstructed labor. But in developing countries like India, obstructed labor still remains a frequent obstetric complication.2
Obstructed labor accounts for about 8% of all maternal deaths in developing countries like India.3 It is a leading cause of hospitalization, comprising up to 39% of all obstetric patients in the developing countries.4 Maternal mortality ranges between 1% and 13% and perinatal
*Junior Resident †Professor ‡Associate Professor Dept. of Obstetrics and Gynecology Govt. Medical College and Rajindra Hospital, Patiala, Punjab Address for correspondence Dr Surya Malik A2A, House No-159, Janakpuri West, New Delhi E-mail: surya85.sm@gmail.com
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mortality between 74% and 92%.5,6 Labor is considered obstructed labor when the presenting part of the fetus cannot progress into the birth canal, despite strong uterine contractions, which lead to various maternal and fetal complications.7 Among the common causes are cephalopelvic disproportion, malpresentation and malposition.8 Obstructed labor causes significant maternal morbidity mainly due to infection and hemorrhage and in the long-term leads to obstetric fistulae, skeletal and neurological complications. Fetal death from asphyxia is also common.9 MATERIAL AND METHODS The present study was conducted on a prospective basis for 1 year, from 1st February 2011 to 31st January 2012 in the Dept. of Obstetrics and Gynecology, Govt. Medical College and Rajindra Hospital, Patiala, Punjab. All patients who presented with obstructed labor as obstetric emergency were admitted and included in this study. Detailed history and thorough general physical examination, local examination, including per abdomen and per vaginum examination was done in every case.
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OBSTETRICS AND GYNECOLOGY RESULTS During this 1 year study period, total number of deliveries in the institution were 2223, out of which 33 cases were diagnosed to have obstructed labor. Hence, the incidence came out to be 1.48%. Table 1 shows the demographic profile of the cases. As depicted in the table, maximum (51.5%) of patients were in the age group of 19-24 years followed by 45.5% of the cases who belonged to the age group category of 25-29 years. Of these 33 cases, 23 (69.7%) patients were nullipara. Maximum patients who presented with obstructed labor were uneducated, unbooked and belonged to rural background. Table 2 depicts the causes of obstructed labor. Cephalopelvic disproportion was the main cause responsible for obstructed labor in the present study accounting for 69.7% of all patients, followed by malpresentation and malposition in 21.2% of all patients. Only 1 (3%) case with congenital anomaly presented as obstructed labor. From Table 3, it is well-depicted that 31 (94%) patients underwent lower segment cesarean section (LSCS). In 2 cases (6%) laparotomy followed by Table 1. Demographic Profile of Cases
subtotal hysterectomy was done as these were the cases who presented with rupture uterus as complication. Table 4 described the complications that were seen in the patients with obstructed labor. Rupture uterus was seen in 2 (6%) cases, wound sepsis in 7 (21.21%) cases, puerperal sepsis in 9 (27.27%) cases, postpartum hemorrhage (PPH) in 2 (6%), vesicovaginal fistula (VVF) in 1 (3%) and intensive care unit (ICU) stay was encountered as a complication in 2 (6%) patients. There was no maternal mortality in the present study as patients were managed efficiently in time. Table 5 shows the fetal outcome in the cases of obstructed labor. It was seen that 27 (81.8%) fetuses were born alive, while there were 6 (18.2%) stillbirths. Table 2. Distribution of Cases According to Causes (n = 33) Causes
No.
%
Cephalopelvic disproportion
23
69.7
Malpresentation and malposition
7
21.2
Transverse lie with hand prolapse
2
6
Congenital anomaly
1
3.03
Total
33
100
Table 3. Surgical Interventions
Age (years)
No.
%
19-24
17
51.5
Interventions
No.
%
25-29
15
45.5
LSCS
31
94
>30
1
3
Total
33
100
0
23
39.9
1-2
9
27.3
2-4
1
3
Total
33
100
Laparotomy followed by subtotal hysterectomy
2
6
Total
33
100
Parity
Background
Table 4. Maternal Complications Maternal complications
No.
%
Rupture uterus
2
6
Wound sepsis
7
21.21
Puerperal sepsis
9
27.27
PPH
2
6
VVF
1
3
ICU stay
2
6
Total
33
100
Rural
31
94
Urban
2
6
Total
33
100
Educated
8
24.24
Uneducated
25
75.75
Total
33
100
Fetal outcome
No.
%
Booked
5
15.15
Alive
27
81.80
Unbooked
28
84.84
Dead
6
18.20
Total
33
100
Total
33
100
Literacy
Booking status
Table 5. Fetal Outcome
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OBSTETRICS AND GYNECOLOGY DISCUSSION Present study had 33 cases of obstructed labor. Total deliveries during this period were 2223, hence incidence came out to be 1.48%. This incidence is comparable to the studies done by Gupta et al10 (1.1%), Rizvi et al11 (1.71%) and Dafallah et al12 (1.27%). It was higher than the study done by Adhikari et al,13 which had 0.56% incidence and lower than the study done by Gessessew et al7 (3.3%). In the present study, 74.2% of the cases were primigravida, which is almost similar to the studies by Gupta et al10 and Rizvi et al11 who had reported 81.43% and 73.3% of the cases respectively as primigravida, while Chuni,14 Rather at al15 and Fantu et al16 had reported 43.5%, 46.15% and 34% of cases, respectively as primigravida. In our study, 94% of the patients were of rural background, which is comparable to the studies by Rizvi et al11 and Gupta et al,10 which had 86.5% and 85.7% patients of rural background, respectively. Maximum cases (84.84%) were unbooked in our study; which is again comparable to the studies by Gupta et al10 (66%) and Rizvi et al11 (78.1)%. Cephalopelvic disproportion was the commonest cause for obstructed labor accounting for 70.9% cases in the present study, which is comparable to the studies by Ohonsi et al,17 Chuni,14 Rather et al,15 Fantu et al16 and Gupta et al10 who had reported 75.5%, 65.3%, 87.2%, 67.6%, 63% cases, respectively. Only 3.2% of cases with congenital anomaly were noted in our study, which is comparable to the study by Chuni14 (4.2%). Present study had 94% LSCS rates which is similar to the studies done by Rizvi et al,11 Gupta et al10 and Rather et al,15 who had reported 83.8%, 92.8% and 92.3% as LSCS rates. Laparotomy with subtotal hysterectomy was done in 2 (6%) cases in the present study, which is comparable to the studies by Gupta et al10 and Chuni14 in which laparotomy with subtotal hysterectomy was done in 7.1% and 8.4% cases, respectively. Fantu et al16 had exceptionally high rates of laparotomy i.e., 32.4% as they had 45.1% of cases as rupture uterus. Destructive procedures had no place in our institution. Present study had 21.2% wound disruption rates which are slightly higher than in the studies by Ohonsi et al17 and Rizvi et al,11 which had 11.76% and 12.8% wound disruption rates, respectively. This is due to the fact that maximum patients were anemic and anemia leads to poor wound healing. In our study, 6% of patients were complicated by PPH, which is comparable to the
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studies by Fantu et al,16 Ohonsi et al17 and Rizvi et al11 in which 8.2%, 8.82% and 9.7% cases were complicated by PPH, respectively. VVF as a complication was seen in 3% of cases which is similar to sudies by Fantu et al16 (4.1%), Gupta et al10 (1.4%) and Rizvi et al11 (1.11%). Present study had 100% survival rates which is comparable to studies by Rather et al15 Gupta et al,10 Ohonsi et al17 and Rizvi et al11 and Chuni14 had comparatively lesser survival rates (i.e., 93.24%). Present study had 81.8% live birth rates which is comparable to studies by Rizvi et al,11 Rather et al15 and Gupta et al10 in which 78.7%, 74.36% and 91.4% cases, respectively had live births. Chuni14 and Fantu et al16 had lower live birth rates, 42% and 45.8%, respectively as patients presented late with rupture uterus as complication. CONCLUSION Obstructed labor has a major contribution towards maternal morbidity and mortality. Maternal deaths occur as a result of rupture uterus as well as genital sepsis in women who undergo cesarean section for obstructed labor. Maternal mortality ratio is a slow moving indicator, since 1990 the Global mortality ratio has declined by only 2.3% annually instead of 5.5%, which is required to achieve the millennium development goal (MDG) 5a. Thus, proper antenatal care, skilled birth attendants, emergency obstetric care and postnatal care are needed for bridging the gaps to attain safe motherhood. REFERENCES 1. Mathai M. The partograph for the prevention of obstructed labor. Clin Obstet Gynecol. 2009;52(2):256-69. 2. Mir S, Kounsar S, Fazli S. Clinical aspects of obstructed labour. JK Practitioner. 2003;10(2):123-4. 3. Cron J. Lessons from the developing world: obstructed labor and the vesico-vaginal fistula. MedGenMed. 2003;5(3):24. 4. Mekbib T, Kassaye E, Getachew A, Tadesse T, Debebe A. The FIGO Save the Mothers Initiative: the Ethiopia-Sweden collaboration. Int J Gynaecol Obstet. 2003;81(1):93-102. 5. Rahman MH, Akhter HH, Khan Chowdhury ME, Yusuf HR, Rochat RW. Obstetric deaths in Bangladesh, 1996-1997. Int J Gynaecol Obstet. 2002;77(2):161-9. 6. Hofmeyr GJ, Say L, GĂźlmezoglu AM. WHO systematic review of maternal mortality and morbidity: the prevalence of uterine rupture. BJOG. 2005;112(9):1221-8. 7. Gessessew A, Mesfin M. Obstructed labor in Adigrat Hospital, Tigray region, Ethiopia. Ethiop J Health Dev. 2003;17(3):175-80.
OBSTETRICS AND GYNECOLOGY 8. Konje JC, Ladipo OA. Nutrition and obstructed labor. Am J Clin Nutr. 2000;72(1 Suppl):291S-297S. 9. Arrowsmith S, Hamlin EC, Wall LL. Obstructed labor injury complex: obstetric fistula formation and the multifaceted morbidity of maternal birth trauma in the developing world. Obstet Gynecol Surv. 1996;51(9):568-74.
13. Adhikari S, Dasgupta M, Sanghamita M. Management of obstructed labour: a retrospective study. J Obstet Gynaecol India. 2005;55(1):48-51. 14. Chuni N. Obstructed labor in Eastern Nepal. Singapore J Obstet Gynaecol. 2008;39(1):1-7.
10. Gupta R, Porwal SK. Obstructed labour: Incidence, causes and outcome. Int J Biol Med Res. 2012;3(3):2185-8.
15. Rather SY, Qureshi A, Paeween S. Obstructed labor– current scenario in a developing country. Int J Gynaecol Obstet. 2010;13(2).
11. Rizvi SM, Gandotra N. Maternofetal outcome in obstructed labour in a tertiary care hospital. Int J Reprod Contracept Obstet Gynecol. 2015;4(5):1410-3.
16. Fantu S, Segni H, Alemseged F. Incidence, causes and outcome of obstructed labor in Jimma University Specialised Hospital. Ethiop J Health Sci. 2010;20(3):145-51.
17. Ohonsi AO, Ashimi AO. Obstructed labour: a six year 12. Dafallah SE, Ambago J, El-Agib F. Obstructed labor in review in Aminu Kano Teaching Hospital, Kano, Nigeria. a teaching hospital in Sudan. Saudi Med J. 2003;24(10): Nigerian Medical Practitioner. 2007;51(4):59-63. 1102-4. ■■■■
Female Sex Hormone Linked to Vision Loss in the Children with NF1-associated Brain Tumors Women with mutant Nf1 gene are more likely to experience vision loss, compared to males with mutations in the same gene. Recently researchers at the Washington University School of Medicine in St. Louis, discovered that Female sex hormones are responsible for vision loss in this rare genetic disorder caused by mutation in Nf1 gene. Also, study suggests that by blocking the female sex hormone, activation of specific immune cells in the brain could be suppressed that might help in preventing the vision loss in the children with NF1-associated brain tumors. David H Gutmann, MD, PhD, the David O Schnuck Family Professor of Neurology and the study's senior author said that "We've identified what leads to this difference in vision loss, and that suggests novel potential therapies to treat this serious medical problem in children. Understanding why boys and girls with mutations in the same gene have different outcomes presents unprecedented opportunities to fix the problem."
US FDA’s Accelerated Approval for Drug Rubraca for the Treatment of Females with Advanced Ovarian Cancer Recently US Food and Drug Administration (US FDA) grants accelerated approval to the drug Rubraca (Rucaparib) indicated for the treatment of women with advanced ovarian cancer and having a mutation in BRCA genes. Moreover, US FDA also approved the next-generation-sequencing (NGS)-based- FoundationFocus CDxBRCA companion diagnostic for use with Rubraca. The NGS test detects the mutation in BRCA genes and if more than one mutation is detected in ovarian cancer patients, the treatment with Rubraca is recommended.
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PEDIATRICS
Changing Trends in Childhood Obesity SIDHANT KAPILA*, SNEH PRABHA GOEL†, ASHISH PRAKASH‡, AJAY PUNJ#
ABSTRACT The word obesity is derived from the Latin term ‘obesus’ which means ‘one who has become plump through eating’. Body mass index (BMI) with >30 meets the criteria for obesity, and those with a BMI 25-30 fall in the overweight range. The National Health and Nutrition Examination Survey, 2009-2010, found 32% of children, 2-19 years old to be overweight or obese and 17% in the obese range. Childhood obesity is a single marker of the child at risk for development of various noncommunicable diseases later in life. The problem of overweight and obesity remains hidden in the community, parents do not seek hospital/healthcare facilities services for its remedy. The prevalence of obesity in America and other developed countries is much higher as seen in many studies due to difference in lifestyle and socioeconomic status. We are indeed sitting on a ‘bomb’ called obesity, it is for us to defuse it now promptly or let it explode and cause damage in the form sufferings from diabetes, heart diseases, hypertension and so on. So, Act now forcefully and effectively. The message should reach not only to healthcare providers but also to the general masses too.
Keywords: Childhood obesity, overweight, noncommunicable diseases, healthcare providers, general masses
T
he word obesity is derived from the Latin term ‘obesus’ which means ‘one who has become plump through eating’. Obesity is a global health problem, sparing only dramatically poor regions with chronic food scarcity such as sub-Saharan Africa and Haiti. Obesity or increased adiposity is defined using the body mass index (BMI), which is an excellent proxy for more direct measurement of body fat. BMI = weight in kg/(height in meters).1 BMI with >30 meet the criteria for obesity, and those with a BMI 2530 fall in the overweight range. Consequently, obesity and overweight are defined using BMI percentiles; children >2 years old with a BMI >95th percentile meet the criterion for obesity, and those with a BMI between the 85th and 95th percentiles fall in overweight range.2 According to a recent article published in The Times of India, “One in 5 Indian is fat”, one in 5 men and women in India is overweight and obese. Childhood obesity is
*Assistant Professor †Professor ‡Professor and Head #Associate Professor Dept. of Pediatrics Subharti Medical College and Hospital, Meerut, Uttar Pradesh Address for correspondence Dr Sidhant Kapila Assistant Professor Dept. of Pediatrics Subharti Medical College and Hospital, Meerut, Uttar Pradesh E-mail: drsidhantkapila@yahoo.com
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a single marker of the child at risk for development of various noncommunicable diseases later in life. In addition, the obese suffer from social bias, prejudice and discrimination on the part, not only of the general public but also of health professional and this may make them reluctant to seek medical assistance.1 EPIDEMIOLOGY The percentage of children aged 6-11 years in the United States who were obese increased from 7% in 1980 to nearly 18% in 2012. Similarly, the percentage of adolescents aged 12-19 years who were obese increased from 5% to nearly 21% over the same period.3,4 In 2012, more than one-third of children and adolescents were overweight or obese.3 The National Health and Nutrition Examination Survey, 2009-2010, found 32% of children, 2-19 years old to be overweight or obese and 17% in the obese range. Children’s risk varies significantly by race/ethnicity. In 2009-2010, 24% of nonHispanic Black, 21% of Hispanic and >20% of American Indian/Alaskan Native children and adolescents were obese compared to 14% of White children.2 Over the last three decades, pediatric obesity has become a global epidemic. Worldwide estimates of childhood overweight and obesity are as high as 43 million and rising.5,6 In the United States, approximately 17% of children aged 2-19 years are obese.7 According to the Centers for Disease Control (CDC), the rate of obesity among US children ages 6-11 years tripled from 1980 to 2008 (6.5% to 19.6%).8 Likewise, there is a significant
PEDIATRICS rise in the prevalence of obesity in developing countries (6.8% in India) associated with rapid urbanization resulting in reduction in energy expenditure and an increased intake of energy-dense foods.9,10 In 2007, the US Youth Risk Behavioral Survey indicated that 35% of high school students watched three or more hours of television per day. Sixty-five percent had not met recommended levels of physical activity during a 1-week time period.11 ETIOLOGY Broadly, causes of obesity can be categorized into endogenous and exogenous causes, out of these we can modify the exogenous causes to great extent. Many factors usually working in combination increase the child’s risk of becoming obese. ÂÂ
Diet: Regular consumption of high calorie foods such as fast foods, baked goods and vending machine snacks contribute to weight gain. Loading up on soft drinks, candy and desserts can also cause weight gain.
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Inactivity: Sedentary kids are more likely to gain weight because they don’t burn calories through physical activity. Inactive leisure activities such as watching television or playing video games, contribute to the problem.
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Genetics: If the child comes from a family of overweight people, he or she may be genetically predisposed to put on excess weight.
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Psychological factors: Some children overeat to cope with problems or to deal with emotions, such as stress or boredom.
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Family/Social factors: Most children don’t shop for the family’s groceries. Indeed, parents are responsible for putting healthy foods in the kitchen at home and leaving unhealthy foods at the store. So, we cannot blame our kids for being attracted to sweet, salt and fatty foods but we can control their access to these foods especially at home.12
COMORBIDITIES OF OBESITY About 50-80% of obese children will continue to be obese during adulthood and fall into risk group of complications like hypertension, hypercholesterolemia, obstructive sleep apnea, hyperinsulinemia and insulin resistance, early menarche, slipped capital femoral epiphyses, blount disease, cholelithiasis, pseudotumor cerebri, low self-esteem, polycystic ovary syndrome, nonalcoholic fatty liver disease, impaired cell-mediated immunity and so on.13 Complications of adult obesity
Table 1. Complications Associated with Childhood Obesity Cardiovascular
Respiratory
yy Coronary heart disease yy Hypertension yy Dyslipidemia yy Insulin resistance type 2 diabetes mellitus yy Left ventricular hypertrophy yy Pulmonary hypertension yy Obstructive sleep apnea yy Increased thrombotic state
yy Dsypnea and fatigue yy Obstructive sleep apnea yy Restrictive lung disease yy Asthma
Neurological yy Stroke yy Pseudotumor cerebri yy Meralgia parasthetica
Musculoskeletal yy Degenerative arthritis yy Low back pain yy Slipped capital femoral epiphysis yy Blount’s disease
are made worse if the obesity begins in childhood. Obesity is harder to treat in adults than in children.12 The various complications associated with childhood obesity are given in Table 1. CURRENT TRENDS IN CHILDHOOD OBESITY During the 19th century, ‘obesity’ (from the Latin obesitas meaning fatness) gradually came to replace polysarcia and other terms such as ‘corpulence’ and ‘embonpoint’.7 International Obesity Task Force (IOTF) - Global prevalence of overweight (including obesity) in children aged 5-17 years is estimated to be approximately 10%.3 This is unequally distributed with prevalence ranging from over 30% in America to <2% in sub-Saharan desert.3 According to a recent article published in The Times of India, “One in 5 in India is fat”, one in 5 men and women in India is overweight and obese. Five out of every 100 boys and girls in the country below the age of 20, too, are overweight and obese, according to the most comprehensive global study to date on obesity rates. Prevalence of obesity in children in various studies is summarized in Table 2.
Impact of Calorie Intake Calorie excess, as a cause of obesity, has not been documented in many studies. However, Kapil et al13 found that 17% of all adolescent boys and girls included in their study had energy intake 100% or more as compared to their recommended dietary allowance (RDA).
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PEDIATRICS Table 2. Prevalence of Obesity in Various Studies Studies Kapil et al (2000-2001),
Delhi13
Age
BMI criteria
10-16
25-Overweight
Prevalence of obesity
Overweight obesity
24.7%
7.4%
27.3%
1.7%
19.9%
5.7%
>30-Obese NFI 2002, Delhi14
4-18
>25-Overweight >30-Obese
Khadilkar et al, 2004,
Pune15
>10-15
>25-Overweight >30-Obese
Ambily et al, Kerala (2008)16
10-15
85-95th percentile overweight >95-Obese
17.73%
4.99%
Mahajan et al, Pondicherry (2011)17
6-12
85-95th percentile overweight >95-Obese
4.41%
2.12%
Kumari et al in 201118
13-17
85-95th percentile overweight >95-Obese
8.4% among girls and 6.9% among boys
The Center for Obesity and its Complication in Health (COACH) is Children’s Medical Center at University of Texas Southwestern Medical Center’s strategy to combat and treat pediatric obesity and to focus on diet and exercise as the cornerstone to therapy.
Physical Activity Laxmaih et al in 2007, found that obesity was significantly lower among those participating regularly in outdoor games ≥6 hours/week (3.1%) and household activities ≥3 hours/day (4.7%).19 Bharati et al in 2008, determined the significant correlates of overweight/obesity in the study population and found children playing outdoor games for less than 30 minutes were significantly overweight/obese among the study population.20 Kaur et al in 2008, conducted a study in NCT of Delhi covering a total of 16,595 children in their study and concluded that physical activity and BMI had a statistically negative correlation in the LIG children (r = -0.0346); p < 0.001), MIG children (r = 0.013; p < 0.001) and HIG children (r = -0.058; p < 0.001).21 A recent examination of Dept. of Education Early Childhood Longitudinal Survey (ECLS-K) found that a 1 hour increase in physical activity per week resulted in 1.8% drop in BMI among over overweight.22
Family History of Obesity Obesity is a curse given to us through our family as seen by many studies such as: Ramesh et al in 2010,23 found the prevalence of overweight/obesity higher among study subjects with family history of overweight/obesity (36.7%) compared
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to those without family history of overweight/obesity (8.9%), which is statistically significant. Family history was explored and it was found that the prevalence was higher among subjects with single parent history of overweight/obesity (52.3%) followed by both parents (36.4%), siblings (18.8%), maternal relative (18.3%), paternal relative (15.3%) and both paternal and maternal relative (13%).
Family History of Diabetes Goyal et al in 2010, found that the prevalence of overweight and obesity was more in children with family history of diabetes and obesity. It was concluded in their study that family history of obesity was more likely to have more prevalence of obesity and overweight than those having family history of diabetes.23
Coronary Heart Disease The Framingham Heart Study ranked body weight, as the third most important predictor is coronary heart disease (CHD) among males after age and dyslipidemia. Framingham study followed cohort individuals for 26 years and showed that each 1 SD increment in relative weight was associated with a 15% increase in the risk of cardiovascular events in men and 22% increase in risk of cardiovascular events in women. It has been estimated that the risk of myocardial infarction is 35-55% less in normal weight compared with obese adults. However, the influence of obesity on cardiovascular risk begins before adulthood. Overweight during adolescence is associated with an increased risk of CHD in both sexes.24
PEDIATRICS HYPERTENSION The relationship between BMI and hypertension cannot be characterized by a threshold effect but indeed represents a continuous relationship, suggesting that increasing BMI percentile translates to increased cardiovascular risk. In community hypertension evaluation clinic, a collaborative screening of more than 1 million subjects overweight was associated with 50% higher prevalence of hypertension in both younger and older children.24 ÂÂ
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Asthma occurs in 7-7.5% of children and its prevalence is increasing. The BMI is higher in the age group of 6-16 years with incidence of asthma perhaps up to 30% in these children. Gastrointestinal effects: Gastroesophageal reflux disease (GERD) and gastric emptying disturbances that affect a minority of obese children may be a consequence of raised intra-abdominal pressure due to increased abdominal fat.25
DISCUSSION AND CONCLUSION Childhood obesity is a single marker of the child at risk for development of various noncommunicable diseases later in life. Childhood obesity is associated with many long-term complications like CHD, hypertension, stroke, certain types of cancer, noninsulin-dependent diabetes mellitus (NIDDM), gallbladder disease, dyslipidemia, osteoarthritis, gout, pulmonary diseases including sleep apnea, etc. More than 30% people including children have potbelly abdominal obesity. Abdominal girth of >90 cm in men and 80 cm in women indicates that the person is vulnerable to future heart attack. Normal weight obesity is the new epidemic. A person could be obese even if his body weight was within the normal range. An extra inch of fat around the abdomen increases the chances of heart disease by 1.5 times.26 Recently, an article published in Indian Pediatrics, which summarized the various aspects of the influence of obesity on pubertal development i.e., increased height and BMI of children, prior to puberty, results in an early onset of puberty.27 There by clearly sending a message that the problem of overweight and obesity remains hidden in the community, parents do not seek hospital/healthcare facilities services for its remedy. The prevalence of obesity in America and other developed countries is much higher as seen in many studies due to difference in lifestyle and socioeconomic status.
We are indeed sitting on a ‘bomb’ called obesity as is obvious from this article. It is for us to defuse it now promptly or let it explode and cause damage in the form of sufferings from diabetes, heart diseases, hypertension and so on. So, act now forcefully and effectively. The message should reach not only to health care providers but also to the general masses too. REFERENCES 1. Childhood Obesity: Complications. Mayoclinic.Com. 2. Kliegman. Nelson Textbook of Pediatrics. Vol. 1 20th First South Asia Ed 2015; Overweight and Obesity 2015. pp. 307-16. 3. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of childhood and adult obesity in the United States, 2011-2012. JAMA. 2014;311(8):806-14. 4. National Center for Health Statistics. Health, United States, 2011: With Special Features on Socioeconomic Status and Health. Hyattsville, MD; U.S. Department of Health and Human Services; 2012. 5. Dietz WH. Overweight in childhood and adolescence. N Engl J Med. 2004;350(9):855-7. 6. Pulgarón ER. Childhood obesity: a review of increased risk for physical and psychological comorbidities. Clin Ther. 2013;35(1):A18-32. 7. Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ, Flegal KM. Prevalence of overweight and obesity in the United States, 1999-2004. JAMA. 2006;295(13):1549-55. 8. U.S. Centers for Disease Control and Prevention. Health Topics: Childhood Obesity. Last revised on January 5, 2011. 9. Bhardwaj S, Misra A, Khurana L, Gulati S, Shah P, Vikram NK. Childhood obesity in Asian Indians: a burgeoning cause of insulin resistance, diabetes and sub-clinical inflammation. Asia Pac J Clin Nutr. 2008;17 Suppl 1: 172-5. 10. Singh RB, Pella D, Mechirova V, Kartikey K, Demeester F, Tomar RS, et al; Five City Study Group. Prevalence of obesity, physical inactivity and undernutrition, a triple burden of diseases during transition in a developing economy. The Five City Study Group. Acta Cardiol. 2007;62(2):119-27. 11. Eaton D, Kann L, Kinchen S, Shanklin S, Ross J, Hawkins J, et al. Youth risk behavior surveillance - United States, 2007. MMWR Surveill Summ. 2008;54:1-131. 12. Park K. Textbook of Preventive and Social Medicine. 18th Edition, Jabalpur, India: Banarsidas Bhanot Publishers; 2005. pp. 316-9. 13. Kapil U, Singh P, Pathak P, Dwivedi SN, Bhasin S. Prevalence of obesity amongst affluent adolescent school children in Delhi. Indian Pediatr. 2002;39(5):449-52. 14. Chatterjee P. India sees parallel rise in malnutrition and obesity. Lancet. 2002;360(9349):1948.
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PEDIATRICS 15. Khadilkar VV, Khadilkar AV. Prevalence of obesity in affluent school boys in Pune. Indian Pediatr. 2004;41(8):857-8. 16. Unnithan AG. Prevalence of overweight, obesity and underweight among school going children in rural and urban areas of Thiruvananthapuram, Kerala. Int J Nutr Wellness. 2006, Vol. 6 No. 2. 17. Mahajan PB, Purty AJ, Singh Z, Cherian J, Natesan M, Arepally S, et al. Study of childhood obesity among school children aged 6 to 12 years in union territory of puducherry. Indian J Community Med. 2011;36(1):45-50. 18. Kumari JD, Krishna BSH. Prevalence and risk factors for adolescents (13-17 years): overweight and obesity. Curr Sci. 2011;100(3):373-7. 19. Laxmaiah A, Nagalla B, Vijayaraghavan K, Nair M. Factors affecting prevalence of overweight among 12- to 17-year-old urban adolescents in Hyderabad, India. Obesity (Silver Spring). 2007;15(6):1384-90. 20. Bharati DR, Deshmukh PR, Garg BS. Correlates of overweight & obesity among school going children of Wardha city, Central India. Indian J Med Res. 2008;127(6):539-43.
school children in Delhi, India. Asia Pac J Clin Nutr. 2008;17(4):592-6. 22. Raj M, Sundaram KR, Paul M, Deepa AS, Kumar RK. Obesity in Indian children: time trends and relationship with hypertension. Natl Med J India. 2007;20(6):288-93. 23. Goyal RK, Shah VN, Saboo BD, Phatak SR, Shah NN, Gohel MC, et al. Prevalence of overweight and obesity in Indian adolescent school going children: its relationship with socioeconomic status and associated lifestyle factors. J Assoc Physicians India. 2010;58:151-8. 24. Sinaiko AR, Donahue RP, Jacobs DR Jr, Prineas RJ. Relation of weight and rate of increase in weight during childhood and adolescence to body size, blood pressure, fasting insulin, and lipids in young adults. The Minneapolis Children's Blood Pressure Study. Circulation. 1999;99(11):1471-6. 25. Shah A, Uribe J, Katz PO. Gastroesophageal reflux disease and obesity. Gastroenterol Clin North Am. 2005;34(1): 35-43. 26. Aggarwal KK. Tackling Obesity in Children AJPP (Editorial). 2015;18(6):5.
27. Unni JC. Onset of puberty in relation to obesity. Indian 21. Kaur S, Sachdev HP, Dwivedi SN, Lakshmy R, Kapil Pediatr (Editorial). 2016;53(5):379-80. U. Prevalence of overweight and obesity amongst ■■■■
Consequences of Reduced-duration vs. Standard-duration Antimicrobial Therapy in Infants with Acute Otitis Media A study published online in The New England Journal of Medicine, assesses whether reducing the duration of antimicrobial therapy reduces the risk of antimicrobial resistance among children with acute otitis media. It was found that reduced-duration of amoxicillin–clavulanate therapy resulted in less favorable outcomes than standard-duration treatment among children aged 6 to 23 months. Moreover, no reduction in adverse events nor in the rate of emergence of antimicrobial resistance was observed.
Experimental Therapy for Prader-Willi Syndrome Shows Promise in Mice A study published online in the journal Nature Medicine, assesses the survival and growth outcomes in mouse model of Prader-Willi syndrome, by activating maternal-silenced-genes responsible for PWS and observed that 2 drugs called NC0638 and UNC0642, can possibly activate the maternal-silenced-genes in mouse model of PWS. Further, it was observed that UNC0642 demonstrated more favorable pharmacological features, in PWS mouse models. Researchers also reported the mechanism of action of NC0638 and UNC0642 drugs, which operates by inhibiting the activity of a protein called G9a, which is among those proteins that are responsible for packing the maternal genes tightly in the chromosome.
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MEDILAW
Maintaining Correct and Updated Medical Records of the Patient A man approached the medical council and filed a complaint against the treating doctor stating that his wife’s treatment was stopped by the treating doctor because of monetary considerations regarding the cost of investigations and the surgical procedure required. The case is dismissed as there is nothing on records to suggest that the treatment was stopped.
I deny the allegations. You may crosscheck from the medical records of the patient. Proceed The doctor stopped my wife’s treatment because of monetary considerations.
Lesson: Maintaining timely and correct medical records can save one from such allegations (DMC/14/2/DC/219/2006 dated 27th March, 2007).
CASE SUMMARY
Course of Events ÂÂ 9.3.2005: Patient Y, a 55-year-old female hospitalized with complaints of severe headache and vomiting. ÂÂ 9.3.2005: Computed tomography (CT) head done, which showed subarachnoid hemorrhage with mild hydrocephalus. ÂÂ 10.3.2005: Cerebral angiography advised; but, the relatives of the patient did not give consent for it. ÂÂ 14.3.2005: Magnetic resonance angiography (MRA) done, which showed moderate narrowing of left middle cerebral artery (MCA) and moderate to marked diffuse narrowing of bilateral anterior cerebral artery (ACA) probably due to spasm with subarachnoid hemorrhage and intraventricular hemorrhage with hydrocephalus. ÂÂ General condition of the patient worsened and she developed right-sided hemiparesis. ÂÂ 16.3.2005: External ventricular drain (EVD) put under high-risk consent with a guarded prognosis.
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ÂÂ
The patient put on ventilator.
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17.3.2005: CT head done, which showed multiple territory infarcts.
ÂÂ
21.3.2005: EVD removed.
ÂÂ
26.3.2005: Patient developed bradycardia; she was resuscitated and put on inotropic support.
ÂÂ
27.3.2005: Another episode of bradycardia followed by sudden cardiac arrest. Despite all resuscitative measures, the patient could not be revived and was declared dead at 9.55 am.
Complainant Allegations ÂÂ
The patient was asked to get the CT scan from an outside center despite CT scan facilities at the said hospital.
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No treatment administered to the patient for 2 hours following admission.
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Treatment being administered to the patient was stopped because of monetary considerations.
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Incompetence of the treating doctor.
MEDILAW monetary considerations. It was found to be incorrect. Records of the patient also did not suggest the same.
OBSERVATIONS OF THE DELHI MEDICAL COUNCIL
Allegation 1 The patient was referred to an outside center for CT scan as the CT scan of the hospital was out of order. Respondent no. 1 admitted to the same. Examination of a copy of the log book maintained by the said hospital also confirmed that on the same day, other patients too were sent outside for CT scan.
Allegation 4
Allegation 2
The Council observed that the treatment strategy adopted for this patient was in line with the accepted professional practices in such cases. The DMC decided that no medical negligence could be attributed on the part of Respondents 1 to 4 in the treatment administered to Patient X.
Respondents 1 to 4 asserted that the patient was administered proper treatment. The records of the hospital also corroborated these assertions made. The allegation was found to be baseless.
Allegation 3 Respondent no. 4 denied that the treatment being administered to the patient was stopped because of
Respondent no. 3 had an M.Ch (Neurosurgery) degree with enough post-M.Ch experience and was competent to perform the required surgical procedure.
Judgment
Reference
1. DMC/14/2/DC/Comp. 219/2006/dated 27th March, 2006. ■■■■
Indian Journal of Clinical Practice, Vol. 27, No. 8, January 2017
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CONFERENCE PROCEEDINGS
46th Annual Conference of Endocrine Society of India (ESICON 2016) DIABETES MANAGEMENT IN RECENT TIMES
ÂÂ
Plasma glucose measurement is important since several chemicals in the blood can interfere with blood glucose measurement.
ÂÂ
Correction of low glucose corrects symptoms: Most symptoms subside in 10-15 minutes. Minor symptoms may last for an hour or two.
ÂÂ
Hypoglycemia in a person not otherwise sick: Draw blood during the episode.
ÂÂ
Check if it is insulin-dependent; check C-peptide and proinsulin and screen for sulfonylurea and meglitinides.
ÂÂ
Postprandial spells of hypoglycemia - months to years after gastric bypass: Multifactorial; precipitated by refined carbohydrates, rapid eating, drinking with food especially fizzy drinks, alcohol.
Dr Prof Subhankar Chowdhury, Kolkata How has the management of diabetes changed in recent times? In the last 10 years, we have moved away from glucocentric to a more holistic approach. Clinicians are gradually shifting away from just the glycemic control. New medications are increasingly becoming available and there is decreased use of insulin. Which new antidiabetic drugs have been introduced? SGLT-2 inhibitors and gliptins are new drugs. In the class of small molecules, 2 new GLP-1 analogues have been introduced this year - lixisenatide and dulaglutide. Hydroxychloroquine is being marketed as an antidiabetic drug in India only. Where does hydroxychloroquine antidiabetic drug armamentarium?
stand
in
the
We are still looking for its right usage as the study based on which it was marketed was a small one. It can probably be advocated as the third-line drug for diabetes. It is important to note that some relative contraindications may be a factor.
LOOKING BEYOND INSULIN-DEPENDENT THERAPIES: THEN AND NOW Dr Serge A Jabbour, US ÂÂ
Most current therapies for T2DM have insulindependent mechanism of action.
ÂÂ
There is a need to look beyond insulin-dependent therapies towards comprehensive treatment options.
ÂÂ
There are several limitations of the current antidiabetic therapies including, risk of hypoglycemia, weight gain, edema, fractures, reports of bladder cancer, etc.
ÂÂ
Managing multiple parameters in diabetes is essential.
ÂÂ
Ideal antidiabetic agent: Oral drug; quick onset of action; significant and sustained A1c reduction; weight neutral or weight loss.
ÂÂ
SGLT-2 inhibitors lower renal threshold for glucose excretion.
ÂÂ
SGLT-2 inhibitors remove excess glucose in urine independently of insulin.
ÂÂ
SGLT-2 inhibitors lower HbA1c and address other CV risk factors - glycemic control, weight loss, BP reduction.
What are the key take home messages from your talk? Hydroxychloroquine probably has a future in the management of type 2 diabetes mellitus. It is effective. However, retinopathy is one major concern. Extrapolation of usage from rheumatoid arthritis studies suggest that the risks are small when used as an antidiabetic drug with additional beneficial action on insulin sensitivity. MMS Ahuja Hoechst India Oration HYPERINSULINEMIC HYPOGLYCEMIA IN PEOPLE WHO DO NOT HAVE DIABETES Dr Pankaj Shah, US ÂÂ
782
Diagnosis of hypoglycemia is essentially made on the documentation of Whipple’s triad: Symptoms caused by hypoglycemia; documentation of low plasma glucose at the time of symptoms; relief of symptoms when plasma glucose is raised to normal.
Indian Journal of Clinical Practice, Vol. 27, No. 8, January 2017
CONFERENCE PROCEEDINGS ÂÂ
SGLT-2 inhibitors seem to be the ideal agents.
ÂÂ
Even if the BMI is normal, SGLT-2 inhibitors will lead to significant A1c drop.
ÂÂ
Dapagliflozin as add-on therapy to metformin Reduction in total body weight principally due to reduction in fat mass; most of this fat loss is visceral fat loss.
ÂÂ
SGLT-2 inhibitors show sustainability over 4 years as an add-on to metformin vs. sulfonylureas.
ÂÂ
Benefits of SGLT-2 inhibitors - Fast action; glucose lowering; weight loss and BP reduction and flexibility.
ÂÂ
Do not use SGLT-2 inhibitors in - T1DM patients; those >65 years of age; those with eGFR <45 mL/ min/1.73 m2; pregnant and nursing women; patients with history of volume depletion and those with dehydration.
ÂÂ
SGLT-2 inhibitors can be used as monotherapy or as add-on therapy.
ÂÂ
Blood glucose starts to improve in the first 24-72 hours.
RESIDUAL OR RECURRENT PHEOCHROMOCYTOMA MANAGEMENT Dr Mala Dharmalingam, Karnataka ÂÂ
Pheochromocytoma is a cause for secondary hypertension.
ÂÂ
Residual or recurrent disease should be thought if it occurs in younger individuals; common causes of residual disease are MEN2, VHL and paragangliomas and NF1.
ÂÂ
A proper follow-up is required for management.
ÂÂ
This includes imaging with MRI and PET scan. Newer genetic analysis can be done.
ÂÂ
Treatment options include surgical ablation, radio beam therapy or combination chemotherapy.
CARDIOVASCULAR OUTCOME TRIALS ARE NOT WORTH THE MONEY SPENT Dr Jubbin Jagan Jacob, Ludhiana
Against the Motion ÂÂ I believe that Cardiovascular Outcome Trials (CVOT) are worth the money especially with the huge number of choices that we have among oral antidiabetic drugs. ÂÂ Huge money spent by Pharma companies on brand marketing is much better utilized in CVOT and other Phase 4 outcome studies.
ÂÂ
The dramatic positive outcomes of EMPA-REG, LEADER & SUSTAIN-6 Trials have now established the benefits of CVOTs beyond establishing safety as originally mandated by the US FDA.
ÂÂ
This also brings attention to the older generic diabetic drugs like metformin, sulfonylureas and human insulin in which money needs to be spent on CVOTs.
THYROID DYSFUNCTION AND PREGNANCY Dr Tushar Bandgar, Mumbai How does thyroid dysfunction affect pregnancy outcomes? It affects both ways as over function can cause hyperthyroidism and less function leads to hypothyroidism. During conception, late treatment can cause infertility. A patient may be pregnant and have minimal thyroid problems in which case the baby puts extra demand on thyroid system of mother. It can often lead to miscarriage in early and late trimester. For mother, complications are hypotension, hemorrhage and placental abruption. For baby, low birth weight, stillbirth and mental retardation can occur if mother is having hypothyroidism. Is there a difference in thyroxine replacement therapy in preconception than during pregnancy? Yes, it is beneficial the earlier it is given. Organ and brain development occurs in first month, thyroid development in 2nd trimester. So, for the first trimester, baby is completely dependent on mother’s thyroid supply. What are the key take home messages from your talk? We need to look for evidence of subclinical thyroid problems. We also need more evidence for autoimmunity, as it can be a risk factor for mother and baby both. APPROACH TO TALL STATURE Dr Pramod Gandhi, Maharashtra How do you approach a case of tall stature? What is the prevalence of such cases? The prevalence of such cases is almost the same as short stature but the referrals are very infrequent, especially in boys; most cases do not seek medical attention. Referral rate is considerably higher among females.
Indian Journal of Clinical Practice, Vol. 27, No. 8, January 2017
783
CONFERENCE PROCEEDINGS The approach is based on clinical evaluation. Ninety percent cases require no clinical intervention. Height, age, bone age and chronological age help in differential diagnosis. What are the key take home messages from your talk?
Hypoparathyroidism: New insights into management - Role of PTH is emphasized with the added advantage of improving bone micro-structure. Twice-daily dosage is preferred for PTH 1-34 whereas, PTH 1-84 is given as a single dose per day.
Most of the times, tall stature is familial. No treatments are required in these cases; assurance from parents is advised for kids. If some organic underlying cause is there, then only treatment options are considered.
Hypoparathyroidism during pregnancy can cause miscarriage, intrauterine fractures and neonatal hypocalcemia. Higher doses of vitamin D are required during pregnancy in those with hypoparathyroidism.
TETE-A-TETE WITH DR ASHU RASTOGI
TETE-A-TETE WITH DR AG UNNIKRISHNAN
Dr Ashu Rastogi, Chandigarh What is your approach to a newly diagnosed type 2 diabetes patient? Best approach is lifestyle and dietary management coupled with metformin. It also depends on the baseline Hb1Ac and blood glucose levels. Which class of antidiabetic drugs is most prescribed according to your clinical experience? Metformin followed sulfonylureas.
by
DPP-4
inhibitors
and
Dr AG Unnikrishnan, Pune What is the prevalence of hyperaldosteronism in the population? Primary hyperaldosteronism is a rare cause of hypertension. Before the era of testing for plasma aldosterone and plasma renin activity, only about 0.5-1% of hypertension could be attributable to primary hyperaldosteronism. After easier availability of appropriate biochemical testing, about 5-10% of hypertension is attributable to primary hyperladosteronism.
What are the key take home messages from your talk?
What are the principal features of hyperaldosteronism?
At present, we need more efficacy and safety data with bromocriptine, hydroxychloroquine and saroglitazar for diabetes management.
The occurrence of hypertension and hypokalemia (in the absence of other factors like vomiting or diuretics to explain the low potassium) should signal to the clinician that mineralocorticoid excess could be present. Glucose intolerance also may be a feature. In suspected cases, plasma aldosterone concentration (PAC):plasma renin activity (PRA) ratio is more than 20 ng/dL per hour plus PAC â&#x2030;Ľ15 ng/dL - indicates that primary hyperaldosteronism is the likely etiology.
THYROID/PARATHYROID SYMPOSIUM Dr Santosh Kumar Singh, Patna
Key Topics from the Chair Thionamide intolerance: Definitive treatment includes radio-iodine therapy and surgery. Interim treatment options are potassium iodide, steroids, lithium and L-carnitine (including treated Gravesâ&#x20AC;&#x2122; disease having TSH receptor antibody). Genetic testing (HLA-B27.07) is advised for patients prone to agranulocytosis with thianomide. Obesity and thyroid cancer: There is definitive association between the two conditions. There is a weak link with obesity genes viz. FTO and insulin receptor gene. There is a high contribution of smoking cessation on increased body weight and thyroid cancer. Interesting observations have been made about association of leptin obesity receptor being harmful for papillary but beneficial for follicular carcinoma. There is an associated link with vitamin D deficiency (more common in obese) and thyroid cancer.
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Indian Journal of Clinical Practice, Vol. 27, No. 8, January 2017
What are the major factors that interfere with the interpretation of aldosterone/plasma renin activity ratio? A number of drugs interfere with the test. These include beta blockers, ACE inhibitors and angiotensin receptor blockers. Moreover, many clinical conditions such as hypokalemia and salt depleted diets can interfere with the test. Certain conditions such as renal artery stenosis may elevate PRA. In many of the conditions, PRS and PACs alter concordantly, keeping the ratios within the upper limit. But disease states like primary hyperladosteronism are typically associated with a high ratio. What are the key take home messages from your talk? While it is important to suspect primary hyperaldosteronism, it is probably equally important
CONFERENCE PROCEEDINGS to correctly interpret the PAC:PRA ratio values. Understanding the limitations of the test, medications interfering with the test, and finally the clinical conditions affecting the values is important to diagnose an abnormal result/ratio, before proceeding towards confirmatory testing, imaging or adrenal venous sampling. MANAGEMENT OF ACROMEGALY: CURRENT CONCEPTS Dr R Khardori, Norfolk, VA ÂÂ
The reported prevalence of acromegaly is as high as 480-1,000/million.
ÂÂ
Diagnosis of acromegaly is based demonstration of elevation of IGF-1.
ÂÂ
Management:
on
the
First-line therapy: Pituitary surgery with initial remission rate of microadenoma: 85%; macroadenoma 40-50%
Should patients with diabetes be followed using different parameters How often to obtain IGF-1/GH paired measurement?
Summary ÂÂ
Surgery is the mainstay of treatment.
ÂÂ
Combined therapy yields much better biochemical and clinical response; adverse effects remain a matter of concern.
ÂÂ
New imaging technology offers better guidance to medical therapy.
ÂÂ
Concept of extrahepatic acromegaly is drawing attention.
ÂÂ
Persistence of clinical symptoms despite biochemical cure is not addressed adequately.
ENDOCRINE DISRUPTING CHEMICALS: IMPLICATIONS IN THYROID DISORDERS
Second-line therapy: Medical treatment: For residual disease after surgery
Dr Barbara Demeneix, Paris
Third-line therapy: Radiotherapy.
Focus on Neurodevelopmental Disease
ÂÂ
In selected cases, medical management can be used as primary therapy.
ÂÂ
There is an increasing incidence of sporadic congenital hypothyroidism in the USA.
ÂÂ
Nonsurgical management: Currently there are three classes of drugs: Dopamine receptor agonists - effective in 10-40%; somatostatin receptor ligands effective in 70%; GH receptor antagonists effective in 90-97%. Chimeric drugs: Interact with both somatostatin and dopamine receptors
ÂÂ
Environmental factors may be implicated in this.
ÂÂ
Japanese data show a correlation between dioxinlike chemicals (PCB/pesticides) and congenital hypothyroidism incidence.
ÂÂ
These compounds can lead to cretinism.
ÂÂ
There is an unexplained increase in autism spectrum disorders (ASD) in the USA.
Radiotherapy.
ÂÂ
Available and investigational drugs that block GH action: Pegvisomant.
Up to 40% of children are diagnosed to have intelligence quotients (IQs) <70.
ÂÂ
Gene-environment suspected.
ÂÂ
ADHD has increased in USA: Latest CDC statistics 14% of boys affected.
ÂÂ
Production by chemical industry is set to increase 300-fold between 1970-2020.
ÂÂ
Many of the industrial chemicals are halogenated and interfere with thyroid hormone signaling.
ÂÂ
Thyroid hormone production and signaling is more prone to disruption than any other endocrine system.
ÂÂ
There is a need for tight control of maternal levels of TSH in early pregnancy.
ÂÂ
ÂÂ
Determinants of response to therapy, survival and detractors: Size of tumor; Somatostatin receptor isoform characteristics Proliferation index Tissue characteristics Presence of AIP mutation.
ÂÂ
In acromegaly patients with diabetes, higher doses of medication may be required.
ÂÂ
Limitations of current therapy: How to reconcile discordance between GH and IGF-1 measurement
interactions
are
strongly
Indian Journal of Clinical Practice, Vol. 27, No. 8, January 2017
785
CONFERENCE PROCEEDINGS ÂÂ
An article by Tim Korevaar and colleagues has shown that both high and low maternal free thyroxine in early pregnancy are associated with a significant decrease in child IQ.
ÂÂ
Shah et al have shown that laparoscopic sleeve gastrectomy is an effective adjunct in the treatment of T2DM in obese individuals in India.
ÂÂ
The COSMID (Comparison of Surgery vs. Medicine for Indian Diabetes) Trial indicates that bariatric surgery is more effective than medical and lifestyle management in controlling type 2 diabetes.
ÂÂ
Surendra Ugale and coworkers showed a 72% remission rate following Ileal Interposition coupled with Diverted Sleeve Gastrectomy (IIDSG).
Conclusion ÂÂ
Chemical testing and regulatory decision making are not keeping pace with scientific knowledge.
ÂÂ
More than 15 chemical classes are found in most adults.
ÂÂ
These chemicals pass the placenta and are found in the amniotic fluid.
ÂÂ
More than 2/3rd of the chemicals disrupt thyroid hormone signaling.
ÂÂ
Maternal exposure to some of these chemicals increases the risk of neurodevelopmental disorders and IQ loss.
ÂÂ
Iodine supplementation for women of childbearing age and children is required.
DIABETES REMISSION AFTER BARIATRIC PROCEDURES: REVIEW OF INDIAN AND ASIAN DATA Dr Mahendra Narwaria, Ahmedabad ÂÂ
Asians generally have a higher percentage of body fat than white people of same age, sex and BMI.
ÂÂ
Obesity is a major risk factor for development of T2DM.
ÂÂ
An important factor for increased T2DM in Asians is excessive insulin resistance.
ÂÂ
Bariatric surgery is the most effective treatment for those who do not respond to lifestyle modification and medication.
ÂÂ
Bariatric surgery improves T2DM in 90% of patients.
ÂÂ
Types of bariatric surgery: Restrictive procedure; malabsorptive procedure; mixed procedure.
ÂÂ
Lee et al reported in a 2012 study that bariatric surgery is recommended for obesity-related T2DM patients with elevated C-peptide.
ÂÂ
T2DM remission is secondary to weight loss and calorie restriction.
ROLE OF DUAL PPAR AGONIST IN THE MANAGEMENT OF ATHEROGENIC DYSLIPIDEMIA Prof Dr Surender Kumar, New Delhi Diabetes is rising rapidly, globally, as well as in India. Major cause of morbidity and mortality in diabetes is cardiovascular disease (CVD). Almost 9 out of 10 diabetic patients suffer from dyslipidemia. Indian phenotype (genetic, behavioral and environmental factors) is associated with higher incidence of insulin resistance, which is associated with atherogenic dyslipidemia, i.e., high triglycerides (TGs) and low HDL. Recent large observational studies have clearly established the positive relationship between plasma TG and adverse CV outcome. High plasma TG is also positively correlated with proportion of small dense LDL particles, which make diabetic patients more vulnerable to atherosclerotic CVD. Various subgroup analyses of TG-lowering studies have shown that TG-lowering therapy translates into significant CV risk reduction in patients with baseline TG >200 mg/dL. Saroglitazar is a novel agent, having dual PPAR-α and -γ agonist action, producing dual action on lipids (TG and non-HDL-C reduction) and blood glucose (improve insulin sensitivity). The drug has been found to be safe and well-tolerated in type 2 diabetes with TG >200 mg/dL. It is not associated with weight gain or edema and there is no adverse effect on renal or liver functions. No muscle related toxicity has been reported. Saroglitazar is a potential therapeutic option for the treatment of atherogenic dyslipidemia in type 2 diabetes with additional beneficial action on insulin sensitivity.
■■■■
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Indian Journal of Clinical Practice, Vol. 27, No. 8, January 2017
CONFERENCE PROCEEDINGS
10th World Stroke Congress 2016 STROKE POLICIES AT WHO - PRIORITIES AND ACTIONS Dr Cherian Varghese, Switzerland ÂÂ
ÂÂ
ÂÂ
ÂÂ
WHO Global NCD Action Plan 2013-2020: Vision: A world free of the avoidable burden of NCDs. Goal: To reduce the preventable and avoidable burden of morbidity, mortality and disability due to NCDs by means of multisectoral collaboration and cooperation at national, regional and global levels. Systems of monitoring: Develop or adapt locally, appropriate systematic monitoring of patients using electronic systems; use a set of appropriate and standardized indicators to assess the program performance and coverage; monitor and report treatment outcomes. Immediate actions for Member States 2014-2015: Set national targets for 2025 in 2013, taking into account 9 global targets; develop national multisectoral NCD policies and plans to attain national targets for 2025, by addressing the three major components of NCD strategy. WHO Global Monitoring Framework on NCDs - Outcome indicators: Mortality and morbidity: Unconditional probability of dying between the ages of 30 and 70 years from CVD, cancer, etc. Risk factors: Harmful use of alcohol, low fruit and vegetable intake, physical inactivity, salt intake, tobacco use. National Systems Response: Cervical cancer screening, drug therapy and counseling, essential NCD medicines and technologies, hepatitis B vaccine and access to palliative care.
ÂÂ
The CT angiography performed aboard the STEMO allows for identification of patients with LVO.
ÂÂ
This optimizes triage of patients who need admission to a center capable of endovascular treatment and has the potential to speed up acute care.
ROLE OF STROKE NURSE IN HOSPITAL, RURAL SETTINGS AND TELE-STROKE Ms Manju Dhandapani, Chandigarh ÂÂ
There is an increasing trend of stroke incidence in the rural population.
ÂÂ
Stroke leaves varying degrees of cognitivefunctional disability and neuropsychiatric symptoms among survivors.
ÂÂ
Stroke associated mortality is high among rural patients.
ÂÂ
Stroke nurses play a pivotal role in all phases of care of stroke patients: Improve public awareness on stroke Identify patients with risk factors and enforce adoption of preventive strategies among these patients Ensure timely assessment and evidencebased care in hospitals Prevent, identify early or manage following complications: Pneumonia, aspiration, pressure sore, nutritional depletion, urinary tract infection, deep vein thrombosis contractures.
ÂÂ
Enforce timely follow-up and rehabilitation.
ÂÂ
Tele-stroke facility, where stroke centers receive guidelines in management of the patient from hub center, may address the issues of stroke diagnosis and care in rural centers.
ÂÂ
The role played by stroke nurses as care provider, educator, manager and researcher can facilitate best stroke care.
STEMO FOR PREHOSPITAL TRIAGE AND TREATMENT Dr Martin Ebinger, Berlin ÂÂ
Prehospital triage has become even more important in the new area of endovascular stroke treatment.
ÂÂ
Clinical scores alone cannot reliably identify patients with large vessel occlusions (LVOs).
ÂÂ
STEMO, a special ambulance with CT scanner and point-of-care laboratory, staffed with a neurologist, a paramedic and a radiology technician, can shorten onset-to-treatment times by performing thrombolysis in a prehospital setting.
GLOBAL BURDEN OF STROKE: HYPERTENSION AT THE CORE Dr Daniel T Lackland, Charleston, USA ÂÂ
High blood pressure is the most prevalent and modifiable global risk factor for stroke.
Indian Journal of Clinical Practice, Vol. 27, No. 8, January 2017
787
CONFERENCE PROCEEDINGS ÂÂ
As populations in developing countries increase in size and age, hypertension will increase the burden.
ÂÂ
In addition to pharmaceutical management of elevated blood pressure, lifestyle modifications including salt reduction, physical activity and weight management can be effective in lowering blood pressure.
ÂÂ
A key to the global prevention and control of hypertension and hypertension-related outcomes including stroke, is blood pressure measurement. The theme of World Hypertension Day is ‘Know Your Numbers’, and all persons, regardless of age or gender, should be aware of their blood pressure.
INTRA-ARTERIAL TREATMENT FOR ACUTE ISCHEMIC STROKE
These patients require vessel imaging like carotid Doppler or digital subtraction angiography. Thrombolysis has bleeding as a potential adverse effect. What is the incidence of intracerebral hemorrhage in patients with stroke who undergo thrombolysis? It depends upon the time of admitting. If it is delayed, hemorrhagic events are more. It also depends on blood pressure on presentation. About 4-6% can develop fatal intracerebral hemorrhage. NURSING ASSESSMENT OF DYSPHAGIA Dr Giselle Carnaby, Orlando, USA ÂÂ
Nurses are well positioned to screen for swallowing issues in acute stroke.
ÂÂ
Current screening methods are subjective, and subject to language and cognition barriers in their application.
ÂÂ
New methods to screen swallowing in acute stroke use a biological marker - Spontaneous swallowing frequency (SFA) - to identify dysphagia. SFA has been shown to be superior to nurse screening and psychometrically valid and reliable. It can predict important negative outcomes in acute stroke patients.
Dr Diederik Dippel, Rotterdam, The Netherlands ÂÂ
Intra-arterial treatment, by means of stent thrombectomy, is safe and very effective for patients with a proximal intracranial thromboembolic occlusion in the anterior circulation.
ÂÂ
The treatment effect is equally large for patients who have been treated with IV-tPA and for patients who were not eligible for IV-tPA.
ÂÂ
ÂÂ
On average it will save 1 patient from death or disability for every 3-7 treated.
STROKE MEDICINE - NOT ONLY ISCHEMIA, AND MORE THAN JUST NEUROLOGY
ÂÂ
Time is crucial; for every hour delay, the benefit of treatment diminishes by 6%.
ÂÂ
The best way to improve your treatment results is by improving the logistics of your acute stroke treatment unit.
ÂÂ
Long-term results are encouraging: treatment effect remains.
A DIALOGUE WITH DR PV RANJITH Dr PV Ranjith, Kannur, Kerala
Dr Walt Johnson, Switzerland ÂÂ
Essentials of resolution: Advocacy and resources development; Care delivery: Access, integration, infrastructure, systems; Information management: Data collection, analysis, monitoring and evaluation, drive health policy; Essential medicines; Workforce training.
ÂÂ
Global burden of stroke: 70% strokes occur in LMICs; 87% burden of DALYs and death in LMICs.
ÂÂ
Global burden of stroke in LMICs: Primary prevention generally ineffective; Virtually no rehabilitation to reintegrate into daily life; Creates economic catastrophe for individual/ families; Huge impact on country’s socioeconomic development; Creates political catastrophe.
ÂÂ
Next Steps: Promote implementation and timely updates of integrated protocols for CV risk reduction and stroke prevention – New WHO “Global Hearts Initiative”. Effective WHO-endorsed resource-stratified acute stroke guidelines. Strengthen management of acute
What is the role of dual antiplatelet therapy in stroke management? Dual antiplatelet therapy is required for patients who develop recurrent stroke when on one antiplatelet drug. For e.g.: Aspirin failure is noted; the patient may require more than one antiplatelet drug to prevent stroke. How would you treat recurrent TIAs? Usually treated with an antiplatelet drug. If not effective, patient might require dual antiplatelet drugs.
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Indian Journal of Clinical Practice, Vol. 27, No. 8, January 2017
CONFERENCE PROCEEDINGS stroke and post-stroke rehabilitation. Restart the Global Stroke Initiative. MAPPING STROKE SERVICES: CAN THE RESOURCES-TO-NEEDS GAP BE CLOSED? Dr Patrice Lindsay, Canada ÂÂ
ÂÂ
WSO Global Stroke Quality Action Plan - even with limited resources available, “at least something can be done” to reduce the severity and risk of stroke. Healthcare professionals and public should know the importance of acronym FAST and use it to recognize the signs and symptoms of Stroke: F: Does one side of the face droop when a person is asked to smile.
A-Arm drift, S-Speech disturbance, T-Time to inform stroke team). Once clinically suspected, their screening for hypertension, diabetes mellitus, sedentary lifestyles, smoking is required. In India, we should screen above 50 years of age. STROKE AND CAROTID ATHEROSCLEROSIS Prof Foad Abd-Allah, Cairo University, Egypt ÂÂ
Stroke is a major health problem, and carotid atherosclerosis is one of the main causes of stroke with different mechanisms contributing to stroke occurrence.
ÂÂ
There are different management strategies for carotid artery disease. There remains a need for more trials assessing the future roles of medical management, carotid stenting and carotid endarterectomy.
ÂÂ
Future trials should be designed with the assumption that some patients will be best managed medically, some with medical therapy plus stenting and some with medical therapy plus endarterectomy. These treatments are complementary and not competing. Varying treatment algorithms including more or less liberal use of each modality can be designed, patients randomly assigned to one of the algorithms, and their results compared.
A: Does one arm drift downwards if he/she is asked to raise his/her arm. S: Strange or slurred speech? T: If any one or all the above signs are observed call for help, immediately. ÂÂ
Proper documentation of time-of-onset of the stroke symptoms must be performed.
ÂÂ
CT scan or MRI must be performed without any delay if focal symptoms of stroke are observed.
ÂÂ
As soon as possible, patient with acute stroke must be admitted to the hospital.
ÂÂ
A significant reduction in mortality and morbidity could be achieved via organized stroke care, which includes implementation of evidence-based clinical practice guidelines, etc.
TETE-A-TETE WITH DR UP SHARMA Dr UP Sharma, Hyderabad Is the outcome of stroke different if the patient gets admitted in a hospital with neurointerventional facilities? Yes, in certain cases of stroke, even thrombolysis is not helpful. Hence, clot retriever therapy is needed which is only possible where neurointervention facilities are available. What screening tools do you recommend to assess the risk of stroke and at what age should one undergo these tests? Stroke is a clinical diagnosis. First, it should be recognized by clinical presentations - (F-Facial droop,
IN CONVERSATION WITH DR CHANDRASHEKHAR MESHRAM Dr Chandrashekhar Meshram, Nagpur How is our stroke technology helping our community? Newer advances in stroke technology are helping patients for better outcome in stroke, if patient reports to hospital at the earliest. Patients and public education about stroke plays an important role. How do stress and anxiety affect neurological disorders? Stress and anxiety have indirect relationship to neurological disorders like stroke via increase in risk factors like hypertension and diabetes. Which neurological disorders affect the mood centers of the brain and cause anxiety related symptoms? Headache, epilepsy, Parkinson’s disease, dementia and stroke affect mood centers and cause anxiety related symptoms.
■■■■
Indian Journal of Clinical Practice, Vol. 27, No. 8, January 2017
789
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Obstetrics and Gynecology Pediatrics Medilaw Medifinance
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Asian Journal of Clinical Cardiology
In This Issue —
Asian Journal of Diabetology
Emerging role of Cardiac MRI in Ischemic and Non-ischemic Cardiomyopathy
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Acute Renal Failure and Silent Myocardial Infarction Following Multiple Honey Bee Stings
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Superficial Brachial Artery: Its Embryological and Clinical Significance
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Glucose Tolerance in Nondiabetic Patients after First Attack of Acute Myocardial Infarction and its Outcome
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A Case of Left Atrial Myxoma Presenting as Severe Pulmonary Hypertension
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Double-Chambered Right Ventricle with Transient 2:1 Atrioventricular Block: A Rare Presentation
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Cornary Artery Air Embolism
Volume 17, Number 5
more...
January-March 2015
Volume 1, Number 1
Asian Journal of OBS & Gynae Practice Asian Journal of Paediatric Practice
Volume 18, Number 3
Dr Swati Y Bhave
Dr KK Aggarwal
Editor
Group Editor-in-Chief
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AROUND THE GLOBE
News and Views Impact of Partially Repealed Affordable Care Act by Newly Elect US Congress More than twice the current number of Americans would lack health insurance till 2019 if the current Affordable Care Act (ACA) is partially repealed by the US Congress, suggests the Urban Institute study. The study also suggests that white, working class and adults with lack of a college degree will be largely affected by this budge. Also, an increment from 11% to 21% in uninsured nonelderly people would be observed with this change. “This scenario does not just move the country back to the situation before the ACA,” the study says. “It moves the country to a situation with higher uninsurance rates than was the case before the ACA’s reforms.” The number of uninsured people would rise from 28.9 million to 58.7 million in 2019.”
World Health Organization Declared Sri Lanka as Malaria Free Country On 5th December, the World Health Organization declared Sri Lanka as “malaria free,” it grabs the second position out of 11 countries of South-East Asian region who have achieved the target of malaria eradication, suggest a report published online in The Hindu newspaper. The first position in malaria eradication was grabbed by Maldives.
Discovery of a an Antibiofilm Protein of Bacterial Origin A study published online in the journal Science, discovered a protein that disrupts and inhibits biofilms of Pseudomonas aeruginosa, which is the primary pathogen in cystic fibrosis (CF) infections. Researchers isolated a small protein called pyocyanin demethylase (PodA) from the soil bacteria Mycobacterium fortuitum, added it to growing cultures of P. aeruginosa, and found that the protein PodA inhibits the bacterial-biofilm development. Hence, the results were promising and could be utilized to develop new therapeutic strategies against the antibiotic-resistant biofilm infection.
Health Benefits of Yoga A study presented at the 68th Annual Conference of the Cardiological Society of India (CSI), suggests that doing yoga an hour per day may help patients with
pre-hypertension as it decreases blood pressure (BP) in patients with prehypertension. It was observed that performing yoga resulted in a decline of both 24 hour-diastolic BP and nighttime diastolic BP to about 4.5 mmHg, significantly. The researchers advised prehypertensive patients to practice “hatha” yoga (a combination of asanas, pranayama and meditation) daily for about an hour, as it may prevent the development of hypertension and in addition give a sense of well-being.
Children with Nystagmus Face Difficulty in Recognising Faces Children suffering from nystagmus are less likely to recognize faces but not other objects, suggests a study conducted at Southampton Children’s Hospital. Because nystagmus makes eyes to ‘wobble’ and generates strobe vision, which results in difficulty in recognizing faces. The findings could provide the basis of a more accurate diagnosis of nystagmus severity and measure of the efficacy of trial treatments, as well as improved social support and understanding for patients,” concludes the author.
Ban on Sale of Teethers Due to Presence of BPA The US and other governments have recently banned various personal care products for kids who were labelled as BPA-free but were found to contain BPA and other endocrine-disruptors that leached at low levels. Also, the researchers found parabens and antimicrobials like triclosan and triclocarban in most of the baby teethers soothe. The study concludes that the current findings could help to develop appropriate policies to protect infants from exposure to potentially toxic chemicals found in teethers.
Sleep Deprivation Associated with Increased Rate of Vehicle Crash Lack of one to two hours of sleep in 24 hours of period doubles the chances of road accidents or vehicle crash, suggests a report - from the AAA Foundation for Traffic Safety. The study also suggests that drowsy driving is equivalent to “drunk and drive” kind of driving that eventually increases the likelihood of vehicle crash. Jake Nelson, director of Traffic Safety Advocacy and Research for AAA comments that: “Managing a healthy work-life balance can be difficult, and far too often we
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AROUND THE GLOBE sacrifice our sleep as a result. Failing to maintain a healthy sleep schedule could mean putting yourself or others on the road at risk.”
Correlation Between Upset Gut and Mood Disorders A study published online in the journal Neuropsychopharmacology, suggests that there is an association between the gut microbiota and mood disorders like anxiety, depression etc. Also, psychiatric medications directly affect the gut microbiome and results in upset stomach or “nervous stomach.” The study conducted on rats who were subjected to chronic stress over a 7-week period reported a decrease in the gut microbiota as well as showed behavioral changes like loss of pleasure and “despair-like” behavior. Moreover, similar human studies demonstrated an association between the reductions in the microbiome and depression and bipolar disorder. Additionally, SSRIs consumption was found associated with changes in tryptophanase-producing bacteria.
Scientists Discovered Protein Responsible for Brachydactyly Loss of a key protein called Spop (Speckle-type POZ Protein) leads to brachydactyly, which is a skeletal defect characterized by short of fingers and toes and reduced bone density, suggests a study published online in the journal Proceedings of the National Academy of Sciences. This discovery open new avenues to design potential target for the diagnosis and treatment of bone diseases like osteoporosis, suggests the authors.
“Columbus Gifted America Malaria” Charles C Mann, journalist, author and scientific writer at the MS Swaminathan Research Foundation on his book, ‘1493: Uncovering the New World Columbus Created’, quoted that when Columbus discovered America, along with people he also brought with him plants, animals, viruses and bacteria and also gifted America with malaria that resulted in to a “collision of ecologies that had been separated for hundreds of years and that.”
Benefits of Consuming Vegetable-based Proteinand Fibre-rich Diet
FSSAI Advisory on the use of Newspaper as Food Packaging Material
Consumption of protein-rich meal comprised of beans and peas contributes to the increased feeling of satiety than compared to protein-rich meal composed of veal/ pork, suggests a study published online in the journal Food & Nutrition Research. The vegetable-based proteinrich-diet contains high amount of fibres, compared to meal composed of pork or veal, which probably fulfils the satiety centres in the brain, suggests the head researcher, Professor Anne Raben of the University of Copenhagen’s Department of Nutrition, Exercise and Sports. Most importantly, consumption of sustainable amount of protein and fibre-rich meal of plant origin was sufficient to fulfil the satiety centres, than compared to high protein diet which is composed of pork/veal.
The Food Safety and Standards Authority of India (FSSAI) has restricted the use of newspaper as food packaging material and has issued an advisory in this regard.
Important Role of Progesterone in Breast Cancer Treatment Progesterone containing-menopausal hormone therapy does not increase breast cancer risk, although plays a key role in the safe and effective management of recurring breast cancer, suggests a study published online in the journal Nature Reviews Cancer. “This gives us a unique opportunity to develop a new hormonal treatment which, when used in conjunction with the current standard of care, would enhance and improve outcomes for many breast cancer patients,” suggests the authors.
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Use of newspapers for wrapping, packing and serving food is a common practice in India. However, this is a food safety hazard. Wrapping food in newspapers is an unhealthy practice and the consumption of such food is injurious to health, even if the food has been cooked hygienically. Indians are being slowly poisoned due to newspaper being widely used as food packaging material by small hotels, vendors and also in homes in lieu of absorbent paper.
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Foods contaminated by newspaper ink raise serious health concerns since the ink contains multiple bioactive materials with known negative health effects. Printing inks may also contain harmful colors, pigments, binders, additives, and preservatives. Besides chemical contaminants, presence of pathogenic microorganisms in used newspapers also poses potential risk to human health.
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Newspapers and even paper/cardboard boxes made of recycled paper may be contaminated with metallic contaminants, mineral oils and harmful chemicals like phthalates which can cause digestive
AROUND THE GLOBE problems and also lead to severe toxicity. Older people, teenagers, children and people with compromised vital organs and immune systems are at a greater risk of acquiring cancer-related health complications, if they are exposed to food packed in such material. ÂÂ
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Newspapers should not be used to wrap, cover and serve food or to absorb excess oil from fried food. There is an urgent need to discourage the use of newspaper as food packaging material by creating awareness among businesses, especially unorganized food business operators and consumers on its harmful effects. Suitable steps need to be taken to restrict and control the use of newspapers for packing of food material. Commissioners of Food Safety of all States/UTs are requested to initiate a systematic campaign for generating awareness amongst all stakeholders to discourage the use of newspapers for packing, serving and storing of food items. (Source: FSSAI, 6th December, 2016)
6 months after an ACS diagnosis, people with ACS were 200% more likely to commit suicide than people in the comparison group. After adjustment for other risk factors, such as mental illness, the rate of suicide declined among ACS patients to around a 15% higher risk, which is still considered significant.
New Psoriasis Guidelines The National Psoriasis Foundation (NPF) in the US has issued measurable “treat-to-target” guidelines to better individualize, evaluate and adjust therapeutic regimens and improve patient outcomes. The preferred acceptable response to treatment after 3 months, as per the guidelines, is either body surface area 3% or less, or body surface area improvement 75% or greater from baseline. The target response to treatment after 3 months is body surface area of 1% or less, and the target response during the maintenance evaluation every 6 months is also body surface area 1% or less. These guidelines are published in the Journal of the American Academy of Dermatology.
Cellular Immunotherapy Targets a Common Human Cancer Mutation
Menopausal Symptoms Adversely Affect Tamoxifen Adherence
In a study of an immune therapy for colorectal cancer that involved a single patient, a team of researchers at the National Cancer Institute (NCI) identified a method for targeting the cancer-causing protein produced by a mutant form of the KRAS gene. This targeted immunotherapy led to cancer regression in the patient in the study reported December 8, 2016, in the New England Journal of Medicine. “This study demonstrates for the first time, that this method of administering TILs, called adoptive T cell transfer immunotherapy, can mediate effective antitumor immune responses against cancers that express the KRAS G12D mutation,” said Dr Steven A Rosenberg, MD, PhD, chief of the Surgery Branch at NCI’s Center for Cancer Research.
Researchers reported at the San Antonio Breast Cancer Symposium (SABCS) that adverse effects of menopause, headaches and nausea/vomiting in particular, had significant associations with lower adherence to both tamoxifen and placebo among women at high-risk for developing breast cancer. This association was found to be strongest during the first 6-12 months of treatment.
More than 30% of all human cancers are driven by mutations in a family of genes known collectively as RAS, which has three members: KRAS, NRAS, and HRAS. Mutations in the KRAS gene are thought to drive 95% of all pancreatic cancers and 45% of all colorectal cancers … (NIH).
Patients with ACS at Increased Risk of Suicide According to new research in Journal of the American Heart Association published December 7, 2016, patients with acute coronary syndrome may be at an increased risk for suicide compared to otherwise healthy people. The study from Taiwan found that during the first
Mongersen has Beneficial Effects in Crohn’s Disease, Says Study Oral mongersen, Smad7 antisense nucleotide, improved stool frequency as well as abdominal pain in patients with significant, longstanding Crohn’s disease, according to findings presented at the Advances in Inflammatory Bowel Diseases meeting in Orlando. Clinical remission was achieved by 32% of patients receiving mongersen for 4 weeks, by 35% of those given the drug for 8 weeks and by 48% of those treated for 12 weeks. Mongersen is a delayed-release, pH-dependent formulation intended to be active only in the distal gastrointestinal tract, with little systemic activity.
Heart Damage Caused by Chemotherapy is Worse in Patients with Diabetes Heart damage caused by chemotherapy is worse in cancer patients who also have diabetes, according to a study presented December 10, 2016 at EuroEcho-Imaging 2016. Patients with hypertension showed a trend toward
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AROUND THE GLOBE greater reductions in ejection fraction. Patients with diabetes had a significantly greater decrease in global longitudinal strain during treatment, despite having baseline levels similar to nondiabetics.
Baseline ASDAS Scores may Identify High-risk Patients with Axial Spondyloarthritis Patients with axial spondyloarthritis (axSpA) who present with baseline Ankylosing Spondylitis Disease Activity Scores (ASDAS) ≥3 are at increased risk of becoming disabled during the next 3 years and this risk persists even in patients treated with tumor necrosis factor inhibitors (TNFis), says a study published online November 25, 2016 in the Annals of the Rheumatic Diseases. Malaria Control Improves for Vulnerable in Africa, but Global Progress Off-track WHO’s World Malaria Report 2016 reveals that children and pregnant women in sub-Saharan Africa have greater access to effective malaria control. Across the region, a steep increase in diagnostic testing for children and preventive treatment for pregnant women has been reported over the last 5 years. Among all populations at risk of malaria, the use of insecticide-treated nets has expanded rapidly. According to the report, less than half (40) of the 91 countries and territories with malaria are on track to achieve the target of 40% reduction in malaria case incidence by the year 2020, compared to a 2015 baseline as defined in the Global Technical Strategy for Malaria 2016-2030 adopted at the 2015 World Health Assembly … (WHO, 13th December, 2016). Promotion of Organ Donation-an Indian Air Force Initiative Indian Air Force has taken the lead in promoting organ donation in the country. A small but significant step towards this noble cause was taken by Air Force on 12 December 2016. A seminar was held at the Air Force auditorium to increase awareness and promote organ donation among the population. Around 500 air warriors and their families joined hands to strengthen the organ donation movement in the country, especially in Indian Air Force. The seminar was organised by Air Force Central Medical Establishment under the aegis of Directorate General Medical Services (Air)… (Press Information Bureau, Ministry of Defence, 12th December, 2016) Children in Low Income Countries at Higher Risk of Death Post Emergency Surgery Children from poor countries were 7 times more likely to die after emergency abdominal surgery to treat conditions such as appendicitis, suggests a study
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published online in the journal BMJ Global Health. Children from middle income countries were around 4 times as likely to die within 30 days. Children from poor countries were much less likely to have undergone keyhole surgery, half as likely to have been operated on by surgeons who used the WHO surgical safety checklist and more likely to have had internal bleeding.
Tool to Identify Obese Women at Risk of Gestational Diabetes An observational study recently published online in PLos One has described a new risk prediction model using biomarker and anthropometric measures to identify obese women at risk of developing gestational diabetes in the early antenatal period. The variables included age, previous gestational diabetes, family history of type 2 diabetes, systolic blood pressure, sum of skin fold thicknesses, waist:height and neck : thigh ratios.
Better Overall Survival with Atezolizumab vs Docetaxel in Previously Treated Nonsmall Cell Lung Cancer Results of phase 3, open-label, multicentre randomized controlled trial reported December 12, 2016 in The Lancet demonstrated that atezolizumab had better overall survival compared to docetaxel. The median overall survival among atezolizumab treated patients was 13.8 months vs 9.6 months among patients treated with docetaxel.
FDA Rules out Removing Bladder Cancer Warning for Pioglitazone The FDA has ruled out removing the current warnings about risk of bladder cancer with pioglitazone saying that an increased risk of bladder cancer associated with the diabetes drug pioglitazone (Actos and other brands) cannot be eliminated.
FDA Approves Bevacizumab for PlatinumSensitive Recurrent Epithelial Ovarian Cancer FDA has approved bevacizumab for use together with chemotherapy, in patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer. Women are said to have a “platinumsensitive” form of the disease if a relapse occurs after more than following the last treatment with a platinumbased chemotherapy. They are considered to have a “platinum-resistant” form of the disease if a relapse occurs less than 6 months after the last treatment with a platinum-based chemotherapy.
AROUND THE GLOBE Pre-eclampsia Associated with Long-term Risk of Maternal Retinal Disorders
First Autologous Cellularized Scaffold for Repair of Knee Cartilage Defects
According to a study published in the January 2017 issue of Obstetrics & Gynecology, compared to women who did not have pre-eclampsia, those who developed pre-eclampsia during pregnancy, particularly severe or early-onset pre-eclampsia, have a significantly higher risk for various retinal disorders such as traction detachments, retinal breaks and diabetic retinopathy.
The US Food and Drug Administration (FDA) has approved Maci (autologous cultured chondrocytes on porcine collagen membrane) for the repair of symptomatic, full-thickness cartilage defects of the knee in adult patients. Maci is the first FDA-approved product that applies the process of tissue engineering to grow cells on scaffolds using healthy cartilage tissue from the patient’s own knee. Maci is composed of a patient’s own (autologous) cells that are expanded and placed onto a bioresorbable (can be broken down by the body) porcinederived collagen membrane that is implanted over the area where the defective or damaged tissue was removed.
New WHO Data Portal to Help Track Progress Towards Universal Health Coverage To mark Universal Health Coverage Day, WHO has launched a new data portal to track progress towards universal health coverage (UHC) around the world. The portal shows where countries need to improve access to services, and where they need to improve information. The portal features the latest data on access to health services globally and in each of WHO’s 194 Member States, along with information about equity of access. In November, the United Nations working group responsible for deciding how to monitor progress towards the SDGs agreed on two measures for UHC: the proportion of a population with access to 16 essential health services; and the proportion of a population that spends more than 25% of household income on health. WHO’s new UHC Data Portal offers data on both indicators in a single place, offering an initial snapshot of the status of UHC globally and by country … (WHO, 12th December, 2016)
National Eligibility-cum-Entrance Test – Super Specialty The National Eligibility-cum-Entrance Test for entrance to DM/MCh in terms of Section 10 of the Indian Medical Council Act, 1956 as amended in 2016 shall be conducted by the National Board of Examinations. The examination shall be held at various cities on 10th June 2017. NEETSS is a single window entrance examination for entry to DM/MCh/PDCC courses. The examination shall be held as a Computer Based Test and shall comprise of 200 Multiple Choice Questions from the MD/MS curriculum followed at medical colleges in India duly prescribed/ adopted by Medical Council of India with prior approval of the Ministry of Health & Family Welfare, Government of India… (Press Information Bureau, Ministry of Health and Family Welfare, 14th December, 2016)
Updated ASCO Guidelines on Sentinel LN Biopsy for Early-stage Breast Cancer In an update, the American Society of Clinical Oncology (ASCO) has recommended that women without sentinel lymph node (SLN) metastases should not receive axillary lymph node dissection as also women with 1-2 metastatic SLNs who are planning to undergo breastconserving surgery with whole-breast radiotherapy. However, women with SLN metastases who will undergo mastectomy should be offered axillary lymph node dissection. These and other recommendations are published online before print December 12, 2016 in the Journal of Clinical Oncology.
Ustekinumab Promotes Endoscopic Healing in Crohn’s Disease According to a study presented at the recent Advances in Inflammatory Bowel Diseases meeting in Orlando, significantly greater changes in the Simplified Endoscopic Score for Crohn’s Disease (SES-CD) were seen in those receiving ustekinumab compared with those receiving placebo among patients with Crohn’s disease who had endoscopic ulceration or inflammation present at baseline.
Antihypertensives may have Protective Effects Against Developing Glaucoma According to a study of the Danish population, although hypertension is positively correlated with glaucoma antihypertensive medication itself may have a preventive effect on the development of glaucoma. The results were published online December 5, 2016 in Hypertension.
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LIGHTER READING
HUMOR
Lighter Side of Medicine JACK’S LAST WILL AND TESTAMENT Jack has died. His lawyer is standing before the family and reads out Jack’s Last Will and Testament: “To my dear wife Esther, I leave the house, 50 acres of land, and 1 million dollars… “To my son Barry, I leave my Big Lexus and the Jaguar… “To my daughter Suzy, I leave my yacht and $250,000… “And to my brother-in-law Jeff, who always insisted that health is better than wealth, I leave my treadmill. WE SHOULD PRAY As my 5-year-old son and I were headed to McDonald’s one day, we passed a car accident. Usually when we see something terrible like that, we say a prayer for those who might be hurt, so I pointed and said to my son, “We should pray.” From the back seat I heard his earnest request: “Please, God, don’t let those cars block the entrance to McDonald’s.”
at a piece of wood with the side of his hand. Meanwhile, another patient was in the room, hanging from the ceiling by his feet. The doctor asked his patient what he was doing, sitting on the floor. The patient replied in an irritated fashion, “Can’t you see I’m sawing this piece of wood in half?” The doctor inquired, “And what is the fellow hanging from the ceiling doing?” “Oh. He’s my friend, but he’s a little crazy. He thinks he’s a light bulb.” The doctor asks, “If he’s your friend, don’t you think you should get him down from there before he hurts himself?” “What? And I work in the dark?!” BLONDE STOP A police car pulled alongside a speeding car on the motorway. Glancing at the car he was astonished to see that the blond behind the wheel was knitting! Realizing that she was oblivious to his flashing lights and siren, the cop rolled down his window and shouted “Pullover!” The blonde rolled down her window and yelled back “No, it’s a scarf!”
WHAT’S THE BIG DEAL The phone bill was exceptionally high. Man called a family meeting to discuss.
Dr. Good and Dr. Bad SITUATION: A patient with insulin resistance developed infarction of the middle cerebral artery.
Dad: This is unacceptable. I don’t use home phone, I use my work phone. Mum: Me too. I hardly use home phone. I use my company phone.
Both are not related.
They are related in terms of persistent arterial occlusions.
Son: I use my office mobile; I never use the home phone. © IJCP Academy
All of them shocked and together look at the maid who’s patiently listening to them. Maid: “What? So we all use our work phones. What’s the Big deal?? AND I WORK IN THE DARK Doctor of psychology was doing his normal morning rounds and he entered a patient’s room to find his patient sitting on the floor, sawing
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LESSON:
A prospective, observational, longitudinal study in consecutive acute ischemic stroke patients presenting with middle cerebral artery (MCA) occlusion who received intravenous thrombolysis concluded that high insulin resistance may be associated with more persistent arterial occlusions and worse long-term outcome after acute ischemic stroke thrombolysis Diabetes Care. 2011;34(11):2413-7.
Information for Authors Manuscripts should be prepared in accordance with the ‘Uniform requirements for manuscripts submitted to biomedical journals’ compiled by the International Committee of Medical Journal Editors (Ann. Intern. Med. 1992;96: 766-767). Indian Journal of Clinical Practice strongly disapproves of the submission of the same articles simultaneously to different journals for consideration as well as duplicate publication and will decline to accept fresh manuscripts submitted by authors who have done so. The boxed checklist will help authors in preparing their manuscript according to our requirements. Improperly prepared manuscripts may be returned to the author without review. The checklist should accompany each manuscript. Authors may provide on the checklist, the names and addresses of experts from Asia and from other parts of the World who, in the authors’ opinion, are best qualified to review the paper. Covering letter –
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The covering letter should explain if there is any deviation from the standard IMRAD format (Introduction, Methods, Results and Discussion) and should outline the importance of the paper. Principal/Senior author must sign the covering letter indicating full responsibility for the paper submitted, preferably with signatures of all the authors. Articles must be accompanied by a declaration by all authors stating that the article has not been published in any other Journal/Book. Authors should mentioned complete designation and departments, etc. on the manuscript.
Manuscript – Three complete sets of the manuscript should be submitted and preferably with a CD; typed double spaced throughout (including references, tables and legends to figures). –
The manuscript should be arranged as follow: Covering letter, Checklist, Title page, Abstract, Keywords (for indexing, if required), Introduction, Methods, Results, Discussion, References, Tables, Legends to Figures and Figures.
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All pages should be numbered consecutively beginning with the title page.
Note: Please keep a copy of your manuscript as we are not responsible for its loss in the mail. Manuscripts will not be returned to authors. Title page Should contain the title, short title, names of all the authors (without degrees or diplomas), names and full location of the departments and institutions where the work was performed,
name of the corresponding authors, acknowledgment of financial support and abbreviations used. – The title should be of no more than 80 characters and should represent the major theme of the manuscript. A subtitle can be added if necessary. – A short title of not more than 50 characters (including inter-word spaces) for use as a running head should be included. – The name, telephone and fax numbers, e-mail and postal addresses of the author to whom communications are to be sent should be typed in the lower right corner of the title page. – A list of abbreviations used in the paper should be included. In general, the use of abbreviations is discouraged unless they are essential for improving the readability of the text. Summary – The summary of not more than 200 words. It must convey the essential features of the paper. – It should not contain abbreviations, footnotes or references. Introduction – The introduction should state why the study was carried out and what were its specific aims/objectives. Methods – These should be described in sufficient detail to permit evaluation and duplication of the work by others. – Ethical guidelines followed by the investigations should be described. Statistics The following information should be given: – The statistical universe i.e., the population from which the sample for the study is selected. – Method of selecting the sample (cases, subjects, etc. from the statistical universe). – Method of allocating the subjects into different groups. – Statistical methods used for presentation and analysis of data i.e., in terms of mean and standard deviation values or percentages and statistical tests such as Student’s ‘t’ test, Chi-square test and analysis of variance or non-parametric tests and multivariate techniques. –
Confidence intervals for the measurements should be provided wherever appropriate.
Results – These should be concise and include only the tables and figures necessary to enhance the understanding of the text.
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Discussion –
This should consist of a review of the literature and relate the major findings of the article to other publications on the subject. The particular relevance of the results to healthcare in India should be stressed, e.g., practicality and cost.
References These should conform to the Vancouver style. References should be numbered in the order in which they appear in the texts and these numbers should be inserted above the lines on each occasion the author is cited (Sinha12 confirmed other reports13,14...). References cited only in tables or in legends to figures should be numbered in the text of the particular table or illustration. Include among the references papers accepted but not yet published; designate the journal and add ‘in press’ (in parentheses). Information from manuscripts submitted but not yet accepted should be cited in the text as ‘unpublished observations’ (in parentheses). At the end of the article the full list of references should include the names of all authors if there are fewer than seven or if there are more, the first six followed by et al., the full title of the journal article or book chapters; the title of journals abbreviated according to the style of the Index Medicus and the first and final page numbers of the article or chapter. The authors should check that the references are accurate. If they are not this may result in the rejection of an otherwise adequate contribution. Examples of common forms of references are: Articles Paintal AS. Impulses in vagal afferent fibres from specific pulmonary deflation receptors. The response of those receptors to phenylguanide, potato S-hydroxytryptamine and their role in respiratory and cardiovascular reflexes. Q. J. Expt. Physiol. 1955;40:89-111.
Figures – Two complete sets of glossy prints of high quality should be submitted. The labelling must be clear and neat. – All photomicrographs should indicate the magnification of the print. – Special features should be indicated by arrows or letters which contrast with the background. – The back of each illustration should bear the first author’s last name, figure number and an arrow indicating the top. This should be written lightly in pencil only. Please do not use a hard pencil, ball point or felt pen. – Color illustrations will be accepted if they make a contribution to the understanding of the article. –
Do not use clips/staples on photographs and artwork.
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Illustrations must be drawn neatly by an artist and photographs must be sent on glossy paper. No captions should be written directly on the photographs or illustration. Legends to all photographs and illustrations should be typed on a separate sheet of paper. All illustrations and figures must be referred to in the text and abbreviated as “Fig.”.
Please complete the following checklist and attach to the manuscript: 1. Classification (e.g. original article, review, selected summary, etc.)_______________________________ 2. Total number of pages ________________________ 3. Number of tables ____________________________ 4. Number of figures ___________________________
Books
5. Special requests _____________________________
Stansfield AG. Lymph Node Biopsy Interpretation Churchill Livingstone, New York 1985.
6. Suggestions for reviewers (name and postal address)
Articles in Books
2.____________ 2.________________
Strong MS. Recurrent respiratory papillomatosis. In: Scott Brown’s Otolaryngology. Paediatric Otolaryngology Evans JNG (Ed.), Butterworths, London 1987;6:466-470.
3.____________ 3.________________
4.____________ 4.________________
Tables –
These should be typed double spaced on separate sheets with the table number (in Roman Arabic numerals) and title above the table and explanatory notes below the table.
Legends – These should be typed double spaces on a separate sheet and figure numbers (in Arabic numerals) corresponding with the order in which the figures are presented in the text. –
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The legend must include enough information to permit interpretation of the figure without reference to the text.
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Indian 1.____________Foreign 1.________________
7. All authors’ signatures________________________ 8. Corresponding author’s name, current postal and e-mail address and telephone and fax numbers __________________________________________
Online Submission Also e-Issue @ www.ijcpgroup.com For Editorial Correspondence
Dr KK Aggarwal
Group Editor-in-Chief Indian Journal of Clinical Practice E-219, Greater Kailash Part-1 New Delhi - 110 048. Tel: 40587513 E-mail: editorial@ijcp.com Website: www.ijcpgroup.com
R.N.I. No. 50798/1990 Date of Publication 13th of Same Month Date of Posting 13-14 Same Month
POSTAL REGISTRATION NO. DL (S)-01/3200/2015-2017 Posted in N.D. PSO New Delhi