Indian journal of clinical practice july 2015 by IJCP

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Volume 26, Number 2

July 2015, Pages 101â&#x20AC;&#x201C;200

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American Family Physician

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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 Padma Shri, Dr BC Roy & National Science Communication Awardee

Dr KK Aggarwal Group Editor-in-Chief

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 ENT Dr Jasveer Singh Dr Chanchal Pal Dentistry Dr KMK Masthan Dr Rajesh Chandna Gastroenterology Dr Ajay Kumar Dr Rajiv Khosla Dermatology Dr Hasmukh J Shroff Dr Pasricha Dr Koushik Lahiri Nephrology Dr Georgi Abraham Neurology Dr V Nagarajan Dr Vineet Suri Journal of Applied Medicine & Surgery Dr SM Rajendran, Dr Jayakar Thomas 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 26, Number 2, July 2015 FROM THE DESK OF THE GROUP EDITOR-IN-CHIEF

106 Lifestyle Modifications to Manage Hypertensio KK Aggarwal

AMERICAN FAMILY PHYSICIAN

108 Dyspareunia in Women Dean A. Seehusen, Drew C. Baird, David V. Bode

114 Practice Guidelines 115 Photo Quiz CARDIOLOGY

118 Current Guidelines for Cardiac Pacemaker Implantation Kamal Kumar, Shivanjali Kumar, Ranjana Kumar

COMMUNITY MEDICINE

122 Understanding Evolution of Resistant Strains in Recent Decades and Approach Towards Antibiotic Therapy Neethu Poulose, Anil Antony, Sreelakshmi Sreedhar, Anil Babu

DERMATOLOGY

130 Carmi Syndrome with a Favorable Outcome: A Case Report Sindhu Desabandhu, Aditya Kumar Bubna, Mahalakshmi Veeraraghavan, Sudha Rangarajan

DIABETOLOGY

134 Management of Diabetic End-stage Renal Disease: Role of Hemodialysis

H Sudarshan Ballal

DRUGS

139 A Short-term Comparative Prospective Observational

Evaluation of Ramipril versus Telmisartan in Hypertensive Patients with Type 2 Diabetes Mellitus Pankaj Kumar, AK Kapoor, HK Singh, Malini Kulshrestha

INTERNAL MEDICINE

145 Hepatic Dysfunction in Dengue Fever: A Retrospective Study from Tertiary Referral Hospital in Rajasthan Monika Maheshwari, Sanjiv Maheshwari, Mukesh

147 Cortical Vein Thrombosis: A Rare Manifestation of Tubercular Meningitis

Anjum Mirza Chughtai, Muhammad Uwais Ashraf, MR Ajmal

NEUROLOGY

151 Headache with Visual Hallucinations: Lessons Learnt Debaprasad Chakrabarti, Anindya Sundar Trivedi, Amrit Kr Bhattacharyya

OBSTETRICS AND GYNECOLOGY

157 A Randomized Comparative Study of Intramuscular

Camylofin Dihydrochloride and Intravenous Drotaverine Hydrochloride on Cervical Dilatation in Labor Binu P

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

164 Pregnancy with Anemia and Severe Thrombocytopenia: Case Series Kavita Agarwal

ONCOLOGY

166 Stereotactic Radiosurgery and Fractionated Stereotactic

Printed at New Edge Communications Pvt. Ltd., New Delhi E-mail: edgecommunication@gmail.com

Radiotherapy in Patients with Single Brain Metastasis Meena J Shah, Rakesh K Vyas

PEDIATRICS

171 Pediatric Syrup Caps: How Safe? Contamination and

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.

Pediatric Dosing Concerns with Syrup Caps–CAPCONS Study Varsha Narayanan, Ganesh Kadhe, Aparna Jairam

178 Clinical Expression of Graves’ Disease in Children: Case Report Jwal B Doctor, Bharat J Kumar

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181 Nonpuerperal Breast Abscesses in South Nigeria Afeyodion Akhator

ALGORITHM

184 Approach to a Patient with Acute Poisoning MEDILAW

185 A Must Read Judgement AROUND THE GLOBE

193 News and Views LIGHTER READING

195 Lighter Side of Medicine

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FROM THE DESK OF THE GROUP EDITOR-IN-CHIEF

Prof. Dr KK Aggarwal

Padma Shri, Dr BC Roy & National Science Communication Awardee Sr. Physician and Cardiologist, Moolchand Medcity President, Heart Care Foundation of India Group Editor-in-Chief, IJCP Group and eMedinewS

Lifestyle Modifications to Manage Hypertension Â

Treatment of hypertension should involve nonpharmacologic therapy (also called lifestyle modification) alone or in concert with antihypertensive drug therapy.

The overall impact of moderate sodium reduction is a fall in blood pressure (BP) in hypertensive and normotensive individuals of 4.8/2.5 and 1.9/1.1 mmHg, respectively.

A high dietary intake of sodium is associated with the development of hypertension.

Some individuals are particularly sensitive to sodium in the diet, and are referred to as being sodium sensitive.

Sodium-sensitive individuals obtain a greater degree of BP reduction with dietary sodium restriction.

Dietary sodium reduction can lower BP in both hypertensive and normotensive individuals, and enhances the response to most antihypertensive therapies.

Dietary sodium reduction may decrease the risk of cardiovascular disease, potentially though, in part, a reduction in BP.

106

In all hypertensive individuals, reduce dietary sodium intake. A reasonable goal is to reduce daily sodium intake to <100 mEq/day (2.3 g of sodium or 6 g of sodium chloride [1 g of sodium = 44 mEq; 1 g of sodium chloride contains 17 mEq of sodium]). Reduce dietary sodium intake to similar levels in the general population with the goal of preventing hypertension and decreasing the risk of adverse cardiovascular events.

Indian Journal of Clinical Practice, Vol. 26, No. 2, July 2015

Weight loss in overweight or obese individuals can lead to a significant fall in BP independent of exercise.

The decline in BP induced by weight loss can also occur in the absence of dietary sodium restriction, but even modest sodium restriction may produce an additive antihypertensive effect.

The weight loss-induced decline in BP generally ranges from 0.5 to 2 mmHg for every 1 kg of weight lost, or about 1 mmHg for every 1 pound lost.

The Dietary Approaches to Stop Hypertension (DASH) dietary pattern is high in vegetables, fruits, low-fat dairy products, whole grains, poultry, fish and nuts and low in sweets, sugarsweetened beverages, and red meats. The DASH dietary pattern is consequently rich in potassium, magnesium, calcium, protein, and fiber, but low in saturated fat, total fat, and cholesterol. DASH dietary pattern reduced BP by 6/4 mmHg compared with typical American-style diet that contained the same amount of sodium and the same number of calories.

DASH diet can reduce the upper BP by 8-14 mmHg.

Combining the DASH dietary pattern with modest sodium restriction produced an additive antihypertensive effect.

Aerobic exercise, and possibly resistance training, can decrease systolic and diastolic pressure by, on average, 4-6 mmHg and 3 mmHg, respectively, independent of weight loss (three to four sessions of moderate-intensity aerobic exercise lasting approximately 40 minutes for a period of 12 weeks.)

FROM THE DESK OF THE GROUP EDITOR-IN-CHIEF Â

Women who consume two or more alcoholic beverages per day and men who have three or more drinks per day have a significantly increased incidence of hypertension compared with nondrinkers. This effect is dose related and is most prominent when intake exceeds five drinks per day.

Decreasing alcohol intake in individuals who drink excessively significantly lowers BP.

Moderate alcohol use (one drink per day for women and one to two drinks per day for men)

has a limited effect on BP, associated with a modest decrease in cardiovascular risk as compared with no alcohol consumption. Â

The benefits of comprehensive lifestyle modification, including the DASH diet and increased exercise are much more than managing a single lifestyle intervention'.

Patient education has been demonstrated to result in improved BP.

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AMERICAN FAMILY PHYSICIAN

Dyspareunia in Women DEAN A. SEEHUSEN, DREW C. BAIRD, DAVID V. BODE

ABSTRACT Dyspareunia is recurrent or persistent pain with sexual activity that causes marked distress or interpersonal conflict. It affects approximately 10% to 20% of U.S. women. Dyspareunia can have a significant impact on a woman’s mental and physical health, body image, relationships with partners, and efforts to conceive. The patient history should be taken in a nonjudgmental way and progress from a general medical history to a focused sexual history. An educational pelvic examination allows the patient to participate by holding a mirror while the physician explains normal and abnormal findings. This examination can increase the patient’s perception of control, improve self-image, and clarify findings and how they relate to discomfort. The history and physical examination are usually sufficient to make a specific diagnosis. Common diagnoses include provoked vulvodynia, inadequate lubrication, postpartum dyspareunia, and vaginal atrophy. Vaginismus may be identified as a contributing factor. Treatment is directed at the underlying cause of dyspareunia. Depending on the diagnosis, pelvic floor physical therapy, lubricants, or surgical intervention may be included in the treatment plan.

Keywords: Dyspareunia, sexual history, pelvic examination, vulvodynia, inadequate lubrication, vaginismus

yspareunia in women is defined as recurrent or persistent pain with sexual activity that causes marked distress or interpersonal conflict.1 It may be classified as entry or deep. Entry dyspareunia is pain with initial or attempted penetration of the vaginal introitus, whereas deep dyspareunia is pain that occurs with deep vaginal penetration. Dyspareunia is also classified as primary (i.e., occurring with sexual debut and thereafter) or secondary (i.e., beginning after previous sexual activity that was not painful).2 Determining whether dyspareunia is entry or deep can point to specific causes, although the primary vs. secondary classification is less likely to narrow the differential diagnosis. The prevalence of dyspareunia is approximately 10% to 20% in U.S. women, with the leading causes varying by age group.3,4 Dyspareunia can have a negative impact on a woman’s mental and physical health, body image, relationships

DEAN A. SEEHUSEN, MD, MPH, is chief of the Department of Family and Community Medicine at Eisenhower Army Medical Center, Fort Gordon, Ga. At the time the article was written, Dr. Seehusen was program director of the Family Medicine Residency Program at Fort Belvoir Community Hospital, Fort Belvoir, Va. DREW C. BAIRD, MD, is the assistant program director and research coordinator at the family medicine residency program at Carl R. Darnall Army Medical Center, Fort Hood, Tex. DAVID V. BODE, MD, is a staff physician at the family medicine residency program at Eisenhower Army Medical Center. Source: Adapted from Am Fam Physician. 2014;90(7):465-470.

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with partners, and efforts to conceive. It can lead to, or be associated with, other female sexual dysfunction disorders, including decreased libido, decreased arousal, and anorgasmia. Significant risk factors and predictors for dyspareunia include younger age, education level below a college degree, urinary tract symptoms, poor to fair health, emotional problems or stress, and a decrease in household income greater than 20%.3 HISTORY Because dyspareunia can be distressing and emotional, the physician should first establish that the patient is ready to discuss the problem in depth. The history should be obtained in a nonjudgmental way, beginning with a general medical and surgical history before progressing to a gynecologic and obstetric history, followed by a comprehensive sexual history.5 Details of the pain can help identify the cause. If the dyspareunia is classified as secondary, the physician should ask about specific events, such as psychosocial trauma or exposure to infection, that might have triggered the pain. A description of the patient’s sensations during sexual activity also can help determine the underlying cause. If penetration is difficult to achieve, the cause may be vulvodynia or accompanying vaginismus. Lack of arousal may be an ongoing reaction to pain. Lack of lubrication can occur secondary to sexual arousal disorders or vaginal atrophy. If the pain is positional, pelvic structural problems, such as uterine retroversion,

AMERICAN FAMILY PHYSICIAN may be present.6 Additional historical features pointing to specific diagnoses are outlined in Table 1. It is also important to establish which aspects of the patient’s life have been impacted. Asking whether dyspareunia has negatively affected relationships or self-esteem can help the physician determine whether additional resources and support are needed.5 Some women benefit from support groups, individual therapy, or couples therapy. PHYSICAL EXAMINATION The physical examination may be deferred initially, providing the opportunity to establish rapport with the patient and allowing for a more focused examination later. An educational pelvic examination often increases the patient’s perception of control, improves selfimage, and clarifies normal and abnormal findings and how they relate to the discomfort. During the educational pelvic examination, the patient is offered the opportunity to participate by holding a mirror while the physician explains the findings.6,7 Physical examination should include visual inspection of the external and internal structures. The mucosal surfaces should be inspected for areas of erythema or discoloration, which may indicate infection or dermatologic disease, such as lichen sclerosus or lichen planus. Abrasions or other trauma indicates inadequate lubrication or forceful entry. For women who describe localized pain, a cotton swab should be used to precisely identify the source of the pain (Figure 1). Overall dryness of the vaginal mucosa suggests atrophy or chronic vaginal dryness, and abnormal discharge may suggest infection. Internal examination should be performed with a single finger to maximize the patient’s comfort. Muscular tightness, tenderness, or difficulty with voluntary contracting and relaxing suggests pelvic floor muscle dysfunction.8 The physician should palpate the urethra, bladder, and cervix for causes of dyspareunia associated with these organs, such as endometriosis, which may also cause rectovaginal nodularity. After the singlefinger examination, a gentle bimanual examination can be used to evaluate pelvic and adnexal structures, if it is not too uncomfortable for the patient (Figure 2).6 Next, a small speculum may be used for visualization of internal structures. Testing for sexually transmitted infections is indicated if the patient has had unprotected intercourse or if discharge or other suggestive physical findings are present.

DIFFERENTIAL DIAGNOSIS Although the differential diagnosis of dyspareunia is large, several features of the history and physical examination can help narrow the possibilities (e.g., type of pain, patient age). For example, vulvodynia is typically most painful with entry dyspareunia, and vaginal atrophy typically occurs in postmenopausal women. Pain that can be localized to the vagina and supporting structures may indicate vulvodynia or vaginitis. Pain that localizes to the bladder, ovaries, or colon points to pathology within those structures. Several of the most common causes of dyspareunia are described here; Table 1 provides a more comprehensive list of diagnostic possibilities.

Vaginismus Vaginismus is involuntary contraction of the pelvic floor muscles that inhibits entry into the vagina. The relative roles of pain, muscular dysfunction, and psychological factors in vaginismus are controversial. Whether vaginismus is a primary cause of dyspareunia or develops in response to another physical or psychosexual condition, there is significant clinical overlap between vaginismus and dyspareunia.8 The Diagnostic and Statistical Manual of Mental Disorders, 5th ed., (DSM-5) now addresses dyspareunia and vaginismus as one entity, characterized by pain, anxiety, problems with penetration, or a combination of these, rather than as separate conditions. In addition, DSM-5 amends its earlier criteria by stating that difficulties must be present for at least six months.9 Therapy typically focuses on treating underlying causes of pain in combination with pelvic floor physical therapy. Cognitive behavior therapy or psychotherapy may be included in the treatment regimen.10 OnabotulinumtoxinA injections are a promising new therapy for vaginismus, but are not within the purview of the primary care physician.11

Vulvodynia Vulvodynia is defined by the International Society for the Study of Vulvovaginal Disease as vulvar discomfort, most often described as burning pain, occurring in the absence of relevant visible findings or a specific, clinically identifiable, neurologic disorder.12 Vulvodynia is classified as provoked, unprovoked, or mixed. In unprovoked vulvodynia, the pain is more or less continuous. In provoked vulvodynia, the pain is triggered by touch, as with tampon insertion or intercourse. Vulvodynia can also be categorized as generalized or localized, depending on the distribution

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AMERICAN FAMILY PHYSICIAN Table 1. Common Causes of Dyspareunia Diagnosis

Entry or deep

Age group

Historical clues

Dermatologic diseases (e.g., lichen planus, lichen sclerosus, psoriasis)

Entry

All ages

Visible lesions; burning; itching; dryness

Inadequate lubrication

Both

Most common in reproductive years

Lack of lubrication in response to sexual stimulation or chronic vaginal dryness

Vagina and supporting structures

Chronic conditions, such as diabetes mellitus, atherosclerosis, or autoimmune disorders History of chemotherapy or radiation therapy Perivaginal infections (e.g., urethritis, vaginitis)

Both

All ages

Dysuria or vaginal discharge

Postpartum dyspareunia

Both

Reproductive years

Postpartum; breastfeeding

Vaginal atrophy

Both

Postmenopausal

Vaginal dryness, itching, or burning; dysuria may be present

Vaginismus

Entry

More common in younger women

Inability or difficulty achieving entry into the vaginal cavity; history of trauma or abuse is possible

Vulvodynia

Entry

All ages

Burning pain caused by slight touch

Adnexal pathology

Deep

All ages

Pain may be described as pelvic or lower abdominal

Endometriosis

Deep

Reproductive years

Chronic pain in pelvis, abdomen, or back

Infections (e.g., endometritis, pelvic inflammatory disease

Deep

All ages

Fever and chills may be present; dysuria or vaginal discharge

Interstitial cystitis

Commonly deep

All ages

Prominent urinary symptoms including frequency, urgency, and nocturia

Pelvic adhesions

Deep

All ages

History of pelvic surgery or pelvic infection

Retroverted uterus

Deep

All ages

May have received diagnosis previously

Uterine myomas

Deep

Reproductive years

Menorrhagia often noted

Other pelvic structures

of the pain.12 There is an association between vulvodynia and psychiatric disorders. Women with depression or anxiety are at increased risk of vulvodynia, and women with vulvodynia are at increased risk of depression and anxiety.13 Physical examination reveals a normal or erythematous vulva. In provoked vulvodynia, light touch with a moist cotton swab reveals areas of

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intense pain, often highly localized. These areas are commonly on the posterior portion of the vestibule. Testing, such as cultures or biopsies, should focus on ruling out other potential causes of vulvar pain, such as infections or dermatologic conditions (e.g., lichen planus, psoriasis).14 A multidisciplinary team approach is needed to treat vulvodynia, and combining multiple

AMERICAN FAMILY PHYSICIAN

Physical examination finding

Additional testing

Therapeutic considerations

Focal mucosal abnormalities; exact appearance depends on the diagnosis

Biopsy is often helpful in making a specific diagnosi

Treatment determined by diagnosis

Vaginal mucosa may be normal or dry; evidence of trauma may be visible

Follicle-stimulating hormone, luteinizing hormone, and estrogen levels can be checked

Treat underlying medical disorders that may be contributing; sexual arousal disorders are typically referred to subspecialists

Vaginal or cervical discharge

Appropriate cultures, DNA probes, vaginal wet mount as indicated

Antibiotic or antifungal therapy should be guided by test results

Evidence of birth trauma; dry mucosa

Generally none needed

Vaginal lubricants; scar tissue massage or surgery for persistent cases

Loss of vaginal rugae; mucosa is thin, pale, and inelastic

Generally none needed

Vaginal lubricants; systemic or local estrogen; ospemifene, 60 mg daily

Involuntary contraction of pelvic floor muscles on attempted insertion of one finge

Identify any contributing factors, such as sexual abuse or pelvic floor dysfunction

Treat any underlying disorder; pelvic floor physical therapy; consider referral for cognitive behavior therapy or psychotherapy

Vulva appears normal or erythematous

Superficial culture for Candida infection

Amitriptyline or lidocaine ointment; focal surgical excision of painful areas may be effective in refractory cases

Fullness of adnexa; pain localized to adnexa

Pelvic imaging or laparoscopy

Determined by diagnosis

Examination may be unremarkable; masses or nodularity of pelvic structures may be found

Transvaginal ultrasonography

Nonsteroidal anti-inflammatory drugs, contraceptives, or gonadotropin-releasing hormone agonists

Vaginal or cervical discharge

Appropriate cultures; DNA probes as indicated

Antibiotic therapy should be guided by test results

Tenderness of bladder on palpation

Anesthetic bladder challenge or cystoscopy

Antispasmodics, immune modulators, tricyclic antidepressants, and benzodiazepines are most often used Bladder dilation and intravesicular instillations of various agents may be performed by subspecialists

Relative lack of mobility of pelvic structures may be noted

Pelvic imaging may be inconclusive

Surgical lysis of adhesions may be considered

Noted on bimanual examination

Pelvic imaging can confirm diagnosis

Uterine suspension surgery; hysterectomy if childbearing is not a concern

Irregularly shaped or enlarged uterus

Pelvic ultrasonography

Gonadotropin-releasing hormone agonists, myomectomy, hysterectomy, or uterine artery embolization

therapies is often required.15 A variety of therapies have been used, most without solid supporting evidence.16 Amitriptyline and lidocaine ointment have been evaluated in small trials.17,18 Patients with provoked vulvodynia that is unresponsive to conservative management may be offered surgical excision of painful areas, which is effective up to 80% of the time.19

Inadequate Lubrication Inadequate lubrication of the vagina leads to friction and microtrauma of vulvar and vaginal epithelium. It may be caused by a sexual arousal disorder or chronic vaginal dryness.10 Female sexual arousal disorder is defined as the inability to attain or maintain an adequate lubrication-swelling response from sexual

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AMERICAN FAMILY PHYSICIAN excitement.1 This may be multifactorial, but important historical clues include satisfaction with current sexual relationships, negative body image, fear of pain during sex, history of sexual trauma or abuse, and restrictive personal beliefs about sexuality. Sexual arousal disorder often requires treatment by a physician with experience treating female sexual dysfunction.10 Chronic vaginal dryness may suggest an underlying medical disorder with a hormonal (e.g., hypothalamicpituitary dysfunction, premature ovarian failure, menopause), vascular (e.g., peripheral atherosclerosis, anemia), neurologic (e.g., diabetic neuropathy, spinal cord injury or surgery), or iatrogenic (e.g., hormonal contraceptive use, chemotherapy, radiation) cause.10 Treatment of underlying disorders and vaginal lubricants are the mainstays of therapy.20

vaginal mucosa becomes thinner, paler, drier, and less elastic. Vaginal rugae are lost, the mucosa may appear irritated and friable, and the vagina shortens and narrows. Lubricants can help treat vaginal atrophy, but the most effective treatment is estrogen replacement. A 2006 Cochrane review of 19 trials involving more than 4,000 women found that estrogen preparations—cream, ring, or tablet—were associated with a statistically significant reduction in symptoms of vaginal atrophy compared with placebo or nonhormonal gels.27 In 2013, the U.S. Food and Drug Administration approved ospemifene, a novel selective estrogen receptor modulator that increases vaginal epithelial cells and decreases vaginal pH, for the treatment of postmenopausal dyspareunia.28 Note: For complete article visit: www.aafp.org/afp.

Postpartum Dyspareunia

REFERENCES

Postpartum dyspareunia is a common and underreported disorder. After first vaginal deliveries, 41% and 22% of women at three and six months, respectively, experience dyspareunia.21 Perineal stretching, lacerations, operative vaginal delivery, and episiotomy can result in sclerotic healing and resultant entry or deep dyspareunia. The postpartum period, especially in breastfeeding women, is marked by a decrease in circulating estrogen, which can lead to vaginal dryness and dyspareunia. The psychosexual issues of the postpartum period can lead to decreased arousal and lubrication, further contributing to dyspareunia.22 Lubricants are the typical first-line treatment. Treatment of dyspareunia specifically associated with perineal trauma during childbirth is lacking robust evidence. Women who have persistent postpartum dyspareunia associated with identifiable perineal defects or scarring may benefit from revision perineoplasty, although this is usually reserved for significant anatomic distortions.23

Lewis RW, Fugl-Meyer KS, Corona G, et al. Definitions/ epidemiology/risk factors for sexual dysfunction. J Sex Med. 2010;7(4 pt 2):1598-1607.

Ferrero S, Ragni N, Remorgida V. Deep dyspareunia: causes, treatments, and results. Curr Opin Obstet Gynecol. 2008;20(4):394-399.

Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictors [published correction appears in JAMA. 1999;281(13):1174]. JAMA. 1999;281(6):537-544.

Simons JS, Carey MP. Prevalence of sexual dysfunctions: results from a decade of research. Arch Sex Behav. 2001;30(2):177-219.

van Lankveld JJ, Granot M, Weijmar Schultz WC, et al. Women’s sexual pain disorders. J Sex Med. 2010; 7(1 pt 2):615-631.

Basson R, Wierman ME, van Lankveld J, Brotto L. Summary of the recommendations on sexual dysfunctions in women. J Sex Med. 2010;7(1 pt 2):314-326.

Huber JD, Pukall CF, Boyer SC, Reissing ED, Chamberlain SM. “Justrelax”: physicians’ experiences with women who are difficult or impossible to examine gynecologically. J Sex Med. 2009;6(3):791-799.

Faubion SS, Shuster LT, Bharucha AE. Recognition and management of nonrelaxing pelvic floor dysfunction. Mayo Clin Proc. 2012;87(2):187-193.

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, Va.: American Psychiatric Association; 2013.

Vaginal Atrophy Dyspareunia is a common presenting symptom in women with vaginal atrophy.24,25 Vaginal atrophy affects approximately 50% of postmenopausal women because of decreasing levels of estrogen.24 It is important to inquire about vaginal symptoms in postmenopaual women. Fewer than one-half of women with vaginal atrophy have discussed it with their physician because of embarrassment, belief that nothing can be done, or that such symptoms are expected with advancing age.26 In early vaginal atrophy, the physical examination may be unremarkable. Later, the

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10. Frank JE, Mistretta P, Will J. Diagnosis and treatment of female sexual dysfunction [published correction appears in Am Fam Physician. 2009;79(3):180]. Am Fam Physician. 2008;77(5):635-642.

AMERICAN FAMILY PHYSICIAN 11. Bertolasi L, Frasson E, Cappelletti JY, Vicentini S, Bordignon M, Graziottin A. Botulinum neurotoxin type A injections for vaginismus secondary to vulvar vestibulitis syndrome. Obstet Gynecol. 2009;114(5):1008-1016. 12. Moyal-Barracco M, Lynch PJ. 2003 ISSVD terminology and classification of vulvodynia. J Reprod Med. 2004;49(10):772-777. 13. Khandker M, Brady SS, Vitonis AF, Maclehouse RF, Stewart EG, Harlow BL. The influence of depression and anxiety on risk of adult onset vulvodynia. J Womens Health (Larchmt). 2011;20(10):1445-1451. 14. ACOG Committee on Gynecologic Practice. ACOG Committee Opinion: Number 345, October 2006: vulvodynia. Obstet Gynecol. 2006;108(4):1049-1052. 15. Nunns D, Mandal D, Byrne M, et al.; British Society for the Study of Vulval Disease (BSSVD) Guideline Group. Guidelines for the management of vulvodynia [published correction appears in Br J Dermatol. 2010;162(6):1416]. Br J Dermatol. 2010;162(6):1180-1185. 16. Andrews JC. Vulvodynia interventions—systematic review and evidence grading. Obstet Gynecol Surv. 2011;66(5):299-315. 17. Reed BD, Caron AM, Gorenflo DW, Haefner HK. Treatment of vulvodynia with tricyclic antidepressants: efficacy and associated factors. J Low Genit Tract Dis. 2006;10(4):245-251.

19. Boardman LA, Stockdale CK. Sexual pain. Clin Obstet Gynecol. 2009;52(4):682-690. 20. Stika CS. Atrophic vaginitis. Dermatol Ther. 2010;23(5): 514-522. 21. Signorello LB, Harlow BL, Chekos AK, Repke JT. Postpartum sexual functioning and its relationship to perineal trauma. Am J Obstet Gynecol. 2001;184(5): 881-888. 22. Leeman LM, Rogers RG. Sex after childbirth: postpartum sexual function. Obstet Gynecol. 2012;119(3):647-655. 23. Woodward AP, Matthews CA. Outcomes of revision perineoplasty for persistent postpartum dyspareunia. Female Pelvic Med Reconstr Surg. 2010;16(2):135-139. 24. Mac Bride MB, Rhodes DJ, Shuster LT. Vulvovaginal atrophy. Mayo Clin Proc. 2010;85(1):87-94. 25. Krychman ML. Vaginal estrogens for the treatment of dyspareunia. J Sex Med. 2011;8(3):666-674. 26. Reiter S. Barriers to effective treatment of vaginal atrophy with local estrogen therapy. Int J Gen Med. 2013;6:153-158. 27. Suckling J, Lethaby A, Kennedy R. Local oestrogen for vaginal atrophy in postmenopausal women. Cochrane Database Syst Rev. 2006;(4):CD001500.

28. Soe LH, Wurz GT, Kao CJ, DeGregorio MW. Ospemifene for the treatment of dyspareunia associated with vulvar 18. Zolnoun DA, Hartmann KE, Steege JF. Overnight 5% and vaginal atrophy: potential benefits in bone and lidocaine ointment for treatment of vulvar vestibulitis. breast. Int J Womans Health. 2013;5:605-611. Obstet Gynecol. 2003;102(1):84-87. ■■■■

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Practice Guidelines JNC 8 GUIDELINES FOR THE MANAGEMENT OF HYPERTENSION IN ADULTS Hypertension is one of the most important preventable contributors to disease and death in the United States, leading to myocardial infarction, stroke, and renal failure when it is not detected early and treated appropriately. The Eighth Joint National Committee (JNC 8) recently released evidence-based recommendations on treatment thresholds, goals, and medications in the management of hypertension in adults. In the general population of adults 60 years and older, pharmacologic treatment should be initiated when the systolic pressure is 150 mm Hg or higher, or when the diastolic pressure is 90 mm Hg or higher. Patients should be treated to a target systolic pressure of less than 150 mm Hg and a target diastolic pressure of less than 90 mm Hg. Treatment does not need to be adjusted if it results in a systolic pressure lower than 140 mm Hg, as long as it is not associated with adverse effects on health or quality of life. In the general population younger than 60 years, pharmacologic treatment should be initiated when the systolic pressure is 140 mm Hg or higher, or when the diastolic pressure is 90 mm Hg or higher. The target systolic pressure in this population is less than 140 mm Hg, and the target diastolic pressure is less than 90 mm Hg.

Hypertension in Patients with CKD or Diabetes For persons 18 years or older with chronic kidney disease (CKD) or diabetes mellitus, the treatment threshold and target blood pressures are the same as those for the general population younger than 60 years (i.e., threshold systolic pressure of 140 mm Hg or threshold diastolic pressure of 90 mm Hg; target systolic

pressure of less than 140 mm Hg; target diastolic pressure of less than 90 mm Hg). There is no evidence that treating patients with CKD to a lower blood pressure goal slows the progression of the disease. Similarly, there is no evidence from randomized controlled trials showing that treatment to a systolic pressure of less than 140 mm Hg improves health outcomes in adults with diabetes and hypertension.

Pharmacologic Treatment In the general nonblack population, including those with diabetes, initial antihypertensive treatment should include a thiazide diuretic, calcium channel blocker, angiotensin-converting enzyme (ACE) inhibitor, or angiotensin receptor blocker (ARB). In the general black population, including those with diabetes, initial treatment should include a thiazide diuretic or calcium channel blocker. If the target blood pressure is not reached within one month after initiating therapy, the dosage of the initial medication should be increased or a second medication should be added (thiazide diuretic, calcium channel blocker, ACE inhibitor, or ARB; do not combine an ACE inhibitor with an ARB). Blood pressure should be monitored and the treatment regimen adjusted until the target blood pressure is reached. A third drug should be added if necessary; however, if the target blood pressure cannot be achieved using only the drug classes listed above, antihypertensive drugs from other classes can be used (e.g., beta blockers, aldosterone antagonists). Referral to a physician with expertise in treating hypertension may be necessary for patients who do not reach the target blood pressure using these strategies. Adults with CKD and hypertension should receive an ACE inhibitor or ARB as initial or add-on therapy, based on moderate evidence that these medications improve kidney-related outcomes in these patients.

■■■■

Source: Adapted from Am Fam Physician. 2014;90(7):503-504.

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Photo Quiz ACTIVE DUTY SOLDIER WITH PUNCTATE MARKS ON THE FEET A 27-year-old man on active military duty presented with severe sweating in both of his feet. He also had malodorous cracking skin and pain in his feet. The symptoms had been present for two years. Multiple home remedies such as frequent changing of his socks, new shoes, and the use of deodorants and drying powders did not improve his symptoms. He did not have excessive sweating in other areas of his body. Physical examination revealed foul-smelling feet with multiple discrete punctate depressions on the plantar surface. The lesions were mostly distal in location (see accompanying figure). Physical examination findings were otherwise normal.

Question Based on the patient’s history and physical examination findings, which one of the following is the most likely diagnosis? A. Dyshidrotic eczema. B. Essential hyperhidrosis. C. Pitted keratolysis. D. Plantar warts. E. Tinea pedis.

Discussion The answer is C: pitted keratolysis. Pitted keratolysis is caused by a bacterial infection (usually Corynebacterium), which is often misdiagnosed as a fungal infection.1 It typically presents as many circular or longitudinal “punched out” depressions in the skin of the weightbearing surfaces of the soles, with associated severe malodor. The diagnosis is clinical, based on history findings and the presence of lesions. Pitted keratolysis is more common in persons younger than 35 years, and in those who wear occlusive footwear, are physically

Source: Adapted from Am Fam Physician. 2014;90(7):487-488.

Figure.

active, have a personal history of hyperhidrosis, or work or are active in a hot or humid environment. It is common in the active duty military population.1,2 Patients should begin with conservative treatment such as keeping the feet dry with frequent sock changes and drying powders. Twice-daily application of topical clindamycin, erythromycin, or mupirocin is the most effective treatment. Oral clindamycin or erythromycin is also effective, but typically not needed with topical treatment. The lesions and odor usually resolve in three to four weeks.3 Dyshidrotic eczema is an idiopathic reaction that often presents as a hand dermatitis, but it can also affect the feet. It is common in patients with environmental allergies.4 Small, intensely pruritic blisters occur in the acute stage. The blisters last three to four weeks before spontaneously resolving. Chronic eczematous changes follow shortly afterward with erythema, peeling, cracking, scaling, and lichenification.1 Essential hyperhidrosis is excess sweating, usually on the palms, soles, and axillae. The sweating is beyond what is needed for thermoregulation and can cause significant embarrassment.5 Hyperhidrosis is most often idiopathic but can be secondary to hyperthyroidism, obesity, diabetes mellitus, and cardiovascular disorders. It can also be an adverse effect of some medications, most commonly tricyclic antidepressants.6 Plantar warts are caused by the human papillomavirus and typically occur at the point of maximal pressure on

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AMERICAN FAMILY PHYSICIAN Summary Table Condition

Characteristics

Dyshidrotic eczema

Vesicular dermatitis appearing most often on the hands, but can affect the feet; common in individuals with environmental allergies

Essential hyperhidrosis

Excess sweating usually on the palms, soles, and axillae; often idiopathic but may be secondary to a chronic medical condition (hyperthyroidism, obesity, diabetes mellitus) or medication use (tricyclic antidepressants)

Pitted keratolysis

Bacterial skin infection affecting the feet; most common in active, younger individuals in hot, humid environments; resolves in three to four weeks with topical antibiotic creams

Plantar warts

Caused by human papillomavirus; occur at the point of maximum pressure on the plantar surface of the foot; small black petechiae within the lesion and loss of dermatoglyphs

Tinea pedis

Toe web maceration is most common; may also present as the classic ringworm pattern or a moccasin-type distribution (i.e., primarily affecting the soles); confirmed with potassium hydroxide testing; typically resolves with antifungal cream

the plantar surface of the foot. Patients may alter their gait if a large callus forms, resulting in pain in other parts of the foot, leg, or back.1 Plantar warts can be distinguished from pitted keratolysis by the multiple small black petechiae within the lesion and the loss of dermatoglyphs.1

Takama H, Tamada Y, Yano K, Nitta Y, Ikeya T. Pitted keratolysis: clinical manifestations in 53 cases. Br J Dermatol. 1997;137(2):282-285.

Zaias N. Pitted and ringed keratolysis. A review and update. J Am Acad Dermatol. 1982;7(6):787-791.

Schuttelaar ML, Coenraads PJ, Huizinga J, De Monchy JG, Vermeulen KM. Increase in vesicular hand eczema after house dust mite inhalation provocation: a double-blind, placebo-controlled, cross-over study. Contact Dermatitis. 2013;68(2):76-85.

Hornberger J, Grimes K, Naumann M, et al.; MultiSpecialty Working Group on the Recognition, Diagnosis, and Treatment of Primary Focal Hyperhidrosis. Recognition, diagnosis, and treatment of primary focal hyperhidrosis. J Am Acad Dermatol. 2004;51(2):274-286.

Connolly M, de Berker D. Management of primary hyperhidrosis: a summary of the different treatment modalities. Am J Clin Dermatol. 2003;4(10):681-697.

7. Habif TP. Clinical Dermatology: A Color Guide to Diagnosis and Therapy. 5th ed. New York, NY: Mosby; 2004. ■■■■

Crawford F, Hollis S. Topical treatments for fungal infections of the skin and nails of the foot. Cochrane Database Syst Rev. 2007;(3):CD001434.

Tinea pedis is the most common dermatophyte infection. Shoes that promote warmth and sweating encourage fungal growth. The condition typically presents as toe web maceration, but may also present as a classic ringworm pattern or a moccasin-type distribution (i.e., primarily affecting the soles).1 Tinea pedis is more common in men and can be confirmed with potassium hydroxide scraping. It usually resolves with topical antifungal cream.7 REFERENCES 1.

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CARDIOLOGY

Current Guidelines for Cardiac Pacemaker Implantation KAMAL KUMAR*, SHIVANJALI KUMAR†, RANJANA KUMAR‡

acemakers, pacing techniques and indications for pacing have evolved since the first pacemaker implantation in 1958. With almost a million pacemakers being installed every year across the globe, guidelines that outline indications for implantation of cardiac pacemakers and other arrhythmia devices have been proposed by the American College of Cardiology/ American Heart Association/Heart Rhythm Society (ACC/AHA/HRS).1-5

More recent guidelines for implantation of cardiac pacemakers based on the class of recommendation and level of evidence were outlined in the 2013 European Society of Cardiology (ESC) guidelines on cardiac pacing and cardiac resynchronization therapy (Tables 1 and 2).6,7 CURRENT INDICATIONS FOR PACEMAKER IMPLANTATION

Symptomatic Bradycardia6,7 Symptomatic bradycardia is a Class 1 Level B indication for permanent pacemaker (PPM) implantation. The commonest cause is sinus node dysfunction. Cardiac pacing relieves symptoms of bradycardia, syncope and heart failure but does not reduce mortality. Asymptomatic bradycardia, bradycardia caused by physiological causes as in athletes or caused by drugs should be excluded.

Acquired AV Block in Adults6,7 Third degree atrioventricular (AV) block is a definite indication for pacing even in asymptomatic cases with

*Senior Consultant †Consultant ‡Senior Consultant (Pediatrics) Heartline Hospital and Cardiac Cath Lab, Allahabad, Uttar Pradesh Address for correspondence Dr Kamal Kumar 29 B/2, Hastings Road, Allahabad - 211 001, Uttar Pradesh E-mail: drkamalkumar@rediffmail.com

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a ventricular rate of more than 40 bpm (Class 1 Level C). Second degree type 2 AV block should be paced irrespective of symptoms or heart rate (Class 1 Level C). Second degree type 1 AV blocks with symptomatic bradycardia, blocks with wide QRS segments located at intra- or infra-His levels on EPS are more likely to progress to complete heart block and should be paced (Class IIa Level C). Exercise-induced second or third degree blocks in the absence of ischemia may be considered for pacing. First degree AV blocks in the presence of neuromuscular disorders like myotonic muscular dystrophy. KearnsSayre syndrome and Erb’s dystrophy are an indication for PPM as the progression of conduction system disease is unpredictable. Permanent pacemaker should not be implanted in asymptomatic first or second degree AV blocks and in situations, where the block may be reversible as in Lyme’s disease, drug toxicity, transient vagotonia or hypoxia in sleep apnea (Class III Level C).

Bundle Branch Block6,7 Indications for PPM implantation include bundle branch blocks with unexplained syncope and abnormal EPS (Class 1 Level B), alternating left and right bundle block (Class 1 Level C) and bundle branch blocks with unexplained syncope (Class IIb Level B). All three conditions are usually accompanied with a high rate of sudden death unless paced. PPM is not indicated for asymptomatic bundle branch block (Class III Level B).

Post Acute Myocardial Infarction3,6,7 Less than 10% of patients who present with AV block after recent myocardial infarction require pacing. (Class I Level C). In the remaining patients, the blocks spontaneously resolve over days or weeks and do not require PPM implantation (Class III Level B). Conventional pacing offers no benefit in transient second and third degree heart blocks associated with new-onset bundle branch blocks after acute myocardial

CARDIOLOGY Table 1. Classes of Recommendations (2013 ESC Guidelines on Cardiac Pacing and Cardiac Resynchronization Therapy) Definitio

Suggested wording to use

Class I

Evidence and/or general agreement that a given treatment or procedure is beneficial, useful, e fective

Is recommended/indicated

Class II

Conflicting evidence and/or a divergence of opinion about the g ven treatment or procedure

Class IIa

Weight of evidence/opinion is in favor of usefulness/efficac

Should be considered

Class IIb

Usefulness/efficacy is less well-established by evidence/opinio

May be considered

Evidence or general agreement that the given treatment or procedure is not useful/effective, and in some cases may be harmful

Is not recommended/indicated

Class III

Table 2. Levels of Evidence (2013 ESC Guidelines on Cardiac Pacing and Cardiac Resynchronization Therapy) Levels of evidence A

Data derived from multiple randomized clinical trials or meta-analyses

Levels of evidence B

Data derived from a single randomized clinical trial or large nonrandomized

Levels of evidence C

Consensus of opinion of the experts and/or small studies, retrospective studies, registries.

infarction (Class III). Such patients should be considered for implantable cardioverter-defibrillators.

Neurocardiogenic Syncope with Hypersensitive Carotid Sinus Syndrome6,7 Pacing may reduce syncopal recurrences in patients with unexplained syncope and positive adenosine triphosphate test (Class IIb Level B). Pacing is not indicated for patients with unexplained syncope in the absence of bradycardia or conduction disturbance (Class III Level C). It is also not indicated for unexplained falls (Class III Level B). A diagnosis of hypersensitive carotid sinus syndrome is made if asystole caused by sinus arrest or AV block persists for more than 3 seconds after carotid sinus stimulation. PPM implantation may benefit such patients (Class I Level B). Pacing may be indicated in tilt-induced cardioinhibitory response with recurrent, frequent and unpredictable syncope if age is more than 40 years and alternative therapies fail (Class IIb Level B). Pacing is not indicated in the absence of tilt-induced syncope (Class III Level B).

Pacing to Prevent Tachycardias6,7 Permanent overdrive pacing previously used to prevent and terminate atrial and ventricular arrhythmias has

now been replaced by insertion of an implantable defibrillator and cardiac resynchronization therapy.

Congenital Heart Disease6,7 Permanent pacemaker implantation in children is indicated in congenital AV block in symptomatic patients and in asymptomatic patients with ventricular dysfunction, prolonged QTc interval, complex ventricular ectopy, wide QRS escape rhythms, ventricular rate less than 50 bpm and ventricular pauses more than 3 cycle-lengths of the underlying rhythm (Class I Level C). In asymptomatic patients with highdegree complete AV blocks pacing may be considered (Class IIb Level C). Advanced second degree or complete AV block persisting for more than 10 days after surgery for congenital heart disease should be paced (Class I Level B). Postoperative bifascicular blocks associated with transient complete AV block should also be paced (Class IIa Level C). Permanent pacing is also indicated for sinus node disease with symptomatic bradycardia or tachybrady disease (Class I Level C). Permanent pacemaker implantation may also be useful in asymptomatic sinus node disease with resting heart rate below 40 bpm or ventricular pauses longer than 3 seconds (Class IIb Level C).

After Cardiac Transplantation or Other Surgical Procedures3,6,7 Bradyarrhythmias are common following cardiac surgical procedures, transcatheter aortic valve replacement (TAVR) and cardiac transplantation. Most bradyarrhythmia recover within 7 days after surgery. After this period guidelines for pacemaker implantation are the same as in un-operated patients (Class I Level C). Pacing should be performed in patients with complete

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CARDIOLOGY heart block occurring in the first 24 hours after mitral or aortic valve surgery, if the block persists beyond 48 hours. Complete AV blocks with a low rate of escape rhythm also require pacing.

Force on Practice Guidelines (Committee on Pacemaker Implantation). Circulation. 1998;97(13):1325-35. 3.

Gregoratos G, Abrams J, Epstein AE, Freedman RA, Hayes DL, Hlatky MA, et al. ACC/AHA/NASPE 2002 guideline update for implantation of cardiac pacemakers and antiarrhythmia devices: Summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2002;106(16):2145-61.

Chronotropic incompetence persisting beyond 3 weeks after cardiac transplantation is an indication for pacing especially if it interferes with the quality-oflife (Class IIa Level C).

Gregoratos G. Indications and recommendations for pacemaker therapy. Am Fam Physician. 2005;71(8): 1563-70.

Conditions requiring implantable defibrillators and cardiac resynchronization therapy have not been described here as they are outside the scope of this article.

Vlay SC. The ACC/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: their relevance to the cardiologist, internist and family physician. J Invasive Cardiol. 2009;21(5):234-7.

ESC Clinical Practice Guidelines. Cardiac Pacing and Cardiac Resynchronization Therapy. [online] Available from http://www.escardio.org/Guidelines-&-Education/ Clinical-Practice-Guidelines/Cardiac-Pacing-andCardiac-Resynchronization-Therapy [Accessed 21 May 2015).

Brignole M, Auricchio A, Baron-Esquivias G, Bordachar P, Boriani G, Breithardt O, et al. 2013 ESC guidelines on cardiac pacing and cardiac resynchronization therapy. The task force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA). Eur Heart J. 2013;34(29):2281-329.

Almost a one-third of patients undergoing TAVR require PPM implantation. Sinus node dysfunction persisting for more than 3 weeks after cardiac transplantation is an indication of PPM implantation (Class I Level C).

REFERENCES 1.

Zhan C, Baine WB, Sedrakyan A, Steiner C. Cardiac device implantation in the United States from 1997 through 2004: a population-based analysis. J Gen Intern Med. 2008;23(Suppl 1):13-9.

Gregoratos G, Cheitlin MD, Conill A, Epstein AE, Fellows C, Ferguson TB, et al. ACC/AHA Guidelines for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices: Executive Summary: a report of the American College of Cardiology/American Heart Association Task ■■■■

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Women in menopause have a lower risk of coronary heart disease (CHD) events compared with men irrespective of race and whether their menopause is natural or the result of surgery, suggests a large cohort study published in the Journal of the American Heart Association. The extent of coronary artery calcification (CAC) is an accurate predictor of 15-year mortality in asymptomatic individuals, suggests a new study published online July 6 in the Annals of Internal Medicine. An updated meta-analysis has shown that individuals who took a proton-pump inhibitor (PPI) in addition to clopidogrel had a significantly increased risk of adverse cardiovascular events, including all-cause mortality, myocardial infarction, acute coronary syndrome, cerebrovascular accident, stent thrombosis and the need for revascularization. The findings are published in Open Heart. Diabetes, stroke and myocardial infarction each double the risk of death alone and multiply the risk further when the trio is combined, suggests a new study published in the July 7 issue of the Journal of the American Medical Association.

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COMMUNITY MEDICINE

Understanding Evolution of Resistant Strains in Recent Decades and Approach Towards Antibiotic Therapy NEETHU POULOSE, ANIL ANTONY, SREELAKSHMI SREEDHAR, ANIL BABU

ABSTRACT Developing resistance to antibiotics is a natural process, and a raising threat to human society. These emergent strains have worsened the burden on the existing regimen of antibiotic therapy. Resistance classified under multidrug resistance (MDR), extensively drug resistance (XDR) and pandrug resistance (PDR) are widely seen in hospital setup. Methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant S. aureus (VRSA), Escherichia coli and Klebsiella (resistant to third-generation cephalosporins), carbapenem-resistant Enterobacteriaceae (CRB) are currently associated with hospital-acquired infection, which calls need of careful and proper antibiotic management. Antibiotic control programs, better hygiene, antibiogram based empirical therapy with improved antimicrobial activity will help limit bacterial resistance.

Keywords: Antibiotics, mechanisms, biofilm resistance, multidrug resistance, extensively drug resistance, pandrug

resistance

iscovery of antibiotic was a mile stone in history of medical science, which revolutionized clinical world. The antibiotics are wonder drugs which have immense role in health sector by reducing morbidity as well as mortality. They are the main weapons against infectious diseases, which is a serious issue at global level and has saved countless lives.

The antibiotic era was started in the 1940s, which changed the profile of infectious diseases and human demography. In course of time, there evolved a large variety of pathogens and discovery of new antibiotics became necessary. However, as antibiotics surprised by acting as magical bullets, infectious agents challenged by rapid appearance of resistance through unbelievable molecular mechanisms. Over a period of 65 years newer antibiotics were introduced in market, which was followed by emergence of resistant strains. Due

Dept. of Pharmacy Practice National College of Pharmacy, Kozhikode, Kerala Address for correspondence Dr Neethu Poulose National College of Pharmacy, Manassery Kozhikode, Kerala - 673 602 E-mail: neethupoulosemadassery@gmail.com

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to increased concern of change in resistance, this is an attempt to point out how far our chemotherapy with antibiotics has reached, emerging-resistant strains, mechanisms, multidrug resistance (MDR), extensively drug resistance (XDR) and pandrug resistance (PDR) and how intense use of reserve antibiotics will affect in future. EVOLUTIONARY CHANGE OF ORGANISMS AFTER ANTIBIOTIC DISCOVERY The intense use and misuse of antibiotics are undoubtedly the major forces associated with the high numbers of resistant pathogenic bacteria worldwide, which is a raising threat to the society.1 The introduction of new antibiotics to counter those pathogen has frequently been closely followed by the emergence of resistant strain. These emergent strains have worsened the burden on existing regimen of antibiotic therapy in both clinical and economical aspects. Some of the examples are Staphylococcus aureus isolates resistant to β-lactams due to β-lactamase as well as extensive-spectrum β-lactamase and many of these are also resistant to β-lactamase-resistant penicillins. Methicillin-resistant S. aureus (MRSA) isolates are one of the most challenging-resistant pathogens now-a-days. Evolutionary pattern of resistant strains of S. aureus is

COMMUNITY MEDICINE infectious agents may get intrinsically resistant to >1 class of antimicrobial agent or may acquire resistance by de novo mutation or via the acquisition of resistance genes from other organisms.

Preantibiotic Era 1940-1950s: 1941–Penicillin discovery; soon after S. aureus developed resistance to penicillin;1959–Methicillinsusceptible to penicillinase producing organisms discovered.

1960-2000: S. aureus MRSA strains first reported soon in1961. MRSA developed resistance to penicillin like antibiotics (penicillin, amoxicillin, oxacillin) erythromycin, aminoglycosides, tetracyclines; drug of choice was vancomycin/linezolid.

Biofilm resistance: Unicellular S. aureus come together to form a community, encased in an exopolysaccharide matrix.

2000s: Vancomycin resistance reported; isolated vancomycinresistant S. aureus. Multidrug resistance, extensively drug resistance and pandrug resistance by resistant strains of S. aureus.

New antibiotic discovery

Combination therapy

Resistance follows soon, if no proper infection control and rational antibiotic regimen implemented.

Figure 1. Evolutionary pattern of resistant S. aureus strain.

given in Figure 1.1 They are usually associated with hospitals and implementation of appropriate control measures usually reduce prevalence to sporadic levels.2 Antibiotic resistance often leads to therapeutic failures of empirical therapy; these conditions call for the need for a revolutionary change by either discovery of new antibiotics or combination antibiotic therapy in future. But, it is also not a rational solution to the problem, because the resistance follows with these approaches. In short, antibiotic resistance is the major challenge associated with chemotherapy against infectious diseases. Resistant pathogens developed are more virulent, so as a first step, knowledge of etiological agents of infections, antibiotic resistance mechanisms, pattern of developing resistance and sensitivities to available drugs is of immense value for the rational empirical therapy of antibiotics and to slow down the process of antibiotic resistance.3 RESISTANT STRAINS IN RECENT DECADES The susceptible populations of bacteria may become resistant to antimicrobial agents through mutation and selection or by acquiring from other bacteria the genetic information that encodes resistance. The

These spontaneous mutations may cause resistance by: (a) altering the target protein to which the antibacterial agent binds by modifying or eliminating the binding site, (b) up-regulating the production of enzymes that inactivate the antimicrobial agent, (c) down-regulating or altering an outer membrane protein channel that the drug requires for cell entry or (d) upregulating pumps that expel the drug from the cell (Table 1).4 However, acquisition of new genetic material by antimicrobial-susceptible bacteria from resistant strains of bacteria may occur through conjugation, transformation or transduction, with transposons often facilitating the incorporation of the multiple resistance genes into the host’s genome or plasmids.5 Some of the important or recently developed resistant strains in our community and the mechanisms of their development are discussed below.

E. coli and Klebsiella: Resistance to Third-generation Cephalosporins E. coli is a common cause of urinary tract infections (UTIs) and bacteremia in humans.6-8 It has been observed that there is a generalized decrease in bacterial susceptibility of common oral antibiotics to community-acquired UTI, which is frequently resistant to aminopenicillins, such as amoxicillin or ampicillin and narrow-spectrum cephalosporins.9,10 Resistance is typically mediated by the acquisition of plasmid-encoded β-lactamases. But, the thirdgeneration cephalosporins are broad-spectrum drugs with intrinsic activity against Gram-negative species. However, resistance to third-generation cephalosporins and monobactams (aztreonam) occurs through the acquisition of extended-spectrum β-lactamases (ESBLs). ESBL are strong bacterial enzymes that raises the burden of resistance to even highly effective antibiotics.11 The problem of resistance due to ESBL, even though more reported on Klebsiella, now-a-days its pattern is similar for E. coli. The different studies showed that ESBL-producer are also resistant to fluoroquinolones, trimethoprim-sulfamethoxazole and aminoglycosides.12,13 However, resistance to cephamycins and other β-lactams may arise as a result of changes in the porins in the outer membrane.14

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COMMUNITY MEDICINE Table 1. Common Antibiotic Resistance Mechanisms and Examples Common resistant mechanisms

Example

Antibiotics

Altering the target protein to which Change in penicillin-binding the antibacterial agent attach protein 2b in pneumococci, which results in penicillin resistance

Penicillin G, ampicillin, amoxicillin, ticarcillin, piperacillin, methicillin.

Up-regulating the production of enzymes that inactivate the antimicrobial agent

Penicillins, monobactams, carbapenems and cephalosporins, aminoglycosides (streptomycin, neomycin, netilmicin, tobramycin, gentamicin, amikacin, etc.)

Erythromycin ribosomal methylase in staphylococci

Down-regulating or altering an OmpF in E. coli outer membrane protein channel that the drug requires for cell entry

β-lactams, carbapenems, fluoroquinolones, chloramphenicol have specific porins

Up-regulating pumps that expel the drug from the cell

Aminoglycosides, ampicillin, ciprofloxacin, chloramphenicol, clindamycin, cephalosporin, erythromycin, fluoroquinolones, macrolides, nalidixic acid, novobiocin, norfloxacin,streptogramin B, tetracycline, tigecycline, trimethoprim, vancomycin.

Efflux of fluoroquinolones i S. aureus

Methicillin-resistant S. aureus Methicillin, the first of the semi-synthetic penicillinaseresistant penicillins, introduced to target strains of penicillinase-producing S. aureus. However, resistance to methicillin was reported very quickly after its introduction in 1960s and detection of MRSA was associated with more severe clinical presentation of community-acquired pneumonia and skin infection.15-17 It was the beginning of global outbreaks of communityassociated methicillin-resistant S. aureus infection.18 MRSA is a common cause of infection among hospitalized patients. Consequently, treatment of these infections has become more difficult and healthcare burden.19 Studies show that MRSA bacteremia is associated with significantly higher mortality rate than methicillin-susceptible S. aureus bacteremia.20 Resistance occurs following the chromosomal acquisition of novel DNA, resulting in the production of a new penicillin-binding protein 2a (PBP2a), with a low-binding affinity for methicillin. PBP2a substitutes for all other penicillin-binding proteins, and because of its low-affinity for all β-lactam antibiotics it confers resistance to all β-lactam agents, including cephalosporins.21 Vancomycin is currently the gold standard for the treatment of MRSA bacteremia, but over the last decade there has been increasing concern about the development of MRSA strains with reduced susceptibility to vancomycin.22

Vancomycin-resistant S. aureus Another major concern after the emergence of MRSA is the vancomycin-resistant strains (VRSA), that is evolution of strains-resistant to vancomycin, which is the typical treatment for MRSA infection. However, the

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therapeutic failure of vancomycin therapy is explained by the reduced susceptibility of glycopeptides susceptibility rather than using the term resistance in clinical world and is associated with minimum inhibitory concentration (MIC). S. aureus strains with reduced susceptibility to glycopeptides can be divided into three categories: VRSA; MIC, ≥16 μg/mL); vancomycin-intermediate strains (VISA; MIC, ≥4 μg/mL) and heterogeneous vancomycinintermediate strains (hVISA; MIC <4 μg/mL).23 Reduced susceptibility versus resistance of vancomycin is controversial, as the term resistance is reserved for those with MIC ≥16 μg/mL.24 However, the prevalence of hVISA among MRSA is rising among three categories.25 The exact mechanism of vancomycin resistance remains unclear, but it probably involves thickening of the organism’s cell wall due to the accumulation of cell wall fragments capable of binding vancomycin extracellularly, thereby prevent them from reaching their bacterial target. High-level vancomycin resistance occurred because of expression of vanA, which is associated with alteration of the vancomycinbinding site in the cell wall. Expression of vanA and other genes made the affinity of vancomycin 1,000 times lower than for the native peptidoglycan precursor and resulted in high-resistant density.26

E. coli, S. aureus, Streptococcus pyogenes: Biofilm Resistance Bacterial biofilm is an emerging mechanism of resistance, as it succeeded in explaining reason of chronic infectious diseases that end in treatment failure. Biofilms are communities of microorganisms attached to a surface. Bacterial biofilms are formed when unicellular organisms come together to form

COMMUNITY MEDICINE a community that is attached to a solid surface and encased in an exopolysaccharide matrix.27 Example-biofilm development in both commensal and pathogenic E. coli, the polysaccharide matrix contributes to development of phenotypic resistance of pathogenic E. coli biofilms and lead to persistent infections.28 Biofilm bacteria show much greater resistance to antibiotics than their free-living counterparts. Its mechanism is entirely different from familiar mechanisms of resistance such as familiar plasmids, transposons and mutations. This emerging mechanism has grabbed attention of clinical world and calls for need for potential antibiotic therapies.29 It has been suggested that this matrix prevents the access of antibiotics to the bacterial cells embedded in the community. However, Staphylococcus epidermidis biofilms formed allowed for the diffusion of rifampicin and vancomycin. These results suggest that inhibition of diffusion cannot always explain resistance to antimicrobial compounds and other mechanisms must be in place to promote biofilm cell survival. Some organisms in biofilms have been shown to express biofilm-specific antimicrobial resistance genes that are not required for biofilm formation. Thirty-eight percent of the E. coli genome is affected by biofilm formation (ompR gene, csgD gene involved in bacterial adhesion).30 However, the exopolysaccharide matrix does act as an initial barrier that can delay penetration of the antimicrobial agent.31 Phenotypic and genotypic characteristics associated with biofilm formation of E. coli, S. aureus, S. pyogenes have been widely studied.32 Other examples of clinical issues: (a) pharyngitis treatment failure-patients with isolates of S. pyogenes which have a biofilm-positive phenotype and increased minimum biofilm eradication concentration (MBEC) for all contemporary antibiotics used to treat acute pharyngitis cases.33 (b) S. epidermidis infections on indwelling medical devices is pointing towards biofilm formation.34 (c) S. aureus infections such as osteomyelitis specifically cases of juvenile osteomyelitis, periodontitis and peri-implantitis, wound infection, endocarditis are types of biofilm infection; devices-mediated infection are also common and such devices need to be replaced more frequently than those infected with S. epidermidis.35 Biofilm infections must be either prevented from forming or be surgically removed once formed in order to resolve the infection together with potential antimicrobial therapy.

Carbapenem-resistant Enterobacteriaceae The pathetical situation has not end with emergence broad-spectrum third-generation cephalosporins. Carbapenems (example: E. coli-resistant to imipenem), which entered the clinical world with extreme potency and broad-spectrum of activity is also showing resistance now-a-days.36 This event may have severe public health consequences, leading to elimination of many effective antimicrobial drug treatment against the most common human bacterial pathogens, leaving us with limited therapeutic option.37 Many studies support the use of carbapenem as an empirical antibiotic for patients with communityonset bacteremia and those with high-risk of resistance.38 Even though, incidence of outbreak is rare in many part of world, itâ&#x20AC;&#x2122;s no longer the case. Increased consumption of carbapenem after rise of third-generation cephalosporin-resistant E. coli and K. pneumoniae may be reason for emergence of carbapenem-resistant strains of organisms. Resistant density of carbapenem-resistant K. pneumoniae is also increasing along with 3GC-resistant E. coli and K. pneumoniae.39 Bacterial acquisition of carbapenemases, a powerful enzyme that inactivates carbapenems, also confers resistance to all cephalosporins, aztreonam, and Î˛-lactamase inhibitors such as clavulanic acid and tazobactam. Carbapenem-resistant Enterobacteriaceae (CRE) isolates are increasingly reported as MDR, XDR or PDR.40,41 In this short time, isolates of E. coli, Klebsiella, Enterobacter, Serratia and Salmonella species have reported carbapenem resistance and it globally changed the epidemiology of resistance.42 Combination regimen or monotherapy of agents such as polymyxins (such as colistin), aminoglycosides, tigecycline and fosfomycin are the available therapeutic options.43 Multidrug Resistance, Extensively Drug Resistance and Pandrug Resistance Multidrug resistance, XDR and PDR have defined differently in medical literatures. The standardized international terminology created by group of international experts came together through a joint initiative by the European Center for Disease Prevention and Control (ECDC) and the Centers for Disease Control and Prevention (CDC) defines these terms as follows. MDR is defined as nonsusceptibility to at least one agent in three or more antimicrobial categories. XDR is defined as nonsusceptibility to at least one

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MDR

XDR

PDR

Figure 2. Relation between MDR, XDR and PDR.

agent in all but two or fewer antimicrobial categories (bacterial isolates remain susceptible to only one or two categories). PDR is defined as nonsusceptibility to all agents in all antimicrobial categories (no agents tested as susceptible for that organism).41 The pictorial representation of relation between MDR, XDR, PDR is shown in Figure 2. Emerging and spreading of MDR (emerged strains are referred as ‘super bugs’) is a natural phenomenon, followed by the inappropriate use of antimicrobial drugs, inadequate sanitary conditions, inappropriate food-handling and poor infection prevention and control practices.44 As we discussed different mechanisms of resistance, efflux pumps are common components of MDR (Pseudomonas aeruginosa MDR) and prevent accumulation of antibacterial drugs. XDR (‘extreme drug resistance’, ‘extensive drug resistance’) was term created initially to describe drug-resistant Mycobacterium tuberculosis; eventually the circumstances changed and the resistance profile of non-Mycobacterium that compromised most standard antimicrobial regimens was also described by same term.45,46 PDR (pan-‘all’) means ‘resistant to all antimicrobial agents. The management of PDR Gramnegative bacterial infections is very difficult, only few drugs including colistin, in combination with β-lactam antibiotics, polymyxins, an old class of antibiotics are recommended.47 Now, the time has reached a point, where there is only limited therapeutic option, even through many antibiotics are in our hand and it’s time to focus on careful handling of antibiotics.

management of critically-ill patients and patients undergoing various operative procedures and other medical interventions are vital, along with hospital antibiotic policies which need frequent revision.48 In the management of infectious diseases, initially more care should be given in the selection of antibiotics based on hospital antibiogram in empirical therapy. More rational selection of antibiotics based on the most likely pathogens for a given infection and the susceptibility profiles of these pathogens that are specific to each institution will reduce density of resistance in and around institution. Antibiogram considerably helps in proper empirical selection of antibiotics. Each practitioner should have updated knowledge about evolutionary stage of resistant isolates in the hospital while prescribing each antibiotic. Proper infection control should be employed in hospitals. In short antibiotic control programs, better hygiene, antibiogram-based empirical therapy and synthesis of agents with improved antimicrobial activity need to limit bacterial resistance. In a developing country like India, there is an urgent need to develop and strengthen antimicrobial policy, standard treatment guidelines in the national, community and hospital level.49 REFERENCES 1.

Barbosa TM, Levy SB. The impact of antibiotic use on resistance development and persistence. Drug Resist Updat. 2000;3(5):303-11.

Schito GC. The importance of the development of antibiotic resistance in Staphylococcus aureus. Clin Microbiol Infect. 2006;12(Suppl 1):3-8.

El-Mahmood AM, Isa H, Mohammed A, Tirmidhi AB. Antimicrobial susceptibility of some respiratory tract pathogens to commonly used antibiotics at the Specialist Hospital, Yola, Adamawa State, Nigeria. J Clin Med Res. 2010;2(8):135-42.

McManus MC. Mechanisms of bacterial resistance to antimicrobial agents. Am J Health Syst Pharm. 1997;54(12):1420-33.

Brown DF, Edwards DI, Hawkey PM, Morrison D, Ridgway GL, Towner KJ, et al. Guidelines for the laboratory diagnosis and susceptibility testing of methicillin-resistant Staphylococcus aureus (MRSA). J Antimicrob Chemother. 2005;56(6):1000-18.

Kwan CW, Onyett H. Community acquired urinary tract pathogens and their resistance patterns in hospitalized children in south-eastern Ontario between 2002 and 2006. Paediatr Child Health. 2008;13(9):759-62.

Bano K, Khan J, Begum RH, Munir S, Akbar N, Ansari JA, et al. Patterns of antibiotic sensitivity of bacterial pathogens among urinary tract infections (UTI) patients in a Pakistani population. Afr J Microbiol Res. 2012;6:414-20.

MANAGEMENT OF ANTIBIOTIC RESISTANCE Most of the antibiotic drug resistance are of nosocomial or hospital origin. In India, one in four patients admitted into hospital acquires nosocomial infection. So, proper

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Dimitrov TS, Udo EE, Emara M, Awni F, Passadilla R. Etiology and antibiotic susceptibility patterns of community-acquired urinary tract infections in a Kuwait hospital. Med Princ Pract. 2004;13(6):334-9. Prais D, Straussberg R, Avitzur Y, Nussinovitch M, Harel L, Amir J. Bacterial susceptibility to oral antibiotics in community acquired urinary tract infection. Arch Dis Child. 2003;88(3):215-8.

10. Sabir S, Ahmad Anjum A, Ijaz T, Asad Ali M, Ur Rehman Khan M, Nawaz M. Isolation and antibiotic susceptibility of E. coli from urinary tract infection in a tertiary care hospital. Pak J Med Sci. 2014;30(2):389-92. 11. Ena J, Arjona F, Martínez-Peinado C, López-Perezagua Mdel M, Amador C. Epidemiology of urinary tract infections caused by extended-spectrum beta-lactamaseproducing Escherichia coli. Urology. 2006;68(6):1169-74. 12. Paterson DL, Ko WC, Von Gottberg A, Mohapatra S, Casellas JM, Goossens H, et al. International prospective study of Klebsiella pneumoniae bacteremia: implications of extended-spectrum beta-lactamase production in nosocomial infections. Ann Intern Med. 2004;140(1):26-32. 13. Paterson DL, Bonomo RA. Extended spectrum betalactamase: a clinical update. Clin Microbiol Rev. 2005;18(4):657-86. 14. Clarke B, Hiltz M, Musgrave H, Forward KR. Cephamycin resistance in clinical isolates and laboratory-derived strains of Escherichia coli, Nova Scotia, Canada. Emerg Infect Dis. 2003;9(10):1254-9. 15. Moran GJ, Krishnadasan A, Gorwitz RJ, Fosheim GE, Albrecht V, Limbago B, et al. Prevalence of methicillinresistant Staphylococcus aureus as an etiology of communityacquired pneumonia. Clin Infect Dis. 2012;54(8):1126-33. 16. Frazee BW, Lynn J, Charlebois ED, Lambert L, Lowery D, Perdreau-Remington F. High prevalence of methicillinresistant Staphylococcus aureus in emergency department skin and soft tissue infections. Ann Emerg Med. 2005;45(3):311-20. 17. King MD, Humphrey BJ, Wang YF, Kourbatova EV, Ray SM, Blumberg HM. Emergence of community-acquired methicillin-resistant Staphylococcus aureus USA 300 clone as the predominant cause of skin and soft-tissue infections. Ann Intern Med. 2006;144(5):309-17. 18. Boucher HW, Corey GR. Epidemiology of methicillinresistant Staphylococcus aureus. Clin Infect Dis. 2008;46(Supplement 5):S344-9. 19. Anderson DJ, Kaye KS, Chen LF, Schmader KE, Choi Y, Sloane R, et al. Clinical and financial outcomes due to methicillin resistant Staphylococcus aureus surgical site infection: a multi-center matched outcomes study. PLoS One. 2009;4(12):e8305. 20. Cosgrove SE, Sakoulas G, Perencevich EN, Schwaber MJ, Karchmer AW, Carmeli Y. Comparison of mortality associated with methicillin-resistant and methicillinsusceptible Staphylococcus aureus bacteremia: a metaanalysis. Clin Infect Dis. 2003;36(1):53-9.

21. Tenover FC. Mechanisms of antimicrobial resistance in bacteria. Am J Med. 2006;119(6 Suppl 1):S3-10. 22. Rasmussen RV, Fowler VG Jr, Skov R, Bruun NE. Future challenges and treatment of Staphylococcus aureus bacteremia with emphasis on MRSA. Future Microbiol. 2011;6(1):43-56. 23. Performance standards for antimicrobial susceptibility testing: seventeenth international supplement M100-S16. Clinical and Laboratory Standards Institute. 2006;M100-S16. 24. Tenover FC, Biddle JW, Lancaster MV. Increasing resistance to vancomycin and other glycopeptides in Staphylococcus aureus. Emerg Infect Dis. 2001;7(2):327-32. 25. Garnier F, Chainier D, Walsh T, Karlsson A, Bolmström A, Grelaud C, et al. A 1 year surveillance study of glycopeptideintermediate Staphylococcus aureus strains in a French hospital. J Antimicrob Chemother. 2006;57(1):146-9. 26. Rizk NG, Zaki SA. Heterogeneous vancomycin intermediate resistance within methicillin-resistant Staphylococcus aureus clinical isolates in Alexandria province. Egypt J Med Microbiol. 2007;16(3):503-11. 27. Stwart PS, Costerton JW. Antibiotic resistance of bacteria in biofilim. Lancet. 2001;358(9276):135-8. 28. Beloin C, Roux A, Ghigo JM. Escherichia coli biofilms. Curr Top Microbiol Immunol. 2008;322:249-89. 29. Davies D. Understanding biofilm resistance to antibacterial agents. Nat Rev Drug Discov. 2003;2(2):114-22. 30. Prigent-Combaret C, Brombacher E, Vidal O, Ambert A, Lejeune P, Landini P, et al. Complex regulatory network controls initial adhesion and biofilm formation in Escherichia coli via regulation of the csgD gene. J Bacteriol. 2001;183(24):7213-23. 31. Mah TF, O’Toole GA. Mechanisms of biofilm resistance to antimicrobial agents. Trends Microbiol. 2001;9(1):34-9. 32. Nascimento HH, Silva LE, Souza RT, Silva NP, Scaletsky IC. Phenotypic and genotypic characteristics associated with biofilm formation in clinical isolates of atypical enteropathogenic Escherichia coli (aEPEC) strains. BMC Microbiol. 2014;14:184. 33. Fiedler T, Köller T, Kreikemeyer B. Streptococcus pyogenes biofilms—formation, biology, and clinical relevance. Front Cell Infect Microbiol. 2015;5:15. 34. Arber N, Pras E, Copperman Y, Schapiro JM, Meiner V, Lossos IS, et al. Pacemaker endocarditis. Report of 44 cases and review of the literature. Medicine (Baltimore). 1994;73(6):299-305. 35. Otto M. Staphylococcal biofilms. Curr Top Microbiol Immunol. 2008;322:207-28. 36. Mangaiarkkarasi A, Erli AI, Gopal R. Antimicrobial susceptibility patterns of clinical isolates of Gramnegative pathogens from a teaching hospital, Pondicherry. Res J Pharm Biol Chem Sci. 2013;4(2):664-73.

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COMMUNITY MEDICINE 37. Goren MG, Carmeli Y, Schwaber MJ, Chmelnitsky I, Schechner V, Navon-Venezia S. Transfer of carbapenemresistant plasmid from Klebsiella pneumoniae ST258 to Escherichia coli in patient. Emerg Infect Dis. 2010;16(6):1014-7. 38. Lee S, Han SW, Kim KW, Song do Y, Kwon KT. Thirdgeneration cephalosporin resistance of community-onset Escherichia coli and Klebsiella pneumoniae bacteremia in a secondary hospital. Korean J Intern Med. 2014;29(1):49-56. 39. Meyer E, Schwab F, Schroeren-Boersch B, Gastmeier P. Dramatic increase of third-generation cephalosporinresistant E. coli in German intensive care units: secular trends in antibiotic drug use and bacterial resistance, 2001 to 2008. Crit Care. 2010;14(3):R113. 40. Yigit H, Queenan AM, Anderson GJ, Domenech-Sanchez A, Biddle JW, Steward CD, et al. Novel carbapenemhydrolyzing beta-lactamase, KPC-1, from a carbapenemresistant strain of Klebsiella pneumoniae. Antimicrob Agents Chemother. 2001;45(4):1151-61. 41. Magiorakos AP, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG, et al. Multidrug resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect. 2012;18(3):268-81.

and other Enterobacteriaceae: an evolving crisis of global dimensions. Clin Microbiol Rev. 2012;25(4):682-707. 43. Perez F, Van Duin D. Carbapenem-resistant Enterobacteriaceae: a menace to our most vulnerable patients. Cleve Clin J Med. 2013;80(4):225-33. 44. Tanwar J, Das S, Fatima Z, Hameed S. Multidrug resistance: an emerging crisis. Interdiscip Perspect Infect Dis. 2014;2014:541340. 45. Michael JS, John TJ. Extensively drug resistant tuberculosis in India: a review. Indian J Med Res. 2012;136(4): 599-604. 46. Siegel JD, Rhinehart E, Jackson M, Chiarello L. Management of multidrug-resistant organisms in health care settings, 2006. Am J Infect Control. 2007;35(Suppl 2): 165-93. 47. Falagas ME, Bliziotis IA, Kasiakou SK, Samonis G, Athanassopoulou P, Michalopoulos A. Outcome of infections due to pandrug-resistant (PDR) Gram-negative bacteria. BMC Infect Dis. 2005;5:24. 48. Banerjee M, Arun A, Gupta SK. Pattern of pathogens and their sensitivity isolated from nosocomial infections in a tertiary care hospital. Int J Curr Microbiol App Sci. 2014;3(12):398-403.

49. Kumar SG, Adithan C, Harish BN, Sujatha S, Roy G, 42. Tzouvelekis LS, Markogiannakis A, Psichogiou M, Tassios Malini A. Antimicrobial resistance in India: a review. J Nat PT, Daikos GL. Carbapenemases in Klebsiella pneumoniae Sci Biol Med. 2013;4(2):286-91. ■■■■

It’s the Western Culture which has Spoiled India The Centers for Medicare and Medicaid Services has shown that 1,400 drug and device companies paid $6.49 billion in 2014 to more than 600,000 physicians and more than 1,100 teaching hospitals. Of this amount, $3.23 billion was for research and $2.56 billion was for general purposes such as consulting and speaking fees, travel, food and gifts. The payments to physicians included $2.02 billion in general payments, $2.52 billion in research payments, and $703 million to physicians who owned or invested in drug and device companies. The research payments to physicians included payments to institutions where a physician was named as a principal investigator on a research project. The hospitals received $543 million in general payments and $705 million in research payments. None of the hospitals had ownership or investment interests in any drug or device companies. Manufacturers are not required this year to disclose payments for continuing medical education activities. The Open Payments program, which was created by the Affordable Care Act, requires drug and device manufacturers to report transfers of value to providers. These include payments, honoraria, and research grants, as well as income from physicians’ industry-related investments. The purpose of the program is to allow individuals to get information about physicians’ financial relationships with the companies that make the products they prescribe or use with patients. CMS invites physicians and teaching hospitals to review the data submitted by manufacturers. The providers who registered to do that reviewed nearly 30% of the total value of the payments reported to the government. The median value of the total payments to registered physicians was $3644 compared with $747 made to nonregistered physicians.

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Carmi Syndrome with a Favorable Outcome: A Case Report SINDHU DESABANDHU*, ADITYA KUMAR BUBNA†, MAHALAKSHMI VEERARAGHAVAN‡, SUDHA RANGARAJAN‡

ABSTRACT Carmi syndrome is a rare but serious condition that comprises the association of junctional epidermolysis bullosa with pyloric atresia. Early detection is therefore essential for timely intervention. However, despite the measures taken, Carmi syndrome is associated with a poor prognosis and a high mortality rate. We report here a case of Carmi syndrome which had a favorable outcome following treatment.

Keywords: Carmi syndrome, junctional epidermolysis bullosa, pyloric atresia

pidermolysis bullosa (EB) comprises an inherited group of disorders characterized by the development of skin blisters on meagre trauma or skin traction.1 EB is further classified as EB simplex, junctional EB and the dystrophic type.2 Out of the three variants, it is the junctional type that is associated with pyloric atresia (PA), though rarely PA may be associated with the simplex variant also. When junctional EB and PA exist together it is referred to as Carmi syndrome (CS), which has an exceeding high mortality rate. However with early surgical intervention, there have been few rare cases that have survived, with regression of blistering as the child grows.

consanguineous parents. At birth the child weighed 2.5 kg, and she was the third child of her parents.

CASE REPORT

A complete investigative work-up revealed the following abnormalities. Hypokalemia was present, in the serum electrolyte assessment, with metabolic alkalosis, in the arterial blood gas analysis. A dilated gastric shadow

A 4-day-old female neonate was referred to the Dept. of Dermatology for evaluation of blisters over the sites of venepuncture. The primary reason for the child being brought to the hospital was for persistent vomiting, which started 2 days after birth. The baby was a preterm child, born at 36 weeks of gestation to third degree

*Resident †Assistant Professor ‡Professor Dept. of Dermatology Sri Ramachandra University, Porur, Chennai, Tamil Nadu Address for correspondence Dr Aditya Kumar Bubna Assistant Professor Dept. of Dermatology Sri Ramachandra University, Porur, Chennai, Tamil Nadu E-mail: zimbabwa21@gmail.com

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Her previous two siblings had died 5 days and 10 days after birth, owing to PA, despite surgical correction. On examination, epigastric fullness and visible gastric peristalsis were noted. A dermatologic examination revealed a 5 × 6 cm bulla over the right knee (Fig. 1), two hemorrhagic bullae, one measuring 2 × 3 cm and another 2 × 2 cm, located over the dorsa of the left hand and the left wrist, respectively, (Fig. 2) and areas of post-inflammatory hypopigmentation with a 1 × 1 cm sized bulla and two vesicles in the left retro-auricular region (Fig. 3).

Figure 1. A 5 × 6 cm sized bulla over the right knee.

DERMATOLOGY with the classical single bubble appearance (Fig. 4) was witnessed on abdominal radiography, and a skin biopsy of the bulla on the wrist demonstrated a split at the level of the dermoepidermal junction with a pauciinflammatory infiltrate (Fig. 5).

Figure 2. Two hemorrhagic bullae, one measuring 2 × 3 cm and another 2 × 2 cm, located over the dorsa of the left hand and the left wrist, respectively.

Immune electron microscopy could not be done due to lack of facilities in our institute. With these findings, a diagnosis of CS was made. Patient was taken up for an emergency laparotomy. During the procedure, a dilated stomach (Fig. 6) secondary to a solid cord, obstructing the pyloric canal (Fig. 7), was identified. A gastroduodenostomy was performed (Fig. 8). After 5 days of the surgery, oral feeds were gradually started. The patient tolerated the oral feeds well. Over the blisters, the use of a topical antibiotic cream was suggested and avoidance of pressure and trauma were

Figure 3. Areas of post-inflammatory hypopigmentation with a 1 × 1 cm sized bulla and two vesicles in the left retroauricular region. Figure 5. Skin biopsy from the bulla on the wrist demonstrated a split at the level of the dermoepidermal junction with a pauci-inflammatory infiltrate.

Figure 4. Dilated gastric shadow with the classical single bubble appearance, witnessed on abdominal radiography.

Figure 6. Dilated stomach identified on laparotomy.

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Figure 7. Solid cord type of pyloric atresia visualized in the gastroduodenal segment.

Figure 10. Child at 7 months of follow-up.

the instructions given to her parents. At 2 months of follow-up, the patient weighed 3.5 kg and had no difficulty, while taking oral feeds. Skin lesions had healed well-leaving behind milia and parchment like scars (Fig. 9). No developmental delay could be identified. At 7 months of follow-up, the child weighed 7 kg and was doing well (Fig. 10). No new blisters were identified. Now the child is 9 years of age and is doing perfectly fine. There have been no recurrence of cutaneous lesions with no gastrointestinal symptoms. DISCUSSION

Figure 8. Gastroduodenostomy being performed.

Pyloric atresia and EB are very rare autosomal recessive disorders. The concurrent occurrence of the two, was first described in 1968 by Swinburne and Kohler.3,4 However, it was Carmi who elucidated the pathophysiology of this disorder and hence the name, CS.5 Though PA is the most frequent gastrointestinal atresia associated, the occurrence of duodenal atresia with EB has also been reported.6 The incidence of PA is estimated to be 1/1,00,000 live births7 and the combination of EB with PA is rarer still. Ninety-three cases of EB with PA have been reported in literature till date.8 The gene for CS has been identified to be ITGA6, located on the long arm of chromosome 2 and ITGB4 located on the long arm of chromosome 17, which encodes the hemidesmosomal protein Îą-6 Î˛-4 integrin that helps in maintaining the dermo-epidermal attachment.

Figure 9. At 2 months of follow-up skin lesions healing well with milia and parchment like scars.

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A mutation occurring here results in a compromise of the adhering between the dermis and the epidermis, which clinically presents in the form of blisters.9 Around 15% of cases of CS result from mutations in the

DERMATOLOGY PLEC gene,10 which instructs in the making of plectin. Plectin, like Îą-6 Î˛-4 integrin, helps maintain the dermoepidermal integrity. Altered plectin makes the skin less resistant to friction and minor trauma heralding cutaneous blisters. Neonates with CS present with nonbilious vomiting as the first symptom, which may even occur immediately after birth. A plain radiograph of the abdomen with an air filled distended stomach and an otherwise gasless abdomen helps in the diagnosis of PA.11 Cutaneous blistering may not appear even as late as 48 hours after birth. Other features occurring due to the disrupted intestinal mucosa include malabsorption, bloody diarrhea and protein losing enteropathy. CS patients may also present with urinary,12 pulmonary and ocular abnormalities.13 Management includes a multidisciplinary approach. Apart from the surgical correction of PA, a meticulous minimal touch principle is advocated for the skin, along with antibiotics and antiseptics to prevent secondary impetiginization. A proper nutritional support is another important aspect of managing these patients. During surgery precautions to prevent any form of trauma is minimized, like coating the face mask with a petrolatum jelly gauze, meticulous intubation using a no cuff endotracheal tube and removal of the adhesive components of the electrodes, while performing an ECG. Appropriate post surgical care is also advocated. Our patient had a solid type of PA, for which the atretic segment was excised and a gastroduodenostomy was performed. In case of a short atretic segment, the surgery of choice would have been Heineke-Mikulicz pyloroplasty. To conclude, CS is a lethal condition with death being a universal result. Inspite of timely surgical intervention, patients are able to survive only for the first few months of life.14 However, there have been reports wherein patients with CS have shown considerable improvement and have survived post infancy as reported by Ha et al,15 Hayashi et al16 and Sahebpoor et al.17 Our case too, survived the post infancy stage and at present is 9 years of age with complete remission of cutaneous blistering and no systemic problems. Though CS is a lethal condition, there have been anecdotal reports of its favorable outcome and so we present this case for its rarity.

REFERENCES 1.

Gedde-Dahl T Jr. Epidermolysis bullosa. A clinical, genetic and epidemiologic study. Baltimore: John Hopkins University Press; 1971. pp. 1-180.

Fine JD, Eady R, Bauer EA, Briggman RA, BrucknerTuderman L, Christiano A, et al. Revised classification system for inherited epidermolysis bullosa: report of the second international consensus meeting on diagnosis and classification of epidermolysis bullosa. J Am Acad Dermatol. 2000;42(6):1051-66.

Birnbaum RY, Landau D, Elbedour K, Ofir R, Birk OS, Carmi R. Deletion of the first pair of fibronectin type III repeats of the integrin beta 4 gene is associated with epidermolysis bullosa, pyloric atresia and aplasia cutis congenita in the original Carmi syndrome patients. Am J Med Genet A. 2008;146A(8):1063-6.

Sarin YK, Nagdeve NG. Carmi syndrome complicated by pharyngoesophageal perforation. Indian Pediatr. 2006;43(1):61-4.

Carmi R, Sofer S, Karplus M, Ben-Yakar Y, Mahler D, Zirkin H, et al. Aplasia cutis congenita in two sibs discordant for pyloric atresia. Am J Med Genet. 1982;11(3):319-28.

Maman E, Maor E, Kachko L, Carmi R. Epidermolysis bullosa, pyloric atresia, aplasia cutis congenita: histopathological delineation of an autosomal recessive disease. Am J Med Genet. 1998;78(2):127-33.

Muller M, Morger R, Engbert J. Pyloric atresia: a report of four cases and review of literature. Pediatr Surg Int. 1990;5:276-9.

Bicakci U, Tander B, Cakmak-Celik F, Ariturk E, Rizalar R. Pyloric atresia associated with epidermolysis bullosa: report of two cases and review of literature. Ulus Travma Acil Cerrahi Derg. 2012;18(3):271-3.

Schaapveld RQ, Borradori L, Geerts D, van Leusden MR, Kuikman I, Nievers MG, et al. Hemidesmosome formation is initiated by the beta 4 integrin subunit, requires complex formation of beta 4 and HD1/plectin, and involves a direct interaction between beta 4 and the bullous pemphigoid antigen 180. J Cell Biol. 1998;142(1):271-84.

10. Pfender E, Uitto J. Plectin gene mutations can cause epidermolysis bullosa with pyloric atresia. J Invest Dermatol. 2005;124(1):111-5. 11. Okoye BO, Parikh DH, Buick RG, Lander AD. Pyloric atresia: five new cases, a new association and a review of the literature with guidelines. J Pediatr Surg. 2000;35(8):1242-5. 12. Pfender E, Uitto J, Fine JD. Epidermolysis bullosa carrier frequencies in the US population. J Invest Dermatol. 2001;116(3):483-4. 13. Lestringant GG, Akel SR, Qayed KI. The pyloric atresiajunctional epidermolysis bullosa syndrome. Report of a case and review of the literature. Arch Dermatol. 1992;128(8):1083-6. Contâ&#x20AC;&#x2122;d on page 138... Indian Journal of Clinical Practice, Vol. 26, No. 2, July 2015

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DIABETOLOGY

Management of Diabetic End-stage Renal Disease: Role of Hemodialysis H SUDARSHAN BALLAL

ABSTRACT Diabetes mellitus is now the most common cause of end-stage renal disease (ESRD) all across the globe including India. In view of the alarming rise in numbers, renal failure due to type 2 diabetes has been termed a “medical catastrophe of worldwide dimensions”. When a patient develops uremic symptoms they need renal replacement therapy. The renal replacement therapies available for all patients with ESRD are hemodialysis, chronic ambulatory peritoneal dialysis (CAPD) and renal transplantation. Kidney transplantation is the best option for patients with diabetic ESRD. The 5-year survival of transplant patients of 75-85% is far superior to the 5-year survival rate of around 25% on dialysis.

Keywords: Diabetes mellitus, end-stage renal disease, renal replacement therapy, hemodialysis CAPD, renal transplantation

iabetes mellitus is now the most common cause of end-stage renal disease (ESRD) all across the globe including India and it is estimated that 30-50% of patients being initiated on renal replacement therapy have diabetes as the cause of their ESRD1 and most of these patients have type 2 diabetes. In view of the alarming rise in numbers, renal failure due to type 2 diabetes has been termed a “medical catastrophe of worldwide dimensions”.2 This article will discuss the management of diabetic ESRD specifically related to type 2 diabetes. RENAL REPLACEMENT THERAPY When a patient’s kidney function, as measured by the calculated glomerular filtration rate has reached <10 mL/min (ESRD) or the patient develops uremic symptoms, they need renal replacement therapy. The renal replacement therapies available for all patients with ESRD are: Â

Hemodialysis

Chronic ambulatory peritoneal dialysis (CAPD)

Renal transplantation.

Though these modalities are available for all patients with ESRD, there are significant differences in the

Director Manipal Institute of Nephrology and Urology Manipal Hospital, Bangalore, Karnataka

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morbidity and mortality of any given modality between the diabetic and the nondiabetic ESRD population. We will discuss some of these issues, specifically the modality of hemodialysis. HEMODIALYSIS FOR DIABETIC ESRD Although hemodialysis prevents death from uremia, the patient survival on hemodialysis is poor especially for patients with diabetes, being approximately 20-25% at 5 years as compared to 40-50% for other causes of ESRD.3 This is worse than many cancers. The survival of patients on maintenance hemodialysis in India seems dismal for both diabetic and nondiabetic population.4 The important contributors for mortality in the diabetic dialysis population are: cardiovascular disease (CVD), adequacy of dialysis and nutritional status. Â

Cardiovascular disease: CVD is the most common cause of death accounting for more than one-half of the cases.5 The main reason for such a high mortality rate, which is of cardiovascular origin in the majority of cases is that the cardiovascular conditions of patients with diabetes are already severely impaired when they start renal replacement therapy, as demonstrated by the high prevalence of coronary artery disease (CAD), stroke, peripheral occlusive disease and amputations. This also explains why patients who have diabetes and are on renal replacement therapy (RRT) are at higher risk of developing de novo CVD, particularly ischemic heart disease, which not only is more frequent, but also has a more aggressive course than in nondiabetic

DIABETOLOGY patients. In view of this, aggressive measures to manage CVD need to be adopted in all diabetic patients even before they reach the stage of dialysis. Ă&#x201A;

Ă&#x201A;

Adequacy of dialysis: Adequacy of dialysis, which also plays an important role in CVD and nutrition (MIA or malnutrition-inflammationatherosclerosis syndrome) is also a contributor to the poor outcome and diabetics in particular seems to be more sensitive than nondiabetics to inadequate dialysis.6 The increase in mortality of these patients largely disappears if there is an improvement in the nutritional status as reflected by an increase in serum albumin and creatinine.7 This is a major problem in India where for various reasons like financial constraints, lack of access and availability of good dialysis units most patients tend to have inadequate dialysis.8 Whenever possible, it is very essential to monitor the adequacy of dialysis by using biochemical measures like urea reduction rates, Kt/V ratio and clinical well-being of patients and to take measures to improve the adequacy of dialysis. Nutrition in dialysis: Nutrition in dialysis patients is closely linked to inadequate dialysis, which

leads to anorexia and poor calorie and protein intake. This is reflected by poor serum albumin and creatinine levels, which are indicators for mortality in dialysis patients. The problems of diabetic gastroparesis and diabetic enteropathy compound the nutritional problems. The help of a good dietician and measures to treat diabetic gastroparesis and enteropathy by motility agents, frequent small foods and appropriate use of broad-spectrum antibiotics to treat bacterial infections in diabetic enteropathy are needed to maintain adequate nutrition. It is to be noted that cisapride is best avoided in this population because of the risk of fatal arrhythmias.9 DIET IN DIABETIC PATIENTS ON DIALYSIS The general recommendation for diet in dialysis patients is given in Table 1. The iron requirement of dialysis patients vary and will need to be addressed on a patient-to-patient basis. In general, water-soluble vitamins are routinely prescribed and calcitriol may be needed in some patients.

Table 1. Daily Dietary Recommendations for Dialysis Patients versus Nonuremicsa Factor

Nonuremic

Protein (g/kg)

0.8

1.2

1.2-1.5

Calories (sedentary) (kcal/kg)

30b

30-40b,c

15-20

Carbohydrate (%)

55-60

55-60d

55-60c,d

Fat (%)

20-30

Balance

Cholesterol (mg)

300-400

Polyunsaturated/saturated fat ratio

2.0:1.0

Sodium (1 g = 43 mEq)

2-6 g

2 g + 1 g/LUO

2-4 g + 1 g/LUO

Fluids (L)

Ad lib

1 L + 1 L/LUO

1.0-2.5 L + L/LUO

Potassium (1 g = 25 mEq)

2-6 g

2 g + 1 g/LUO

4 g + 1 g/LUO

Calcium (g)

0.8-1.2

Diet + 1.2

Phosphorus (g)

1.0-1.8

0.6-1.2

Magnesium (g)

0.35

0.2-0.3

Protein (%)

Crude fiber (g

a All

intakes calculated on the basis of normalized body weight (i.e., the average body weight of normal persons of the same age, height and sex as the patient). bThese levels of caloric intake are rarely attained in practice. cIncludes glucose absorbed from dialysis solutions. dCarbohydrate intake should be decreased in patients with hypertriglyceridemia. HD = Hemodialysis; PD = Peritoneal dialysis; LUO = Liters of urine output per day.

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DIABETOLOGY BLOOD SUGAR CONTROL IN DIABETIC DIALYSIS PATIENTS

chlorpropamide and tolazamide are excreted to a large extent in the urine.

There are certain special problems about blood sugar control in dialysis patients:

These drugs should not be used in dialysis patients because their half-lives will be greatly prolonged in the absence of renal function, possibly resulting in severe and prolonged hypoglycemia. The excretion of glyburide is 50% hepatic and prolonged hypoglycemia has been reported using this drug in dialysis patients. Metabolism of glipizide, tolbutamide, and gliclazide is almost completely hepatic.

Altered insulin metabolism: In uremic patients (both diabetic and nondiabetic), insulin secretion by the β cells of the pancreas is reduced and the responsiveness of peripheral tissues (e.g., muscle) to insulin is depressed. On the other hand, the rate of insulin catabolism (renal and extrarenal) is decreased, and therefore, the half-life of any insulin present in the circulation is prolonged. All of these abnormalities are only partially corrected after institution of maintenance dialysis therapy. Increased sensitivity to insulin: In diabetic dialysis patients treated with exogenous insulin, the importance of reduced insulin catabolism overrides the impact of insulin resistance; when exogenous insulin is administered, its effect may be intensified and prolonged. Thus, smaller than usual doses should be given. Insulin therapy: Tight control of sugars are sometimes difficult to achieve in diabetic dialysis patients. Nevertheless good glucose control is worthwhile with split doses of insulin preferably. The “amount of insulin” per day required for patients receiving maintenance hemodialysis is usually small; optimum control of glycemia is achieved by administration of long-acting insulin at two separate times during the day (split dosing) and by supplementing with regular insulin for meals as needed. The proportions of long-acting and regular insulin, as well as the total insulin doses vary widely among different patients. Hypoglycemia is quite common in diabetic dialysis patients usually due to reduced insulin catabolism and reduced intake of food and/or poor absorption. A fasting serum glucose of <140 mg/dL and a postprandial value <200 mg/dL is a reasonable goal to achieve.

Oral hypoglycemic agents: Lack of clinical studies on use of OHA’s in dialysis patients restricts the use of these agents.

Nevertheless, these agents are useful adjuncts in the treatment of diabetics and are used by many nephrologists. The safety of sulfonyureas depends on their mode of metabolism and their half-life. Use of short-acting agents primarily metabolized by the liver is, in general, safer in dialysis patients. Acetohexamide,

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Consequently, the last three drugs should be considered if an oral hypoglycemic agent is desired. Many drugs frequently used in dialysis patients either antagonize (phenytoin, nicotinic acid, diuretics) or enhance (sulfonamides, salicylates, warfarin, ethanol) the hypoglycemic action of sulfonylureas. Metformin, a biguanide, is associated with increased incidence of lactic acidosis in dialysis patients and should not be used. Acarbose inhibits α-glycosidase in the enteric mucosa and moderates postprandial hyperglycemia. It may prove to be a useful adjunct to other diabetic medications in diabetic patients. Troglitazone and other thiazolidinediones sensitize the target tissues to insulin and may be of help in obese, type 2 diabetics with insulin resistance. However, the use of this class of drugs may be associated with the risk of severe hepatotoxicity. In general, insulin use is preferable in diabetic dialysis patients, but judicious use of appropriate oral hypoglycemia agents can be done. SPECIFIC PROBLEMS OF HEMODIALYSIS IN DIABETIC PATIENTS Â

Difficulty in creating and maintaining a vascular access because of severe peripheral vascular disease (PVD) in older diabetic patients. Inability to tolerate volume shifts giving rise to hypotension during hemodialysis because of autonomic neuropathy and CVD.

Risk of infection.

Progression of diabetic retinopathy.

In view of all these problems, meticulous planning and appropriate management should start in the predialysis period well before dialysis is anticipated and would involve a special diabetic team consisting of an ophthalmologist, vascular surgeon, podiatrist, endocrinologist, cardiologist, neurologist and dietician to help the nephrology team in keeping the patient as fit as possible before they reach the stage of dialysis.

DIABETOLOGY TIMING OF DIALYSIS IN DIABETIC ESRD In general, most nondiabetic patients are initiated on dialysis when the creatinine clearance is <10 mL/min. In diabetic patients, dialysis may have to be initiated at creatinine clearance even >15 mL/min.9 The reasons for this being: Â Renal functions deteriorate rapidly in this group Â Hypertension is very difficult to control in patients with severe renal failure Â Most patients have CVD with volume overload Â Uremic symptoms may manifest earlier than in nondiabetic patients. In spite of these recommendations, dialysis in usually started as an emergency in most Indian patients because of uremia, pulmonary edema or severe hyperkalemia; culprits being poor awareness, financial constraints and lack of facilities for dialysis.4,8 ROLE OF CHRONIC AMBULATORY PERITONEAL DIALYSIS Chronic ambulatory peritoneal dialysis is another modality of treatment in diabetic ESRD. Though it has its advantages and disadvantages, the following factors decide the modality of dialysis.

for comorbid condition have not found a statistically significant survival difference between the two modalities.11 TRANSPLANTATION Kidney transplantation is the best option for patients with diabetic ESRD. The 5-year survival rate of 75-85% of transplant patients, though less than that of nondiabetic ESRD is still far superior to the 5-year survival rate of around 25% of patients on dialysis.3,12 Though in general healthier patients go onto transplant and sicker patients remain on dialysis, the survival rates are better even when these are factored in. Transplantation is also associated with a better quality-of-life and higher degree of rehabilitation. The pre- and post-transplant care of diabetic patients is generally similar to that of nondiabetics. However, in view of the high prevalence of CVD in this population, meticulous attention has to be paid to screen these patients for CVD prior to the transplantation.13 RECOMMENDATIONS FOR TREATMENT OF DIABETIC ESRD PATIENTS Kidney transplant remains the best option of RRT for patients with diabetic ESRD in all suitable candidates.

Comorbid conditions

Family and home support

Recommendations transplantation.

Financial support

CAPD is recommended for patients with:

Cardiovascular and PVD leading to poor vascular access for dialysis

Hemodynamic stability

Availability of hemodialysis centers.

CAPD is 30-50% more expensive than hemodialysis in India and is generally used for patients who do not have access to hemodialysis, have severe chronic heart failure (CHF), hemodynamic instability, poor vascular access and are not candidates for transplantation. The patient and the family should be motivated and have adequate financial support. Table 2 gives the comparison of two modalities of dialysis. SURVIVAL ON HEMODIALYSIS AND PERITONEAL DIALYSIS There have been conflicting data about the survival of patients on CAPD compared to hemodialysis. Initial data from Michigan suggested an advantage for CAPD.10 However, most studies after adjustment

Â Â

for

those

not

suitable

for

Poor vascular access because of PVD Severe CVD with hemodynamic instability during hemodialysis

Nonavailability of hemodialysis centers

Good family and financial support

Motivated patients.

Hemodialysis is the treatment for all the remaining which is the treatment available for the vast majority of patients with diabetic ESRD in India who are not candidates for transplantation. In view of the multiple, associated comorbid conditions, a multidisciplinary approach is needed to prevent and manage the complications of vascular diseases, malnutrition and retinopathy in diabetic dialysis patients. REFERENCES 1.

Ballal HS. Diabetic nephropathy: Indian scene, scientific proceedings, 1st National Conference in Prevention of chronic kidney disease in India; 2005.

Indian Journal of Clinical Practice, Vol. 26, No. 2, July 2015

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DIABETOLOGY 2.

Ritz E, Rychlík I, Locatelli F, Halimi S. Renal failure in type 2 diabetes: a medical catastrophe of worldwide dimensions. Am J Kidney Dis. 1999;34(5):795-808.

Collins AJ, Kasiske B, Herzog C, Chen SC, Everson S, Constantini E, et al. United States Renal Data System. Excerpts from the USRDS 2003 annual data report: atlas of end stage renal disease in the United States. Am J Kidney Dis. 2003;42(6 Suppl 5):A5-7, S1-230.

Rao M, Juneja R, Shirly RB, Jacob CK. Hemodialysis for end stage renal disease in Southern India: a perspective from a tertiary referral care centre. Nephrol Dial Transplant. 1998;13(10):2494-500.

Kher V. End-stage renal disease in developing countries. Kidney Int. 2002;62(1):350-62.

Tzamaloukas AH, Friedman EA. Diabetes. In: Daugirdas JT, Blake PG, Ing TS (Eds.). Handbook of Dialysis, 3rd Edition. Philadelphia: Lippincott Williams and Wilkins; 2001. pp. 453-65.

10. Nelson CB, Port FK, Wolfe RA, Guire KE. Comparison of continuous ambulatory peritoneal dialysis and hemodialysis patient survival with evaluation of trends during the 1980s. J Am Soc Nephrol. 1992;3(5):1147-55. 11. Jaar BG, Coresh J, Plantinga LC, Fink NE, Klag MJ, Levey AS, et al. Comparing the risk for death with peritoneal dialysis and hemodialysis in a national cohort of patients with chronic kidney disease. Ann Intern Med. 2005;143(3):174-83.

Brunner FP, Selwood NH. Profile of patients on RRT in Europe and death rates due to major causes of death groups. Kidney Int Suppl. 1992;38:S4-15.

Collins AJ. How can the mortality rate of chronic dialysis patients be reduced? Semin Dial. 1993;6:102.

Lowrie EG, Lew NL, Huang WH. Race and diabetes as death predictors in hemodialysis patients. Kidney Int 13. Scandling JD. Kidney transplant candidate evaluation. Suppl. 1992;38:S22-31. Semin Dial. 2005;18(6):487-94. ■■■■

12. Locatelli F, Pozzoni P, Del Vecchio, L. Renal replacement therapy in patients with diabetes and end-stage disease. J Am Soc Nephrol. 2004;15(Suppl 1):S25-9.

Spinal Cord Stimulation Benefit Ongoing in Diabetic Neuropathy Most patients treated with spinal cord stimulation (SCS) because of painful diabetic peripheral neuropathy maintain effective pain relief in the long-term, according to Dutch researchers. As Dr Maarten van Beek told Reuters Health by email, “Spinal cord stimulation serves as a successful last resort treatment modality for the duration of at least 2 years in 65% of diabetic patients with painful neuropathy.”

New Mutation Associated with Severe Obesity A single-gene mutation that shuts down production of the carboxypeptidase-E (CPE) enzyme, and causes severe obesity and type 2 diabetes, has been identified. The mutation affects insulin processing and appetite suppression and leads to intellectual disability and reproductive problems, according to the new research published in PLoS One. The discovery adds to the growing list of single-gene causes for morbid obesity, and suggests that “inherited conditions may be much more common among the severely obese than has previously been recognized,” said Alex Blakemore, PhD, of Imperial College, London, UK, who led the study. Affected people will need lifelong management and access to genetic counseling services, she added.

...Cont’d from page 133 14. Dank JP, Kim S, Parisi MA, Brown T, Smith LT, Waldhausen J, et al. Outcome after surgical repair of junctional epidermolysis bullosa-pyloric atresia syndrome: a report of 3 cases and review of literature. Arch Dermatol. 1999;135(10):1243-7. 15. Ha D, Idikio H, Krol A, Lin AN. Junctional epidermolysis bullosa with pyloric atresia - a case with a favourable outcome. J Cutan Med Surg. 1998;3(2):102-4.

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16. Hayashi AH, Galliani CA, Gillis DA. Congenital pyloric atresia and junctional epidermolysis bullosa: a report of long-term survival and a review of the literature. J Pediatr Surg. 1991;26(11):1341-5. 17. Sahebpoor AA, Ghaffari V, Shokoohi L. Pyloric atresia associated with epidermolysis bullosa: a report of 4 survivals in 5 cases. Iran J Pediatr. 2007;17: 369-74.

DRUGS

A Short-term Comparative Prospective Observational Evaluation of Ramipril versus Telmisartan in Hypertensive Patients with Type 2 Diabetes Mellitus PANKAJ KUMAR*, AK KAPOOR†, HK SINGH‡, MALINI KULSHRESTHA$

ABSTRACT Aim: To comparatively evaluate the antihypertensive efficacy and tolerability of ramipril and telmisartan in stage 1 hypertensive diabetic patients. Material and methods: This short-term, prospective, randomized, comparative study was conducted amongst 53 patients of stage 1 hypertension with type 2 diabetes (27 ramipril and 26 telmisartan patients), aged 30 years and above. Ramipril was administered 5 mg/day and telmisartan 40 mg/day, respectively throughout the study period of 3 months. Blood pressure (BP) was measured using mercury sphygmomanometer. Paired and unpaired student t-test was applied. Results: Mean systolic BP (SBP) was 153.2 and 154.52 mmHg and mean diastolic BP (DBP) 87.6 and 87.57 mmHg in ramipril and telmisartan group, respectively. During follow-up, the mean SBP and DBP consistently decreased. At 3 months, the mean SBP was 124.72 and 123.83 mmHg in ramipril and telmisartan group, respectively. Similarly, the mean DBP at 3 months, was 78.16 and 76.7 mmHg in ramipril and telmisartan group, respectively. Although the lowering of BP (both systolic and diastolic) by ramipril or telmisartan individually was statistically significant yet comparatively reduction of BP between the two groups was not significant. Conclusion: Both regimens were equally effective and well-tolerated with minimal incidence of adverse effects including cough.

Keywords: Ramipril, telmisartan, systolic and diastolic blood pressure

ypertension is a multifactorial disease affecting one billion population worldwide. It is most common, readily identifiable and reversible risk factor for myocardial infarction, stroke, heart failure, atrial fibrillation, aortic dissection and peripheral arterial disease.1 Hypertension is an extremely common comorbid condition in diabetes, affecting 20-60% patients with diabetes.2 It substantially increases the risk of both macrovascular and microvascular complications including stroke, coronary artery disease, peripheral vascular disease, retinopathy, nephropathy and neuropathy.2 The renin-angiotensin-aldosterone system (RAAS) plays an important role in the

*JR-II Pharmacology †Professor and Head ‡Professor $Associate Professor, Dept. of Pharmacology Rohilkhand Medical College and Hospital, Bareilly, Uttar Pradesh Address for correspondence Dr AK Kapoor Professor and Head, Dept. of Pharmacology Rohilkhand Medical College and Hospital, Bareilly - 243 006, Uttar Pradesh E-mail: drakkapoor@rediffmail.com

pathogenesis of atherosclerosis and pathophysiology of cardiovascular disease. Therefore, despite a large number of antihypertensive agents, belonging to different pharmacological classes and modifying different physiological parameters, being currently available, yet in the present study only ramipril and telmisartan are selected because these agents not only are long-acting, but have shown clinically documented antihypertensive efficacy, better compliance and tolerability as well as prevented hypertension related end-organ damage, thus conferring cardiovascular protection.3 Moreover, telmisartan has been developed with twin objectives of improving blood pressure (BP) control as well as controlling early morning rise of BP, thus offering cardiovascular protection both in uncomplicated and complicated hypertension and possesses favorable metabolic profile (particularly on insulin sensitivity).4 Further, angiotensin-converting enzyme inhibitors (ACEIs) trials have suggested that RAAS blockade to be among the most efficient cardioprotective interventions. Additionally, modulation of RAAS with ACEI ramipril and angiotensin receptor blocker (ARB) telmisartan

Indian Journal of Clinical Practice, Vol. 26, No. 2, July 2015

139

DRUGS not only reduces a range of adverse cardiovascular outcomes but also affords renoprotection. It may be mentioned that goal of antihypertensive therapy is to prevent complications of hypertension with their superior efficacy, though Asian population respond less favorably to ACEIs as compared to Westerners.5

3 months (fourth follow-up) for evaluation of BP control and monitoring of adverse effects. The data obtained were statistically analyzed using paired and unpaired student t-test using SPSS Software Version 21.

The present study has been designed to compare the antihypertensive efficacy and tolerability of the two regimens in patients of hypertension with type 2 diabetes mellitus since the data on Asian population are scarce and comparative evaluation data in Indian population are few.

Out of a total of 53 enrolled patients, 27 patients were in ramipril group and 26 patients in telmisartan group. Five patients, 3 in ramipril group and 2 in telmisartan group dropped out during the study period. A higher prevalence of hypertension was noted in females compared to males. M:F ratio was 0.39:1. The urban rural ratio was 0.65:1 (Table 1).

MATERIAL AND METHODS This prospective observational study of 3-month duration (July-September 2013) was carried out by the Dept. of Pharmacology in collaboration with Dept. of Medicine, Rohilkhand Medical College and Hospital, Bareilly, Uttar Pradesh. Ethical clearance from Institutional Ethical Committee was obtained. Written informed consent from all enrolled participants was undertaken. A total of 53 newly diagnosed essential hypertension patients conforming to stage 1 Seventh report of the Joint National Committee (JNC-7), who were 30 years and above and also suffering from type 2 diabetes were enrolled and constituted the sample size. For randomization all test subjects were allotted study numbers on first come first serve basis and subsequently odd numbers were allotted to ramipril group 5 mg/day and even study numbers to telmisartan group 40 mg/ day throughout 3-month study period. The exclusion criteria included symptomatic heart failure, significant valvular heart disease, pericardial constriction or effusion, congenital heart disease, uncontrolled hypertension (BP >160/100 mmHg), stroke due to subarachnoid hemorrhage, significant renal disease and known hypersensitivity or intolerance to ARB or ACEI. The study involved the use of a structured, pretested and predesigned questionnaire to collect the demographic informations and BP was measured with standardized calibrated mercury column type sphygmomanometer and stethoscope on two occasions at 5-minute interval after the patient had rested for 15 minutes. Adverse effects, if any, were noted down for both regimens. Patients under treatment were subsequently monitored and reassessed at 2 weeks (first follow-up), 1 month (second follow-up), 2 months (third follow-up) and

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RESULTS AND OBSERVATION

Table 2 depicts age- and education-wise distribution of patients. An increasing trend of hypertension was noted with increasing age though majority of patients belonged to 41-50 years age group. Educational statuswise 18 (34%) hypertensive diabetic patients were illiterate, 14 (26%) were less than high school pass, 11 (21%) were high school or more and 10 (19%) were graduate, postgraduate and professionals. Mean SBP at enrollment was 153.2 ± 1.65 and mean DBP was 87.6 ± 1.54 in ramipril group (Table 3). Similarly, mean SBP at enrollment was 154.52 ± 3.02 and mean DBP was 87.57 ± 1.93 in telmisartan group (Table 4). Thus, mean SBP and mean DBP were comparable between the two groups. After therapy with ramipril in all the four followups, the mean SBP and mean DBP were significantly reduced statistically (p < 0.05) as compared to baseline values (Table 3). Similarly, following 3 months therapy with telmisartan in all the four follow-up, the mean SBP and mean DBP were significantly reduced statistically (p < 0.05) when compared to baseline values (Table 4). Table 5 shows comparative evaluation of SBP and DBP following therapy with the two regimens. Although, SBP showed a significant reduction from baseline to the end of treatment, it may be noted SBP reduced at the end of treatment by 28.48 mmHg in ramipril Table 1. Distribution of Male and Female in Rural and Urban Population Groups

Rural

Urban

Total

Male

Female

Male

Female

Ramipril

Telmisartan

Total

DRUGS group and by 30.69 mmHg with telmisartan group (p < 0.05 for both groups). However, the difference in mean reduction of SBP and DBP between the two groups was not statistically significant (p > 0.05). It was also observed that both regimens decreased DBP though telmisartan was found to be more efficacious in reducing DBP (10.87 mmHg in telmisartan group vs. 9.44 mmHg in ramipril group). However, no statistically significant difference in DBP reduction was noted on comparing the results of two regimens (p > 0.05), at the baseline and each of follow-up visits

and at final follow up. Thus, the difference in the mean reduction of DBP between the two groups were not statistically significant (p > 0.05). The most common adverse effect seen with ramipril was dry cough (4%), whereas no adverse effect was seen with telmisartan in prescribed dosages. DISCUSSION Affecting one billion people world over, hypertension remains one of the leading causes of death worldwide

Table 2. Age Distribution and Educational Status in the Two Groups of Patients Age group (years)

Groups

Total (%)

Ramipril

Telmisartan

Up to 40

6 (11%)

41-50

51-60

61-70

Educational status

Groups

Total (%)

Ramipril

Telmisartan

Illiterate

18 (34%)

28 (53%)

< High school

14 (26%)

9 (17%)

≥ High school

11 (21%)

6 (11)

Graduate

5 (9.5%)

Postgraduate

5 (9.5%)

Total

53 (100%)

>70

4 (8%)

Total

53 (100%)

Table 3. Comparative Follow-up Values of SBP and DBP with Ramipril (n = 24) SBP

DBP

Mean (SBP ± SEM)

Follow-up (SBP ± SEM)

T value

P value

Mean (SBP ± SEM)

Follow-up (SBP ± SEM)

T value

P value

0 (153.2 ± 1.65)

1 (135.36 ± 1.7)

8.6110

<0.05 Significan

0 (87.6 ± 1.54)

1 (84.84 ± 1.33)

1.1624

>0.05 Not significan

0 (153.2 ± 1.65)

2 (130.16 ± 1.05)

14.9927

<0.05 Significan

0 (87.6 ± 1.54)

2 (80.56 ± 1.12)

4.0545

<0.05 Significan

0 (153.2 ± 1.65)

3 (126.24 ± 0.83)

15.6308

<0.05 Significan

0 (87.6 ± 1.54)

3 (80.56 ± 1.0)

3.6558

<0.05 Significan

0 (153.2 ± 1.65)

4 (124.72 ± 0.94)

17.1314

<0.05 Significan

0 87.6 ± 1.54

4 (78.16 ± 0.89)

5.3158

<0.05 Significan

Table 4. Comparative Follow-up Values of SBP and DBP with Telmisartan (n = 24) SBP

DBP

Mean (SBP ± SEM)

Follow-up (SBP ± SEM)

T value

P value

Mean (SBP ± SEM)

Follow-up (SBP ± SEM)

T value

P value

0 (154.52 ± 3.02)

1 (135.39 ± 2.16)

7.5890

<0.05 Significan

0 (87.57 ± 1.93)

1 (82.57 ± 1.85)

2.6044

<0.05 Significan

0 (154.52 ± 3.02)

2 (130.7 ± 1.3)

8.2785

<0.05 Significan

0 (87.57 ± 1.93)

2 (79.48 ±1.15)

4.0883

<0.05 Significan

0 (154.52 ± 3.02)

3 (126.43 ± 1.04)

9.6261

<0.05 Significan

0 (87.57 ± 1.93)

3 (79.04 ± 1.22)

4.8506

<0.05 Significan

0 (154.52 ± 3.02)

4 (123.83 ± 0.81)

10.7405

<0.05 Significan

0 (87.57 ± 1.93)

4 (76.7 ± 0.66)

5.9536

<0.05 Significan

Indian Journal of Clinical Practice, Vol. 26, No. 2, July 2015

141

DRUGS Table 5. Antihypertensive (SBP and DBP) Efficacy of Ramipril (n = 24) versus Telmisartan (n = 24) Visits

SBP

DBP

Ramipril (n = 25)

Telmisartan (n = 23)

T value

P value

Mean (SBP ± SEM)

Baseline enrollment

0 (153.2 ± 1.65)

0 (154.52 ± 3.02)

0.3919

0 (87.57 ± 1.93)

0.0123

>0.05 Not significan

Follow-up 1 (2 weeks)

1 (135.36 ± 1.7)

1 (135.39 ± 2.16)

>0.05 Not significan

1 1 (84.84 ± 1.33) (82.57 ± 1.85)

0.7878

>0.05 Not significan

2 (130.7 ± 1.3)

0.3253

>0.05 Not significan

2 2 (80.56 ± 1.12) (79.48 ± 1.15)

0.6728

>0.05 Not significan

Follow-up 3 3 3 (2 months) (126.24 ± 0.83) (126.43 ± 1.04)

0.1443

>0.05 Not significan

3 (80.56 ± 1.0)

3 (79.04 ± 1.22)

0.9727

>0.05 Not significan

Follow-up 4 4 4 (3 months) (124.72 ± 0.94) (123.83 ± 0.81)

0.7114

>0.05 Not significan

4 (78.16 ± 0.89)

4 (76.7 ± 0.66)

1.3028

>0.05 Not significan

Follow-up 2 2 (1 month) (130.16 ± 1.05)

T value

P value

Ramipril (n = 25)

Telmisartan (n = 23)

Mean (SBP ± SEM)

>0.05 Not significan

0 (87.6 ± 1.54)

0.0110

and making it a public health problems. Evidence has shown that the humoral system (RAAS) plays a key role in the development and progression of hypertension and hypertension related end-organ damage as well as constitutes an important target for pharmacological intervention.3 Moreover, the rennin angiotensin system (RAS) plays a pivotal role in the regulation of cardiovascular function, with angiotensin II being involved in hemodynamic and nonhemodynamic mechanisms in the pathophysiology of cardiovascular disease.6 Further, using either an ACEIs or ARB confers cardiovascular protection.3 Thus, in the present study the two chosen agents for comparative evaluation basically modify RAAS for control of hypertension and have proven efficacy. Moreover, in the doses applied these agents cause minimal adverse effects profile and are well-tolerated. The study was conducted to verify these observations. Out of a total 53 enrolled patients, 5 patients (3 in ACEIs and 2 patients in ARB group) dropped out during the short span of 3 months probably because of increased cost of medicine on prolonged administration, loss of follow-up, adverse effects and more importantly due to poor awareness that despite an adequate control of BP one has to take medicine almost throughout his/her life over and above their antidiabetic drug dose. In the present study, the females predominate over males and M:F ratio is 0.51:1. This is consistent with the observations reported in the serial epidemiological studies conducted in Jaipur by Gupta et al7,8 where the prevalence of hypertension was lower (30% and 36%, respectively) among males as compared to (34% and 38%, respectively) in females. Other workers have also

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mentioned a similar larger involvement of females as compared to males. The incidence of hypertension in diabetic individuals has been observed less in urban population, the urban-rural ratio 0.65:1. The observation in respect to lesser involvement of urban population is probably due to the fact that mostly poor villagers and rural population attend to our OPD, besides their shattered economy and poverty leading to stressful life thus contributing to hypertension. However, contrasting trend of larger involvement of urban population in hypertension has been reported by earlier workers in the field.9,10 In the present study, increasing age is associated with increased prevalence of hypertension as well as diabetes. Majority of newly diagnosed patients of hypertension belonged to 41-50 years age group. These observations are in line with those of other workers.11-14 Rising atherosclerotic changes in vascular system with increasing age may probably the prime cause. Moreover, presence of type 2 diabetes usually associated with altered lipid profile may also contribute towards hypertension. Further, in type 2 diabetes both telmisartan and ramipril increased nitric oxide activity of the renal endothelium significantly, which in turn may support the preservation of cardiovascular and renal function.15 In this study, the incidence of hypertension is more (66%) in literate individuals as compared to illiterate. This is probably attributable to greater awareness towards hypertension and diabetes among literate person in recent times, and because of more stressful professional life, whereas illiterate are usually more

DRUGS involved with more physical work and farming activities to earn their livelihood. Currently, the diagnosis and treatment of hypertension is based on the BP values recorded at the office and the therapies designed to lower BP values have been found to have a positive impact on micro - and macrovascular endpoints in diabetes.16 In the present study, the BP was recorded in office settings and the two groups were well-balanced with respect to initial SBP and DBP. Besides, other baseline characteristics were also comparable in the ramipril and telmisartan groups for proper comparative evaluation. Although office BP recordings are quite convenient yet recent studies have demonstrated that ambulatory BP monitoring is better correlated to end-organ damage and cardiovascular morbidity from hypertension.17,18 Following treatment with either drugs, the mean SBP and DBP consistently decreased significantly in all the four follow-ups when compared to baseline values (p < 0.05). Other workers in the field have also observed a similar statistically significantly reduction in BP (both systolic and diastolic) with ACEIs and ARBs. Williams et al,19 while observing the antihypertensive efficacy of telmisartan (80 mg) versus ramipril (5 or 10 mg), over the 24-hour dosing period including the critical early morning hours using ambulatory BP monitoring, noted that the baseline mean ambulatory SBP and DBP (approximately 148/93 mmHg) had been decreased. Further, in one meta-analysis of 28 randomized controlled trials involving 5, 157 patients, telmisartan had a superior BP control over different ACEIs (enalapril, ramipril and perindopril), fewer drugrelated adverse events and better tolerability in hypertensive patients.20 Moreover, PRISMA-1 and -11 (Prospective, Randomized Investigation of the Safety and efficacy of Micardis vs ramipril) also observed that after 14 weeks, telmisartan was found to be more effective than ramipril in controlling BP throughout the 24-hour period and during early morning period (mean systolic/diastolic â&#x20AC;&#x201C; 4.1/-3.0 mmHg, p < 0.0001). These results may be attributable to the long duration of telmisartan, which is sustained throughout the 24-hour dosing period. The superior antihypertensive effect of telmisartan over ramipril in the above noted studies are in contrast to our observations as we observed that both these agents were almost equally effective antihypertensive agents; though we can not comment on the effect of telmisartan over early morning rise of BP.

CONCLUSION It is observed that both ramipril and telmisartan are almost equally effective as antihypertensive agents in causing lowering of BP. Both treatments are welltolerated and adverse events including cough are less common with telmisartan. Further, studies with large number of patients with longer duration of follow-up are required to validate these observations. In short, the prevalence of adverse effect is more with ramipril group as compared to telmisartan and there is lower rate of treatment discontinuation with telmisartan. Moreover, hypotension, angioedema and hyperkalemia were not observed in any of treated patient in the present study. Absence of cough and angioedema are notably the major advantages of ARB over ACEIs. Short comings besides short span of therapy, included small sample size, as well as test subjects were not matched on the risk factor history between two groups. REFERENCES 1.

Victor RG. Systemic hypertension: mechanisms and diagnosis. In: Bonow RO, Mann DL, Zipes DP, Libby P (Eds.). Braunwaldâ&#x20AC;&#x2122;s Heart Disease: A Textbook of Cardiovascular Medicine, 9th Edition. Philadelphia, Pa: Saunders Elsevier; 2011. pp. 935-54.

Arauz-Pacheco C, Parrott MA, Raskin P; American Diabetes Association. Treatment of hypertension in adults with diabetes. Diabetes Care. 2003;26(Suppl 1):S80-2.

Victor RG. Pathophysiology of target-organ disease: does angiotensin II remain the key? J Clin Hypertens (Greenwich). 2007;9(Suppl. 4):4-10.

Grassi G, Quarti-Trevano F, Mancia G. Cardioprotective effects of telmisartan in uncomplicated and complicated hypertension. J Renin Angiotensin Aldosterone Syst. 2008;9(2):66-74.

Jamerson K, DeQuattro V. The impact of ethinicity on response to antihypertensive therapy. Am J Med. 1996;101(3A):22S-32S.

Schmieder RE, Hilgers KF, Schlaich MP, Schmidt BM. Renin-angiotensin system and cardiovascular risk. Lancet. 2007;369(9568):1208-19.

Gupta R, Prakash H, Majumdar S, Sharma S, Gupta VP. Prevalence of coronary heart disease and risk factors in an urban population of Rajasthan. Indian Heart J. 1995;47(4):331-8.

Gupta R, Gupta VP, Sarna M, Bhatnagar S, Thanvi J, Sharma V, et al. Prevalence of coronary heart disease and risk factors in an urban Indian population: Jaipur Heart watch-2. Indian Heart J. 2002;54(1):59-66.

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DRUGS 9.

Chadha SL, Gopinath N, Shekhawat S. Urban-rural differences in the prevalence of coronary heart disease and its risk factors in Delhi. Bull World Health Organ. 1997;75(1):31-8.

16. Marshall SM. Clinical features and management of diabetic nephropathy. In: Pickup JC, Williams G (Eds.). Text Book of Diabetes, 3rd Edition. Oxford, UK: Blackwell Publishing Co; 2003. pp. 1-22.

10. Gupta R. Trends in hypertension epidemiology in India. J Human Hypertens. 2004;18:73-8.

17. Kikuya M, Hansen TW, Thijs L, Björklund-Bodegård K, Kuznetsova T, Ohkubo T, et al. Diagnostic thresholds for ambulatory blood pressure monitoring based on 10 year cardiovascular risk. Circulation. 2007;115(16): 2145-52.

11. Sindhu S, Kumar K, Prabhjot. Socio-demographic variables of hypertension among adult Punjabi females. J Hum Ecol. 2005;17(3):211-5. 12. Mehan MB, Srivastav N, Panya H. Profile of noncommunicable disease risk factors in an industrial settings. J Postgrad Med. 2006;52(3):167-73. 13. Deshmukh PR, Gupta SS, Dongre AR, Bharambe MS, Maliye C, Kaur S, et al. Relationship of anthropometric indicators with blood pressure levels in rural Wardha. Indian J Med Res. 2006;123(5):657-64. 14. Prasanth TS, Vijay Kumar KV. Prevalence of systemic hypertension among the rural residents of Kerala. Calicut Medical J. 2008;6(3):1-4.

18. Hansen TN, Jappersen J, Rasmusen, Insen H, TorpPedersen C. Ambulatory blood pressure monitoring and risk of cardiovascular disease: a population based study. Am J Hypertens. 2006;19(3):243-50. 19. Williams B, Lacourciere Y, Schumacher H, Gosse P, Neutel JM. Antihypertensive efficacy of telmisartan vs ramipril over the 24 hour dosing period including the critical early morning hours: a pooled analysis of the PRISMA-1 and 11 randomized trials. J Hum Hypertens. 2009;23(9): 610-8.

20. 15. Schmieder RE, Delles C, Mimran A, Fauvel JP, Ruilope LM. Impact of telmisartan versus ramipril on renal endothelial function in patients with hypertension and type 2 diabetes. Diabetes Care. 2007;30(6):1351-6. ■■■■

Zou Z, XiG L, Yuan HB, Zhu QF, Shi XY. Telmisartan versus angiotensin converting enzyme inhibitors in the treatment of hypertension: a meta-analysis of randomized controlled trials. J Hum Hypertens. 2009;23(5): 339-49.

FDA Approves Valsartan/Sacubitril (Entresto) Combination for Heart Failure The US Food and Drug Administration (FDA) has now approved the combination tablet valsartan/sacubitril (Entresto, Novartis) for the treatment of patients with heart failure. The combination drug, formerly known as LCZ696, is the first approved agent in the angiotensin receptor-neprilysin inhibitor (ARNI) class and exerts its effect within and beyond the renin-angiotensin system. Chemically, the agent consists of the angiotensin receptor blocker valsartan affixed to the neprilysin inhibitor sacubitril. TNF Inhibitors Spare the NSAIDs in Axial Spondyloarthritis 43% of patients completely discontinued NSAID treatment Intake of nonsteroidal anti-inflammatory drugs (NSAIDs) declines in a daily practice setting among patients with early axial spondyloarthritis who are treated with tumor necrosis factor (TNF) inhibitors. Data from a prospective multicenter observational study indicate a rapid and sustained decrease in NSAID intake among this population compared with a matched group not treated with TNF inhibitors, according to French researchers, led by Anna Molto at Pitié-Salpêtrière in Paris. Despite the decline in NSAID use with TNF inhibitors, "it is worth noting that only 43% patients completely discontinued their NSAID treatment after the 2 years of follow-up, suggesting that complete withdrawal is not always feasible," the authors wrote in Arthritis and Rheumatology. Average doses of NSAIDs, however, were low in patients taking TNF inhibitors.

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INTERNAL MEDICINE

Hepatic Dysfunction in Dengue Fever: A Retrospective Study from Tertiary Referral Hospital in Rajasthan MONIKA MAHESHWARI*, SANJIV MAHESHWARI†, MUKESH‡

ABSTRACT Introduction: Acute liver injury is a severe complicating factor in dengue infection, predisposing to thrombocytopenia, lifethreatening hemorrhage, disseminated intravascular coagulation and encephalopathy. Therefore, we sought to determine the frequency of hepatitis in 50 serologically confirmed cases of dengue fever (DF), admitted in medical wards of JLN Hospital, Ajmer. Results: Analysis of the liver profile showed that liver dysfunction was common in dengue infection. Elevated levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were observed more frequently. The mean range of serum ALT levels were 103.17 U/L and AST levels were 177.75 U/L. Conclusion: Liver damage with elevated aminotransferases and reactive hepatitis is a common complication of dengue virus infection, thus in endemic or epidemic areas, DF should be included in the differential diagnosis of acute hepatitis.

Keywords: Dengue fever, aminotransferase, hepatic injury

engue fever (DF) is an acute infectious disease caused by an arbovirus in the Flavivirus genus. It has four serotypes (1-4) and the mosquito Aedes aegypti is the vector. It is endemic over large areas of tropics and subtropics, especially in Southeast Asia.1 Classic DF is an acute, self-limiting illness characterized by fever, headache, bone-pain, myalgia, rash, prostration, leukopenia and thrombocytopenia.

MATERIAL AND METHODS

Over the last few years, atypical manifestations of dengue have been described, including involvement of the central nervous system, cardiac alterations and elevations in aminotransferase levels, with reactive hepatitis characterized by pain in the right hypochondrium, hepatomegaly and jaundice.2 In view of the emerging trend in dengue infection, we have undertaken a review on 50 dengue patients admitted in the medical wards of JLN Hospital, Ajmer. The purpose of this study was to examine their extent and pattern of the liver dysfunction in DF.

Patients were excluded from this study if they were pregnant, immunocompromised, had coexisting immunological or hematological disorders, had received hepatotoxic or myelotoxic drugs or had just been transfused with blood or blood products. On admission, blood was obtained for complete blood count, blood urea and electrolytes, liver profile (serum bilirubin, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), alkaline phosphatase and coagulation profile.

*Associate Professor †Professor and Unit Head ‡1st Year Resident JLN Medical College, Ajmer, Rajasthan Address for correspondence Dr Monika Maheshwari Naveen Niwas 434/10, Bapu Nagar, Ajmer, Rajasthan E-mail: opm11@rediffmail.com

Fifty patients (36 males and 14 females) with a mean + SD age of 3.0 + 5.6 years (range 26-45) were included in this study. All patients showed typical clinical symptoms and signs of DF and all were serologically positive for dengue immunoglobulin M (IgM) enzymelinked immunosorbent assay (ELISA).

RESULTS Hepatomegaly (liver span ranging from 14 to 16 cm subcostally was observed in 11 (22%) patients. Fatty liver was found in 4 (8%) patients. Hyperbilirubinemia was noted in 2 (4%) patients. The mean range of elevated serum ALT levels were 103.17 U/L and AST levels were 177.75 U/L. Levels of serum AST were elevated more frequently than ALT. Acalculous cholecystitis was seen in two patients.

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INTERNAL MEDICINE DISCUSSION Currently dengue is perhaps the most commonly rapidly emerging viral epidemic throughout the world. Throughout the tropics, this infection has an annual incidence of 100 million cases of DF with another 2.5 lacs cases of dengue hemorrhagic fever (DHF) and mortality rate of 24,000-25,000/year.3 Although the liver is not the main target organ for this disease, histopathological findings, including centrilobular necrosis, fatty alterations, hyperplasia of the Kupffer cells, acidophil bodies and monocyte infiltration of the portal tract have been detected in patients with dengue.4 The results of the present study also show that many patients with dengue viral infection had some degree of liver involvement as indicated by the abnormal liver function test results, especially in the serum transaminase levels. In hepatitis, the levels of these enzymes reach a maximum on the 9th day after the onset of symptoms and they gradually return to normal levels within 3 weeks.5 One characterisitic feature of hepatic involvement during dengue virus infection is greater elevation in AST than ALT levels. This information is useful for differential diagnosis of acute hepatitis caused by A, B or C virus in which this phenomenon is infrequently observed. Hepatic dysfunction in dengue infection may result from multifactorial conditions, such as the use of hepatotoxic drugs, as a consequence of host response to infection, or due to the direct aggression/ replication of the dengue virus.6 Activated lymphocyte subsets have been shown to be responsible for the severe thrombocytopenia and plasma leakage in DHF and thus these cells may also be involved in the mechanism of liver dysfunction seen in DHF.7 Morens8 observed hepatomegaly in up to 90% of Thai children and 60% of adults with DF. Nimmanniya9 noted that the liver function derangement is related to the severity of dengue viral infection. Mean ALT levels were significantly raised in DHF fever than DF. Kuo et al5 have reported higher bleeding episodes in those who had high levels of AST and ALT, suggesting

that deranged liver functions have significant role in bleeding in addition to thrombocytopenia. CONCLUSION We conclude that majority of the patients with dengue infection have hepatitis. Severe hepatitis in dengue infection has got worse outcome in terms of length of stay, mortality and complications. Though majority of the patients had self-resolving course of illness, they can be potential candidates for acute fulminant hepatic failure. Hence, the message to the physicians is that apart from routine hepatotropic viruses, DF should be considered in differential diagnosis when liver functions are deranged in any febrile patient. REFERENCES 1.

Gubler DJ. Epidemic dengue/dengue hemorrhagic fever as a public health, social and economic problem in the 21st century. Trends Microbiol. 2002;10(2):100-3.

Samanta J, Sharma V. Dengue and its effects on liver. World J Clin Cases. 2015;3(2):125-31.

Halstead SB. Is there an inapparent Dengue explosion? Lancet. 1999;353(9158):1100-1.

Souza L, Alves JG, Nogueria R, Neto C, Basatos D, Siqueris E, et al. Aminotransferase changes and acute hepatitis in patients with dengue fever. Analysis of 1,585 cases. Braz J Infect Dis. 2004;8(2):156-63.

Kuo CH, Tai DI, Chang-Chien CS, Lan CK, Chiou SS, Liaw YF. Liver biochemical tests and dengue fever. Am J Trop Med Hyg. 1992;47(3):265-70.

Lum LC, Lam SK, George R, Devi S. Fulminant hepatitis in dengue infection. Southeast Asian J Trop Med Public Health. 1993;24(3):467-71.

Wahid S, Sansui S, Zawawi M, Ali R. A comparison of the pattern of liver involvement in dengue hemorrhagic fever with classic dengue fever. Southeast Asian J Trop Med Public Health. 2000;31(2):259-63.

Morens DM. Dengue fever and dengue shock syndrome. Centers for disease control. Hosp Pract (Off Ed). 1982;17(7):103-7.

Nimmanniya S. Clinical spectrum and management of dengue haemorrhagic fever. Southeast Asian J Trop Med Public Health. 1987;18(3):392-7.

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CBT Effective for Comorbid Insomnia A new meta-analysis has provided further evidence supporting cognitive-behavior therapy for insomnia (CBT-I) when the difficulty sleeping occurs with another medical or psychiatric condition. “We are putting the evidence out there. CBT-I is an effective treatment for insomnia even when it occurs with an underlying medical or psychiatric condition. Physicians need to consider this an option,” study coauthor, Jason C. Ong, PhD, Rush University Medical Center, Chicago, Illinois, told Medscape Medical News.

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INTERNAL MEDICINE

Cortical Vein Thrombosis: A Rare Manifestation of Tubercular Meningitis ANJUM MIRZA CHUGHTAI*, MUHAMMAD UWAIS ASHRAF†, MR AJMAL‡

ABSTRACT Tuberculosis is one of the commonest infectious diseases still prevailing in the Indian subcontinent. Tubercular meningitis is one of the most dreaded forms of tuberculosis in Indian subcontinent. A myriad of complications have been reported in connection with tuberculous meningitis; however, cortical vein thrombosis (CVT) secondary to tuberculous meningitis is a rare complication of tuberculosis. Factors predisposing to CVT include infections like bacterial meningitis, pregnancy and puerperium, hypercoagulable states, acquired and congenital heart diseases, malignancies, connective tissue disorders, severe dehydration, liver disease, major trauma, etc. We present here a rare case report of CVT secondary to tuberculous meningitis. In the past, very few cases of tuberculous meningitis have been reported to present with CVT.

Keywords: Tuberculosis, tubercular meningitis, complications, cortical vein thrombosis

uberculosis is one of the commonest infectious diseases still prevailing in the Indian subcontinent. It is estimated that in India, the incidence rate of tuberculosis is around 25.3/1,00,000 population as per the records available.1 In the global context, tuberculosis is responsible for more than 1.5 million deaths every year.1 Tubercular meningitis is one of the most dreaded forms of tuberculosis in Indian subcontinent. A myriad of complications have been reported in connection with tuberculous meningitis; however, cortical vein thrombosis (CVT) secondary to tuberculous meningitis is a rare complication of tuberculosis.

Thrombosis of the cortical venous system is a fatal condition; however, the mortality rate has considerably come down in recent years to approximately 5-10%.2 Factors predisposing to CVT include infections like bacterial meningitis, pregnancy and puerperium, hypercoagulable states, acquired and congenital heart

*Assistant Professor †Senior Resident ‡Chairman Dept. of Medicine JN Medical College, AMU, Aligarh, Uttar Pradesh Address for correspondence Dr Muhammad Uwais Ashraf Senior Resident Dept. of Medicine JN Medical College, AMU, Aligarh - 202 002, Uttar Pradesh E-mail: uwaisashraf@gmail.com

diseases, malignancies, connective tissue disorders, severe dehydration, liver disease, major trauma, etc.3 Since, these conditions are being effectively and promptly managed these days, the overall incidence of CVT has considerably come down. We present here a rare case report of CVT secondary to tuberculous meningitis. In the past, very few cases of tuberculous meningitis have been reported to present with CVT.4,5 CASE REPORT A 22-year-old male patient presented with complaints of fever for 2 months and altered sensorium for 4 days. There was also history of multiple episodes of abnormal movements. However, there was no history of similar episodes in the past or any chronic ailment in the past. There was also no associated history of head trauma, prolonged medical therapy, ear discharge, alcohol intake or any neurosurgical intervention in the recent past. Family history was not related to his current illness. Patient had three more siblings (two sisters and one brother) and all of them were healthy and none had any similar illness at any age and both the parents were alive and healthy. On examination, the vitals were stable. His temperature was 98.6°F, EMV was 7/15, plantar response was bilaterally extensor. Neck rigidity was marked and Kerning’s sign was positive. However, there was no focal deficit. There were bilateral coarse crepitations on the auscultation of the chest. Fundoscopy was normal. Baseline

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INTERNAL MEDICINE investigations revealed hemoglobin of 10.9 gm%, total leukocyte count (TLC) was 8,800, differential leukocyte count (DLC) was P74L26. Mean corpuscular volume (MCV) was 88 fl. Blood urea was 18 mg% and serum creatinine was 0.6 mg%. Liver function tests and serum uric acid were normal. Chest X-ray revealed a military pattern (Fig. 1). Human immunodeficiency virus (HIV) serology was negative. Based on these

Figure 1. Chest X-ray showing military pattern.

clinical findings and basic investigations, a working diagnosis of tuberculous meningitis was made. Cerebrospinal fluid (CSF) examination was done, which revealed proteins (200), sugar (55), cells (36), P20L80, ADA 10.3 U/L. Antitubercular therapy (ATT) was started along with steroids and decongestive therapy and anticonvulsants. However, there was no improvement in the patientâ&#x20AC;&#x2122;s status. A magnetic resonance imaging (MRI) brain was done which revealed Ill-defined, heterogeneous, altered signal intensity lesion involving the genu of corpus callosum, parasagittal bilateral frontal lobe grey and white matter, caudate nucleus and medial part of temporal lobe with areas of curvillinear hyperintensities showing blooming foci on susceptibility weighted imaging (SWI) sequences (bleed) with post-contrast gyriform enhancement with adjacent leptomeningeal enhancement (Fig. 2 a and b). These findings were commensurate with the diagnosis of tuberculous meningitis with CVT. The magnetic resonance spectroscopy revealed a reversal of choline and creatinine ratio with a high lactate peak, which was also in concert with a diagnosis of hemorrhagic infarction (Fig. 3). Based on these results,

Figure 2 a and b. Ill-defined, heterogeneous, altered signal intensity lesion involving the genu of corpus callosum,

parasagittal bilateral frontal lobe grey and white matter, caudate nucleus and medial part of temporal lobe with areas of curvillinear hyperintensities showing blooming foci on SWI sequences (bleed) with post-contrast gyriform enhancement with adjacent leptomeningeal enhancement.

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INTERNAL MEDICINE had improved when the patient came for follow-up after a week. A repeat MRI scan was done after 3 weeks, which showed regression of the lesion (Fig. 4). DISCUSSION

Figure 3. Magnetic resonance spectroscopy showing findings suggestive of CVT.

In 1825, Ribes described a case of a 45-year-old man who died after a 6-month history of epilepsy, seizures and delirium. The autopsy examination revealed thrombosis of the superior sagittal sinus, the left lateral sinus and a cortical vein in the parietal region. This was probably the first detailed description of extensive cerebral venous sinus thrombosis (CVST). Since then, the literature describing this disease has comprised of case reports, series and some newer prospective studies, including recent reviews and guidelines (statement) on the diagnosis and management of CVST.6,7 The dural sinuses and the cerebral and emissary veins have no valves, which allow blood to flow in either direction according to pressure gradients in the vascular system. This makes these venous systems vulnerable to septic thrombosis resulting from spreading of infection from adjacent locations. Any part of the cerebral venous system can be affected by septic thrombophlebitis, but certain sinuses are more prone than others. The cavernous followed by lateral and then sagittal sinuses are most commonly affected. CVT can be idiopathic or secondary to infectious and noninfectious etiologies. Infection-related CVT is usually due to bacterial (mainly pneumococcal), fungal or parasitic infections. Tuberculosis was associated to CVT in few patients reported on literature. Two of them have disseminated tuberculosis with no involvement of central nervous system,8 one has only pulmonary disease and another had chronic granulomatous meningitis.

Figure 4. A repeat MRI showing regression of lesion.

patient was put on anticoagulation with low molecular heparin, which was overlapped with warfarin.

Follow-up of the Patient Two days later, patient became fully conscious. The clinical status improved drastically. Patient was discharged on oral warfarin. The neurological signs

The pathophysiologic processes that can explain the relation between tuberculosis and CVT includes: (1) injury to endothelium, (2) alterations in normal blood flow and (3) alterations in the blood coagulability. Blood stasis occurs because intracranial sinus is a lowpressure system without valve. Hypercoagulable state occurs in patients with tuberculosis, because they show increased platelet aggregability.9 Arteries running, though the subarachnoid space may show obliterative end-arterites with inflammatory infiltrates in their walls, and marked intimal thickening. Actually, tuberculosis is a disease with a wide variety of clinical presentations and recently, the association between inflammation, hemostatic changes and a hypercoagulable state has been established.9,10

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INTERNAL MEDICINE Robson et al research study suggested that elevated plasma fibrinogen, impaired fibrinolysis coupled with decreased levels of antithrombin III and reactive thrombocytosis appeared to favor the development of DVT in pulmonary TB.10 Similar observations were made by Turken et al in a case-control study, regarding these hemostatic disturbances in 45 patients with active pulmonary tuberculosis. Moreover, it stated that these changes improved with ATT within 4 weeks.9 On the other hand, there is also data supporting a relationship between this prothrombotic phase and a high frequency of antiphospholipid antibodies and protein deficiency.11

Aundhakar SC, Mahajan SK, Mane MB, Agrawal S. Cortical venous thrombosis - a rare complication of tuberculous meningitis. Int J Med Update. 2013;8(1):31-3.

Fiorot Júnior JA, Felício AC, Fukujima MM, Rodrigues CA, Morelli VM, Lourenço DM, et al. Tuberculosis: an uncommon cause of cerebral venous thrombosis? Arq Neuropsiquiatr. 2005;63(3B):852-4.

Siddiqui FM, Kamal AK. Incidence and epidemiology of cerebral venous thrombosis. J Pak Med Assoc. 2006;56(11):485-7.

Brown WR, Thore CR. Review: cerebral microvascular pathology in ageing and neurodegeneration. Neuropathol Appl Neurobiol. 2011;37(1):56-74.

Kakkar N, Banerjee AK, Vasishta RK, Marwaha N, Deodhar SD. Aseptic cerebral venous thrombosis associated with abdominal tuberculosis. Neurol India. 2003;51(1):128-9.

Finsterer J, Kladosek A, Nagelmeier IE, Becherer A, Matula C, Stradal KH, et al. Chronic granulmatous meningitis with multiple cranial nerve lesions hydrocephalus, stroke, sinus thrombosis and epilepsy. South Med J. 2000;93(11):1108-11.

Turken O, Kunter E, Solmazgul E, Cerrahoglu K, Ilvan A. Hemostatic changes in active pulmonary tuberculosis. Int J Tuberc Lung Dis. 2002;6(10):927-32.

CONCLUSION Cerebral venous thrombosis is a rare disease that can occur at any age. Its occurrence in tuberculous meningitis is rare and so its clinical picture is routinely confused and falsely attributed to tuberculous meningitis. A very high index of suspicion is required to correctly diagnose the complication as its timely aggressive treatment results in an excellent outcome for the patient in the form of complete recovery. REFERENCES 1.

Antunes FA. Situação epidemiológica da tuberculose e resultados em Dezembro de 2008. Programa Nacional de Luta Contra a Tuberculose (PNT). Março de. 2009;2:9333.

10. Robson SC, White NW, Aronson I, Woollgar R, Goodman H, Jacobs P. Acute-phase response and the hypercoagulable state in pulmonary. Br J Haematol. 1996;93(4):943-9.

11. Suárez Ortega S, Artiles Vizcaíno J, Balda Aguirre I, Melado Sánchez P, Arkuch Saade ME, Ayala Galán E, et al. Tuberculosis as risk factor for venous thrombosis. An Med Ameri A, Bousser MG. Cerebral venous thrombosis. Interna. 1993;10(8):398-400. Neurol Clin. 1992;10(1):87-111. ■■■■

Coronary Artery Calcification Predicts All-cause Mortality The extent of coronary artery calcification (CAC) is an accurate predictor of 15-year mortality in asymptomatic individuals, according to a new study published online July 6 in the Annals of Internal Medicine. Leslee J. Shaw, PhD, from Emory University School of Medicine in Atlanta, Georgia, and colleagues found that individuals without CAC had 15-year all-cause mortality rate of 3%. In contrast, overall mortality increased to 28% for individuals with CAC scores of 1,000 or higher (p < 0.001).

Sleep Apnea: Mixed Results for Mandibular Appliance Mandibular advancement devices improved the number of apneas and hypopneas, but did not improve daytime sleepiness or quality-of-life, compared with placebo in a single-blind randomized study of patients with snoring or mild to moderate obstructive sleep apnea. Marie Marklund, PhD, DDS, from the Dept. of Odontology, Faculty of Medicine, Umeå University, Sweden, and colleagues, report their findings online June 1 in JAMA Internal Medicine. “Continuous positive airway pressure is a highly effective treatment for patients with daytime sleepiness and sleep apnea, but adherence problems as a result of nasal stuffiness, claustrophobia, and the risk of disturbing bed partners limit the overall usefulness of this therapy,” the researchers write. However, it is unclear from prior studies whether a mandibular appliance will provide the same symptomatic relief.

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NEUROLOGY

Headache with Visual Hallucinations: Lessons Learnt DEBAPRASAD CHAKRABARTI*, ANINDYA SUNDAR TRIVEDI†, AMRIT KR BHATTACHARYYA‡

ABSTRACT Neurocysticercosis (NCC) is the single most common cause of epileptic seizures in the developing world. Visual hallucination may be the occasional presenting symptom of NCC with occipital seizure with striking similarity to the visual aura of migraine. We report here a case of NCC who presented with features mimicking classical migraine with aura.

Keywords: Neurocysticercosis, visual hallucination, migraine

ysticercosis, an infection caused by larval stage of Taenia solium, is the most common parasitic disease of the central nervous system (CNS). The clinical presentation of cysticercosis depends on the number and location of cysticerci as well as the extent of associated inflammatory responses or scarring. Seizures are associated with inflammation surrounding cysticerci in the brain parenchyma.1 These seizures may be generalized, focal or Jacksonian. Cysticercosis is the most common cause of seizure in endemic regions such as India and South America.

Visual hallucinations, the most common feature of aura of migraine,2 may also be the presenting symptoms of neurocysticercosis (NCC) with occipital seizure,3 which may lead to error in diagnosis. We describe a case where the patient had multiple NCC and whose clinical presentation consisted of stereotyped episodes of visual hallucinations. CASE REPORT A 23-year-old male patient presented to us with episodic headache localized at the vertex and right temporoparietal region for 4 years. But over the past

*Associate Professor †Postgraduate Trainee ‡Professor and Head Dept. of Medicine Tripura Medical College and Dr BRAM Teaching Hospital, Hapania, Agartala, Tripura Address for correspondence Dr Debaprasad Chakrabarti Associate Professor Dept. of Medicine Doctors Qtr. E/1, Tripura Medical College and Dr BRAM Teaching Hospital Hapania, Agartala, Tripura (West) - 799 014 E-mail: drdebaprasad2007@ rediffmail.com

Figures 1 and 2. Showing T1 and T2 MRI images of brain with multiple NCC in vesicular stage.

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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 HCI ̀ und ̀ 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 und ̀ 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 organiing Ě&#x20AC; 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

NEUROLOGY DISCUSSION Visual hallucination is the most common feature of aura of migraine and may appear in many forms, including the scintillating scotoma, stationary flickering white or colored lights, stars, pinwheels, rings or triangles. The hallucination typically lasts from 5 to 30 minutes and shows a marching or build-up phenomenon. It may be followed by a throbbing headache.

Figure 3. Contrast MRI images of brain with multiple NCC with viable scolex.

2 years, he noticed flashes of bright light over the right temporal field associated with blurring of vision lasting for few minutes before getting migraine like headache. Following the visual aura, headache used to persist for 10-12 hours or relieved with analgesics. However, migraine prophylaxis did not work for him. There was no history of vomiting, loss of consciousness or tonicclonic movements. General physical and systemic examination was unremarkable. Ophthalmological examination, including fundoscopy, was normal. Routine blood chemistry was normal except mild peripheral eosinophilia. Ultrasonography (USG) whole abdomen and chest X-ray did not reveal any abnormality. Computed tomography (CT) scan of brain was done to rule out any alternative diagnosis, which showed multiple noncalcified cystic lesions suggestive of NCC. Toxoplasma antibody and Mantoux test were negative. Findings were confirmed by magnetic resonance imaging (MRI) which revealed extensive NCC in vesicular stage (Figs. 1-3). Electroencephalogram (EEG) examination did not reveal any epileptic abnormality. Diagnosis of NCC was made according to adult criteria of Del Brutto et al.4 Due to multifocal involvement, patient was treated conservatively with antiepileptics alone and migraine prophylaxis was withdrawn. On follow-up, he was doing well without any further episode of headache or visual hallucination.

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Indian Journal of Clinical Practice, Vol. 26, No. 2, July 2015

Visual hallucinations associated with seizures differ from those of migraine in that they: (1) are of short duration, (2) lack a fortification spectrum, (3) are typically invariant from one episode to another, (4) lack a march or build-up of the visual disturbance across the visual field and (5) always occur in the same hemifield (contralateral to the lesion).1,5,6 However, sometimes there may be similarities with migrainous visual hallucinations in that they may be colored and may spread across the whole field. Focal seizures are common in parenchymal NCC. They may be motor or sensory, depending on the location of the cyst in the brain. Seizures occur during the degenerative phase of the cyst, as the death of the cysticercus releases larval antigen that can stimulate or exacerbate an inflammatory host response. The occurrence of headache without any other evidence of increased intracranial pressure has been reported in several series of NCC patients with a prevalence that may be as high as 30% of cases.7 Such headaches are intermittent and resemble those seen in migraine, tension-type headache or other primary headache disorders, raising the question of whether they are related to cysticercosis or may occur as an incidental finding in areas where both conditions are highly prevalent.8 However, until recently, there was no convincing evidence of a cause-and-effect relationship between these two conditions. It is possible that periodic remodeling of intracranial calcifications exposing parasitic antigenic material to the host causes transient inflammatory changes in the brain parenchyma that may be the cause of transient and recurrent episodic headache mimicking a primary headache disorder, thus providing a rationale for the association between headache and NCC. In our case, the patient presented with migraine like headache and visual hallucinations evading a proper diagnosis for a long time. Regarding treatment of NCC, there is no uniformly accepted approach yet. NCC

NEUROLOGY is not a single disease for which one therapy can be recommended to all. Treatment must be individualized based on the number, location as well as depending on the viability of the parasites.8 As of today, clear cut recommendations are yet to be made regarding antiparasite treatment in NCC. Controversy still exists regarding the resolution of active cysts and better clinical outcome with cysticidal drugs. There are proponents of no albendazole therapy, short-course therapy (7 days) and 28 days course of full dose albendazole therapy.8 Anticysticercal drugs are however contraindicated for spinal, ventricular or ophthalmic cysticercosis.9 There is also no consensus regarding anticysticercal treatment when infection burden is heavy for fear of life-threatening adverse events. However, the most recent guideline favors the use of cysticidal drugs even in heavy infection particularly in vesicular stage of NCC.10 Cysticercal drugs are no alternative to antiepileptic therapy, which forms the principal management of seizures in NCC. This case report emphasizes that in an endemic region like India, cysticercosis should always be suspected in patients with visual hallucinations with headache, particularly if these hallucinations have distinctive clinical features such as monotonous unilaterality, brief duration and lack of build-up phenomena. The case is presented here to sensitize the physicians regarding migraine like presentation of NCC, which may lead to delay and error in diagnosing and treating such cases.

REFERENCES 1.

Del Brutto OH. Neurocysticercosis. Continuum (Minneap Minn). 2012;18(6):1392-416.

Hupp SL, Kline LB, Corbett JJ. Visual disturbances of migraine. Surv Ophthalmol. 1989;33(4):221-36.

Williamson PD, Thadani VM, Darcey TM, Spencer DD, Spencer SS, Mattson RH. Occipital lobe epilepsy: clinical characteristics, seizure spread patterns, and results of surgery. Ann Neurol. 1992;31(1):3-13.

Del Brutto OH, Rajshekhar V, White AC Jr, Tsang VC, Nash TE, Takayanagui OM, et al. Proposed diagnostic criteria for neurocysticercosis. Neurology. 2001;57(2):177-83.

Panayiotopoulos CP. Elementary visual hallucinations in migraine and epilepsy. J Neurol Neurosurg Psychiatry. 1994;57(11):1371-4.

Deonna TW. Paroxysmal disorders which may be migraine or maybe confused with it. In: Hockaday JM (Ed.). Migraine in Childhood and Other Nonepileptic Paroxysmal Disorders, London: Butterworth; 1988. pp. 75-87.

Carabin H, Ndimubanzi PC, Budke CM, Nguyen H, Qian Y, Cowan LD, et al. Clinical manifestations associated with neurocysticercosis: a systematic review. PLoS Negl Trop Dis. 2011;5(5):e1152.

García HH, Evans CA, Nash TE, Takayanagui OM, White AC Jr, Botero D, et al. Current consensus guidelines for treatment of neurocysticercosis. Clin Microbiol Rev. 2002;15(4):747-56.

Gracia HH, Nash TE, Del Brutto OH. Clinical symptom, diagnosis and treatment of neurocysticercosis. Lancet Neurol. 2014;13(12):1202-15.

10. Del Brutto OS, García HH. Cysticercosis of the Human Nervous System. Berlin, Heidelberg: Springer-Verlag; 2014. pp. 109-23. ■■■■

Cognitive Deficits Present Years Before Alzheimer’s Develops Deficits in cognitive function can be present up to 18 years before the development of clinically evident Alzheimer’s disease (AD), a new study shows. Led by Kumar B. Rajan, PhD, investigators at Rush University in Chicago, Illinois, found that overall performance on tests of cognitive function differed substantially between individuals who subsequently developed Alzheimer’s and those who remained free of the disease up to 18 years before diagnosis.

Diabetes Linked to ALS Risk A new study finds an association between type 2 diabetes and a lower risk for amyotrophic lateral sclerosis (ALS), while type 1 diabetes was associated with a higher risk. Along with other recent research that points in a similar direction, the findings should help move the field forward to improve understanding of the relationship between diabetes and ALS, said lead author Marianthi-Anna Kioumourtzoglou, ScD, Dept. of Environmental Health, Harvard School of Public Health, Boston, Massachusetts.

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OBSTETRICS AND GYNECOLOGY

A Randomized Comparative Study of Intramuscular Camylofin Dihydrochloride and Intravenous Drotaverine Hydrochloride on Cervical Dilatation in Labor BINU P

ABSTRACT Background: Both maternal and perinatal morbidity are greatly affected by the duration of labor. Uterine activity and the rate of cervical dilatation are the principal factors that determine the duration of labor. However, despite good uterine contractions, cervical dilatation may be impeded due to the inhibitory impulses in the form of spasm, thus resulting in prolonged labor. Objectives: The purpose of the current study was to compare the effectiveness of intravenous drotaverine hydrochloride and intramuscular camylofin dihydrochloride on the following variables: Rate of cervical dilatation; duration of active phase of first stage of labor; mode of delivery and total duration of labor. The study also investigated the effectiveness of the above drugs in shortening the duration of labor and their potential adverse reactions on the mother and fetus. Methods: One hundred twentysix women in active labor were segregated into two groups consisting of 63 patients each. Group I received intramuscular camylofin dihydrochloride and Group II received intravenous drotaverine hydrochloride. The drugs were compared for their effectiveness in cervical dilatation. Results: Duration of active phase of labor was 332.54 ± 59.93 minutes in Group I and 356.78 ± 68.93 minutes in Group II. Although the mean duration of active phase of first stage of labor was shorter in Group I (332.54 minutes) as compared to Group II (356.78 minutes), it was not statistically significant. Mean cervical dilatation rate was significantly more in Group I (1.78 cm/hr) than Group II (1.61 cm/hr). Mean induction delivery interval was longer in Group II (228.38 minutes) than in Group I (207.96 minutes). The lengths of the second stage (39.49 ± 11.21 in Group I, 36.78 ± 10.9 in Group II) and third stage (5.39 ± 1.58 in Group I, 6.02 ± 2.01 in Group II) were statistically similar in both the groups. Conclusion: It was concluded that the duration of active phase of labor was shorter in camylofin group than drotaverine group, but it was statistically insignificant. The rate of cervical dilatation was more in camylofin group than drotaverine group, which is statistically significant. Induction delivery interval was significantly longer in drotaverine group than in camylofin group. No major maternal or fetal side effects were observed. Intramuscular camylofin dihydrochloride appeared to be more effective than intravenous drotaverine hydrochloride for cervical dilatation.

Keywords: Camylofin dihydrochloride, drotaverine hydrochloride, cervical dilatation

abor is an important and memorable event in a woman’s life.1 A painless and short labor is every mother’s desire and an obstetrician’s aim. Progressive cervical dilatation and progressive descent of the presenting part determine the progress of labor.1 Cervical dilatation is the outcome of all the driving forces of uterine contraction acting against tissue resistance and significantly determines the duration of labor. Failure of the cervix to dilate in labor may lead to prolonged labor.1 The hazards of prolonged labor have long been recognized for both the mother and the fetus. While the mother faces a risk of obstructed

Dept. of Obstetrics and Gynecology Rajiv Gandhi University of Health Sciences, Bangalore, Karnataka

labor, ketosis and infection, the fetus is exposed to the risks of infection, birth asphyxia and excessive cranial moulding.2 Labor is said to be prolonged if its duration exceeds 18 hours. In multiparous women, the labor is considered as prolonged if it exceeds 12 hours. This generally refers to prolongation of the first stage of labor associated with slow dilatation of the cervix. The second stage may be randomly defined as prolonged after 2 hours in primigravidae and 1 hour in multigravidae.3 The commonest causes of prolonged labor include: inadequate contractions, resistance by bony pelvis or soft tissues, and abnormal position and presentation. Prolonged labor is managed with intravenous fluids; analgesics; prophylactic antibiotics - whenever there is membrane rupture more than 12 hours, repeated per vaginum (PV)’s in case of pyrexia and tachycardia and

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OBSTETRICS AND GYNECOLOGY assessment of contractions, PV examination for cervical dilatation, descent and position of presenting part, malpresentation and abnormal pelvic architecture, use of partogram, augmentation by oxytocin and artificial rupture of membranes. Specific treatment involves use of oxytocin, artificial rupture of membranes and cesarean section if indicated, in the first stage and instrumental delivery or cesarean section if indicated, in the second stage.3,4

Exclusion criteria were: Â

Pre-eclampsia

Eclampsia

Antepartum hemorrhage

AIMS The present study aimed to compare and evaluate the rate of cervical dilatation from onset of active labor to full cervical dilatation in patients randomized to receive intramuscular camylofin dihydrochloride and intravenous drotaverine hydrochloride. OBJECTIVES Â

To compare the effectiveness of intravenous drotaverine hydrochloride and intramuscular camylofin dihydrochloride on:

Any obstetric complications: Cephalopelvic disproportion, abnormal presentations and twin pregnancy. Medical disorders: Renal and hepatic dysfunction, cardiac disease and obstructive airway disease

Known hypersensitivity to drug

Patient in latent phase of labor.

Patients qualifying for the study were assigned groups by simple random table. Two groups consisting of 63 patients each were formed. Group I was randomized to receive drotaverine 40 mg (one vial) intravenously; second injection was repeated after 2 hours. Group II received camylofin 25 mg (one vial) intramuscularly, single injection. Few cases were given second injection after 2 hours.

Rate of cervical dilatation

Duration of active phase of first stage of labor

Maternal and fetal status was evaluated clinically in reference to the following points:

Mode of delivery

Patient’s name, husband’s name, age, address

Total duration of labor.

Registration number, date and time of admission

Occupation of the patient

Period of gestation

To find out the efficacy of the above drugs in shortening the duration of labor. To study the adverse drug reactions on the mother and fetus.

Duration of labor pains/history of leak or bleeding PV

METHODS

The time of induction in case of induced labor

The study was conducted in MS Ramaiah Hospital, Bangalore from October 2010 to 2012 on a random population of pregnant females.

Menstrual and marital history

General physical examination

Systemic examination

Inclusion criteria were: Â

Primigravidae

Age 18-35 years

Cervical dilatation >3 cm

Vertex presentation

Singleton full-term gestation (37-40 weeks)

Intact fetal membranes

Spontaneous and induced labor

158

The effect of epidural analgesia and sedatives on cervical dilatation was controlled by matching the two groups i.e., camylofin group receiving epidural analgesia or sedatives was compared with drotaverine group receiving the same.

Indian Journal of Clinical Practice, Vol. 26, No. 2, July 2015

Per abdomen examination: To determine height of the uterus, number and duration of contractions, to assess the liquor clinically, to assess the number of fetal pole palpable per abdomen.

Patients were encouraged to keep their bladder empty. Any side effects were noted and treated accordingly. After the delivery of the placenta, cervix and the vagina were inspected to rule out any trauma to the cervix. The study methodology stated that if at any point in the study, there appeared an indication for maternal or fetal health being jeopardized, the investigational drug would be stopped and adjunctive measures to affect delivery would be carried out immediately and the patient would be excluded from the study.

OBSTETRICS AND GYNECOLOGY The primary endpoint of the study was delivery of baby. Following parameters were monitored in every patient: Â

Progress of labor using a partogram: Frequency and duration of uterine contractions were evaluated clinically by abdominal palpation every 30 minutes; cervical effacement and dilatation were monitored every 2 hours by PV examination; station and position of presenting part were noted. PV examination was done earlier if: Rupture of membranes occurred, patient started bearing down, significant changes in fetal heart sound (FHS) were found or meconium-stained liquor was observed. Maternal well-being was assessed by pulse rate; blood pressure; any side effects like nausea, vomiting, palpitations, tachycardia, dryness of mouth, flushing, headache, hypotension, nausea, vomiting, pain at injection site were noted and treated accordingly. Fetal well-being was assessed by checking fetal heart rate; color of amniotic fluid and Apgar score at 1 and 5 minutes.

The effectiveness of intravenous drotaverine hydrochloride and intramuscular camylofin dihydrochloride was compared on the following grounds: Â

Total duration of active phase of first stage of labor

Rate of cervical dilatation

Total duration of labor

Mode of delivery

Any complication in the third stage

Neonatal condition at birth.

Routine investigations included hemoglobin (Hb), blood grouping, Rhesus (Rh) factor, urine (albumin and sugar) and blood sugar. Ultrasonography (USG) and other investigations were done as required. Data obtained was compiled and analyzed regarding comparative efficacy, safety and acceptability of the two methods involved.

Statistical Analysis Descriptive and inferential statistical analyses were conducted in the present study. Results on continuous measurements were presented on mean + SD (minmax) and results on categorical measurements were presented in number (%). Significance was assessed at 5% level of significance. Student t-test (two-tailed, independent) was used to find the significance of study

parameters on continuous scale between two groups on metric parameters. Chi-square/Fisher exact test helped to determine the significance of study parameters on categorical scale between two or more groups. OBSERVATIONS AND RESULTS The study assessed the incidence of lower segment cesarean section (LSCS) in the two groups with 63 subjects each, which was found to be comparable in both the groups. Therefore, in order to avoid confusion in calculation of the duration of active phase, second and third stage of labor, rate of cervical dilatation, injection delivery interval and the number of injections required, patients who had LSCS were excluded from these statistics. The difference in the age groups in two groups was not statistically significant (p value of 0.422). Most patients were 21-25 years of age (49.2% in camylofin group and 61.9% in drotaverine group, respectively) (Table 1). The distribution of booked/unbooked patients was statistically similar in the two groups with p = 1.000. Nearly 93.6% patients were booked in each group. About 17.5% in the camylofin group and 4.8% in the drotaverine group were between 37 and 38 weeks of gestation. Nearly 27.0% in camylofin group and 42.8% in drotaverine group were between 38 and 39 weeks. About 55.5% in camylofin group and 52.4% in drotaverine group were between 39 and 40 weeks of gestation. Period of gestation was statistically significant in the two groups (p = 0.032). All the patients in both the groups belonged to 37-40 weeks of gestation (Fig. 1). Distribution of spontaneous labor and induced labor was statistically similar in the two groups with p = 0.849. About 66.7% in camylofin group and 68.3% in drotaverine group had spontaneous labor, while 33.3% in camylofin group and 31.7% in drotaverine group had induced labor (Fig. 2). Oxytocin acceleration was statistically similar in both the groups of patients with p = 1.000. About 90.5% in both the groups had oxytocin acceleration. Mean duration of active phase of first stage of labor was shorter in camylofin group (332.54 minutes) as compared to the drotaverine group (356.78 minutes); however, the difference was not statistically significant (p = 0.142). Mean duration of second stage of labor was 39.49 minutes in camylofin group versus 36.78 minutes in drotaverine group; again a statistically insignificant difference with p value of 0.185. Mean duration of third stage of labor was 5.39 minutes in camylofin group and 6.02 minutes in drotaverine

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OBSTETRICS AND GYNECOLOGY Table 1. Age Distribution of Patients Age (years)

Camylofi

Table 3. Rate of Cervical Dilation in Centimeter/Hour Drotaverine

No.

15-20

21-25

20.6

14.3

49.2

61.9

26-30

30.2

Total

100.0

Mean ± SD

23.67 ± 2.94

100 90

No.

1-1.5

20.3

37.2

1.5-2.0

55.9

52.5

23.8

>2.0

23.7

10.1

100.0

Total

100.0

Mean ± SD

1.78 ± 0.31

100

Drotaverine

55.5

Percentage (%)

Camylofi

94.9

1.61 ± 0.28

Drotaverine 91.5

70 52.4

42.8

40 30

37-38 weeks

38-39 weeks Period of gestation

Induced

39-40 weeks

33.3

31.7

67.7

68.3

Camylofi

Drotaverine

40 30 20 10 0

Figure 2. Distribution of spontaneous and induced labor in study groups.

Table 2. Comparison of Duration of Stage 1, 2, 3 and Total Labor Among Patients Studied Variables (minutes)

Camylofi

Drotaverine

P value

Stage 1 labor (active phase)

332.54 ± 59.63

356.78 ± 68.93

0.142

Stage 2 labor

39.49 ± 11.21

36.78 ± 10.9

0.185

Stage 3 labor

5.39 ± 1.58

6.02 ± 2.01

0.062+

378.94 ± 63.22

394.75 ± 71.87

0.207

Total labor

30 8.4 1

5 No. of required

group but not statistically significant with p value of 0.062. The mean of total duration of labor was shorter in camylofin group (378.94 minutes) than in drotaverine group (394.75 minutes); not statistically significant (p = 0.207) (Table 2).

Not induced

70 60

Figure 3. Percentage of patients requiring 1 or 2 injections.

100 80

Figure 1. Period of gestation in study groups.

4.8

17.5

Percentage (%)

Drotaverine

160

Camylofi No.

23.25 ± 2.76

Camylofi

Cx rate (cm/hour)

Indian Journal of Clinical Practice, Vol. 26, No. 2, July 2015

Mean cervical dilatation rate was significantly more in camylofin group (1.78 cm/hour) as compared to the drotaverine group (1.61 cm/hour) with p = 0.002. Table 3 summarizes the rate of cervical dilation in study subjects. About 94.9% patients in camylofin group delivered after one injection; 5% required two injections. However, 91.5% of the patients in drotaverine group required two injections, and only 8.4% delivered after one injection (Fig. 3). Thus, significantly more number of injections were required for patients given drotaverine (p ≤ 0.001). The incidence of side effects are statistically similar in the two groups (p = 1.000). About 8.4% patients in each group developed side effects. One patient developed nausea, two patients developed vomiting and two patients developed dryness of mouth in camylofin group. Nausea, vomiting, headache, hypotension and fetal tachycardia were observed in one patient, respectively in the drotaverine group. Of note, mean induction delivery interval was significantly more in drotaverine group (228.38 minutes) as compared to the camylofin

OBSTETRICS AND GYNECOLOGY Table 4. Induction Delivery Interval in Minutes Camylofi

LSCS

Drotaverine

No.

<200

45.7

30.5

200-300

44.0

54.2

>300

10.1

15.2

Total

100.0

Mean ± SD

207.96 ± 53.90

228.38 ± 55.68

IDI: Induction delivery interval.

100 90 80 Percentage (%)

IDI (minutes)

6.3 6

17.5

60 50 40 30 20 10

Present

Nil

100

Camylofi

Mode of delivery

Drotaverine

Figure 5. Mode of delivery in the study groups.

27.1

80 Percentage (%)

6.3

Normal

Table 6. Comparison of Apgar Score of Neonates in Two Groups

70 60 50

Variables

40 30 20 10 0

Instrumental

Camylofi

Epidural

Camylofi

Drotaverine

P value

Apgar 1 (mean)

6.38 ± 0.705

6.43 ± 0.730

0.438

Apgar 5 (mean)

8.30 ± 0.585

8.35 ± 0.570

0.350

statistically significant; p = 0.424). Nearly 6.3% of patients in both groups had LSCS (two patients for nonprogression of labor and two patients for fetal distress in both groups, respectively) (Fig. 5).

Drotaverine

Figure 4. Percentage of patients receiving epidural.

Table 5. Comparison of Rate of Cervical Dilatation According to Presence/Absence of Epidural in Study Patients Rate of cervical dilatation

Camylofi

Drotaverine

P value

No epidural

1.80 ± 0.33

1.63 ± 0.29

0.010

Epidural

1.72 ± 0.25

1.53 ± 0.28

0.058

P value

0.406

0.307

group (207.96 minutes) with p = 0.045 (Table 4). Number of patients who received epidural was similar in both groups with p = 0.385 (27.1% camylofin; 22.0% drotaverine; Fig. 4). Rate of cervical dilatation was statistically similar in camylofin group irrespective of whether they received epidural or not (p = 0.406). Rate of cervical dilatation was statistically similar in drotaverine group irrespective of whether they received epidural or not (p = 0.307). Rate of cervical dilatation in camylofin group was more than drotaverine group irrespective of whether they received epidural (p = 0.058) or not (p = 0.010) (Table 5). About 17.5% in camylofin group had instrumental delivery, compared to 6% in drotaverine group (not

About 4% of patients in both groups experienced third stage complication (p = 1.00). In camylofin group, atonic postpartum hemorrhage (PPH) and vaginal tear were seen in two patients each. In drotaverine group, two patients had atonic PPH, one had third-degree perineal tear and one had cervical tear. Mean blood loss was statistically similar in the two groups (camylofin 257.62 ± 100.3; drotaverine 253.17 ± 98.34; p = 0.804). Mean Apgar at 1 and 5 minutes was statistically similar in both groups (Table 6). Mean birth weight was also statistically similar in the two groups with p = 0.428 (camylofin 2.85 ± 0.306 kg vs drotaverine 2.89 ± 0.347). DISCUSSION Both the groups were comparable with respect to the distribution of age of patients. The mean age in this study population was comparable to other studies, such as those by Sharma et al, Warke et al and Singh et al.1,2,5 The range of age of the patients in the present study was also comparable to the range taken in various other studies. Maximum number of patients belonged to the age group of 21-25 years in this study. This was comparable to several studies where maximum patients belonged to the age group of 20-25 years.

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161

OBSTETRICS AND GYNECOLOGY About 55.5% subjects in Group I and 52.4% in Group II were in 39-40 weeks of gestation. All the patients in both the groups belonged to 37-40 weeks of gestation period. In the study by Sharma et al,1 mean period of gestation was 38.8, 38.9 and 38.6 in drotaverine group, valethamate group and control group, respectively. In the study by Warke et al,2 the average gestational age was 39.1 weeks and 38.4 weeks in the camylofin and control group, respectively. In the study by Singh et al,5 mean gestational period was 39.36 in drotaverine group and 39.17 in the control group. The range of period of gestation of the patients in present study was comparable to the range taken in various other studies. In present study, the mean duration of active phase of labor was shorter in camylofin group (332.54 minutes) than in drotaverine group (356.78 minutes); however, the difference was not statistically significant with p value of 0.142. Singh et al5 noted in their study that the mean duration of active phase of labor was shorter in drotaverine group (265.44 minutes) than placebo group (312.32 minutes). Similarly, Sharma et al1 demonstrated that the mean duration of active phase of labor was shorter in drotaverine group (194 minutes) than valethamate bromide group (220.7 minutes). Warke et al2 demonstrated that the mean duration of active phase of labor was shorter in camylofin group (3 hours, 35 minutes) than placebo group (5 hours, 34 minutes). While there are no studies on comparison between camylofin and drotaverine for cervical dilatation, individual studies on the two agents are available. However, the result of present study was not comparable with other studies, as the mean duration of active phase of labor in drotaverine group in other studies was between 2.7 and 4.4 hours and the present study demonstrated it to be 5.9 hours. The mean duration of active phase of labor in camylofin group in other studies was 3-5 hours, but in the present study it was 5.5 hours. Nearly 94.9% patients in camylofin group delivered after one injection, whereas only 8.4% in drotaverine group delivered after one injection. In a study by Sharma et al,1 66% of patients in drotaverine group delivered with two injections. Warke et al2 gave camylofin injection as intramuscular single dose to all patients in their study group. Thus, the present study was comparable with respect to the number of injections required in both groups. In the present study, mean cervical dilatation rate was significantly more in camylofin group (1.78 cm/hour) than drotaverine group (1.61 cm/hour). Mean cervical dilatation rates are comparable in the present study and in the study by Warke et al2 for the camylofin group. However, the dilatation rates in the present study and other such studies are not comparable for

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drotaverine. The mode of delivery in the present study was comparable to that in other studies. The incidence of third stage complications in this study was similar to that in other studies. The present study revealed that both the drugs were free from fetal side effects and appeared to decrease perinatal mortality and morbidity by decreasing the duration of labor. CONCLUSION The following conclusions were drawn from this study: Â

The duration of active phase of labor was shorter in camylofin group than drotaverine group, but it was not statistically significant (332.54 minutes vs 356.78 minutes; p = 0.142). Rate of cervical dilatation was more in camylofin group than drotaverine group, which was statistically significant (1.78 cm/hour vs 1.61 cm/ hour; p = 0.002). Induction delivery interval was significantly more in drotaverine group than in camylofin group (228.38 minutes vs 207.96 minutes; p = 0.045). No major maternal or fetal side effects were observed.

Therefore, in modern obstetrics, no woman should be made to suffer in pain and agony of labor. Drugs which hasten labor should be embraced by both obstetrician and the laboring mother. The two drugs studied were effective in shortening the duration of labor. Intramuscular camylofin dihydrochloride was more efficacious than intravenous drotaverine hydrochloride in shortening the duration of labor. REFERENCES 1.

Sharma JB, Pundir P, Kumar A, Murthy NS. Drotaverine hydrochloride vs. valethamate bromide in acceleration of labor. Int J Gynaecol Obstet. 2001;74(3):255-60.

Warke HS, Chauhan AR, Raut VS, Ingle KM. The efficacy of camylofin dihydrochloride in acceleration of labor. A randomized double blind trial. Bombay Hospital Journal. [online] Available from http://www.bhj.org.in/ journal/2003_4503_july/theefficacy_420.htm [Accessed May 7 2015].

Percival R, Holland, Brews. Normal labour. In: Daftary SN, Chakravarti S (Eds.). Manual of Obstetrics, 5th Edition. New Delhi: India, B.I. Churchill Livingstone; 1993. pp. 325-8.

Cunningham FG, Mac Donald PC, Gant NF, Leveno KJ, Gilstrap LC, Nankins GDV, et al. Dystocia abnormalities of the expulsive forces. Williams Obstetrics, 23rd Edition. Appleton and Large; 1997.pp. 415-32.

Singh KC, Jain P, Goel N, Saxena A. Drotaverine hydrochloride for augmentation of labor. Int J Gynecol Obstet India. 2004;84(1):17-22.

OBSTETRICS AND GYNECOLOGY

Pregnancy with Anemia and Severe Thrombocytopenia: Case Series KAVITA AGARWAL

ABSTRACT In pregnancy, severe thrombocytopenia occurs commonly and may result from diverse etiologies. However, it is rarely caused by megaloblastic anemia. Three pregnant women with severe thrombocytopenia, anemia and normal red blood cell indices were proven to have megaloblastic anemia and are being reported.

Keywords: Megaloblastic anemia, thrombocytopenia, pancytopenia, pregnancy

CASE 1 Mrs X, 21 years old, G2P1L1 with 37+5 weeks gestation was admitted with severe anemia and bleeding gums. On admission, hemoglobin (Hb) was 4.5 g/dL, total leukocyte count (TLC) 1,700/mm3, platelet count 17,000/mm3, red blood cell (RBC) indices were normal, peripheral smear showed dimorphic anemia and lactate dehydrogenase (LDH) was 2,000 IU/L. Even after 4 units packed cells and 10 units platelet rich plasma (PRP), there was further fall in Hb, TLC and platelet count (4.1 g/dL, 1,000/mm3 and 10,000/mm3). Bone marrow aspiration revealed megaloblastic anemia. Vitamin B12 and folic acid levels were found to be very low, 1.09 pg/mL (normal range 180-914 pg/mL) and 2.3 ng/mL, (normal range 3.5-20 ng/mL), respectively. CASE 2 Mrs Y, 24 years old, G2P1L1 with 33+4 weeks gestation was admitted with complaints of swelling all over the body for 5-6 days. On admission, Hb was 3.4 g/dL, TLC 3,600/mm3, platelet count 11,000/mm3, RBC indices were normal, peripheral smear showed dimorphic anemia and LDH was 1,600 IU/L. Even after 7 units PRP, platelet counts dropped to 2,000/mm3. Bone marrow aspiration

showed megaloblastic anemia, vitamin B12 levels were normal but folic acid levels were significantly reduced (1.12 ng/mL). Both cases received intravenous vitamin B12, folic acid and iron sucrose, rise in platelet count was seen in 3-4 days (Tables 1 and 2). CASE 3 Mrs Z, 27 years old, G2P1L1 with 9 months amenorrhea was admitted in labor room with mild pre-eclampsia, severe anemia in active labor. On admission, Hb was 6.9 g/dL, TLC 3,700/mm3, platelet count 17,000/mm3, Table 1. Hematological Profile Before and After Treatment (Case 1) Investigations Hb (g/dL)

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After 8 days of treatment

4.1

8.8

TLC (mm3)

1,000

11,700

Platelet count (mm3)

10,000

2,07,000

Table 2. Hematological Profile Before and After Treatment (Case 2) Investigations

Assistant Professor Dept. of Obstetrics and Gynecology Safdarjung Hospital, New Delhi Address for correspondence Dr Kavita Agarwal 92, Vrindavan Apartment, Gali No. 4, Krishna Nagar Safdarjung Enclave, New Delhi - 110 029 E-mail: drku93@gmail.com

Before treatment

Hb (g/dL) TLC

(mm3)

Platelet count (mm3)

Before treatment

After 5 days of initiation of therapy

After 11 days of initiation of therapy

3.4

7.0

7.9

3,600

9,600

11,000

2,000

84,000

2,78,000

OBSTETRICS AND GYNECOLOGY Table 3. Hematological Profile Before and After Treatment (Case 3) Investigations Hb (g/dL)

Before treatment

After 9 days of initiation of therapy

6.9

8.0

TLC (mm3)

3,700

9,600

Platelet count (mm3)

17,000

3,69,000

RBC indices were normal, peripheral smear showed dimorphic anemia and LDH was 1,502 IU/L. Serum folic acid levels were low. She delivered vaginally within 4 hours of admission. There was no postpartum hemorrhage. Learning the lesson from previous two cases, platelet transfusions were not given and intravenous vitamin B12, folic acid and iron sucrose was started without bone marrow aspiration. On Day 9 of treatment, platelet count was 3,69,000/mm3 (Table 3). All pregnancies were unsupervised; women were mainly vegetarian with low intake of dairy products. All patients were discharged on dietary advice, oral iron and folic acid. DISCUSSION Over the last two to three decades, incidence of megaloblastic anemia seems to be increasing. Of the two micronutrients, vitamin B12 deficiency is five times more common than that of folic acid.1 Megaloblastic anemia

usually presents with complaints ascribed to anemia and thrombocytopenia.2 Bleeding manifestations are seen in 17-20% cases of megaloblastic anemia3 and a case of unilateral macular hemorrhage as the only presentation of megaloblastic anemia in pregnancy has also been reported.4 Increased LDH values suggest intramedullary hemolysis due to ineffective erythropoiesis.5 Severe vitamin B12 deficiency can cause pancytopenia with a normal mean cell volume (MCV). Peripheral smear should be evaluated in cases of thrombocytopenia associated with anemia or pancytopenia, independent of MCV value.5 Administration of B12 and folic acid reduces number of blood and platelet transfusions, avoids invasive procedure like bone marrow aspiration and response to therapy is dramatic. REFERENCES 1.

Chandra J. Megaloblastic anemia: back in focus. Indian J Pediatr. 2010;77(7):795-9.

Khanduri U, Sharma A. Megaloblastic anaemia: prevalence and causative factors. Natl Med J India. 2007;20(4):172-5.

Gomber S, Kela K, Dhingra N. Clinico-hematological profile of megaloblastic anemia. Indian Pediatr. 1998;35(1):55-8.

Haddadin AA, Shammas AG, Maayah JF. Unilateral macular hemorrhage as the only presentation of megaloblastic anemia in pregnancy. Saudi Med J. 2000;21(9):880-1.

Sekhar J, Stabler SP. Life-threatening megaloblastic pancytopenia with normal mean cell volume: case series. Eur J Intern Med. 2007;18(7):548-50.

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Cell-free Fetal DNA Testing Warrants Caution, Committee Says The Committee on Genetics of the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine has released an opinion on the “advantages and limitations” of cell-free DNA screening for fetal aneuploidy in the general obstetric population, published online June 26. “We have tried to produce guidelines for reasonable application of the screen, underscoring that more information can be gained from conventional screening,” Nancy C Rose, MD, director, Reproductive Genetics, Intermountain Healthcare; professor of obstetrics and gynecology at the University of Utah, Salt Lake City; and a member of the committee that drafted the opinion, told Medscape Medical News.

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ONCOLOGY

Stereotactic Radiosurgery and Fractionated Stereotactic Radiotherapy in Patients with Single Brain Metastasis MEENA J SHAH*, RAKESH K VYAS†

ABSTRACT Objective: The objective of this study was to analyze the outcomes of stereotactic radiosurgery (SRS) and stereotactic radiotherapy (SRT) using X-knife. Material and methods: From March 1998 to December 2001, 30 patients with brain metastasis were treated with X-knife at Gujarat Cancer and Research Institute, Ahmedabad. Twenty patients were treated with SRS, while SRT was selected for 10 patients that were >3 cm or in close proximity to critical structures. However, selection of treatment technique (SRS/SRT) was based not only on tumor factors, such as tumor size, shape and location, but also on patient preference. In SRS, dose of 13-15 Gy was delivered in single fraction and in SRT, the prescribed dose of 30 Gy was delivered in 10 fractions. Results and complications: Complete response was achieved in 13/20 (65%) patients in SRS arm and 7/10 (70%) patients in SRT arm, while 7/20 (35%) patients in SRS arm and 3/10 (30%) patients in SRT arm achieved partial response. There were no significant difference in local control and complications between treatment schedules. Conclusion: SRS is a well-known modality for treating solitary brain metastasis. SRT is a noninvasive procedure and is well-tolerated. It leads to good local tumor control and can be practiced by radiation oncologists without help of neurosurgeons. However, optimal fractionation schedule is still controversial and practicality of using SRS and SRT varies according to level of experience of institution.

Keywords: Stereotactic radiosurgery, stereotactic radiotherapy, brain metastasis

rain metastases represent a significant cause of morbidity and mortality among cancer patients. The cornerstones of treatment are surgery (S), whole brain radiotherapy (WBRT) and stereotactic radiosurgery (SRS).1 Stereotactic radiotherapy (SRT) has been recognized as alternative to surgery in patients with solitary brain metastasis. Many authors have reported efficacy of SRS to obtain local control (LC).2-4 The addition of SRS to WBRT may improve median survival and intracranial tumor control when compared to WBRT alone in select patients.5,6 Additionally, SRS is increasingly being used as a primary treatment

*Associate Professor Dept. of Radiation Oncology Government Medical College and New Civil Hospital, Surat, Gujarat †Incharge Director Dept. of Radiation Oncology Gujarat Cancer and Research Institute, Ahmedabad, Gujarat Address for correspondence Dr Meena J Shah B-404, Arjun Complex, Opp. Ratnadeep Society Behind Police Tenament, Bhatar-Althan Road, Surat - 395 017, Gujarat E-mail: drmeena.maheshwari@gmail.com

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modality in attempts to prevent or delay the known neurocognitive toxicities of WBRT.7 The main prognostic factors for patients with brain metastases are Karnofsky performance status (KPS) (≥70 vs. <70), age (<65 vs. ≥65 years), control of primary tumor, absence of extracranial metastases and number of brain lesions. However, fractionated SRT seems more appropriate with increase in tumor size and in lesions with close proximity to critical structures (optic chiasma, cochlea or brainstem) as fractionation provides radiobiological advantage over single dose SRS.8 Another radiobiological advantage with fractionated radiotherapy is derived from differences in α/β ratio between tumor and normal tissue; it is usually assumed that α/β ratio is 2-3 Gy for normal brain tissue and up to 10 Gy for malignant tumors. It is worth noting that most of the patients treated for brain metastases die of extracranial disease.9 This is an important consideration because, although most studies have used overall survival as the main endpoint, survival is probably not the best parameter to measure the efficacy of the existing therapeutic modalities.10

ONCOLOGY MATERIAL AND METHODS X-knife was installed on 3rd March 1998 at Dept. of Radiotherapy, Gujarat Cancer and Research Institute, Ahmedabad. From March 1998 to December 2001, 30 patients underwent Linac-based SRS/SRT and were included in this study. Prior to treatment, complete history and physical examination including neurological examination was performed on all patients before treatment. For a patient with a small to medium-sized tumor, SRS was usually offered. Metastasis >3 cm in diameter and/or in close proximity to critical structures were typically not considered acceptable candidates for single fraction radiosurgery. However, dose fractionations for SRT were selected based not only on tumor factors, such as tumor size, shape and location, but also on individual patient preference. There were 9 males and 11 females in SRS arm and 6 males and 4 females in SRT arm. The eligibility criteria for SRS/ SRT were as follows: (1) maximum tumor diameter ≤4 cm; (2) no cerebrospinal fluid dissemination; (3) control of primary tumor; (4) absence of extracranial metastasis; (5) no concurrent chemotherapy and (6) single brain metastasis. Evaluation of tumor control and complications were recorded accordingly. RADIATION TECHNIQUE The SRS/SRT techniques in this study were performed with the linear accelerator-based system (6 MV modified Linac [SL-20 Philips] with fixed circular collimators 12.5-40 mm diameter, 2.5 mm steps with X-knife planning system version 4 [radionics couch mounted radiosurgery system]). In the SRS technique, the Brown-Robert-Wells (BRW) stereotactic frame was applied with the assistance of a neurosurgeon. This differs from the SRT technique in which the relocatable Gill-Thomas-Cosman (GTC) frame was applied and bite block was used to reproduce the same exact position between fractions. Individual treatment planning was done in a work-station using an image set from a contrast-enhanced CT scan of 1.25 mm slice thickness (transferred to treatment planning computer through network (PACS). Target and critical organ contouring was done by radiation oncologists, and a treatment plan was generated by medical physicists. A median total margin for GTV to PTV expansion was 2 mm (range 0-10 mm). Tolerance of the discrepancy between the radiation iso-center and the patient isocenter was <1 mm. The GTC depth helmet was used to evaluate the accuracy of the repositioning of the patient relative to the CT position. Measurements at

26 directions were recorded during the initial CT scan. For each fraction, these measurements were repeated and compared with the initial measurement. The tolerance for the setup error was 2 mm between the pretreatment and the initial measurements. The collimator size that covered at least 90% of the target volume was selected. Multiple iso-centers were used in irregularly shaped targets. Arc selection (3-6) was performed, and was mainly noncoplanar. In SRS technique, the prescribed dose was be 13-15 Gy in single fraction for a small lesion (≤3 cm) at 80-90% isodose line to the tumor margin. The median maximum diameter was 1.7 cm (range, 0.8-3). SRT with the prescribed dose of 30 Gy in 10 fractions was delivered in large lesions near critical organs (prescribed at 90% isodose line). The maximum tumor diameter was 4 cm. Every effort was made to achieve the best possible plan with respect to desired dose delivery to the target and minimal dose to the critical structures. RESULTS AND COMPLICATIONS All patients were seen at 4-6 weeks after completing treatment for a first follow-up visit, then every 2-3 months with maximum follow-up of 1 year. Thirteen (65%) patients in SRS arm had complete response and seven (35%) patients had partial response. In SRT arm, seven (70%) patients had complete response and three (30%) patients had partial response. There were no acute adverse events of Grade 3 or higher in both arms. Overall 10/30 patients experienced immediate side effects within 2 weeks. Most of these were mild and consisted of headache in 5, nausea in 2, vertigo/ dizziness in 1 and seizures in 2 patients. Only one patient had Grade 2 nausea during treatment. There were no acute adverse events of Grade 3 or higher in both arms. The late adverse events were Grade 2 neurologic dysfunction observed in 2 patients. There was no radiation necrosis in both arms with our limited sample size and with short follow-up. DISCUSSION In the present study, we evaluated the clinical outcome and the treatment-related complications in 30 patients of brain metastasis treated with SRS/SRT. Based on the present results and published data, SRS alone as initial treatment strategy in patients with either single or multiple metastases is a feasible therapeutic option associated with high local control although the superiority of SRS versus other treatment options in terms of improved survival remains to be demonstrated.

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ONCOLOGY In previous studies, single-fraction SRS for brain metastases yielded 12-month LC rates of about 80%.11,12 A recent study reported LC rate of 92%, but severe neurological complications (Radiation Therapy Oncology Group (RTOG) Grade 3 and 4) occurred in 5.8% of the patients.13 The reported risk of radionecrosis after SRS is variable in the published series depending on different radiosurgical techniques, type of lesion treated, length of follow-up and patientâ&#x20AC;&#x2122;s selection. Research indicates that SRT may be as effective as surgery for the treatment of some patients with brain metastases.14 A review of outcomes from patients with a single brain metastasis treated at the Mayo Clinic indicates that 56% of patients who received SRT and 62% patients treated with surgery lived 1 year or more after treatment, a difference that was not statistically significant. Furthermore, tumor control was better for the patients treated with SRT. None of the patients who received SRT had local recurrence of cancer, compared to 58% patients treated with surgery. The use, safety and efficacy of hypofractionated SRT is supported by previously published series with short-term follow-up and varying radiation dose and fractionation schedules described. However, data reporting long-term outcomes is limited and the optimal dose-fractionation schedule for HR (hypofractionated radiotherapy) is undefined. Some studies of SRT are listed in Table 1.

metastasis. We found fraction dose was not statistically significant factors with regard to local tumor control with our limited sample size. We also confirmed that tumor size is a strong prognostic factor for local tumor control. Large lesions at high-risk of radiation-induced complications especially when located in/near eloquent areas should be considered for SRT. CONCLUSIONS SRS is well-known modality for treating brain metastasis. SRT is noninvasive procedure and is welltolerated. It leads to good local tumor control and can be practiced by radiation oncologists without help of neurosurgeons. Optimum dose and fractionation has to be decided according to merits of tumor. We believe that there is a need for a larger prospective study to establish dosing guidelines for SRT and for a randomized trial to compare single-fraction SRS with a hypofractionated SRT approach.

Acknowledgments The authors are grateful to the whole team of SRS/SRT for their valuable help in this study.

REFERENCES 1.

In the current study, we found SRT to be comparable to single-fraction SRS in terms of local tumor control and toxicity, and thus we believe it provides an alternative treatment choice for patients with single brain

MĂźller-Riemenschneider F, Bockelbrink A, Ernst I, Schwarzbach C, Vauth C, von der Schulenburg JM, et al. Stereotactic radiosurgery for the treatment of brain metastases. Radiother Oncol. 2009;91(1):67-74.

Table 1. Prospective Studies of Large Brain Metastasis Treated with Fractionated SRT

Aoyama H, Shirato H, Tago M, Nakagawa K, Toyoda T, Hatano K, et al. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases. JAMA. 2006;295(21):2483-91.

Mehta MP, Tsao MN, Whelan TJ, Morris DE, Hayman JA, Flickinger JC, et al. The American society for therapeutic radiology and oncology (ASTRO) evidence-based review of the role of radiosurgery for brain metastases. Int J Radiat Oncol Biol Phys. 2005;63(1):37-46.

Sanghavi SN, Miranpuri SS, Chappell R, Buatti JM, Sneed PK, Suh JH, et al. Radiosurgery for patients with brain metastases: multi-institutional analysis, stratified by the RTOG recursive partitioning analysis method. Int J Radiat Oncol Biol Phys. 2001;51(2):426-34.

Andrews DW, Scott CB, Sperduto PW, Flanders AE, Gaspar LE, Schell MC, et al. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet. 2004;363(9422):1665-72.

Kondziolka D, Patel A, Lunsford LD, Kassam A, Flickinger JC. Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with

Study

Med volume (cm3)

KPS

Multiple lesions (%)

MS (mo)

Alexender (1995)

9.4

Auchter (1996)

Breneman (1997)

Shiou (1997)

1.3

Shirato (1997)

>2 cm:36%

Pizhall (1998)

5.5

Kim (2000)

2.1

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ONCOLOGY multiple brain metastases. Int J Radiat Oncol Biol Phys. 1999;45(2):427-34. 7.

Chang EL, Wefel JS, Hess KR, Allen PK, Lang FF, Kornguth DG, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol. 2009;10(11):1037-44.

Hall EJ, Brenner DJ. The radiobiology of radiosurgery: rationale for different treatment regimes for AVMs and malignancies. Int J Radiat Oncol Biol Phys. 1993;25(2):381-5.

Khuntia D, Brown P, Li J, Mehta MP. Whole brain radiotherapy in the management of brain metastases. J Clin Oncol. 2006;24(8):1295-304.

11. Chen JC, Petrovich Z, O’Day S, Morton D, Essner R, Giannotta SL, et al. Stereotactic radiosurgery in the treatment of metastatic disease to the brain. Neurosurgery. 2000;47(2):268-79. 12. Hasegawa T, Kondziolka D, Flickinger JC, Germanwala A, Lunsford LD. Brain metastases treated with radiosurgery alone: an alternative to whole brain radiotherapy? Neurosurgery. 2003;52(6):1318-26. 13. Minniti G, Clarke E, Lanzetta G, Osti MF, Trasimeni G, Bozzao A, et al. Stereotactic radiosurgery for brain metastases: analysis of outcome and risk of brain radionecrosis. Radiat Oncol. 2011;6:48.

14. Auchter RM, Lamond JP,Alexander E, Buatti JM, Chappell R, Friedman WA, et al. A multi-institutional outcome and 10. Berk L. An overview of radiotherapy trials for the prognostic factor analysis of radiosurgery for resectable treatment of brain metastases. Oncology (Williston Park). single brain metastasis. Int J Radiat Oncol Biol Phys. 1995;9(11):1205-12: discussion 1212-6, 1219, 1996;35(1):27-35. ■■■■

Longevity in Advanced Cancer Attributed to Relationships Relationships trump treatment when it comes to beating the odds in advanced cancer, at least according to one small group of patients who have far outlived their prognoses. Fifteen patients with advanced lung or pancreatic cancer attributed their longevity to their relationships with their doctor and their family, rather than the type of treatment they received. An article outlining their cases was published online in Future Oncology. Although most of the patients in this small cohort used some form of complementary and alternative medicine, they did not consider it to be a main cause of their survival. Rather, the main recurrent themes in most of the interviews were patient-doctor communication, family support, and the patient’s proactive attitude in accounting for their remarkable survival.

Single-dose Anti-emetic Reduces Chemotherapy-induced Nausea A single IV dose of fosaprepitant helped reduce chemotherapy-induced nausea and vomiting in a new phase III trial. Adding the neurokinin-1 (NK1) receptor antagonist to ondansetron and dexamethasone produced a roughly 10% better response compared to the two other drugs alone among patients on moderately emetogenic chemotherapy, according to findings presented May 30 in a poster at the American Society of Clinical Oncology meeting in Chicago.

Statins and Lower Cancer Mortality: Risk Cut by Up to a Half Statin use is associated with a significant reduction in cancer mortality, conclude two separate studies, one in women, the other in men. Both were presented here at the American Society of Clinical Oncology (ASCO) 2015 Annual Meeting. Specifically, statin use was associated with a 22% reduction in deaths from various cancer types in women and a 55% reduction in deaths from bone/connective tissue cancers. The study in men looked at statin use together with the antidiabetes medication metformin and found a 40% reduction in prostate cancer mortality, with the effect more pronounced in men with obesity/metabolic syndrome.

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PEDIATRICS

Pediatric Syrup Caps: How Safe? Contamination and Pediatric Dosing Concerns with Syrup Caps– CAPCONS Study VARSHA NARAYANAN*, GANESH KADHE†, APARNA JAIRAM‡

ABSTRACT Introduction: Currently, no standard practice or recommendation is available for cleaning or sterilizing the syrup caps. With an objective to understand the hygiene practice followed by parents with regard to the use of pediatric syrup caps, a market research study was conducted. Methods: The details of children recently prescribed syrups for various conditions were collected and the parents/guardians were interviewed using a specifically designed 10 point questionnaire. The syrup caps were collected and sent for bacterial analysis. A detailed report on the hygiene practices followed by the parents on syrup caps was prepared. Results: A total of 500 subjects were interviewed. Washing the caps with tap water was the preferred method used to clean the cap before use (80%). After the use, majority of subjects used tap water (78%) for washing followed by boiling (17%), purified water (5%) and others (1%). Among all the caps washed with tap water, 2% had serious contaminants and 82% showed Bacillus only; while among those who boiled, none had any contamination. The contamination with a significant organism capable of causing human infection was found in 9.4% caps. Bacillus was observed in 81.4% (407/500) of caps. The contamination with Bacillus was more when the subjects had put back the cap on the syrup bottle (83.3%). Conclusion: Our findings suggest that syrup caps for pediatric use can be contaminated if not properly sterilized; hence a standard hygiene protocol or alternatives to caps must be designed for better and hygienic mode for syrup administration.

Keywords: Contamination, Bacillus, syrup caps

edicines in form of syrup are in use since 1976.1 Syrup caps are commonly used to administer medicines to children. Most of the syrups given to children are sweet and sticky due to sugar base in order to aid compliance.2,3 The left over syrup droplets on the caps or the sides of the bottle lids might serve as a source of microbial contamination. Scarce information is available about the magnitude of this contamination and the effects per se. Bacteria like Bacillus which are environmentally widely distributed are a common cause of contamination.4,5 The strains

*Senior Medical Advisor †AVP, Medical Affairs Wockhardt Ltd., Wockhardt Towers Bandra Kurla Complex, Mumbai, Maharashtra ‡Chief of Operations and Immunology SRL Labs, Udyam, Ranade Road, Shivaji Park, Mumbai, Maharashtra Address for correspondence Dr Varsha Narayanan Senior Medical Advisor Wockhardt Ltd., Wockhardt Towers, Bandra Kurla Complex, Mumbai - 400 051, Maharashtra E-mail: vnarayanan@wockhardt.com

of Bacillus including Bacillus subtilis are strongly proteolytic and the main producers of the food spoilage enzymes.6 Microbial infections are not only caused by the presence of microorganisms alone but also by their metabolites or toxins released, which are harmful even if present in minute quantity.7 A potential infection hazard may be caused by organisms transferred through fingers and other surfaces; e.g., a stainless steel bowl or a clean laminate surface.8 There is a lack of awareness about maintaining adequate hygiene for the syrup caps. Currently, no standard practice or recommendation is available for cleaning or sterilizing the syrup caps to maintain hygiene. Further, dosing errors by parents are highly prevalent with caps compared with droppers, calibrated spoons or syringes.9 At present, no data is available to understand the hygiene practices followed by parents while using syrup caps and presence of contaminants, if any following these hygiene practices. We conducted a market research study to understand the hygiene practice followed by parents with regard to the use of pediatric syrup caps.

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PEDIATRICS METHODOLOGY

Study Population The pediatricians from 10 Indian cities viz. Ahmedabad, Bangalore, Bhubaneswar, Cochin, Coimbatore, Delhi, Jaipur, Mumbai, Mysore and Patna were identified. Around 25% of the children were <2 years of age, 40% were between 2-4 years and 35% were â&#x2030;Ľ4 years. Around 60% children were from urban areas and 20% each from semi-urban and rural areas.

Analysis of the Objective This was a survey with the objective to study and understand hygienic and dosing practices of various populations with regard to syrups and assess the contamination status of the syrup caps. The percentage of syrup caps showing microbiological contamination was assessed. Laboratory analysis of these bacteria was done to correlate the contamination to the kind of cleaning and hygienic practices assessed through a questionnaire. The caps were analyzed for general contamination with B. subtilis and serious contaminants including Klebsiella pneumoniae, Acinetobacter baumanni, Escherichia coli, Pseudomonas aeruginosa, Serratia and Enterococcus faecalis.

Study Design and Procedure The present study of 500 patients was a market research study. An initial pilot study was conducted in two cities with a total population of 50 to validate the questionnaire, assess the microbiological contamination rate and help in calculating sample size for the main study. The questionnaire was validated with feedback from the interviewer and the parents with respect to ambiguity/clarity of questions and ease in answering and inclusion of any other information, which the parent desired to give. Only after validating the questionnaire for consistency and clarity in responses, questionnaire was adapted for the final study. Ethics Committee opinion and approval was taken for the study. The database which included only name and contact number of the patients who had been prescribed syrups for various causes was taken in the most confidential manner from the pediatricians in each of the 10 cities. The parents of the subjects were contacted first on telephone and their consent and approval was taken after explaining nature of the survey and questionnaire. Thereafter, it was ascertained from the parent as to when will the course of their syrup prescription be over and accordingly

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suitable appointment was taken from the parent. At the visit, the parent filled out the questionnaire and the syrup caps were collected in a sterile container and sent to a diagnostic laboratory (SRL Diagnostics) in each city for bacterial analysis. A common protocol was followed for the collection and transfer of caps and evaluation of contaminants. To maintain confidentiality, a specific code was given to each questionnaire and the sterile container in which the cap was sent. Information was sought regarding the name/brand of the medicine, dosage schedule, condition or indication of syrup prescribed, frequency of children requiring syrup, etc. The data on the questionnaire was recorded and analyzed and a detailed report on the hygiene practices followed by the parents on syrup caps was prepared.

Statistical Analysis The sample size was calculated by assuming 90% expected cases of bacterial growth with 3% margin of error and 95% confidence interval (CI). Based upon these assumptions, the sample size was estimated to be 385. The sample size of 500 was considered to estimate bacteria growth prevalence with high precision and to perform exploratory statistical analysis. The formula used to calculate the sample size (N) was [Z2 * p (1-p)] /d2 where N is sample size, Z is statistic for 95% level of confidence (Z = 1.96), p is expected proportion of bacteria growth (0.90), d is margin of error (0.03). The proportions of cases with bacteria growth and serious bacteria growth were calculated with associated 95% CI. The association between storage method, cleaning methods, class (urban, semi-urban and slum) and the contaminantsâ&#x20AC;&#x2122; growth was tested for statistical significance using Chi-squared test. RESULTS

Subjects A total of 500 subjects were interviewed (10% from each city).

Condition/Indication of the Syrup Prescribed The pediatricians had prescribed around 34 different types of medicines. The syrup was majorly prescribed to the subjects having cough (38%); followed by fever (26%) and cold (18%). The frequency of a disease in majority of children was four times a year. The maximum dose recommended by the pediatricians was <2 mL (49%), 3 times a day (51%) and for 1-5 days (54%).

PEDIATRICS Overall, 92% of subjects were comfortable with the usage of the caps for administering syrup.

with Bacillus growth was observed when the subjects had put back the cap on the syrup bottle (83.3%).

Microbial Contamination

Organisms Detected vs. Method Used to Clean the Syrup Cap Before the Next Usage

Amongst all the caps analyzed, contamination with a significant organism capable of causing human infection was found in 9.4% caps. Bacillus was observed in 81.4% (407/500) of caps. The proportion of observed bacterial growth was 91% (95% CI: 88.49%, 93.51%). The proportion of observed serious contaminant growth was 2.4% (95% CI: 1.06%, 3.74%).

The percentage of subjects who washed the cap before the next usage was 94% (80%: tap water, 3%: boiling, 17%: purified water). Among all the caps washed Table 1. Response to the Questionnaire Asked During Study

Methods of Cleaning Caps Before and After Use

Questions

Table 1 shows the response of the subjects to the questionnaire asked during the study. Washing the caps with tap water was the preferred method used to clean the cap before use (80%). Majority of subjects used tap water (78%) for washing caps after use followed by boiling (17%), purified water (5%) and others (1%). Around 21% subjects mentioned that the calibrated spoon was hygienic and easy to use, while 7% of the respondents were looking for a better option for syrup administration.

Yes (%) No (%)

Was the overall cap usage comfortable?

Any difficult in reading the markings on the cap. When the cap was empty?

When the cap was filled with syrup

Cap kept at eye level while filling the syru

Left over syrup in cap after pouring in childâ&#x20AC;&#x2122;s mouth

Spillage encountered while giving to child

Was cap cleaned immediately after use?

Organisms Detected vs. Methods of Storing Caps After Use (Fig. 1)

Was cap cleaned again before giving the next dose?

After cleaning, 72% subjects put back the cap on the bottle, 15% subjects kept the cap in open and 3% subjects kept the cap in a closed space (drawers, cupboards, etc.) along with other kitchen articles. Only 9% subjects kept the cap in a fridge and 1% in a specific and separate box/closed container. More contamination

Preference on an alternate mode of giving the syrup like the calibrated spoon shown

Would you be happy if you were informed about a standard way of maintaining hygiene of the cap/spoon along with the information on the syrup?

Bacillus

No growth

Other organism

100 90 80

Serious contamination 91.1

83.3

80 72.4

No. of patients (%)

70 60

53.3

50 40 30

26.7 17.1

20 10 0

8.1 6.4

13.3

9.2 2.2

Put back on the bottle

1.3 Kept in open

20 6.7

0 4.4 4.4

Kept in closed space/ covered Method of storage

Kept in fridge

Kept in box

Figure 1. Contamination vs. methods of storing caps after use.

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PEDIATRICS with tap water, 2% had serious contaminants and 82% showed Bacillus only; while among those who boiled, none had serious contaminants.

Organisms Detected vs. Socioeconomic Class (Urban, Semi-urban and Slum) The association between class and bacteria growth was statistically significant (p < 0.05). More Bacillus growth (253/300) was observed in the syrup caps used in the urban class. The percentage of serious contaminants was more in the caps used by semi-urban (3%) and slum (3%) class compared to the urban class (2%). DISCUSSION Administering medications to children with syrup caps is a common practice. In the present study, children were receiving medications for cough, fever, cold, vomiting, dehydration, weakness, etc. Other studies have also identified cough as the most common problem in the children especially of preschool age.10,11 Mugoyela et al conducted a study on microbial contamination of nonsterile pharmaceuticals in public hospital settings and reported that all the tested products were microbiologically contaminated with half of the tested products heavily contaminated predominantly with Klebsiella, Bacillus and Candida species. Of the tested tablets and other formulations, cough syrups were the most heavily contaminated with a bacterial load of 6.0 Ă&#x2014; 103 cfu/mL.12 Further, when tested for antibiotic sensitivity, the isolated Bacillus and Klebsiella species were resistant to most of the antibiotics. Though, some previous studies have recognized and tested pharmaceutical products for microbial contamination and the related health hazards,13,14 hardly any study has tried to study the mode of administration of drugs and associated contamination. The present study was a market research survey that showed that the large percentage of syrup caps used to administer medicine to children was contaminated most frequently with Bacillus. B. subtilis is a common contaminant found in dust and soil. These aerobic spore-forming bacteria produce heat-labile cytotoxic substances and have important spoilage and/or toxigenic potential.6 In addition, we also observed serious contaminants like K. pneumoniae, A. baumanni, E. coli, P. aeruginosa, Serratia and E. fecalis in the caps. These serious contaminants can cause various healthcare-associated infections. Acinetobacter causes a variety of diseases, ranging from pneumonia to serious blood or wound

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infections.15 E. coli can cause diarrhea or illness outside of the intestinal tract.16 Klebsiella can cause pneumonia, bloodstream infections, wound or surgical site infections and meningitis.17 P. aeruginosa causes ear infections, especially in children and skin rashes.18 P. aeruginosa also causes infections in immunocompromised patients.19 The presence of these contaminants underscores the need of proper handling of the syrup caps and awareness among the users about the hygienic practices associated with their use. In order to minimize the risks caused by these contaminants, it is necessary to follow proper hygienic procedures. But, there is a paucity of information and nonavailability of a standardized protocol for cleaning the syrup caps. In our study, we observed that all the respondents followed their own hygiene practices with regards to syrup caps usage. Majority of subjects used tap water for cleaning the syrup caps; consequently more contamination was found in those caps. In a recent study by de Abreu et al, bacterial species like P. aeruginosa, and E. faecalis that are the major agents for nosocomial infections, were isolated from tap water.20 In another study by Flores Ribeiro et al Pseudomonas spp. were isolated from the tap drinking water produced from karstic hydrosystems.21 Ahmad et al analyzed the quality of drinking water from different sources like hand pumps, tube wells and tap water and, observed P. aeruginosa (26.67%) and K. pneumoniae (40%) as the most common contaminants. These species also showed greater multiple antibiotic resistances.22 Sterilization of the caps through boiling was followed by a miniscule of the subjects. Boiling of the heatresistant items in water helps in reducing pathogen load to a great extent.23 No serious contaminants was seen when the subjects boiled the caps in our study. Sterilization in boiling water has historical precedence and is the safest method of sterilization that is used to kill all pathogens.24 Therefore, we recommend that the syrup caps be sterilized through boiling in water before usage. We also studied the storage pattern of the syrup caps before next usage and presence of contamination in these stored caps. Majority of subjects after the syrup usage had kept the cap back onto the bottle and only 1% had kept the cap in a specific and separate box/closed container. Keeping the caps back on to the bottle resulted in more contamination possibly due to the surrounding dust. In a previous study, Justin-Temu et al interviewed 400 traditional herbalists using a questionnaire to establish the stage at which contamination takes place during the processing of herbal medicine preparations.

PEDIATRICS They found that the 72% of subjects were aware that dust was a source of harmful contaminants for their medicines, while 91.5% of subjects felt storage of medicines in a clean environment could avoid dust.25 This indicates that though most of the people are aware of dust as the source of most common contaminant but proper education and reinforcing hygienic practices might help to nurture the habit of storing syrup caps in a separate closed box away from dust. Alternate methods have been suggested previously to administer syrups. Shadnia et al recommended the use of child-resistant containers for dispensing syrup and adding a coloring agent or special flavor to the syrup.26 We suggest the use of a calibrated spoon stored in a separate re-sealable pouch as an alternate to the use of syrup caps. The use of calibrated spoons might also help in reducing dosing error that is reported to be the most frequent medication error.27 Additional instructions on proper washing and sterilization of the calibrated spoon might also help prevent the contamination that we observed in the syrup caps. We tried to review if the subjects of our study were comfortable using syrup caps or were looking for alternate methods. We found that a fairly high number of subjects (92%) were comfortable with the usage of the caps that indicated the acceptance of the caps for feeding syrup among the subjects, but at the same time they are willing to try the calibrated child friendly spoon (87%) or other alternative options for feeding the syrup to the child. Respondents wanted to have standard instructions on how to maintain the hygiene of caps/spoon along with the syrup. Summarizing, the present survey was planned to primarily assess the hygienic practices of Indian parents during syrup administration to their children. It was noted that many parents are not maintaining adequate hygiene for administration of pediatric medicine by caps. We observed common contaminants like Bacillus and some serious contaminants in the caps used to administer medicine to children. We did not measure the bacterial load of these contaminant bacteria in the caps. Although, studies suggest that the concentration of contamination presenting threat to an individualâ&#x20AC;&#x2122;s health is unknown.28 We suggest that a standard protocol must be designed for better and hygienic mode for syrup administration. Further, our results indicate an urgent need to educate patients on the hygienic practices followed during storage and dispensing of the

syrup medicines especially in children. A home-based hygiene counseling and education can also be planned. As it was seen that no contamination was present when caps were boiled or stored in a specific closed place away from other articles, a standardized protocol for boiling and using a calibrated spoon with a possible zip pouch for storage can be suggested in order to maintain proper hygiene. The calibrated spoon must be washed with 2-3 drops of detergent and placed back into the zip pouch. Before the next usage, the spoon must be sterilized in boiling water. The sticker on the syrup bottles or the leaflets highlighting hygiene instructions on usage of the medicine could be helpful. To our knowledge, this is the first study to analyze the contamination of syrup caps and understand the hygiene practice followed by parents. A better understanding of the indoor contamination and following hygienic practices could help in preventing harmful effects in future.

Key Messages Many parents are not maintaining adequate hygiene for administration of pediatric medicine by caps. Syrup caps can be contaminated if not properly sterilized. We suggest that a standard protocol must be designed for better and hygienic mode for syrup administration.

Acknowledgments The authors acknowledge Knowledge Isotopes Pvt. Ltd. (www.knowledgeisotopes.com) for the writing support.

Contribution of Authors Varsha Narayanan has contributed in the literature search, clinical studies, experimental studies, data acquisition, data analysis, statistical analysis, manuscript preparation, manuscript editing. Varsha Narayanan and Ganesh Kadhe have substantial contribution to the conception, design and definition of intellectual content. Varsha Narayanan, Ganesh Kadhe and Dr Aparna Jairam have reviewed and approved the manuscript. Dr Ganesh Kadhe is the guarantor for this article, and takes responsibility for the integrity of the work as a whole.

Conflict of Interest None of the authors of the above manuscript has any conflict of interest, which may arise from being named as an author on the manuscript. The authors did not get compensation for their efforts and time in cash or kind from the sponsor. This study is not influenced by any product or brand associated with Wockhardt or any other company, and is an independent study.

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PEDIATRICS REFERENCES 1.

Maguire A, Rugg-Gunn AJ. Medicines in liquid and syrup form used long-term in paediatrics: a survey in the Northern Region of England. Int J Paediatr Dent. 1994;4(2):93-9.

Rugg-Gunn AJ. Nutrition and Dental Health. Oxford: Oxford University Press; 1993.

Hobson P. Sugars and dental health in young children. In: Rugg-Gunn AJ (Ed.). Sugarless: The Way Forward. Elsevier Science Publishers Ltd; 1991. pp. 125-33.

Ash C, Farrow JA, Dorsch M, Stackebrandt E, Collins MD. Comparative analysis of Bacillus anthracis, Bacillus cereus, and related species on the basis of reverse transcriptase sequencing of 16S rRNA. Int J Syst Bacteriol. 1991;41(3):343-6.

Logan NA. Bacillus species of medical and veterinary importance. J Med Microbiol. 1988;25(3):157-65.

De Jonghe V, Coorevits A, De Block J, Van Coillie E, Grijspeerdt K, Herman L, et al. Toxinogenic and spoilage potential of aerobic spore-formers isolated from raw milk. Int J Food Microbiol. 2010;136(3):318-25.

Nester MT, Anderson AD, Roberts CE Jr, Pearsall NN. Microbiology – A Human Perspective. Genitourinary Infections and Antimicrobial Medications, 3rd Edition. Madrid, Spain: MacGraw Hill; 2002.

Scott E, Bloomfield SF. The survival and transfer of microbial contamination via cloths, hands and utensils. J Appl Bacteriol. 1990;68(3):271-8.

Yin HS, Mendelsohn AL, Wolf MS, Parker RM, Fierman A, van Schaick L, et al. Parents’ medication administration errors: role of dosing instruments and health literacy. Arch Pediatr Adolesc Med. 2010;164(2):181-6.

10. Hay AD, Wilson A, Fahey T, Peters TJ. The duration of acute cough in pre-school children presenting to primary care: a prospective cohort study. Fam Pract. 2003;20(6): 696-705. 11. Kai J. What worries parents when their preschool children are acutely ill, and why: a qualitative study. BMJ. 1996;313(7063):983-6. 12. Mugoyela V, Mwambete KD. Microbial contamination of nonsterile pharmaceuticals in public hospital settings. Ther Clin Risk Manag. 2010;6:443-8. 13. Akarele J, Ukoh G. Aspects of microbial contamination of tablets dispensed in hospitals and community pharmacies in Benin City, Nigeria. Trop J Pharm Res. 2002;2:23-8. 14. Mwambete K, Justin-Temu M, Fazleabbas S. Microbiological assessment of commercially available quinine syrups and water for injections in Dar es Salaam, Tanzania. Trop J Pharm Res. 2009;8:441-7.

www.cdc.gov/HAI/organisms/acinetobacter.html. [Accessed on July 2015]. 16. Centers for Disease Control and Prevention. General Information, Escherichia coli (E. coli). [online] Available from: http://www.cdc.gov/ecoli/general/index.html. [Accessed on July 2015]. 17. Centers for Disease Control and Prevention. Klebsiella pneumoniae in Healthcare Settings. [online] Available from: http://www.cdc.gov/HAI/organisms/klebsiella/ klebsiella.html. [Accessed on July 2015]. 18. Centers for Disease Control and Prevention. Pseudomonas aeruginosa in Healthcare Settings. [online] Available from: http://www.cdc.gov/hai/organisms/pseudomonas.html. [Accessed on July 2015]. 19. Fawell J, Nieuwenhuijsen MJ. Contaminants in drinking water. Br Med Bull. 2003;68:199-208. 20. de Abreu PM, Farias PG, Paiva GS, Almeida AM, Morais PV. Persistence of microbial communities including Pseudomonas aeruginosa in a hospital environment: a potential health hazard. BMC Microbiol. 2014;14:118. 21. Flores Ribeiro A, Bodilis J, Alonso L, Buquet S, Feuilloley M, Dupont JP, et al. Occurrence of multi-antibiotic resistant Pseudomonas spp. in drinking water produced from karstic hydrosystems. Sci Total Environ. 2014;490:370-8. 22. Ahmad B, Lilaquat M, Ali M, Bashir S, Mohammad S, Abbas S, et al. Microbiology and evaluation of antibiotic resistant bacterial profiles of drinking water in Peshawar, Khyber Pakhtunkhwa. World Appl Sci J. 2014;30:1668-77. 23. Sattar S. Cleaning, disinfection and sterilisation. IFIC Basic Concepts of Infection Control, 2nd Edition. 2011. pp. 167-84. 24. Center for Disease Control and Prevention. A Guide to Drinking Water Treatment and Sanitation for Backcountry & Travel Use. [online] Available from: http://www.cdc. gov/healthywater/drinking/travel/backcountrywater treatment.html. [Accessed on July 2015]. 25. Justin-Temu M, Lyamuya EF, Makwaya CK. Sources of microbial contamination of local herbal medicines sold on the open market in Dar es Salaam, Tanzania. East Cent Afr J Pharm Sci. 2009;12(1):19-22. 26. Shadnia S, Rahimi M, Hassanian-Moghaddam H, Soltaninejad K, Noroozi A. Methadone toxicity: comparing tablet and syrup formulations during a decade in an academic poison center of Iran. Clin Toxicol (Phila). 2013;51(8):777-82. 27. Kaushal R, Bates DW, Landrigan C, McKenna KJ, Clapp MD, Federico F, et al. Medication errors and adverse drug events in pediatric inpatients. JAMA. 2001;285(16):2114-20.

28. Sebastian A, Larsson L. Characterization of the microbial community in indoor environments: a chemical-analytical 15. Centers for Disease Control and Prevention. Acinetobacter approach. Appl Environ Microbiol. 2003;69(6):3103-9. in Healthcare Settings. [online] Available from: http:// ■■■■

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PEDIATRICS

Clinical Expression of Graves’ Disease in Children: Case Report JWAL B DOCTOR*, BHARAT J KUMAR†

ABSTRACT Thyrotoxicosis is infrequently encountered in childhood. The clinical expression is attributed to accelerated metabolism from excessive level of circulating thyroid hormones. We present the case of a 7-year-old female child admitted in Pediatric Ward in Civil Hospital with chief complaint of increased appetite for 6 months and emotional disturbances accompanied by motor hyperactivity for 2 months; child became irritable and easily excitable; failure to thrive, loose stools and increased sweating for 2 months. Clinical signs of goiter, exophthalmos, increased appetite, hyperactivity, tachycardia, increased sweating, weight-15 kg, height-120 cm. Investigations: Hb-10.5 gm%, ESR-26 mm/hr, chest X-ray normal, ECG-sinus tachycardia, ECHO-normal, serum T3-3.46 ng/mL, serum T4-180.0 ng/mL, serum TSH-<0.05 MicroU/mL, TSH-receptor antibody serum by ELISA-28.46 IU/L, USG neck-thyromegaly with bilateral cervical lymphadenopathy. Thyroid scan - findings show bilateral thyromegaly, which increase trapping function in given clinical content. The uptake pattern favors hyperfunction of thyroid gland, possibly Graves’ disease.

Keywords: Failure to thrive, increased sweating, goiter, exophthalmos, increased appetite, hyperactivity, tachycardia, thyroid scan, bilateral thyromegaly

yperthyroidism refers to increased hormone production by thyroid gland. It is infrequently encountered in childhood with an increase in incidence during adolescence. The clinical manifestations are attributed to accelerated metabolism due to excessive level of thyroid hormones. The most common cause of thyrotoxicosis in children is Graves’ disease (GD), which accounts for 10-15% of childhood thyroid disease in the Western world.

shown an incidence of 5.7% in children and adolescents. Two large series from India reported an incidence of 3% and 6%, the incidence increasing with age. It is rare before 5 years of age and peaks during adolescence (10-15 years of age). This disease is more common in girls, ratio of girls: boys being 3.1:6.1. Signs of diffuse toxic goiter thyroid eye sign (exophthalmos, lid retraction, lid lag, impaired convergence, ophthalmoplegia), pretibial myxedema observed in GD.

Causes include chronic lymphocytic thyroiditis, excess thyroid hormones ingestion (fictitious thyrotoxicosis), iodine-induced disease, McCune-Albright syndrome or constitutively activated thyrotropin (TSH) receptor. Acute or subacute thyroiditis which tends to transient, TSH secreting pituitary tumors, toxic adenoma, multinodular goiter causing hyperthyroidism are rare in children. One thousand cases of all ages of GD have

CASE REPORT

*Institute of Pharmacy Nirma University, Ahmedabad, Gujarat †Associate Professor Dept. of Pediatrics BJ Medical College, Civil Hospital, Ahmedabad, Gujarat Address for correspondence Dr Bharat J Kumar G-103, Shilalekh, Opp Police Stadium Shahibaug, Ahmedabad - 380 004, Gujarat E-mail: kajupharma@hotmail.com

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A 7-year-old female child was admitted in Pediatric Ward in Civil Hospital with chief complaint of increased appetite for 6 months, emotional disturbances: motor hyperactivity, irritability and easily excitable for 2 months, failure to thrive, loose stools and increased sweating for 2 months. We noticed weight of 15 kg approximately, height of 120 cm, failure to thrive, goiter, exophthalmos (Figs. 1-3), hyperactivity, tachycardia and increased sweating. On investigation: Hemoglobin (Hb)-10.5 g/dL, erythrocyte sedimentation rate (ESR)-26 mm/hour, chest X-ray was normal, electrocardiogram (ECG) sinus tachycardia, echocardiographic stress (ECHO) was normal, serum T3-3.46 ng/mL, serum T4-180.0 ng/mL, serum TSH-<0.05 microU/mL, TSH-receptor antibody serum by enzyme-linked immunosorbent assay

PEDIATRICS

Figure 1. Sign of exophthalmos. Figure 3. Failure to thrive.

Diagnosis The total T3 and T4 levels are elevated with suppressed TSH. The thyroid receptor antibody (TRAb) is positive in more than 90% of children with GD.

Management and Outcome The treatment modality consists of medical management with antithyroid drug, radioactive iodine ablation or surgery. Medical management keeps thyroid hormone levels within normal range till natural remission occurs. The other two modalities of treatment result in thyroid gland ablation and bring relief. Medical management is preferred in children. Medical therapy consists of propylthiouracil, methimazole and carbimazole.

Figure 2. Sign of thyromegaly.

(ELISA)-28.46 IU/L. Ultrasonography (USG) neckthyromegaly with bilateral cervical lymphadenopathy, thyroid scan - findings show bilateral thyromegaly, which increase trapping function in given clinical content. The uptake pattern favors hyperfunction of thyroid gland, possibly GD.

Improvement starts around 2 weeks and it may take as much as 6-8 weeks before hormone level T3 and T4 are normalized. Î˛-blocker propranolol 0.5-2.0 mg/kg/day 8-hour dose was given for about 1 month for marked palpitation tremors. Monitoring of white blood cell (WBC) count was done during antithyroid drug therapy. Lower dose of irradiation is associated with future malignancy and hence higher and single dose are recommended. Surgical therapy with total thyroidectomy offers the most rapid resolution of thyrotoxicosis and is indicated when the goiter is too large.

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PEDIATRICS SUGGESTED READING

Lee JA, Grumbach MM, Clark OH. The optimal treatment for paediatric Graves’ disease is surgery. J Clin Endocrinol Metab. 2007;92(3):801-3.

Lazar L, Kalter-Leibovici O, Pertzelan A, Weintrob N, Josefsberg Z, Phillip M. Thyrotoxicosis in prepubertal children compared with pubertal and postpubertal patients. J Clin Endocrinol Metab. 2000;85(10):3678-82.

Rivkees SA, Dinauer C. An optimal treatment for paediatrics Graves’ disease in radioiodine. J Clin Endocrinol Metab. 2007;92(3):797-800.

LaFranchi SH. Hyperthyroidism in the neonatal and childhood. Werner and Ingbara acquired hyperthyroidism in the thyroid a fundamental and clinical text. 2013;10:803-14.

Bauer AJ. Approach to paediatric patients with Grave disease: what is definitive therapy warranted? J Clin Endocrinol Metab. 2011;96(3):580-8.

Zimmerman D, Lteif AN. Thyrotoxicosis in children. Endocrinol Metab Clin North Am. 1998;27(1):109-26.

9. Kraem Z. Grave disease in the children. J Pediatr Endocrinol Metab. 2001;13:229-33. ■■■■

Desai MP. Disorders of thyroid gland in India. Indian J Pediatr. 1997;64(1):11-20.

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New research suggests that measuring the circumference of the mid-upper arm was the most accurate predictor of under-nutrition in children with diarrhea, and that children with diarrhea are misdiagnosed more often if weight is sole criterion. The research was published in the Journal of Nutrition. Alan R. Schroeder, MD, from the Dept. of Pediatrics, Santa Clara Valley Medical Center, San Jose, California, and colleagues report in the June issue of Pediatrics that urinalysis in young infants with bacteremic urinary tract infection (UTI) is more sensitive than previous research suggested it was in infants with UTI in general. A large, cross-sectional study of almost 7,000 children aged 7-9 years has confirmed that visual impairment is rarely the cause of pediatric reading problems. Hence, the common practice of vision-based interventions is unlikely to help in treating youngsters with severe reading impairment. The findings were published online May 25 in Pediatrics. Infants who live at higher altitudes may be at greater risk of sudden infant death syndrome (SIDS), suggested a new study published in Pediatrics. Researchers noted that infants who resided at an altitude of 8,000 ft or higher were at 2.3 times greater risk of SIDS, compared with infants who lived at an altitude below 6,000 ft. Infants who undergo regional anesthesia are less likely to experience apnea after surgery than infants who undergo general anesthesia, suggest two multinational studies published online in Anesthesiology. Obese male teenagers are more than twice as likely to develop colorectal cancer by middle age, and those with a high level of systemic inflammation are also at increased risk, suggests a large cohort study published online May 26 in Gut.

Indian Journal of Clinical Practice, Vol. 26, No. 2, July 2015

SURGERY

Nonpuerperal Breast Abscesses in South Nigeria AFEYODION AKHATOR

ABSTRACT Introduction: Nonpuerperal breast abscesses are divided into peripheral and central abscesses with differing risk factors. The presentation and management of nonpuerperal breast abscesses in South Nigeria is reviewed. Material and methods: A 5-year retrospective study of all nonpuerperal breast abscesses seen in the breast clinic of Central Hospital, Warri from 1st January 2005 to 31st December 2009 was done. The case notes and proforma of women that presented with nonpuerperal breast abscess were retrieved and analyzed. Results: There were 78 cases of breast abscesses available for study. Of these, 68 cases (87.18%) were of nonpuerperal breast abscesses. Fifty-seven cases were central and 11 peripheral in location. The mean age of the women was 36.91 years, with a range of 17-51 years. Repeated trauma from loosened metal support from the bra was identified as an additional risk factor. Traditional incision and drainage was successful in majority of the cases with a 7.02% recurrence rate. Recurrent abscess was treated with excision of the underlying ducts. Conclusion: Incidence of nonpuerperal breast abscesses seems to be increasing. Repeated trauma from loosened metal support of the brassiere is a possible risk factor.

Keywords: Nonpuerperal, breast abscess, trauma from brassiere

reast abscess is defined as localized collection of pus under the skin in the breast tissue,1 or as an acute inflammatory lump, which yields pus on incision/aspiration.2 Breast abscesses are divided into lactating (puerperal) and nonlactating (nonpuerperal) breast abscesses.3 Nonpuerperal breast abscesses are divided into subareolar (central) and peripheral breast abscesses.3 Ninety percent of subareolar breast abscesses are associated with smoking and have been speculated to be caused by either the direct toxic effects of smoking or hormonal changes related to smoking.3,4

Smoking causes squamous metaplasia of the lactiferous ducts and subsequent obstruction of the ducts leading to an increased risk for infection. Recurrent nonpuerperal subareolar breast abscess associated with fistula formation is called Zuskaâ&#x20AC;&#x2122;s disease.5 Peripheral nonpuerperal breast abscesses are less common and are often associated with an underlying condition such

Dept. of Surgery Faculty of Clinical Medicine, College of Health Sciences Delta State University, PMB1, Abraka, Delta State, Nigeria Address for correspondence Dr Afeyodion Akhator Dept. of Surgery Faculty of Clinical Medicine, College of Health Sciences Delta State University, PMB1, Abraka, Delta State, Nigeria E-mail: doc_akhator@yahoo.com

as diabetes, rheumatoid arthritis, steroid treatment or trauma.3 Nonpuerperal breast abscesses has been reported not to be common in Nigeria, making 5% of all breast abscesses in the country.6 However, they are a cause of frustration for the patient and the surgeon because of their high recurrence rate and associated mammary duct fistula. This study reviews the presentation and management of nonpuerperal breast abscess in the breast clinic in Central Hospital, Warri, Nigeria. MATERIAL AND METHODS This is a retrospective study done in the breast clinic of Central Hospital, Warri, Nigeria. The breast clinic keeps a proforma on all patients attending the clinic, comprising of the biodata, clinical presentation, investigations and treatment. The proforma for patients diagnosed with nonpuerperal breast abscess from 1st January 2005 to 31st December 2009 were retrieved and analyzed. In cases where data were missing, the patientâ&#x20AC;&#x2122;s case notes were retrieved from records. The laboratory records were also assessed to get the microbiology of the culture results where these were not in the notes. The data were entered into Microsoft Excel 2010 and analyzed. The results are presented as percentages and tables. Cases of breast abscesses treated in the accident and emergency department and in other clinics were not included in the study because information in those

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SURGERY cases were scanty and incomplete. Tuberculosis of the breast and inflammatory breast cancer were also excluded. Approval for the study was obtained from the Central Hospital, Warriâ&#x20AC;&#x2122;s Ethical Committee.

lactiferous ducts. There was no case of mammary duct fistula.

RESULTS

Nonpuerperal breast abscesses have been reported to constitute only 5% of breast abscesses in Nigeria6 and is reported to be as high as 24% in Saudi Arabia.7 Other authors have reported varying incidence of nonlactational breast abscess, ranging from 38% by Singh et al8 to 86% by Bharat et al.9

There were 621 new cases in the breast clinic in the 5 years of the review. There were 78 cases (12.56%) of breast abscess during this period and 68 cases (10.95% of total cases and 87.18% of breast abscess cases) were diagnosed as nonpuerperal breast abscess. The age and site distribution is shown in Table 1. The age range was 17-51 years with a mean age of 36.91 years Âą 8.38 (SD) years, median of 36 years. All patients presented with pain and swelling in the breast; two patients with subareolar abscess, had previous incision and drainage done. Thirty-six cases occurred on the right side and 32 on the left side. None of the patients had constitutional symptoms. Diagnosis was confirmed by breast ultrasound scan and needle aspirate was taken and sent for microscopy, culture and sensitivity. There were 57 patients (83.82%) with subareolar abscess, while 11 patients (16.18%) had peripheral abscess (Table 1). Nine of the peripheral cases had history of repeated trauma from the metal support of their brassiere. There was no case with nipple piercing. Fourteen patients (20.59%) were diabetic and none was positive for human immunodeficiency virus (HIV). There were no smokers in the study. Aspirate was sent for microbiology and 58 grew Staphylococcus aureus, five grew Escherichia coli, three Pseudomonas aeruginosa and two mixed flora. Sixty-six patients had incision and drainage done with daily saline packing of the wound. They were all given amoxicillin/clavulanic acid for 7 days. The two cases with recurrent subareolar abscess had additional excision of the underlying ducts done. There were four recurrences in the subareolar abscesses (7.02%) within a year. They had to undergo excision of the underlying Table 1. Age and Site Distribution Age

Subareolar

Peripheral

Total

10-19

20-29

30-39

40-49

50-59

Total

57 (83.82%)

11 (16.18%)

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DISCUSSION

This study has a much higher incidence of nonpuerperal breast abscesses. This may be explained by the pattern of referral in the center; puerperal breast abscesses which are usually easily recognized, were usually managed in the accident and emergency department and very few cases got referred to the breast clinic, while the more insidious nonpuerperal breast abscesses were more difficult to diagnose and were sent to the breast clinic for full evaluation. Also, of note, because of better hygiene and breastfeeding practices, the incidence of puerperal breast abscess may actually be declining. The age range of 17-51 years and mean of 36.91 years in this study is similar to other reports of 32 years.1,8 The etiology for nonpuerperal breast abscess differs between subareolar (central) and peripheral abscesses. Cigarette smoking has been implicated in the etiology of subareolar breast abscesses and peripheral breast abscesses are linked to trauma.3,4,10 In this study, none of the women smoked cigarette and this supports earlier reports from Calaber, Nigeria.6 Nine of the 11 women with peripheral breast abscess reported having been injured in the inner lower quadrant of the breast by the metal support of their brassiere. The underlying metal support of the brassiere breaks free from its protective cotton cover after several usages and can injure the breast. This is another source of breast trauma that should be enquired about when taking history from these women. Studies have reported that up to 75% of women who had nonpuerperal breast abscess had diabetes or develop it within 5 years.1 While 20.59% of this study population had diabetes, the rest patients were at increased risk of developing diabetes and should be counseled, as suggested by Newnham et al.1 The microbiology for majority of the cases was S. aureus as supported by other reports;6,8,9 however, due to limitation of the available laboratory support in the center, anaerobic organisms are not easily identified,

SURGERY so the true microbiological picture is not presently clear. The traditional treatment of incision and drainage was successful in majority of our patients, with only 7% of the subareolar breast abscesses having recurrence. Needle aspiration and percutaneous catheter drainage are advocated because of the better healing and similar recurrence rate. It provides a more acceptable option for treating nonpuerperal breast abscess.8,11 Recurrent subareolar breast abscesses will still require excision of the underlying duct to prevent further recurrences.12 CONCLUSION The incidence of nonpuerperal breast abscess appears to be increasing. Breast trauma plays a major role in the etiology of peripheral breast abscess; injuries to the breast from the metal support of the brassiere should be enquired about. Traditional incision and drainage is effective for these abscesses, but recurrent subareolar breast abscesses require excision of the underlying ducts.

Acknowledgment I want to thank Dr CP Oside for allowing the inclusion of his patients in this study, and for his support and encouragement.

REFERENCES 1.

in Jamaican women is there need for a paradigm shift? West Indian Med J. 2012;61(3):245-8. 2.

Scholefield JH, Duncan JL, Rogers K. Review of a hospital experience of breast abscesses. Br J Surg. 1987;74(6): 469-70.

Dixon JM. ABC of breast diseases. Breast infection. BMJ. 1994;309(6959):946-9.

Bundred NJ, Dover MS, Coley S, Morrison JM. Breast abscesses and cigarette smoking. Br J Surg. 1992;79(1): 58-9.

Passaro ME, Broughan TA, Sebek BA, Esselstyn CB Jr. Lactiferous fistula. J Am Coll Surg. 1994;178(1):29-32.

Efem SE. Breast abscesses in Nigeria: lactational versus non-lactational. J R Coll Surg Edinb. 1995;40(1):25-7.

Abdel Hadi MSA, Bukharie HA. Non-lactating breast abscess. J Family Community Med. 2005;12(3):133-7.

Singh G, Singh G, Singh LR, Singh R, Singh S, Sharma KL. Management of breast abscess by repeated aspiration and antibiotics. J Med Soc. 2012;26(3):189-91.

Bharat A, Gao F, Aft RL, Gillanders WE, Eberlein TJ, Margenthaler JA. Predictors of primary breast abscesses and recurrence. World J Surg. 2009;33:2582-6.

10. Gollapalli V, Liao J, Dudakovic A, Sugg SL, ScottConner CE, Weigel RJ. Risk factors for development and recurrence of primary breast abscesses. J Am Coll Surg. 2010;211(1):41-8. 11. Elagili F, Abdullah N, Fong L, Pei T. Aspiration of breast abscess under ultrasound guidance: outcome obtained and factors affecting success. Asian J Surg. 2007;30(1):40-4.

Newnham MS, Brown H, Martin AC, Plummer JM, 12. Maier WP, Au FC, Tank CK. Nonlactational breast infection. Am Surg. 1994;60(4):247-50. Mitchell DI, Cawich SO. Management of breast abscesses ■■■■

Outcomes Good with Cataract Surgery, Lens Implant in Infants Infants who have cataract surgery and posterior intraocular lens (IOL) implantation at 7-22 months of age have fewer adverse events than younger children, with favorable vision outcomes, according to a new review. “The use of intraocular lens implant in children under 2 years of age has been historically not widely accepted and so this study really is the first one to look at this particular age group,” author Dr Michael C Struck of the University of Wisconsin in Madison told Reuters Health by phone. “This study showed that those kids did extremely well with having had primary lens implant surgery.”

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ALGORITHM

Approach to a Patient with Acute Poisoning Patient presents with acute poisoning

Assess general condition of the patient

Patient unstable

Patient stable

Resuscitation and stabilization of patient

GI decontamination

Intubate the patient, initiate ALS

y y

Activated charcoal (single dose) Gastric lavage

Give antidote (for specific toxin) Whole bowel irrigation

Re-assess general condition of the patient

Patient hemodynamically stable

Yes

Correct hypovolemia

Multiple doses of oral activated charcoal

Patient unstable

Continue resuscitation

Patient stable

Enhancing elimination or excretion of toxin

Yes

Toxin eliminated by kidneys? Hemodynamic instability may not allow use of extracorporeal technique

Toxin eliminated by extracorporeal removal technique?*

*Extracorporeal removal techniques • Hemodialysis • Hemoperfusion • Hemofiltration • Hemodialysis-hemoperfusion • Continuous renal replacement therapy (CRRT) • Sustained low efficiency dialysis (SLED) • Plasmapheresis • Peritoneal dialysis

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Yes

Alkalinization of urine

Select and initiate appropriate extracorporeal removal technique

Adapted from Chapter 110. Acute poisoning. Goldman’s Cecil Medicine. 24th Edn., 2012.

MEDILAW

A Must Read Judgement In the High Court of Judicature at Patna Criminal Miscellaneous No. 40712 of 2012 Arising Out of PS Case No. - 12 Year - 2008 Thana - Null District - Bhagalpur 1. Dr Ashok Kumar Singh, S/o Sri Manelal Singh, R/o Sinha Stone and Laparoscopic Clinic Zeromile, PS - Zeromile, District - Bhagalpur 2. Dr Abha Sinha W/o Dr Ashok Kumar Singh, R/o Sinha Stone and Laparoscopic, Clinic Zeromile, PS - Zeromile, District - Bhagalpur ... ... Petitioner Versus 1. The State of Bihar 2. Wakil Choudhary, S/o Late Deo Narayan Choudhary, R/o Village - Rani Talab, PS. Industrial Area, District - Bhagalpur ... ... Opposite Party Appearance: For the Petitioner/s:

Mr Ramakant Sharma, Senior Advocate

For the Opposite Party-State:

Mr S Dayal, APP

For the Opposite Party No. 2:

Mr Akhileshwar Prasad Singh, Senior Advocate

Coram: Honourable Mr Justice Ashwani Kumar Singh Oral Judgement Date: 18-05-2015

he petitioners, who are medical professionals, have challenged the order dated 16.07.2012 passed by the learned Sessions Judge, Bhagalpur, whereby the revision application filed by the petitioners against an order dated 15th March, 2012 passed by the learned Judicial Magistrate, 1st Class, Bhagalpur in connection with Complaint Case No. 1951 of 2009, holding that a prima facie case is made out for the offences under Sections 304-A, 420 read with 34 of the Indian Penal Code (IPC) against the petitioners and one another and summoning them to face trial, has been dismissed. 2. The prosecution case, in brief, as alleged by the complainant in his written report filed before the learned Chief Judicial Magistrate, Bhagalpur with regard to an occurrence which took place on 9.3.2008 is that the complainantâ&#x20AC;&#x2122;s brother Pankaj Chaudhary was taken to the clinic of petitioner

No. 1, Dr Ashok Kumar Singh for treatment of his ailment. The medical history of the patient was told to him and all earlier prescriptions relating to treatment of the patient was also shown to him. After examining the patient and going through his medical history, Petitioner No. 1 Dr Ashok Kumar Singh advised him for operation of hernia. He told that he would charge ` 5,500/- as operation fee and the anesthetist assisting him would charge ` 800/as his fee. On 8th March, 2008, the complainant paid ` 2,800/- to the Petitioner No. 1 and promised to pay the remaining amount after operation. On 9.3.2008 at 10.00 am, the patient was taken to the clinic of Petitioner No. 1 and on the same day, at about 4.15 pm, he was taken to the operation theatre for operation of hernia. After a few while, the family members of the complainant heard cry of the patient and when they tried to inquire about

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MEDILAW the same, the nurse chided them. At about 6.00 pm, the nurse told them that the operation was successful and the patient would be taken out of the operation theatre very soon. After about half an hour, when Petitioner No. 2 Dr Abha Singh was contacted by the family members of the complainant in order to inquire about the condition of the patient, she also reprimanded them, but after a few while, Petitioner No. 1 told that the condition of the patient was deteriorating and a senior doctor had to be called to attend the patient. Thereafter, the family members of the complainant rushed into the operation theatre. They were shocked to see that the patient was already dead by that time. When they questioned the necessity of calling the senior doctor when the patient was already dead, they were pushed out of the clinic.

examined in course of inquiry conducted under Section 202 of the Code. 8. After perusal of the complaint petition, the statement of the complainant made on oath and the statement of witnesses recorded during inquiry, the learned Judicial Magistrate-1st Class, Bhagalpur summoned the petitioners and one another namely, Dr Vikash Kumar to face trial for the offences punishable under Sections 304-A and 420 read with 34 of the IPC vide order dated 15th March, 2012. 9. The aforementioned order dated 15th March, 2012 was challenged in revision before the learned Sessions Judge, Bhagalpur in Criminal Revision No. 191 of 2012. After hearing the parties, the learned Sessions Judge, Bhagalpur dismissed the revision application vide impugned order dated 16.07.2012.

6. During pendency of investigation of the police case, the aforementioned complaint case was filed before the learned Chief Judicial Magistrate, Bhagalpur on 20.03.2008 in the form of protest petition. While accepting the final report submitted by the police, the learned Chief Judicial Magistrate, Bhagalpur directed the protest petition to be registered as a complaint pursuant to which Complaint Case No. 1951 of 2009 was registered.

10. Mr Ramakant Sharma, learned senior counsel for the petitioners, has submitted that both the petitioners are qualified doctors and are serving the patients since long. They have good track record of their service and till date no one has raised any grievance against them. The Petitioner No. 1 is an eminent surgeon of the State. The patient was brought to his clinic on 6th March, 2008. Prior to that he was being treated by other doctors and was suffering from the protrusion of tissue through its opening in surrounding walls in the abdominal region. After taking into consideration the seriousness of problem, as the patient was in severe pain, he was advised for operation of hernia. The attendants were informed about seriousness of the deceased and the risk involved in the operation and after obtaining consent of the patient and his attendant Gopal Lal Chaudhary, his operation was conducted on 9.3.2008 after taking all necessary precautions by Petitioner No. 1. The operation was successful and the patient was brought out of the operation theatre. However, suddenly his condition started deteriorating and then the doctors attending him tried their best to save his life, but unfortunately, the efforts of the petitioners to save the life of the patient failed and the patient died. He has submitted that the facts alleged do not make out even a prima facie case against the Petitioner No. 2.

7. In the complaint case, the statement of complainant was recorded on solemn affirmation under Section 200 of the Code of Criminal Procedure (hereinafter referred to as â&#x20AC;&#x153;the Codeâ&#x20AC;?). Apart from the complainant, four other witnesses were also

11. It is further submitted that in the police case lodged by the Opposite Party No. 2, after thorough investigation and supervision by senior police officers, the accusation against the petitioners was found false and final form was submitted.

3. It has further been alleged in the complaint that the matter was reported to the police, pursuant to which, Industrial Area PS Case No. 12 of 2008 was registered. The anesthetist, Dr Vikash Kumar, was arrested and taken to the police station but he was released on police bail after initial inquiry. It has been claimed that due to the medical negligence of the petitioners, the patient had died. 4. As noted above, on the basis of the written complaint submitted by the complainant to the police, Bhagalpur Industrial Area PS Case No. 12 of 2008, was already registered under Section 304-A of the IPC on 9.3.2008 itself. 5. The allegations made in the first information report are verbatim the same as alleged in the present complaint petition. The police investigated the case and on completion of investigation, found the accusation to be false. Accordingly, a final report was submitted by the police in the matter.

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MEDILAW 12. It is further submitted that the impugned order passed by the learned Magistrate, whereby summons have been issued against the petitioners for the offences under Sections 304-A and 420 of the IPC is patently bad, as the same has been passed mechanically and without judicial application of mind. According to him, despite there being no allegation of cheating, the Magistrate has taken cognizance for the offence under Section 420 of the IPC. 13. Per Contra, Mr Akhileshwar Prasad Singh, learned senior advocate, appearing on behalf of the Opposite Party No. 2, has submitted that it is a gross case of medical negligence and the brother of the complainant died due to the negligence of the petitioners as necessary precautions were not taken before the surgical interference caused on the person of the deceased patient. 14. Mr Singh has further submitted that there is no illegality in the impugned order by which the learned Magistrate has summoned the petitioners and one another to face trial for the offences punishable under Sections 304-A and 420 read with 34 of the IPC, as the complainant has fully supported the allegations made in the complaint petition in his statement made on oath and the statement of the complainant has duly been corroborated by the four witnesses examined in course of inquiry conducted under Section 202 of the Code. According to him, the doctor who conducted postmortem examination on the dead body of the deceased had opined that the death was caused due to cardiogenic shock precipitated by anesthetic and surgical procedure. He has further contended that the conduct of the petitioners was clearly in violation of the established practice of medical profession and, hence, a clear case of gross negligence warranting punishment for the offences punishable under Sections 304-A and 420 of the IPC is made out. 15. Mr S Dayal, learned Additional Public Prosecutor for the State has also supported the contention of the learned counsel for the Opposite Party No. 2. He has submitted that there is no error either in the order passed by the learned Magistrate or in the revisional order passed by the learned Sessions Judge, Bhagalpur. According to him, it is not the stage when the defence of the petitioners is required to be sifted and weighed. The materials placed before the Court disclosed a prima facie case against the petitioners and, hence, this Court should not exercise its inherent jurisdiction to interdict a criminal prosecution at the initial stage.

16. I have heard respective counsel for the parties and with their assistance perused the materials available on record. I find that there is absolutely no allegation of cheating in the complaint petition against any accused person. I am completely at a loss as to how the Magistrate could even think of taking cognizance for the offence punishable under Section 420 IPC the materials on record do not make out case against the petitioners under Section 420 IPC There was no dishonest intention on the part of the petitioners right from the beginning to induce the patient into parting with money for his treatment. 17. The only other section under which cognizance has been taken is section 304-A of the IPC. Section 304-A of the IPC states that whoever causes the death of a person by a rash or negligent act not amounting to culpable homicide shall be punished with an imprisonment for a term of 2 years or with fine or with both. 18. It would appear from the allegations made in the complaint petition that there is a vague and omnibus allegation of negligence against the Petitioner No. 1 and the anesthetist, Dr Vikash Kumar, which has not been supported by an independent medical expert. In absence of any medical expert report, it would be unsafe to straightway draw a conclusion that there is a prima facie case against the petitioners for committing the offence of criminal medical negligence. 19. It is a matter of concern that after happening of some unfortunate event, there is a tendency to put blame upon medical professionals. The changing doctor-patient relationship and commercialization of modern medical practice has brought spurt in launching prosecution against the medical professionals in recent times. On the one hand, there can be unfavourable result of treatment and on the other hand, the patient/attendant suspects negligence as a cause of their suffering. 20. However, the medical professionals are duly protected if the action is taken in good faith. The criminal law has invariably placed the medical professionals on a pedestal different from ordinary mortals. 21. Section 80 of the IPC states that nothing is an offence which is done by accident or misfortune, and without any criminal intention or knowledge in the doing of a lawful act in a lawful manner by lawful means and with proper care and caution. It protects a person from criminal liability if the act

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MEDILAW which killed the other person is done “with proper care and caution”, which can be expected of him by a prudent and reasonable man in the circumstances of a particular case. 22. Similarly, Section 81 IPC states that nothing is an offence merely by reason of its being done with the knowledge that it is likely to cause harm, if it be done without any criminal intention to cause harm, and in good faith for the purpose of preventing or avoiding other harm to person or property. 23. Thus, in view of the provisions of Sections 80 and 81 of the Indian Penal Code, a doctor cannot be held criminally responsible for a patient’s death unless it is shown that he/she was negligent or incompetent, with such disregard for the life and safety of patient that it amounted to a crime against the State. 24. Section 88 of the IPC provides for exemption for acts not intended to cause death, done by consent in good faith for person’s benefit. The illustration given in Section 88 of 1860 of the Indian Penal Code is of great importance which reads as under: “A, a surgeon, knowing that a particular operation is likely to cause the death of Z, who suffers under a painful complaint, but not intending to cause Z’s death, and intending, in good faith, Z’s benefit, performs that operation on Z, with Z’s consent. A has committed no offence”. 25. From a bare perusal of the illustration given under Section 88 of the Indian Penal Code, it is manifest that a medical professional has been given total protection, if the action is taken in good faith for the person’s benefit after taking his consent whether express or implied. 26. Section 92 of the Indian Penal Code provides for exemption of acts done in good faith for the benefit of a person without his consent though the acts cause harm to the person and that person has not consented to suffer such harm. 27. The illustration (c) of the proviso to Section 92 would be important for considering a case of medical negligence which reads as under: “92(c) A, a surgeon, sees a child suffer an accident which is likely to prove fatal unless an operation be immediately performed. There is no time to apply to the child’s guardian. A performs the operation in spite of the entreaties of the child, intending, in good faith, the child’s benefit. A has committed no offence.”

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28. Section 93 of the Indian Penal Code saves from criminality certain communications made in good faith. It is introduced to protect the innocent without cloaking the guilty. It requires that the communication should have been made (1) in good faith, and (2) for the benefit of the person to whom it is made. 29. The illustration given in Section 93 of the Indian Penal Code speaks of a surgeon. It reads as under: “A, a surgeon, in good faith, communicates to a patient his opinion that he cannot live. The patient dies in consequence of the shock. A has committed no offence, though he knew it to be likely that the communication might cause the patient’s death”. 30. A careful scrutiny of Sections 80, 81, 88, 92 and 93 IPC would make it clear that the Indian Penal Code, 1890 has taken care to ensure that a medical professional, who act in good faith, should not be punished. 31. Despite the protection given to the medical professionals under the penal code, the increasing trend of litigation by unsatisfied patients drew attention of the Supreme Court in more than one case. It has recognized the fact of malicious prosecution of medical professionals and ruled against their criminal prosecution unless gross negligence is established. It has held that a medical practitioner cannot be held liable simply because things went wrong from mischance or misadventure or through an error of judgement in choosing one reasonable course of treatment in preference of another. A medical practitioner would be liable only when conduct fell below that of standards of a reasonably competent practitioner in his field. 32. In a landmark judgment in Jacob Mathew v. State of Punjab & Another [(2005) 6 SCC 1], while dealing with the case of negligence by professionals, the Supreme Court succinctly stated in the following words: “18. In the law of negligence, professionals such as lawyers, doctors, architects and others are included in the category of persons professing some special skill or skilled persons generally. Any task which is required to be performed with a special skill would generally be admitted or undertaken to be performed only if the person possesses the requisite skill for performing that task. Any reasonable man entering into a profession which requires a particular level of learning to be called a professional of that branch, impliedly assures the person dealing with him that the skill which he professes to possess shall be exercised with reasonable degree of care and caution. He

MEDILAW does not assure his client of the result. A lawyer does not tell his client that the client shall win the case in all circumstances. A physician would not assure the patient of full recovery in every case. A surgeon cannot and does not guarantee that the result of surgery would invariably be beneficial, much less to the extent of 100% for the person operated on. The only assurance which such a professional can give or can be understood to have given by implication is that he is possessed of the requisite skill in that branch of profession which he is practising and while undertaking the performance of the task entrusted to him he would be exercising his skill with reasonable competence. This is all what the person approaching the professional can expect. Judged by this standard, a professional may be held liable for negligence on one of two findings: either he was not possessed of the requisite skill which he professed to have possessed, or, he did not exercise, with reasonable competence in the given case, the skill which he did possess. The standard to be applied for judging, whether the person charged has been negligent or not, would be that of an ordinary competent person exercising ordinary skill in that profession. It is not necessary for every professional to possess the highest level of expertise in that branch which he practises. In Michael Hyde and Associates v. J.D. Williams & Co. Ltd. 2001 PNLR 233(CA) Sedley, L.J. said that where a profession embraces a range of views as to what is an acceptable standard of conduct, the competence of the defendant is to be judged by the lowest standard that would be regarded as acceptable.” 33. The Court further observed higher the acuteness in emergency and higher the complication, more are the chances of error of judgments. It held in para 25 as under: “25. A mere deviation from normal professional practice is not necessarily evidence of negligence. Let it also be noted that a mere accident is not evidence of negligence. So also an error of judgment on the part of a professional is not negligence per se. Higher the acuteness in emergency and higher the complication, more are the chances of error of judgment. At times, the professional is confronted with making a choice between the devil and the deep sea and he has to choose the lesser evil. The medical professional is often called upon to adopt a procedure which involves higher element of risk, but which he honestly believes as providing greater chances of success for the patient rather than a procedure involving lesser risk but higher chances of failure. Which course is more appropriate to follow, would depend on the facts and circumstances of a given case. The usual practice prevalent nowadays is to obtain the

consent of the patient or of the person incharge of the patient if the patient is not in a position to give consent before adopting a given procedure. So long as it can be found that the procedure which was in fact adopted was one which was acceptable to medical science as on that date, the medical practitioner cannot be held negligent merely because he chose to follow one procedure and not another and the result was a failure.” 34. Further, in para 28 and 29, the Court observed about a doctor faced with an emergency as under: “28. A medical practitioner faced with an emergency ordinarily tries his best to redeem the patient out of his suffering. He does not gain anything by acting with negligence or by omitting to do an act. Obviously, therefore, it will be for the complainant to clearly make out a case of negligence before a medical practitioner is charged with or proceeded against criminally. A surgeon with shaky hands under fear of legal action cannot perform a successful operation and a quivering physician cannot administer the end-dose of medicine to his patient. 29. If the hands be trembling with the dangling fear of facing a criminal prosecution in the event of failure for whatever reason — whether attributable to himself or not, neither can a surgeon successfully wield his lifesaving scalpel to perform an essential surgery, nor can a physician successfully administer the life-saving dose of medicine. Discretion being the better part of valour, a medical professional would feel better advised to leave a terminal patient to his own fate in the case of emergency where the chance of success may be 10% (or so), rather than taking the risk of making a last ditch effort towards saving the subject and facing a criminal prosecution if his effort fails. Such timidity forced upon a doctor would be a disservice to society.” 35. The Court went on to remind in Para 47 as under: “47. ………………………………..Indiscriminate prosecution of medical professionals for criminal negligence is counter-productive and does no service or good to society.” 36. The Court exhaustively considered various aspects of negligence on the part of a doctor and summed up its conclusions in para 48 as under: “48. We sum up our conclusions as under: (1) Negligence is the breach of a duty caused by omission to do something which a reasonable man guided by those considerations which ordinarily regulate the conduct of human affairs would do, or doing something which a prudent and

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MEDILAW reasonable man would not do. The definition of negligence as given in Law of Torts, Ratanlal & Dhirajlal (edited by Justice G.P. Singh), referred to hereinabove, holds good. Negligence becomes actionable on account of injury resulting from the act or omission amounting to negligence attributable to the person sued. The essential components of negligence are three: “duty”, “breach” and “resulting damage.” (2) Negligence in the context of the medical profession necessarily calls for a treatment with a difference. To infer rashness or negligence on the part of a professional, in particular a doctor, additional considerations apply. A case of occupational negligence is different from one of professional negligence. A simple lack of care, an error of judgment or an accident, is not proof of negligence on the part of a medical professional. So long as a doctor follows a practice acceptable to the medical profession of that day, he cannot be held liable for negligence merely because a better alternative course or method of treatment was also available or simply because a more skilled doctor would not have chosen to follow or resort to that practice or procedure which the accused followed. When it comes to the failure of taking precautions, what has to be seen is whether those precautions were taken which the ordinary experience of men has found to be sufficient; a failure to use special or extraordinary precautions which might have prevented the particular happening cannot be the standard for judging the alleged negligence. So also, the standard of care, while assessing the practice as adopted, is judged in the light of knowledge available at the time of the incident, and not at the date of trial. Similarly, when the charge of negligence arises out of failure to use some particular equipment, the charge would fail if the equipment was not generally available at that particular time (that is, the time of the incident) at which it is suggested it should have been used. (3) A professional may be held liable for negligence on one of the two findings: either he was not possessed of the requisite skill which he professed to have possessed, or, he did not exercise, with reasonable competence in the given case, the skill which he did possess. The standard to be applied for judging, whether the person charged has been negligent or not, would be that of an ordinary competent person exercising ordinary skill in that profession. It is not possible for every professional to possess the highest level of expertise or skills in

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that branch which he practices. A highly skilled professional may be possessed of better qualities, but that cannot be made the basis or the yardstick for judging the performance of the professional proceeded against on indictment of negligence. (4) The test for determining medical negligence as laid down in Bolam case (1957) 1 WLR 582, WLR at p. 586§ holds good in its applicability in India. (5) The jurisprudential concept of negligence differs in civil and criminal law. What may be negligence in civil law may not necessarily be negligence in criminal law. For negligence to amount to an offence, the element of mens rea must be shown to exist. For an act to amount to criminal negligence, the degree of negligence should be much higher i.e. gross or of a very high degree. Negligence which is neither gross nor of a higher degree may provide a ground for action in civil law but cannot form the basis for prosecution. (6) The word “gross” has not been used in Section 304-A IPC, yet it is settled that in criminal law negligence or recklessness, to be so held, must be of such a high degree as to be “gross”. The expression “rash or negligent act” as occurring in Section 304-A IPC has to be read as qualified by the word “grossly.” (7) To prosecute a medical professional for negligence under criminal law it must be shown that the accused did something or failed to do something which in the given facts and circumstances no medical professional in his ordinary senses and prudence would have done or failed to do. The hazard taken by the accused doctor should be of such a nature that the injury which resulted was most likely imminent. (8) Res ipsa loquitur is only a rule of evidence and operates in the domain of civil law, specially in cases of torts and helps in determining the onus of proof in actions relating to negligence. It cannot be pressed in service for determining per se the liability for negligence within the domain of criminal law. Res ipsa loquitur has, if at all, a limited application in trial on a charge of criminal negligence.” 37. While dealing with a case of medical negligence, the Supreme Court in case of Kusum Sharma & others v. Batra Hospital & Medical Research

MEDILAW patient rather than a procedure involving lesser risk but higher chances of failure. Just because a professional looking to the gravity of illness has taken higher element of risk to redeem the patient out of his/her suffering which did not yield the desired result may not amount to negligence.

Centre and others [(2010) 3 SCC 480] observed in para 87 as under: “87. To prosecute a medical professional for negligence under Criminal Law it must be shown that the accused did something or failed to do something which in the given facts and circumstances, no medical professional in his ordinary senses or prudence would have done or failed to do. The hazard taken by the accused doctor should be of such a nature that the injury which resulted or most likely imminent.” 38. The Court considered leading cases of medical negligence and observed in Para 89 as under: “89. On scrutiny of the leading cases of medical negligence both in our country and other countries specially the United Kingdom, some basic principles emerge in dealing with the cases of medical negligence. While deciding whether the medical professional is guilty of medical negligence following well-known principles must be kept in view: I.

II.

Negligence is the breach of a duty exercised by omission to do something which a reasonable man, guided by those considerations which ordinarily regulate the conduct of human affairs, would do, or doing something which a prudent and reasonable man would not do. Negligence is an essential ingredient of the offence. The negligence to be established by the prosecution must be culpable or gross and not the negligence merely based upon an error of judgment.

III. The medical professional is expected to bring a reasonable degree of skill and knowledge and must exercise a reasonable degree of care. Neither the very highest nor a very low degree of care and competence judged in the light of the particular circumstances of each case is what the law requires. IV. A medical practitioner would be liable only where his conduct fell below that of the standards of a reasonably competent practitioner in his field. V.

In the realm of diagnosis and treatment there is scope for genuine difference of opinion and one professional doctor is clearly not negligent merely because his conclusion differs from that of other professional doctor.

VI. The medical professional is often called upon to adopt a procedure which involves higher element of risk, but which he honestly believes as providing greater chances of success for the

VII. Negligence cannot be attributed to a doctor so long as he performs his duties with reasonable skill and competence. Merely because the doctor chooses one course of action in preference to the other one available, he would not be liable if the course of action chosen by him was acceptable to the medical profession. VIII. It would not be conducive to the efficiency of the medical profession if no doctor could administer medicine without a halter round his neck. IX. It is our bounden duty and obligation of the civil society to ensure that the medical professionals are not unnecessarily harassed or humiliated so that they can perform their professional duties without fear and apprehension. X.

The medical practitioners at times also have to be saved from such a class of complainants who use criminal process as a tool for pressurising the medical professionals/hospitals, particularly private hospitals or clinics for extracting uncalled for compensation. Such malicious proceedings deserve to be discarded against the medical practitioners.

XI. The medical professionals are entitled to get protection so long as they perform their duties with reasonable skill and competence and in the interest of the patients. The interest and welfare of the patients have to be paramount for the medical professionals.” 39. In MARTIN F. D’SOUZA Vs. MOHD. ISHFAQ [(2009) 3 SCC 1], a two-Judge Bench of the Supreme Court has lucidly and elaborately explained the subject of medical negligence and held in Para 106 as under: “106. We, therefore, direct that whenever a complaint is received against a doctor or hospital by the Consumer Fora (whether District, State or National) or by the criminal court then before issuing notice to the doctor or hospital against whom the compliant was made the Consumer Forum or the criminal court should first refer the matter to a competent doctor or committee of doctors, specialised in the field relating to which the medical negligence is attributed, and only after that doctor or

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MEDILAW committee reports that there is a prima facie case of medical negligence should notice be then issued to the doctor/hospital concerned. This is necessary to avoid harassment to doctors who may not be ultimately found to be negligent. We further warn the police officials not to arrest or harass doctors unless the facts clearly come within the parameters laid down in Jacob Mathew case [Jacob Mathew v. State of Punjab, (2005) 6 SCC 1], otherwise the policemen will themselves have to face legal action.â&#x20AC;? 40. Applying the aforementioned law to the facts of the present case, it is evident that the minimum requirement of the law as regards evidence of a competent medical expert has not been satisfied. 41. As noted above, the patient was suffering from certain ailment. He needed immediate medical attention. He was being treated by different doctors from before. The patient was taken to the Nursing Home of the Petitioner No. 1 by the complainant and others. The patient and his attendant had consented for operation of hernia. It is also an admitted fact that the petitioners are qualified doctors. Petitioner no. 1 had conducted the operation with assistance of an anesthetist. Unfortunately, the condition of the patient deteriorated after the operation and despite efforts taken by the doctors, the life of the patient could not be saved. These admitted facts

make it amply clear that it was not a case of gross medical negligence or rashness of such a degree as to indicate a mental state that can be described as totally apathetic towards the patient for which the petitioners could have been criminally prosecuted. 42. I further find that there is absolutely no allegation in the complaint against the Petitioner No. 2, but the learned Magistrate mechanically summoned her to face trial. While passing the order, neither the court of magistrate nor the revisional court has appreciated the facts or the law involved in the case. 43. For all the aforementioned reasons, I am of the opinion that there was no prima facie material against the petitioners for summoning them for the offence of criminal medical negligence or for the offence of cheating. 44. Accordingly, the order dated 15th March, 2012 passed by the learned Judicial Magistrate, 1st Class, Bhagalpur in Complaint Case No. 1951 of 2009 and the order dated 16.07.2012 passed by the learned Sessions Judge, Bhagalpur in Criminal Revision No. 191 of 2012, as well as the entire criminal prosecution arising out of Complaint Case No. 1951 of 2009, pending before the learned Judicial Magistrate-1st Class, Bhagalpur, are quashed. 45. The application stands allowed.

Sanjeet/U

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(Ashwani Kumar Singh, J.)

AROUND THE GLOBE

News and Views Â

People over age 50 with persistent depression have double the risk for stroke compared with their nondepressed, age-matched counterparts, according to findings from a nationally representative cohort study of US adults. A study published online in JAMA Neurology has suggested that having celiac disease, an autoimmune disorder characterized by a sensitivity to gluten, more than doubles the risk for neuropathy.

For entecavir-resistant hepatitis B virus infection, tenofovir alone appears to be as effective as a tenofovir/entecavir combination, suggests new research published online in Gut.

The American College of Obstetricians and Gynecologists (ACOG) maintains that the preponderance of scientific evidence indicates that fetuses do not likely experience pain before the third trimester.

The US House has passed a Republican-sponsored bill that would outlaw abortions at 20 weeks of gestation based on the disputed premise that fetuses that young can experience pain. The vote of 242 to 184 closely followed party lines. During the first year after kidney transplantation, vitamin D3 supplementation does not reduce the risk for acute rejection episodes or infection, and might promote the development of hypercalcemia, results from a randomized controlled trial suggest. (Ursula Thiem, MD, from the Medical University of Vienna). Patients with end-stage renal disease (ESRD) receiving dialysis have been reported to have increased risk of cancer. When the FDA advisory committee met this month to consider approvability of two PCSK9 inhibitors, the big question was not lipid-lowering efficacy but which group of patients would get an indication. The panelists voted in favor of approval of both evolocumab (Repatha) and alirocumab (Praluent) based on a slew of trials in a variety of settings showing that LDL fell by an absolute 30% to 60% from baseline. Antibiotic treatment of patients with computed tomography (CT)-proven, uncomplicated

appendicitis may be as effective as appendectomy, according to a new study (JAMA). Â

Daily baricitinib, an oral Janus kinase (JAK)1/2 inhibitor, produces rapid clinical improvement in the signs and symptoms of rheumatoid arthritis in patients with active disease who have failed at least one tumor necrosis factor (TNF) inhibitor, the RABEACON trial indicates.

A large cohort study suggests that lifestyle factors might explain why men who take popular phosphodiesterase type 5 (PDE5) inhibitors for erectile dysfunction ? sildenafil, vardenafil and tadalafil ? are at a slightly but significantly increased risk of developing malignant melanoma. The findings are published online June 23 in JAMA.

New phase 2 data on the investigational calcitonin gene-related peptide (CGRP) monoclonal antibodies show significant efficacy in preventing migraine attacks with no major safety signals. The data were presented at the American Headache Society (AHS) 57th Annual Scientific Meeting.

In patients with ankylosing spondylitis, smoking might interact with epigenetic factors and promote radiographic progression, suggests new study presented at the European League Against Rheumatism Congress 2015.

Adding metformin to lifestyle change lowers body mass index (BMI) and improves menstrual cyclicity, compared with lifestyle change alone, in women with polycystic ovary syndrome (PCOS), suggests a recent meta-analysis published online in Human Reproduction Update.

The first large panic disorder trial to compare cognitive-behavioral therapy (CBT), panic-focused psychodynamic psychotherapy (PFPP), and applied relaxation training (ART) showed that although all treatments improved panic disorder, CBT performed most consistently. PFPP also demonstrated efficacy. The findings are published online in the Journal of Clinical Psychiatry.

The Cardiorespiratory Fitness on Arrhythmia Recurrence in Obese Individuals with Atrial Fibrillation (CARDIO-FIT) study suggests that cardiorespiratory fitness (CRF) not only helps with relieving symptoms of atrial fibrillation (AF),

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AROUND THE GLOBE but it also predicts recurrence in patients who are obese. The findings were presented at the European Heart Rhythm Association (EHRA) EUROPACECARDIOSTIM 2015 meeting. Â

For warfarin-treated patients with atrial fibrillation undergoing an elective surgery or invasive procedure, perioperative bridging with low-molecular-weight heparin (LMWH) was not associated with a reduction in stroke, systemic embolism or transient ischemic attack compared with no bridging but did significantly increase the risk of bleeding, reported a new study presented at the International Society for Thrombosis and Hemostasis (ISTH) 2015 Congress.

The use of a single, narrow-spectrum antibiotic such as ampicillin/penicillin is increasingly the first-line of treatment for children hospitalized with community-acquired pneumonia (CAP), suggests a new study published online June 22 in Pediatrics.

Children whose parents smoked when they were toddlers are likely to have a wider waist and a higher BMI by time they reach 10 years of age, suggest researchers at the University of Montreal.

Menopausal women experiencing a decline in executive functions, including difficulty with time management, attention, organization, memory and problem solving, may benefit from lisdexamfetamine, a drug already approved to treat attention-deficit/ hyperactivity disorder (ADHD), suggests new research published online in Psychopharmacology.

Sumatriptan is less effective in migraine attacks with aura than in those without, suggest new data from an analysis of previous clinical trial results, presented at the American Headache Society (AHS) 57th Annual Scientific Meeting.

Patients who have taken opioids for pain relief within 24 hours of esophageal pressure tomography are more likely to have esophageal dysfunction as compared to those who stopped treatment earlier, suggested new research published online in the American Journal of Gastroenterology.

There is a significant association between in utero exposure to the pesticide DDT and the risk for breast cancer in young women, suggests new research published online in the Journal of Clinical Endocrinology and Metabolism.

Acupuncture can reduce pain and increase qualityof-life in men with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), suggests new research published online in Prostate Cancer and Prostatic Diseases.

Low-dose oral tetrahydrocannabinol (THC) does not reduce behavioral disturbances in patients with dementia, but it is well-tolerated, suggests a new study published online in Neurology.

Risk assessment for hereditary cancer is the key to identifying patients and families who may be at increased risk of developing certain types of gynecologic cancer, suggests a new committee opinion from the American College of Obstetrics and Gynecology (ACOG). The guidelines, published in the June issue of Obstetrics & Gynecology, recommend that patients be referred to a genetic specialist if the initial screening points towards a familial risk.

Botox may improve the pliability and elasticity of skin for up to 4 months, suggests a new study published in the journal JAMA Facial Plastic Surgery.

Bariatric surgery may restore sudomotor and cardiac autonomic-nerve dysfunction to near normal in obese patients with type 2 diabetes, suggest preliminary data from a new study presented at the American Association of Clinical Endocrinologists’ 2015 Annual Scientific and Clinical Congress.

In elderly patients with distributive shock in critical care, a higher target for mean arterial pressure leads to an increase in mortality, warns a pilot study presented at the American Thoracic Society 2015 International Conference.

Results of a study presented at the American Association of Clinical Endocrinologists’ 2015 Annual Scientific and Clinical Congress by Zdravko Kamenov, MD, PhD, from Alexandrovska University Hospital, Sofia, Bulgaria suggest that measuring an obese patient’s neck may prove to be of greater value than waist circumference in assessing cardiometabolic risk.

Statin use for primary prevention of cardiovascular disease among healthy adults has been linked to an increased risk for diabetes, diabetes complications, and overweight/obesity in a new retrospective cohort study in individuals followed for an average of 6.5 years. The findings are published in the Journal of General Internal Medicine.

Patients report meaningful improvements in vision after ocriplasmin treatment for vitreomacular adhesion, suggests new research published in JAMA Ophthalmology. ■■■■

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LIGHTER READING

Kauffman’s Paradox of the Corporation: The less important you are to the corporation, the more your tardiness or absence is noticed. The Salary Axiom: The pay raise is just large enough to increase your taxes and just small enough to have no effect on your take–home pay.

LAUGH-A-WHILE

Work Wisdom

Two old men were arguing the merits of their doctors. The first one said, “I don’t trust your fancy doctor.

Have you looked for the door?” The person says, “Well, there’s one door that leads to the bathroom. There’s a second door that goes into the closet. And there’s a door I haven’t tried, but it has a ‘do not disturb’ sign on it.”

He treated old Jake Waxman for a kidney ailment for nearly a year, and then Jake died of a liver ailment.”

“Because when my doctor treats you for a kidney ailment, you can be sure you’ll die of a kidney ailment.

A high-school student came home one night rather depressed. “What’s the matter, Son?” asked his mother. “Aw, gee,” said the boy, “It’s my grades. They’re all wet.” “What do you mean ‘all wet?’” “You know,” he replied, “…below C level.”

A person checks into a hotel for the first time in his life, and goes up to his room. Five minutes later he calls the desk and say, “You’ve given me a room with no exit. How do I leave?” The desk clerk says, “Sir, that’s absurd.

Kidneys and Livers

“So what makes you think your doctor is any better?” asked his friend.

My Grades

No Exit

QUOTES

“Creativity is intelligence having fun.” — Albert Einstein “Difficulties increase the nearer we get to the goal.” — Johann Wolfgang von Goethe

Communication Technician A communication technician drafted by the army was at a firing range. At the range, he was given some instruction, a rifle and 50 rounds. He fired several shots at the target. The report came from the target area that all attempts had completely missed the target. The technician looked at his weapon, and then at the target. He looked at the weapon again, and then at the target again.

Dr. Good and Dr. Bad SITUATION: A patient with hypertension had nonresponding cough.

Take an X–ray

Stop ACE inhibitors

He then put his finger over the end of the rifle barrel and squeezed the trigger with his other hand. The end of his finger was blown off, whereupon he yelled toward the target area: “It’s leaving here just fine, the trouble must be at your end!”

©IJCP Academy

HUMOR

Lighter Side of Medicine

LESSON: The commonest cause of cough in a patient with high blood pressure is the intake of ACE inhibitors.

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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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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,

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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.

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These should be concise and include only the tables and figures necessary to enhance the understanding of the text.

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 firs 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. –

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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) Indian 1. ___________Foreign 1. _______________

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. ___________

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