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Best of IJCP (January - December 2010)
Happy New Year 2011
Dr KK Aggarwal
Group Editor-in-Chief
Head Office: 39 Daryacha, Hauz Khas Village, New Delhi, India. e-Mail: emedinews@gmail.com, Website: www.ijcpgroup.com
emedinews is now available online on www.emedinews.in or www.emedinews.org From the Desk of Editor in Chief Padma Shri and Dr BC Roy National Awardee
Dr KK Aggarwal
President, Heart Care Foundation of India; Sr Consultant and Dean Medical Education, Moolchand Medcity; Member, Delhi Medical Council; Past President, Delhi Medical Association; Past President, IMA New Delhi Branch; Past Hony Director. IMA AKN Sinha Institute, Chairman IMA Academy of Medical Specialities & Hony Finance Secretary National IMA; Editor in Chief IJCP Group of Publications & Hony Visiting Professor (Clinical Research) DIPSAR
8th January 2011, Saturday Top 10 Stroke Risks Responsible for 90% of Risks of Stroke Scientists have identified the top 10 stroke risks responsible for 90% of risks of stroke. In INTERSTROKE study, published online first and in a forthcoming edition of the Lancet, Canadian authors from McMaster University used data from 6,000 people (3,000 cases of stroke and 3,000 controls) in 22 countries around the world. They looked at patients who’d had a first acute stroke and compared them with people who’d not had a stroke. The authors found the following 10 risk factors to be significantly associated with stroke: High blood pressure, smoking, waist-tohip ratio (abdominal obesity), diet, physical activity, blood lipids, diabetes mellitus (type 2), alcohol intake, stress and depression and heart disorders. Put together, these risk factors accounted for 90% of risks for all stroke. These risk factors were all significant for ischaemic stroke - caused by a blood clot blocking a blood vessel in the brain. High blood pressure, smoking, waist-to-hip ratio, diet and alcohol intake were significant risk factors for intracerebral haemorrhagic stroke - bleeding into the brain tissue. The ratio of bad to good blood lipids (apolipoproteins) was an important risk for ischemic stroke but not for haemorrhagic stroke. Targeted population-based interventions that reduce blood pressure and smoking, and promote physical (WebMD) Dr KK Aggarwal Editor in Chief ———————————————————————————— International News The 2010 AHA Guidelines on Cardiac Arrest Care Change from “A-B-C” to “C-A-B.” A major change in basic life support is a step away from the traditional approach of airwaybreathing-chest compressions (taught with the mnemonic “A-B-C”) to first establishing good chest compressions (“C-A-B”). There are several reasons for this change. • Most survivors of adult cardiac arrest have an initial rhythm of ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT), and these patients are best treated initially with chest compressions and early defibrillation rather than airway management. • Airway management, whether mouth-to-mouth breathing, bagging, or endotracheal intubation, often results in a delay of initiation of good chest compressions. Airway management is no longer recommended until after the first cycle of chest compressions –– 30 compressions in 18 seconds. The 30 compressions are now recommended to precede the 2 ventilations, which previous guidelines had recommended at the start of resuscitation. • Only a minority of cardiac arrest victims receive bystander CPR. It is believed that a significant obstacle to bystanders performing CPR is their fear of doing mouth-to-mouth breathing. By changing the initial focus of resuscitation to chest compressions rather than airway maneuvers, it is thought that more patients will receive important bystander intervention, even if it is limited to chest compressions. −Dr GM Singh
IV Fluids may not be Best Treatment for Trauma Victims Intravenous fluids given to a trauma victim at an accident site may not be the best treatment and in many cases may actually be counterproductive, increasing the risk that a patient will die, according to a study published online in the Annals of Surgery journal. −Dr Monica and Brahm Vasudev
Daily Consumption of Three Portions of Whole-grain Foods may Carry Lower Cardiovascular Risk Daily consumption of 3 portions of whole-grain foods is linked to lower cardiovascular disease risk in healthy, middle-aged people mainly by lowering blood pressure, according to the results of a
randomized controlled dietary trial reported in the American Journal of Clinical Nutrition. HCC Treated with Resection has Lower Recurrence Rate vs Radiofrequency Ablation Hung-Hsu Hung and colleagues report in the January issue of Clinical Gastroenterology and Hepatology even though percutaneous radiofrequency ablation and surgical resection for small hepatocellular carcinomas have comparable survival rates, patients who underwent the ablation procedure have a higher rate of cancer recurrence than those who had surgical resection. The authors stated that these observations stress upon the need for close surveillance after local ablation therapy.” Insecticidal Nets don’t Reduce Leishmania Risks Results of a paired cluster-randomized trial note that using durable insecticidal nets do not significantly improve on existing measures to control Leishmania donovani infection on the Indian subcontinent. The trial included villages in three Nepalese and one Indian district with a high reported incidence of visceral leishmaniasis. Intervention clusters were given durable insecticidal nets, deltamethrin treatment; control clusters continued with existing conventional strategies of irregular insecticide residual spraying and use of untreated nets. The results showed no significant reduction in the rate of L. donovani infection in Indian and Nepalese villages receiving long-lasting insecticidal nets vs usual control measures. There is also no effect on the rate of clinical leishmaniasis. The study is published online 29 December 2010 in BMJ. Infertility Update What is IUI? What is the Average Success Rate of IUI? How many Cycles of IUI can be Tried? IUI is a simple OPD procedure. In this procedure, washed capacitated sperms are put in the uterus. The ovary is stimulated by giving hormone injections to produce multiple follicles and the procedure is carried out when the eggs are about to be released. We have had a good success rate with this method and recommend it as the first line of treatment in patients who have patent tubes and a reasonably good semen count. Success rate varies according to the indication but around 15-18% can be considered good. Most couples conceive within first three cycles of IUI, in subsequent cycles the positive outcome is less. One can try up to six IUI cycles then probably turn to IVF-ET. −Dr. Kaberi Banerjee
Women’s Health: Preventing Top 10 Threats (Mayo Clinic) Injuries The leading cause of fatal accidents among women is motor vehicle crashes. To reduce your risk of a deadly crash: • Wear your seat belt. • Follow the speed limit. • Don’t drive under the influence of alcohol or any other substances. • Don’t drive while sleepy Falls and poisoning also pose major women’s health threats. Take common-sense precautions, such as having your vision checked, using nonslip mats in the tub and placing carbon monoxide detectors near the bedrooms in your home. Lab Update Allergies are hypersensitivities, overreactions of the immune system to substances that do not cause reactions in most people. Allergen specific IgE testing: Immunoassay and LINE BLOT TESTS are blood tests that are used to screen for type I allergen-specific IgE antibodies. −Dr Arpan Gandhi and Dr Navin Dang
Indian Journal of
Online Submission
Clinical Practice
Volume 21, Number 8, January 2011
Contents
An IJCP Group Publication Dr Sanjiv Chopra Prof. of Medicine & Faculty Dean Harvard Medical School Group Consultant Editor Dr Deepak Chopra Chief Editorial Advisor
Dr KK Aggarwal CMD, Publisher and Group Editor-in-Chief Dr Veena Aggarwal Joint MD & Group Executive Editor Anand Gopal Bhatnagar Editorial Anchor
From the desk of group editor-in-chief
Top 5 Medical News Stories of 2010 Relevant to India
425
KK Aggarwal
Original article
Gastroprotection with Gasex Tablets in GI Disorders and Preradiographic Preparation: A Meta-analysis
427
Mohd. Ali, D. Palaniyamma
IJCP Editorial Board Dr Alka Kriplani Asian Journal of Obs & Gynae Practice Dr VP Sood Asian Journal of Ear, Nose and Throat Dr Praveen Chandra Asian Journal of Clinical Cardiology Dr Swati Y Bhave Asian Journal of Paediatric Practice Dr Vijay Viswanathan The Asian Journal of Diabetology Dr M Paul Anand, Dr SK Parashar Cardiology Dr CR Anand Moses, Dr Sidhartha Das Dr A Ramachandran, Dr Samith A Shetty Diabetology Dr Ajay Kumar Gastroenterology Dr Koushik Lahiri Dermatology Dr Georgi Abraham Nephrology Dr Sidharth Kumar Das Rheumatology Dr V Nagarajan Neurology Dr Thankam Verma, Dr Kamala Selvaraj Obs and Gyne Advisory Bodies Heart Care Foundation of India Non-Resident Indians Chamber of Commerce & Industry World Fellowship of Religions
Practice Guidelines
Updated Recommendations on Daily Aspirin Use in Patients with Diabetes
433
Infectious disease
Seasonal Influenza - Role of Amantadine in Combination Therapy
435
Avinash Kulkarni, Abhay Chowdhary, K Krishnaprasad, R Lalchandani, Jejoe Karankumar
Clinical Practice
Measuring Blood Pressure
442
Detection of Atypical Bacterial Infections in Asthma Patients by IgM ELISA
445
Sunita D Deshpande, Kirti S Kulkarni, Manish S Pathak, Sangeeta J Pednekar, Shekhar T Nabar
Photo Quiz
Adolescent with a Diffuse, Progressive Rash
448
case report
Hemoglobin 2 gm%: A Common Occurrence in India KK Aggarwal, Archna Gupta
454
Indian Journal of
Clinical Practice
Volume 21, Number 8, January 2011
Contents
Published, Printed and Edited by Dr KK Aggarwal, on behalf of IJCP Publications Pvt. Ltd. and Published at Daryacha, 39, Hauz Khas Village New Delhi - 110 016 E-mail: editorial@ijcp.com
Case Report
Adenocarcinoma of the Jejunum: A Rare Cause of Intestinal Obstruction in Young Adults
Printed at IG Printers Pvt. Ltd., New Delhi E-mail: igprinter@rediffmail.com printer_ig@yahoo.com
456
Jyotsna Madan, S Mitra, U Madan
Š Copyright 2011 IJCP Publications Pvt. Ltd. All rights reserved. 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 Pvt. Ltd. No part of this publication may be published in any form whatsoever without the prior written permission of the publisher.
Disseminated Intravascular Coagulation: A Rare Complication of Enteric Fever 459 Vikas R Pandey, Sandip Shah, Nilay Thakore, Ilesh Mehta
Symposium on Child Health
Update on Some Common Problems in Neonatology
Editorial Policies The purpose of IJCP Academy of CME is to serve the medical profession and provide print continuing medical education as a part of their social commitment. The information and opinions presented in IJCP group publications reflect the views of the authors, not those of the journal, unless so stated. Advertising is accepted only if judged to be in harmony with the purpose of the journal; however, IJCP group reserves the right to reject any advertising at its sole discretion. Neither acceptance nor rejection constitutes an endorsement by IJCP group of a particular policy, product or procedure. We believe that readers need to be aware of any affiliation or financial relationship (employment, consultancies, stock ownership, honoraria, etc.) between an author and any organization or entity that has a direct financial interest in the subject matter or materials the author is writing about. We inform the reader of any pertinent relationships disclosed. A disclosure statement, where appropriate, is published at the end of the relevant article.
461
Anjali Kulkarni
Symposium on Neurology
Diagnostic Tools for DPNP
469
Alejandra Gonzalez-Duarte, David M Simpson
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From the Desk of Group Editor-in-Chief From the Desk of Group Editor-in-Chief
Top 5 Medical News Stories of 2010 Relevant to India
N
ew Guidelines for Prostate Cancer Dr KK Aggarwal Screening: PSA screening can in some Padma Shri and Dr BC Roy National Awardee cases save lives with early treatment. Sr Physician and Cardiologist, Moolchand Medcity President, Heart Care Foundation of India However, these tests can also pose new dilemmas, Group Editor-in-Chief, IJCP Group as the American Cancer Society (ACS) emphasized Editor-in-chief, eMedinewS Chairman Ethical Committee, Delhi Medical Council on March 3 when it updated its prostate cancer Director, IMA AKN Sinha Institute (08-09) screening guidelines. The test picks up benign Hony. Finance Secretary, IMA (07-08) disease in addition to cancer, and it can’t Chairman, IMA AMS (06-07) President, Delhi Medical Association (05-06) distinguish between aggressive and mild forms of emedinews@gmail.com the disease. In some cases, PSA screening has led http://twitter.com/DrKKAggarwal Krishan Kumar Aggarwal (Facebook) to expensive and invasive treatments in patients who might never have experienced symptoms. So the ACS is calling on physicians to spend more time counseling patients about their options. The PSA controversy intensified when the scientist who discovered PSA in 1970, Richard Ablin, PhD, from the University of Arizona College of Medicine in Tucson, said categorically that the test should not be used to screen all men older than 50 years. That’s a direct contradiction of the ACS guidelines. Revised Diabetes Guidelines Highlight A1C: Screening technology popped up in the news again in December 2009 when the American Diabetes Association (ADA) published new clinical practice recommendations. The guidelines promote the use of the hemoglobin A1C (A1C) as a faster, easier diagnostic test that could help reduce the number of undiagnosed patients and better identify patients with prediabetes. A1C measures average blood glucose levels for a period of upto three months. Previously it was used only to evaluate diabetic control with time, but because it doesn’t require fasting, A1C testing will encourage more people to get tested, leading to treatments and lifestyle changes that could prevent the worst effects of the disease. Calcium Boosts Heart Attack Risk: Prevention guidelines also made headlines when a large study found that calcium supplements taken without vitamin D may increase the risk for heart attack as much as 30%. Researchers reported the finding online July 29 in BMJ, based on their meta-analysis of 15 randomized trials with upto 11,921 participants. Most guidelines for osteoporosis currently recommend the supplements, despite relatively small benefits in bone health, but senior author Dr Ian R Reid, from the University of Auckland in New Zealand, said that in most cases, ‘discontinuation of calcium would seem appropriate.’ The study raised many questions, such as why calcium could have this effect during a relatively short period of time. Pending further research, some experts advised eating foods high in calcium, rather than taking supplements. FDA Warns against Quinine for Cramps: What do you do when no one pays attention to your guidelines? Issue them again. That was the approach taken by the US FDA July 8 after it noticed that most of the quinine being prescribed in the United States isn’t for the approved indication - uncomplicated malaria - but, rather, for leg cramps. Taking quinine may result in serious and life-threatening hematologic adverse effects. Task Force Revises Mammography Guidelines: 2010 also may also be remembered as the year of the mammoth mammography muddle. On November 17, 2009, the US Preventive Services Task Force called for an end to routine mammography for women younger than 50 years, citing a lack of evidence for benefits in women that young, sparking outrage from screening advocates. On January 6, 2010, however, the American College of Radiology and the Society of Breast Imaging directly contradicted the task force, recommending routine mammography at age 40 years and older. The debate got further fuel from a Swedish epidemiological study of breast cancer, touted as the largest ever, which found that mammography produced a 26% reduction in mortality from breast cancer in women aged 40-49 years. Another study from Norway found that the benefits from mammography screening were modest, however, and an accompanying editorial highlighted the delicate balance between potential benefit and potential harm, concluding that the decision to undergo mammography is ‘a close call.’ As 2011 approaches, that controversy looks likely to continue, along with many others that caught readers’ attention this year. Source: Medscape Indian Journal of Clinical Practice, Vol. 21, No. 8, January 2011
425
Original article
Gastroprotection with Gasex Tablets in GI Disorders and Preradiographic Preparation: A Meta-analysis Mohd. Ali,* D. Palaniyamma**
Abstract The present meta-analysis was conducted to evaluate the efficacy and short- and long-term safety of Gasex tablets in gastrointestinal disorders and in preradiographic preparation of patients, as reported in 17 published study reports. These 17 clinical studies were conducted between 1971 and 1997 in patients with gastrointestinal disorders or those who were sent for preradiographic preparation (790 patients with gastrointestinal disorders and 2,910 patients sent for preradiographic preparation). Patients with gastrointestinal disorders were administered two tablets three times a day for a period of three days to eight weeks, whereas patients sent for preradiographic preparation were administered two tablets three times a day or four tablets four times a day for a period of three days prior to the radiography procedure. Relief from gastrointestinal symptoms and gas-free radiographic findings were taken into consideration. Changes in various parameters from baseline values and values at the end of the study were pooled and analyzed cumulatively using Fisher’s exact test. Statistical analysis was performed using GraphPad Prism Software (Version 4.03). Results of the study showed that patients treated with Gasex tablets had statistically significant relief from gastrointestinal disorders and they also ensured better radiological interpretation in patients sent for preradiographic preparation. No adverse effects were either reported or observed during any of the studies and the overall compliance to the drug was good. Therefore, it can be concluded that Gasex is safe and effective in patients with gastrointestinal disorders and ensures better radiographic images in patients sent for preradiographic preparations. Key words: Gasex, meta-analysis, gastrointestinal
G
astrointestinal disorders form a large group of subjective and objective symptoms known as dyspeptic symptoms, which are prevalent worldwide and are quite common in India in general medical practice. Dyspepsia, also known as stomach upset or indigestion, refers to a condition of impaired digestion.1 Dyspepsia is often used to refer to upper abdominal pain or discomfort but may also encompass symptoms of early satiety, postprandial abdominal bloating or distension, nausea and vomiting.2,3 Dyspepsia can be episodic or persistent with its prevalence ranging from 26% in the United States to 41% in England.4,5 Although only 20-25% of individuals with dyspepsia seek medical care, the problem is responsible for 2-5% of visits to primary care physicians.6 Dyspepsia results in substantial healthcare costs, both direct (due to visits to doctors, expensive tests and medications) and *Professor, Dept. of Gastroenterology MMC and GGH, Chennai **Medical Advisor, R&D Center The Himalaya Drug Company, Makali, Bangalore Address for correspondence Dr D. Palaniyamma Medical Advisor R&D Center, The Himalaya Drug Company Makali, Bangalore - 562 123, Karnataka E-mail: dr.palani@himalayahealthcare.com
Indian Journal of Clinical Practice, Vol. 21, No. 8, January 2011
indirect (due to absenteeism from work and diminished productivity in the workplace).7 An organic cause is found in 40% of patients with dyspeptic symptoms. The most common organic disorders causing dyspepsia include gastroduodenal ulcer, gastroesophageal reflux disease and gastric cancer. In 50% of the patients, no cause is apparent and the dyspepsia is considered to be idiopathic; that is, the diagnosis is essential, functional or nonulcer dyspepsia. The history and physical examination do not reliably differentiate organic from nonulcer dyspepsia.8 Empirical therapy, such as prokinetic therapy, acid suppression, eradication of Helicobacter pylori, psychotropic therapy or antinociceptive therapy, is advisable in patients who do not have signs or symptoms of an underlying organic disorder, such as gastric ulcer or cancer. But there may be few limitations such as short- and long-term effects of the various therapies on symptoms and quality-of-life and costbenefit analyses. Radiographic studies are a great help in visualizing changes in gastrointestinal tract for the diagnosis of pertinent clinical conditions. For accurate and unambiguous radiological diagnosis, a clear picture of the gastrointestinal tract is an important prerequisite. 427
Original article Adequate preradiographic instructions should be given to the patient preparing for the radiographic technique so that the gastrointestinal tract is free from air bubbles, a problem that hampers the technique despite all efforts. On an experimental basis, Gasex tablets were found to be useful in radiography to obtain an accurate diagnosis by showing good contrast in the skiagram by dispelling abdominal gases. Various clinical trials have reported that Gasex tablets are effective in reducing flatulence and dyspepsia and in relieving common gastrointestinal complaints such as flatulence, gaseous abdominal distension, feeling of fullness and colic in the left colonic flexure. Its judicious treatment corrects digestive discomforts and function. Therefore, a metaanalysis was conducted to evaluate the efficacy and short- and long-term safety of Gasex tablets in patients with gastrointestinal disorders and in those who were sent for preradiographic preparation. Meta-analysis is a two-stage process; the first stage is the extraction of data from each study and calculation of the result for each study. The second stage involves deciding whether it is appropriate to calculate a pooled average result across studies. This process gives greater weightage to the results from the studies that give more information because these are likely to be more accurate.9 Advantages of meta-analysis include deriving and statistical testing of overall factors/ effect size parameters in related studies, generalization to the population of studies, ability to control for between-study variation, including moderators to explain variation. Aim of the Study The aim of the present study was to perform a metaanalysis on the efficacy and short- and long-term safety of Gasex in patients with gastrointestinal disorders and in those who were sent for preradiographic preparations, as reported in 17 published study reports.
were sent for preradiographic preparation). Of the 17 trials, 10 (7 open and 3 controlled) were conducted in gastrointestinal disorders and seven (6 open and one controlled trial) were conducted in patients who were sent for preradiographic preparations (Table 1). Demographic details of the meta-analysis are given in Table 2, and symptom-wise distribution of gastrointestinal disorders is listed in Table 3. Table 1. Details of the Studies Included in the Metaanalysis Author
Publication details
No. of subjects
Capsule 1977;8:177
100
Curr Med Pract 1971;2:621
50
Mediscope 1977; xix(12):287
200
Capsule 1978;6:126
46
Probe 1978:XVII(3): 237-238
50
Chandra R, et al24
Indian Pract 1978;3:127
100
al25
Pal V, et al19 Saksena HC, et Ahmed I21 Deshpande SG22 al23
Habibullah CM, et
Balsara AB, et
Probe 1980:XIX(3)187-9
50
Deshmukh RR26
Med Surg 1980;(3):25
50
Mishra DN, et al27
Probe 1981;XX(3):208-211
100
Probe 1982:XXII(1):30-31
100
Probe 1984;XXIII(3):161-3
1,000
Capsule 1985;Aug./ Sep.:57.
100
Saodekar MG, et al31
Med Surg 1985;25(5):10
100
Singh I, et al32
Ind Med J 1986;80(6):87
570
Sarin AK33
Probe 1986;XXV(4):352-3
35
Probe 1987;XXVI(2):132-3
1,000
Probe 1991:XXX(2):128-30
148
Srivastava
PC28
Ashraf Md, et Sharma
al29
N30
Ranjan A34 Srivastava SK, et
al35
Table 2. Demographic Details at Entry No. of patients (n = 3,700)
A (790) Symptomatic relief of GI symptoms including postoperative complaints
B (2,910) preradiographic preparations
Study Design
Age
10-80 years
4-80 years
The present study is a cumulative meta-analysis of 17 published clinical studies of Gasex that were conducted between 1971 and 1997 in patients with gastrointestinal disorders or who were sent for preradiographic preparations (790 patients with gastrointestinal disorders and 2,910 individuals who
Dose and duration of treatment
2 t.i.d., 3 days to 8 weeks
2 t.i.d. to 4 q.i.d. along with/without laxatives
Type of trials
7 open trials 3 controlled/placebocontrolled trials
6 open trials 1 comparative controlled trial
Material and Methods
428
al20
Number of studies: 17
Indian Journal of Clinical Practice, Vol. 21, No. 8, January 2011
Original article Table 3. Symptom-wise Distribution of Patients with Gastrointestinal Disorders (n = 790) Symptom
No. of patients
Percent
Belching/eructation
520
65.82
Flatulence
672
85.06
Fullness of abdomen and abdominal discomfort
372
47.09
Abdominal pain
162
20.51
Epigastric burning/discomfort and hyperacidity
634
80.25
Nausea/vomiting
220
27.85
Irregular bowel habits
69
8.73
Inclusion Criteria
All published studies, which evaluated the role of Gasex in gastrointestinal disorders and preradiographic preparations, were included in the meta-analysis irrespective of the study design. The meta-analysis included clinical trials, which were either controlled or open clinical studies. There were no restrictions regarding sex, age or duration of the disease. The outcome variables included measurement data on changes in clinical symptoms and signs, laboratory results, and incidence of adverse events during/after the treatment and gas-free radiogram. Exclusion Criteria
Phase I studies were excluded from the meta-analysis. Study Procedures
Patients with gastrointestinal disorders were administered two tablets three times a day for a period of three days to eight weeks, whereas patients sent for preradiographic preparation were administered two tablets three times a day or four tablets four times a day with or without laxatives. Relief from gastrointestinal symptoms, clinical recovery and gas-free preradiographic findings were taken into consideration. Also, incidence of adverse events during the study period and compliance to the treatment were also evaluated. Primary and Secondary Outcome Measures
Primary predefined outcomes included clinical recovery from gastrointestinal disorders or preradiographic bowel preparation to ensure a clear radiographic image. Secondary endpoints included safety and compliance to Gasex tablets. Indian Journal of Clinical Practice, Vol. 21, No. 8, January 2011
Statistical Analysis
Statistical analysis was done according to the intentionto-treat principles. Changes in various parameters from baseline values and values at the end of the study were pooled and analyzed cumulatively using Fisherâ&#x20AC;&#x2122;s exact test. Values are expressed as mean Âą SD or as incidences of patients with or without symptoms. The minimum level of significance was fixed at 95% confidence limit and a two-sided p value <0.05 was considered significant. Statistical analysis was performed using GraphPad Prism Version 4.03 for Windows, GraphPad Software, San Diego, California, United States, www. graphpad.com. Results Results of the study showed that belching, which was reported in 520 individuals at entry, was significantly improved in 89.61% of patients treated with Gasex (p < 0.0001) and only 54 patients had the symptoms at the end of the treatment. Flatulence, which was reported in 622 patients at entry, was improved in 92.56% with a significance of p < 0.0001. Also, fullness of abdomen, abdominal discomfort, abdominal pain, epigastric burning, discomfort and acidity, nausea and vomiting, and irregular bowel habits showed significant improvements (p < 0.0001). The overall symptomatic relief was significant in 91.39% of the patients (p < 0.0001). The effect of Gasex tablets in patients with gastrointestinal disorders is shown in Table 4. Gastrointestinal discomfort as evaluated in three controlled clinical trials showed that of the 175 patients treated with Gasex, 152 showed overall symptomatic relief (p < 0.0001), whereas only 38 of the 125 patients responded to the treatment in the placebo group (Table 5). Radiographic procedure-wise distribution of the patients (2,910) are listed in Table 6 with the maximum number of patients being subjected to plain X-ray of the abdomen (1,785) followed by cholecystography (300), intravenous pyelography (170) and other investigations such as dorsolumbar and barium meal (655). Among the 1,785 patients subjected to plain X-ray of the abdomen, 95.6% showed gas-free radiographs with a significance of p < 0.0001. Of the 300 patients who underwent cholecystography, 429
Original article Table 4. Symptomatic Relief in Presenting Symptoms of Gastrointestinal Disorders Parameter
Treatment Present Absent Significance (% protection)
Overall symptomatic relief
Before After
790 68
0 722
p < 0.0001* (91.39%)
Belching/ eructations
Before After
520 54
270 736
p < 0.0001* (89.61%)
Flatulence
Before After
622 50
118 740
p < 0.0001* (92.56%)
Fullness of abdomen and abdominal discomfort
Before After
372 63
418 727
p < 0.0001* (83.06%)
Abdominal pain
Before After
162 65
628 725
Epigastric Before burning/ After discomfort and hyperacidity
634 78
156 712
Nausea/ vomiting
Before After
220 62
570 728
Irregular bowel habits
Before After
69 8
721 782
Percent
Plain X-ray of abdomen
1,785
61.34
Cholecystography
300
10.31
IVP
170
5.84
Others (dorsolumbar and lumbosacral spine, barium meal follow through, calculi in KUB and hysterosalpingography
655
22.51
Table 7. Gasex Meta-analysis - Preradiographic Preparation Significance (% protection)
p < 0.0001* (59.88%)
Overall response
Before After
2,910 0 97 2,813
p < 0.001 (96.7)
p < 0.0001* (87.70%)
Plain X-ray of abdomen
Before After
1,785 0 79 1,706
p < 0.0001 (95.6)
Cholecystography
Before After
300 10
0 290
p < 0.0001 (96.7)
p < 0.0001* (71.82%)
IVP
Before After
170 5
0 165
p < 0.0001 (97.1)
p < 0.0001* (88.41%)
Others (dorsolumbar and lumbosacral spine, barium meal follow through, calculi in KUB and hysterosalpingography
Before After
655 3
0 652
p < 0.0001 (99.5)
Overall symptomatic relief
Statistical analysis: Fisher’s exact test
Gasex
Placebo Gasex
Placebo
100
50
50
43/50
14/30
Table 8. Comparison of Placebo-controlled Trials versus Gasex in Preradiographic Preparation (Plain X-ray of Abdomen)
150
100
50
88/100
16/50
Group
50
25
25
21/25
8/25
300
175
125
152/175 (86.86%)
38/125 (30.4%)
Statistical analysis: Fisher’s exact test
radiographic findings were good in 290 with a significance of p < 0.0001. In individuals who were sent for intravenous pyelography and other investigations, significantly clear radiographic images were observed in those treated with Gasex tablets. The overall response to the treatment was good with 2,813 of 2,910 patients showing significant improvement in their symptoms (p < 0.0001; Table 7). 430
No. of patients
Treatment Contrast
Table 5. Meta-analysis of Gasex in Relief of GI Symptoms Including Postoperative Complaints: Placebo-controlled Trial No. of patients
Radiography procedure
Radiography procedure
*Statistical analysis: Fisher’s exact test
Total no. of patients
Table 6. Radiography Procedure-wise Distribution of Patients (n = 2,910)
Control (no treatment) Gasex
Total no. of patients 20
Response significance
Response (%)
4/20 (NS)
20
1,785
1,706/1,785 (p < 0.0001) 31/40 (p < 0.0001)
95.6
Charcoal enzyme 40 (comparative control)
77.50
In the comparative controlled clinical study for preradiographic preparation, response to Gasex was found to be >90% as compared to 77.5% of patients treated with placebo (Table 8). There were Indian Journal of Clinical Practice, Vol. 21, No. 8, January 2011
Original article no adverse effect in all the studies included in the metaanalysis and compliance to the study drug was good. Discussion The number of papers published on meta-analysis in medical research has increased sharply in the past decade; however, the merits and perils of the metaanalysis continue to be debated in the medical community.10,11 A useful definition of meta-analysis was given by Huque as: “A statistical analysis that combines or integrates the results of several independent clinical trials considered by the analyst to be combinable.”12 A single study often cannot detect or exclude with certainty clinically relevant differences in the effects of two treatments. Cumulative meta-analysis is defined as the repeated performance of meta-analysis whenever a new trial becomes available for inclusion. Such cumulative meta-analysis can retrospectively identify the point in time when a treatment effect first reached conventional levels of significance.13 Meta-analysis thus not only consists of the combination of data but also includes the epidemiological exploration and evaluation of results (‘epidemiology of results’).14 Therefore, new hypotheses that were not posed in single studies can be tested in metaanalyses.15 The number of patients included in clinical trials is often inadequate, as in some cases the required sample size may be difficult to achieve.16 Meta-analysis may, nevertheless, lead to the identification of the most promising or urgent research question and may permit a more accurate calculation of the sample sizes needed in future studies.17 Goals of the meta-analysis are to enable the overall significance of an effect to be evaluated, based on the multiple studies available, to estimate an overall effect size by combining the individual estimates in multiple studies.18 In the present meta-analysis, clinical trials and their details were tabulated and analyzed statistically. The outcome of this analysis showed marked improvement with Gasex in patients with gastrointestinal disorders and those who were sent for preradiographic preparations. The efficacy of Gasex tablets may be attributed to the synergistic actions of the potent gastroprotective herbs in the formulation. One such herb, Aconitum palmatum is found to be effective in dyspepsia, stomach irritability and nausea36 due to its gastro-supportive activity. Roots of the herb Indian Journal of Clinical Practice, Vol. 21, No. 8, January 2011
contain diterpenoid alkaloids–15-deacetyl vakogavine, plamidine, palmasine, and hetidine. Cowrie, the wellknown name of natural processed calcium carbonate, is used in dyspepsia, indigestion, sprue, duodenal and gastric ulcers, and hyperacidity.37,38 In Indian system of medicine, Shankha bhasma derived from conch shell is used in the treatment of ulcers, dysentery, dyspepsia, indigestion, and jaundice. The constituent of Shankha bhasma is mainly silicate of magnesia. It may act as a gastric cytoprotective agent by modulating the scavenging of free radicals. In one of the trials, it was noted that Shankha bhasma showed dose-dependent reduction of ulcer index in indomethacin-treated rats as well as in rats subjected to cold restraint stress, when compared with control. It showed reduction in thiobarbituric acid reactive substance content of stomach tissue in indomethacintreated ulcer group.39 The major principles present in the fruits of Piper nigrum include piperine and pipertine. Piperine is reported to have antioxidant activity and may contribute to the prevention of gastric ulcerations.40 It is known to protect the stomach against ulceration by decreasing the volume of gastric juice, gastric acidity and pepsin-A activity in doses of 1.5 mg/kg and 25 mg/kg after intravenous and oral administrations, respectively.41 Also, the herb is reported to have inhibitory effect on Escherichia coli. Embelia ribes has been found to be effective against helminthes and is also reported to have analgesic and antibacterial activities, which may help in preventing gastric ulcerations.42 Triphala, a homogenous mixture of three fruits— Emblica officinalis, Terminalia chebula and Terminalia bellerica—is one of the most commonly used herbal remedies in Ayurveda. It is a rich source of vitamin C, ellagic acid, gallic acid, and chebulinic acid. Triphala extract is found to be able to scavenge free radicals such as DPPH and superoxide. The phenolic compounds present in these extracts are mostly responsible for their radical scavenging activity, and may be helpful in various gastric problems.43,44 Zingiber officinale, used to treat various gastrointestinal tract disorders, is known to possess anti-emetic, stomachic and carminative properties. The diterpene lactone present in Z. officinale may be responsible for 431
Original article its antipeptic ulcer activity, which indicates a significant cytoprotective and gastric anti-ulcer activity.45 Gasex tablet renormalizes the intestinal transit time. It has prebiotic, antiflatulent and antacid, antiulcer, anti-inflammatory, hepatoprotective, cholagogue, membrane-modulating, antimicrobial, anti-amebic and antioxidant activities. Due to the above-specified activities, Gasex tablet exerts carminative and antispasmodic actions that support the digestive function. Summary and Conclusion The outcome of the meta-analysis of 17 clinical studies showed that treatment with Gasex tablets significantly improved the presenting symptoms of gastrointestinal disorders and helped in preradiographic bowel preparation by eliminating gas shadows, ensuring better radiological interpretation, avoiding repeated exposures and reducing the cost. In all the trials, the overall drug compliance was good. Gasex tablet is a multi-ingredient formulation recommended for the management of common digestive disorders. It expels trapped gas, provides quick relief from flatulence and bloating, corrects digestive dysfunction, and eases abdominal discomfort. References 1. Talley NJ, et al. Am J Gastroenterol 2005;100(10): 2324-37. 2. Camilleri M. Mayo Clin Proc 1996;71(6):614-22. 3. Barbara L, et al. Dig Dis Sci 1989;34(8):1272-6. 4. Talley NJ, et al. Gastroenterology 1992;102(4 Pt 1): 1259-68. 5. Jones R, et al. BMJ 1989;298:30-2. 6. Brown C, et al. BMJ 1990;300:829-30. 7. NyrĂŠn O, et al. J Clin Gastroenterol 1986;8(3 Pt 2): 339-45.
13. 14. 15. 16. 17.
18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40.
8. Johannessen T, et al. Scand J Gastroenterol 1990; 25(7):689-97.
41.
9. 10. 11. 12.
42. 43. 44. 45.
Green S. Singapore Med J 2005;46(6):270-3. Naylor CD. BMJ 1997;315:617-9. Bailar JC 3rd. N Engl J Med 1997;337(8):559-61. Huque MF. Proc Biopharm Sect Am Stat Assoc 1988;2:28-33.
Lau J, et al. N Engl J Med 1992;327(4):248-54. Jenicek M. J Clin Epidemiol 1989;42(1):35-44. Gelber RD, et al. Stat Med 1987;6(3):371-8. Collins R, et al. BMJ 1992;304:1689. Chalmers I. Randomised controlled trials of fetal monitoring 1973-1977. In: Perinatal Medicine. Thalhammer O, Baumgarten K, Pollak A, (Eds.), Thieme: Struttgart 1979:260. Andrews G, et al. Arch Gen Psychiatry 1981;38: 1203-8. Pal V, et al. Capsule 1977;8:177. Saksena HC, et al. Curr Med Pract 1971;2:621. Ahmed I. Mediscope 1977;XIX(12):287. Deshpande SG. Capsule 1978;6:126. Habibullah CM, et al. Probe 1978:XVII(3):237-8. Chandra R, et al. Indian Pract 1978;3:127. Balsara AB, et al. Probe 1980:XIX(3):187-9. Deshmukh RR. Med and Surg 1980;3:25. Mishra DN, et al. Probe 1981;XX(3):208-11. Srivastava PC. Probe 1982;XXII(1):30-1. Ashraf Md, et al. Probe 1984;XXIII(3):161-3. Sharma N. Capsule 1985;Aug./Sept.:57. Saodekar MG, et al. Med Surg 1985;25(5):10. Singh I, et al. Ind Med J 1986;80(6):87. Sarin AK. Probe 1986;XXV(4):352-3. Ranjan A. Probe 1987;XXVI(2):132-3. Srivastava SK, et al. Probe 1991; XXX(2):128-130. Khare CP. Encylopedia of Indian Medicinal Plants. Springer, Germany 2004:16. Mishra S. Ayurvediya Rasa Shastra. Chaukhamba Orientalia Varanasi. 7th edition, 1997:481. Collings KL, et al. Aliment Pharmacol Ther 2002;16(12): 2029-35. Pandit S, et al. Ind J Pharmacol 2000;32:378-80. Khare CP. Encylopedia of Indian Medicinal Plants. Springer, Germany 2004:379. de Sousa FalcĂŁo H, et al. Molecules 2008;13(12): 3198-223. Tabassum N, et al. JK Practitioner 2003;10(1):43-4. Sabina EP, et al. Res J Med Plant 2007;1(2):54-9. Naik GH, et al. Phytother Res 2005;19(7):582-6. Al-Yahya MA, et al. Am J Chin Med 1989;XVII, (1-2):51-6.
n
432
n
n
Indian Journal of Clinical Practice, Vol. 21, No. 8, January 2011
Practice Guidelines
Updated Recommendations on Daily Aspirin Use in Patients with Diabetes
P
ersons with diabetes mellitus have two to four times the risk of cardiovascular events compared with persons of the same age and sex who do not have the disease. Coronary heart disease (CHD) is responsible for more than two-thirds of deaths in persons with diabetes who are older than 65 years. Although aspirin has been proven to reduce cardiovascular morbidity and mortality rates in high-risk patients with myocardial infarction or stroke, its benefit is unclear in patients without a history of cardiovascular events. In 2007, the American Diabetes Association and American Heart Association recommended aspirin therapy (75 to 162 mg daily) for primary prevention in patients with diabetes who had increased CHD risk (e.g., older than 40 years, smoking, family history of cardiovascular disease). Since these recommendations were published, new evidence has raised questions about the effectiveness of this strategy. The U.S. Preventive Services Task Force recently recommended that physicians encourage aspirin use in men 45 to 79 years of age and in women 55 to 79 years of age, regardless of whether they have diabetes. To address the uncertainties about aspirin use in persons with diabetes, experts from the American Diabetes Association, American Heart Association, and American College of Cardiology Foundation reviewed the current evidence and updated the 2007 recommendations. The group organized its recommendations around the following questions: What is the evidence for aspirin in preventing initial cardiovascular events in patients with diabetes? How can the conflicting results of various primary prevention trials be reconciled? What are the risks of aspirin therapy, and are these risks similar for patients with diabetes compared with those for patients without the disease? What is the recommended dosage? How should the potential benefits and risks of aspirin therapy be integrated to determine which patients should take aspirin daily for the primary prevention of cardiovascular events? Source: Adapted from Am Fam Physician. 2010;82(12):1559-1563.
The current evidence on aspirin therapy for prevention of cardiovascular disease includes three trials conducted in patients with diabetes, and six trials containing subgroups of patients with diabetes. None of these trials provides definitive results, so the group performed a meta-analysis to reconcile the available data. Data from subgroups of patients with diabetes from the six trials were included in a previous meta-analysis by the Antithrombotic Trialists’ Collaboration. These were combined with data from the Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes study, the Prevention of Progression of Arterial Disease and Diabetes trial, and the Early Treatment of Diabetic Retinopathy Study. A random-effects model showed that aspirin use is associated with nonsignificant decreases in the risk of CHD events (relative risk [RR] = 0.91; 95% confidence interval [CI], 0.79 to 1.05) and of stroke (RR = 0.85; 95% CI, 0.66 to 1.11). The results of the diabetes-specific analyses are consistent with the findings of the previous meta-analysis, and suggest that aspirin use likely reduces the risk of cardiovascular disease to a modest degree in patients with diabetes. Adverse effects of aspirin therapy include intracranial bleeding (hemorrhagic stroke) and extracranial bleeding (mainly gastro-intestinal [GI]). Several cardiovascular risk factors also increase the risk of extracranial bleeding, which suggests that persons at higher risk of CHD events are also at higher risk of aspirinrelated adverse effects. Current evidence supports the use of proton pump inhibitors to decrease the risk of recurrent aspirin-related GI bleeding. However, routine use of these agents may not be cost-effective, and it is not clear whether they should be recommended for primary prevention of GI bleeding. The optimal dosage of aspirin for prevention of CHD events is not clear. The average daily dosage used in primary prevention trials that included persons with diabetes ranged from 50 to 650 mg. The risk reductions achieved with low dosages (75 to 162 mg per day) seem to be similar to those obtained with higher dosages. Although platelets from patients with diabetes have Cont’d on page 441...
Indian Journal of Clinical Practice, Vol. 21, No. 8, January 2011
433
Infectious disease
Seasonal Influenza - Role of Amantadine in Combination Therapy Avinash Kulkarni*, Abhay Chowdhary**, K Krishnaprasad†, R Lalchandani†, Jejoe Karankumar†
Abstract Influenza remains an enigma and rears its ugly head time and again, with the recent outbreaks being a pointer to this direction. However, seasonal influenza often remains endemic that is neglected or underdiagnosed. The overlapping respiratory symptoms and aftermath of uncontrolled infection in such cases often leads to secondary bacterial infections including otitis media, bronchitis and pneumonia in high-risk population including pediatrics. Early treatment with antivirals or virostatic agents in diagnosed or clinically suspected cases not only reduces the hospitalization rate but also further spread of the disease by reducing the extent or quantity of viral shedding. Amantadine belonging to adamantanes was the first antiviral agent suitable for general use in the management of seasonal influenza A. Despite the regulated availability of newer advanced antiviral agents, international guidelines including WHO (2010) and IDSA (2009) continue to recommend amantadine use in seasonal influenza A (H1N1) even in suspected cases. This was again confirmed in a local in vitro study conducted at Haffkine Institute, Mumbai where the current prevalent strains of seasonal influenza were found to be sensitive to amantadine. Amantadine, unlike the other antivirals, checks the early step of viral cycle by preventing its uncoating thereby decreasing the duration of illness or further spread by reducing the viral load. However, due to the concomitant presence of respiratory symptoms at the time of diagnosis, ancillary administration of an analgesic, antihistaminic and decongestant along with amantadine would be useful in taking care of the viral load and associated symptoms. Key words: Seasonal influenza A (H1N1), pediatrics, amantadine
I
nfluenza remains an enigma and better known for the wrong reasons since it has an uncanny ability to cause ‘outbreaks’ that have high rates of morbidity and mortality. Seasonal Influenza Seasonal influenza is an acute viral infection caused by an influenza virus. Seasonal influenza virus has a long history with its first appearance in 1977. This was apparently through an accidental laboratory release but more importantly it still continues to circulate in humans1,2 causing endemic infection that often remains neglected or underdiagnosed. There are three types of seasonal influenza virus strains viz. A, B and C. Of these, Type A influenza virus is highly virulent and further subdivided into subtypes according to different kind or combination of virus surface proteins for hemagglutinin (H) and neuraminidase (N) as shown in Figure 1.
*Consultant Pediatrician, New Delhi **Director, Haffkine Institute, Mumbai †Medical Team, Glenmark Pharmaceuticals Ltd.
Indian Journal of Clinical Practice, Vol. 21, No. 8, January 2011
Nucleoprotein (RNA) Neuraminidase (N) (Sialidase) Lipid envelope Capsid
Hemagglutinin (H)
Figure 1. Seasonal influenza A virus anatomy.
Amongst the Type A influenza viruses, H1N1 and H3N2 are currently in circulation in several parts of the globe including India.1 In tropical countries including India, these influenza viruses tend to circulate throughout the year but they usually peak during monsoon and winters. In one of the epidemiological studies done in India at Haffkine Institute, Mumbai, out of the ≅5,000 respiratory isolates collected during August 2009-10, 15% were related to seasonal influenza A.3 Influenza A H1N1 is of two types: Seasonal and Pandemic strains. Pandemic influenza is differentiated 435
Infectious disease
Complication (%)
by different subtype protein present on the surface of the virus. In an observational study by Centers of Disease Control (CDC), USA, that was published in JAMA,4 patients with Pandemic or Seasonal influenza A were compared for serious outcome or complication rates during the course of the disease. 10 9 8 7 6 5 4 3 2 1 0
Seasonal Pandemic
3.7 1.5
2.5
Pneumonia
1.5 Hospitalization
Figure 2. Serious outcome rates in patients with seasonal or pandemic influenza.
Seasonal influenza caused similar rates of complications including pneumonia compared to pandemic influenza (1.5 vs 2.5) with higher rates of hospitalization (3.7 vs 1.5) as shown in Figure 2. As against the Type A influenza viruses, Type B and C influenza viruses cause only mild illness in children and are of less clinical significance.5 Clinical Profile Symptoms traditionally associated with influenza include fever, myalgia, malaise, nonproductive cough, sore throat, headache, inability to carry out daily activities and need for bed rest. The symptoms are overlapping with other respiratory conditions6 and in such cases fever (>38°C), cough, headache, rhinorrhea, a normal chest radiograph and absence of leukocytosis are usually predictive of seasonal influenza.7 The diagnosis of seasonal influenza amongst the other viral strains is extremely difficult since it involves detection of minor changes on the surface of the virus. The only specific or sensitive diagnostic test available in this line remains reverse transcriptase polymerase chain reaction (RT-PCR). This however has its own set of limitations, with the respiratory secretions or samples needed to be collected within three days of symptom onset, the procedure being costintensive with nonavailability of diagnostic centers in other parts of the country. 436
Complications Seasonal influenza often has the potential to cause complications including bacterial pneumonia, otitis media, sinusitis, bronchitis, dehydration, worsening of chronic medical conditions. Apart from elderly individuals, certain patients with seasonal influenza virus infection are recognized to be at higher risk of developing severe or complicated illness. These include: Infant and young children Person of any age with chronic pulmonary disease (e.g., asthma, COPD) Person of any age with chronic cardiac disease (e.g. congestive cardiac failure) Person with metabolic disorders (e.g. diabetes) Person with chronic renal disease, chronic hepatic disease Immunosuppressive conditions, such as HIV infection, or secondary conditions, such as immunosuppressive medication or malignancy Children receiving chronic aspirin therapy The high rate of complications in this high-risk population was again highlighted in an epidemiological study conducted by the CDC.8 The results as shown in Table 1, showed that children had higher incidence of serious outcomes including hospitalization rate as a result of seasonal influenza virus infection. Table 1. Hospitalization Rates with Seasonal Influenza in Children and Adults Age group
Hospitalization rate High-risk group
Non High-risk group
0-11 months
808
274
1-2 years
471
72
3-4 years
231
39
5-14 years
92
23
15-44 years
62
16
45-64 years
318
22
>65 years
507
182
Indian Journal of Clinical Practice, Vol. 21, No. 8, January 2011
Infectious disease Management While in most cases of influenza, management is usually supportive and symptomatic, antiviral therapy is particularly recommended for high-risk patients with seasonal influenza A. Since, there is a high-degree of underdiagnosis and therefore related complication rate, therapy with antiviral drugs is recommended even in suspected cases of seasonal influenza. Antiviral therapy for influenza typically comprises of Adamantanes (Amantadine, Rimantadine) and Neuraminidase inhibitors (Oseltamivir and Zanamivir). Amantadine Amantadine hydrochloride (1-adamantamine hydrochloride) was the first antiviral to be licensed worldwide for infections of influenza A (H1N1, H2N2 and H3N2) and has extensive clinical evidence as compared to rimantadine. Amantadine acts by inhibiting the specific ion channel or protein (M2), as shown in Figure 3, which are present on the outer surface of the seasonal influenza virus. Neuraminidase Hemagglutinin
RNA Amantadine
X M2 protein
Figure 3. Site of action for amantadine.
international guidelines. The recently updated guidelines by CDC May 201010 have shown continued susceptibility of seasonal influenza A strains to amantadine according to their in vitro susceptibility studies. In addition, according to WHO, Feb. 201011 ‘Where the infection is known or suspected to be due to seasonal influenza A (H1N1) virus, oseltamivir is unlikely to be effective, but amantadine be used in such cases’. Oseltamivir is usually reserved for swine flu or pandemic influenza. However, in line with IDSA 2009, guidelines12 on the management of influenza, use of antiviral therapy is usually recommended based on the local patterns of viral strains in circulation and their sensitivity to the drugs. Amantadine Sensitivity to Local Strains: Haffkine Study
In an in vitro study conducted at the Haffkine Institute of Virology, Mumbai, the current prevalent strains viz. seasonal influenza A H1N1/Pune/2009 and seasonal influenza A H3N2/Pune/2010 were tested for sensitivity to amantadine.3 The virus was grown in MDCK cells with varying concentrations of amantadine hydrochloride in titre wells. Additionally, there was a virus control (VC) arm where the virus was grown without instilling amantadine. The system was incubated for five days and the virus titer was estimated by Hemagglutination Assay (HA). The results showed that amantadine in varying concentrations of 1 to 10 µg/ml showed hemagglutination. Hemagglutination as depicted as ‘Button’ signifies inhibition of influenza virus as shown in Figure 4.
Inhibition of this M2 ion channel prevents the uncoating or release of viral RNA that is essential for its replication and therefore growth. This contributes to the virostatic action of amantadine.9 Amantadine therefore acts on the second step of the viral cycle, ultimately preventing infection and formation of new daughter viruses while oseltamivir inhibits the last step of viral cycle, preventing only the release of these newly formed viruses. Despite its long history of use, amantadine still continues to be recommended by most of the Indian Journal of Clinical Practice, Vol. 21, No. 8, January 2011
Figure 4. Hemagglutination assay for seasonal influenza A, H1N1 and H3N2 strains.
437
Infectious disease
Amantadine at concentrations of 5 and 10 µg/ml showed complete inhibition of influenza Type A (H1N1 and H3N2) as compared to VC arm viral control as shown in Table 2. Table 2. Seasonal Influenza Viruses Inhibited at Different Concentrations of Amantadine HCl Amantadine concentration
Hemagglutinin Titer A (H1N1)
A (H3N2)
10 µg/ml
-
-
5 µg/ml
-
-
2.5 µg/ml
1:4
-
1 µg/ml
1:4
-
Virus control
1:16
1:16
At the same time there was a fourfold decrease in the virus titer from 1:16 (virus control arm) to 1:4 when the system was incubated with amantadine in varying concentrations of 1 to 2.5 µg/ml for A (H1N1). This confirmed the virostatic action of amantadine that is relevant while managing patient with seasonal influenza. Clinical Benefits with Amantadine
Decreases viral load and inflammation thereby decreasing associated symptoms of pyrexia and peripheral airway dysfunction found in such cases.9 Decreases viral load and therefore viral shedding preventing further spread in children who are in close contact.13 Virostatic action of amantadine improves immunological response of the body by decreasing further chances of recurrence or severe infection.14
Clinical Efficacy Studies with Amantadine
The efficacy of amantadine in managing influenza A has been established extensively in several trials with different virus strains. Amantadine when given within 48 hours of symptom onset results in more rapid abatement of fever, decreased duration of illness, a shortened period of virus shedding.13 438
Kitamoto15 found more rapid abatement of fever in 30 children with influenza A, when amantadine therapy was started within 48 hours of the onset of the illness. Baker, Shock and Iezzoni in a controlled, doubleblind study of 13 patients of influenza showed clearing of symptoms within 36 hours.16
Clinical Efficacy of Amantadine Compared to NSAIDs
Clinical studies have clearly demonstrated the benefits of amantadine when administered within the first two days of symptoms for patients with seasonal influenza. Lao et al17 therefore conducted a comparative study evaluating the efficacy of amantadine versus nonsteroidal anti-inflammatory drugs (NSAID) therapy since supportive therapy in form of antipyretics usually forms the initial line of management in such cases. An open, randomized study was conducted on 60 patients with clinical suspicion of seasonal influenza, who presented with sudden onset of illness with chills and fever and marked prostration, tiredness or body weakness, anorexia, muscular aches/pains, cough/coryza, flushed face, conjunctival redness and leukopenia. Amantadine or NSAID, were administered for four days. The results as depicted in Figure 5 showed that on the 3rd day of follow-up, there were better patient responder rates in terms of rapid relief of symptoms by 83.3% in the amantadine group as against 16.6% in the NSAID group. 90
83.3
80 Patients with rapid relief at the end of 3rd day (%)
The VC arm did not show any hemagglutination or ‘Button’, signifying growth of the virus.
70 60 50 40 30 20
16.6
10 0
Amantadine
NSAID
Figure 5. Percentage patients with rapid relief of symptoms at the end of 3rd day with amantadine or NSAIDs.
Indian Journal of Clinical Practice, Vol. 21, No. 8, January 2011
Infectious disease Amantadine administration compared to NSAID therapy resulted in significantly greater relief from the symptoms of influenza on the 3rd day of follow-up. In line with the antiviral action of amantadine, nearly all of patients on NSAIDs who had symptomatic control had subsequent recurrence of symptoms. This has indirect impact on patient compliance and QOL since the continued persistence of symptoms often increases complication rate and therefore the need for antibiotics. In addition, none of the patients developed any of the central or gastrointestinal side effects with amantadine during the course of the study. Similarly, in yet another double-blind, randomized study by Younkin et al,18 the efficacy and safety of amantadine was compared to NSAIDs in virologically confirmed cases of seasonal influenza. In this study, 47 patients with at least two of the following symptoms (of less than 48-hour duration) including headache, myalgia, cough or feverishness were administered either amantadine or NSAID for five days. At the end of four days, patients on NSAID had quicker disappearance of fever; however, significantly more number of these patients had recurrence of symptoms since there was persistence of influenza virus in this group. This was confirmed by the high rate of viral shedders in the NSAID group at the end of four days of therapy. As shown in Figure 6, the percentage of patients showing viral shedding was higher in NSAID group (92% vs 62%) as compared to amantadine. The only side effects noted were dizziness, insomnia
Patients with shedding virus on 4th day (%)
130 120 110 100
92
90 80 62
60 50
Role of Amantadine in Combination Therapy Amantadine is highly specific for the influenza virus, taking care of the viral load rapidly. This was further highlighted by Wingfield et al19 who conducted a double-blind randomized study in influenza patients with amantadine. The results showed that amantadine therapy resulted in quicker resolution of fever compared to the concomitant respiratory symptoms. Taking this into consideration and the drawbacks associated with definitive diagnosis of influenza, a combination of amantadine with supportive therapy involving antihistaminic, decongestant and analgesic would be useful in taking care of the entire spectrum of symptoms. This would also be desirable and clinically relevant in most of the cases, since influenza with its short incubation period has the potential to cause complications rapidly if left untreated. Similarly, the synergy in this combination therapy was again highlighted by Junker et al13 and Younkin et al18 who looked into the specific issues of insomnia and slow action with amantadine. This combination therapy is therefore expected to offer quicker, symptomatic relief not only from fever (amantadine reduces viral load) but also from associated symptoms of rhinitis, nasal block, bodyache. At the same time, combination therapy improves patient compliance and convenience since there is less number of concomitant medications to be given. This has important implications since the high-risk population is extremely susceptible to developing severe symptoms or complications that may require hospitalization.
140
70
and concentration difficulties; however, these did not require treatment discontinuation.
Amantadine
NSAID
Figure 6. Percentage viral shedders in amantadine group compared to NSAID group at the end of four days.
Indian Journal of Clinical Practice, Vol. 21, No. 8, January 2011
Summary Influenza virus infection has significant societal impact since it causes high rates of morbidity and mortality, especially in young children who may be immunocompromised or suffering from allergic disorders including asthma. Otherwise too, children generally have higher viral load than adults, and shed virus for at least 10 days20 leading to concomitant affliction of family members or spread in schools 439
Infectious disease where there are in close contact. Early treatment with antiviral therapy is helpful in preventing the complications and the spread of the disease even in suspected cases as recommended by international guidelines. Local sensitivity and WHO/IDSA guidelines continue to recommend amantadine in the management of seasonal influenza A. However, taking into consideration the concomitant presence of respiratory symptoms at the time of diagnosis, ancillary administration of analgesic (paracetamol), antihistaminic (chlorpheniramine maleate), phenylephrine (decongestant) along with amantadine is useful in taking care of the viral load and symptoms associated with seasonal influenza.
abnormalities in influenza. A study in 15 students with natural influenza. A study in 15 students with natural influenza A infection. Ann Intern Med 1976;85(2): 177-82. 10. Flu View. A Weekly Influenza surveillance report prepared by Influenza Division, CDC. 2009-2010 Influenza Season - Week 19, Ending, May 16, 2009. 11. WHO Guidelines for Pharmacological Management of Pandemic Influenza A (H1N1) 2009 and other Influenza Viruses. Revised Feb., 2010, Part I: Recommendations.
References
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3. Mukherjee S, Roy S, Dahake R, Chowdhary A. Invitro susceptibility of influenza viruses to amantadine hydrochloride. Bull Haffkine Institute 2011;13(1):58‑9.
15. Kitamoto O. Therapeutic effectiveness of amantadine hydrochloride in naturally occurring Hong Kong influenza: double-blind studies. Jpn J Tuberc Chest Dis 1971;17(1):1-7.
4. Belongia EA, Irving SA, Waring SC, Coleman LA, Meece JK, Vandermause M, et al. Clinical characteristics and 30-day outcomes for influenza A 2009 (H1N1), 20082009 (H1N1), and 2007-2008 (H3N2) infections. JAMA 2010;304(10):1091-8.
16. Baker LM, Shock MP, Iezzoni DG. The therapeutic efficacy of Symmetrel (amantadine hydrochloride) in naturally occurring influenza A2 respiratory illness. J Am Osteopath Assoc 1969;68(12):1244-50.
5. Wright PF, Webster RG. Orthomyxoviruses. In: Fields Virology. Knipe DM, Howley PM (Eds.), Lippincott Williams and Wilkins, Philadelphia 2001:1533-79. 6. Ebell MH, White LL, Casault T. A systematic review of the history and physical examination to diagnose influenza. J Am Board Fam Pract 2004;17(1):1-5. 7. Barry MA. A 29-year-old woman with flu-like symptoms: review of influenza diagnosis and treatment. JAMA 2010;304(6):671-8. 8. Influenza and influenza vaccines. Clinicians outreach and communication activity, CDC 2007-2008 season. http://www.bt.cdc.gov/coca/ppt/Influenza102307.ppt. Accessed on 24th Dec’ 2010. 9. Little JW, Hall WI, Douglas RG Jr, Hyde RW, Speers DM. Amantadine effect on peripheral airways
17. Lao LM, Lao MLM, Gonzaga Z, Mijanes G. Amantadine in the treatment of influenza: an open randomized trial. Phil J Microbiol Infect Dis 1980;9(2):129-34. 18. Younkin SW, Betts RF, Roth FK, Douglas RG Jr. Reduction in fever and symptoms in young adults with influenza A/Brazil/78 H1N1 infection after treatment with aspirin or amantadine. Antimicrob Agents Chemother 1983;23(4):577-82. 19. Wingfield WL, Pollack D, Grunert RR. Therapeutic efficacy of amantadine HCI and rimantadine HCI in naturally occurring influenza A2 respiratory illness in man. N Engl J Med 1969;281:579-84. 20. Frank AL, Taber LH, Wells CR, Wells JM, Glezen WP, Paredes A. Patterns of shedding of myxoviruses and paramyxoviruses in children. J Infect Dis 1981; 144(5):433-41.
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Practice guidelines ...Contâ&#x20AC;&#x2122;d from page 433 altered function, it is not clear whether this affects the recommended dosage of aspirin for cardioprotection. There are alternate pathways for platelet activation and aggregation that are independent of thromboxane A2 and are therefore not sensitive to the effects of aspirin. The evidence is insufficient to empirically recommend higher dosages of aspirin for patients with diabetes. In adults with cardiovascular risk greater than 1 percent per year, the number of CHD events prevented will be approximately equal to or greater than the number of bleeding events induced, although these events (myocardial infarction, stroke, and GI bleeding) do not have equal effects on long-term health. Recommendations Low-dose aspirin therapy is reasonable in adults with diabetes and no history of vascular disease, whose 10year risk of CHD events is greater than 10 percent, and who are not at increased risk of bleeding (i.e., no history of GI bleeding or peptic ulcer disease, and no concurrent use of other medications that increase bleeding risk). Adults with diabetes who are at increased risk of CHD events include most men older than 50 years and women older than 60 years who have at least one additional major risk factor (i.e.,
smoking, hypertension, dyslipidemia, albuminuria, or family history of premature cardiovascular disease). Aspirin should not be recommended in adults with diabetes who are at low risk of cardiovascular events (men younger than 50 years and women younger than 60 years with no additional major risk factors). The potential adverse effects from bleeding offset the potential benefits in these patients. Low-dose aspirin therapy may be considered for patients with diabetes who are at intermediate risk of CHD events (younger patients with at least one risk factor, older patients with no risk factors, or patients with a 10-year risk of 5 to 10 percent). These recommendations depend on the accurate assessment of CHD risk. Not all patients with diabetes are at high risk, and the use of a risk prediction tool is essential. There are several Web-based tools available, such as the UK Prospective Diabetes Study Risk Engine (http://www.dtu.ox.ac.uk/riskengine/index.php) and the Atherosclerosis Risk in Communities CHD Risk Calculator (http://www.aricnews.net/riskcalc/html/ RC1.html). Risk should be reassessed periodically, because patients may acquire additional risk factors over time. n
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Measuring Blood Pressure
has been taken, it may be normal or even below normal; it will gradually increase to potentially hypertensive levels until the next dose is taken.
M
easuring blood pressure (BP) is an expert’s job. It’s not the job of quacks, paramedics or the patients to learn it as they invariably will default. Most often doctor’s default on this very essential part of examination. Accurate measurement of BP is important not only to diagnose but treat high BP as well.
Even 2-5 mm variation can make a difference in the treatment. A 5 mm reduction in BP can reduce chances of heart attack by 21%.
Correct measurement and interpretation of BP is essential. Proper machine calibration, training of personnel, positioning of patient and selection of cuff size are essential. Most doctors do not follow correct steps leading to potential errors in diagnosis and management. Time of measurement: To diagnose high BP, multiple readings should be taken at various times throughout the waking hours. To monitor treatment, BP should be measured before anti-BP drugs are taken. If BP is measured soon after a drug
Source: Indian Journal of Clinical Practice 2010;21(3):160-62.
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Factors that influence BP, such as food intake, strenuous exercise (can lower the BP), smoking and caffeine, should be avoided in the 60 minutes prior to evaluation. Smoking transiently raises the BP. One may underestimate BP in a heavy smoker who has not smoked for >30 minutes before the BP is measured. Caffeine intake can raise the BP acutely in nonhabitual coffee drinkers. Measuring BP in a cool room (12ºC or 54ºF) or while the patient is talking can raise the BP value by 8-15 mmHg. Type of BP instrument: Mercury sphygmomanometers are the most accurate. Aneroid instruments should be checked against a mercury device since the air gauge may be in error. Automated oscillometric BP measuring devices are now available. The readings are typically lower than BP obtained with the auscultatory method. The oscillometric method has a somewhat greater inherent error and requires a proper AC atmosphere. Proper timing, patient positioning, cuff size and placement are still necessary, as is evaluation of machine accuracy at periodic intervals. Cuff size: Use of a proper-sized cuff is essential. If too small a cuff is used, the pressure generated by inflating the cuff may not be fully transmitted to the brachial artery; in this setting, the pressure in the cuff may be considerably higher than the intraarterial pressure, which can lead to overestimation of the upper systolic pressure by as much as 10-50 mmHg in obese patients. The length of the BP cuff bladder should be 80% and the width at least 40% (46%) of the circumference of the upper arm. This is often difficult to achieve in obese patients. Indian Journal of Clinical Practice, Vol. 21, No. 8, January 2011
Clinical Practice
Appropriate cuff size for a designated arm circumference: n
22-26 cm: ‘Small adult’ cuff, 12 × 22 cm
n
27-34 cm: ‘Adult’ cuff, 16 × 30 cm
n
35-44 cm: ‘Large adult’ cuff, 16 × 36 cm
n
45-52 cm: ‘Adult thigh’ cuff, 16 × 42 cm
A lack of manufacturing standards also results in designated cuffs differing by several cm in both width and length depending on the manufacturer. Pseudohypertension: This is a condition of falsely elevated BP and is found in patients with stiff vessels due to marked arterial calcification. Here, compression of the brachial artery requires a cuff pressure greater than systolic. Pseudohypertension is characterized by systolic upper and diastolic lower pressures estimated from the sphygmomanometer that are ≥10 mmHg above the directly measured intra-arterial or oscillometric pressure. Patient position: The BP should be taken in the sitting position with the back supported. Supine values are different, with the systolic pressure higher by 2-3 mmHg and the diastolic pressure lower by a similar degree.
acute rise in BP. About 20-30% of patients with hypertension in the clinic are normotensive outside the clinic. This is called ‘white coat’ or isolated office hypertension and should be suspected in any patient with marked high BP in the absence of end-organ damage or with normal ambulatory BP taken at work or at home.
In the elderly, supine and standing measurements should always be taken to detect postural hypotension (fall of BP on standing). The arm should be supported at the level of the heart. The BP should be taken with the patient’s arm supported at the level of the heart; allowing the arm to hang down when the patient is sitting or standing will result in the brachial artery being 15 cm below the heart. As a result, the measured BP will be elevated by 10-12 mmHg due to the added hydrostatic pressure induced by gravity. The opposite is true if the arm is above the level of the heart. The mercury manometer should be visible but does not have to be at the level of the heart. The patient should sit quietly for five minutes before the BP is measured. Even under optimal conditions, many patients are apprehensive when seeing a doctor. This causes an
Indian Journal of Clinical Practice, Vol. 21, No. 8, January 2011
The presence of white coat hypertension can be diagnosed by 24-hour ambulatory BP monitoring or self-recorded readings or by having a nurse measure the BP. The white-coat effect can persist for years. Cuff placement: The BP cuff should be placed with the bladder mid-line over the brachial artery pulsation, with the arm without restrictive clothing. The sleeve should not be rolled up as this may act as a tourniquet. Lower end of the BP cuff should be 2-3 cm above the antecubital fossa to minimize artifactual noise related to the stethoscope touching the cuff. The cuff should be inflated to a pressure 30 mmHg greater than upper systolic, as estimated from the disappearance of the pulse in the brachial artery by palpation. In some patients, the Korotkoff sounds transiently disappear as the cuff is deflated. As an example, the Korotkoff sounds in a patient with a systolic pressure of 180 mmHg may be first heard at 180 mmHg, disappear at 165 mmHg and then be re-heard at 140 mmHg. This auscultatory gap is associated with increased arterial stiffness and carotid atherosclerosis. Neither the patient nor the doctor should talk during the measurement. The stethoscope should be placed lightly over the brachial artery. The use of excessive pressure can increase turbulence and delay the disappearance of sound. The lower diastolic pressure reading may be artifactually reduced by upto 10-15 mmHg. The cuff should be deflated slowly at a rate of 2-3 mmHg per heartbeat. The systolic pressure is equal to the pressure at which the brachial pulse can first be palpated or at which the pulse is first heard by auscultation (Korotkoff phase I). 443
Clinical Practice
As the cuff is deflated below the systolic pressure, the pulse continues to be heard until there is abrupt muffling (phase IV) and approximately 8-10 mmHg later, disappearance of sound (phase V). The diastolic pressure is generally equal to phase V. The point of muffling should be used in those patients in whom there is >10 mmHg difference between phases IV and V. This can occur in children, and in high-output states such as thyrotoxicosis (hyperfunction of the thyroid), anemia (low Hb), and aortic regurgitation (leaking valve).
The BP should be measured initially in both arms. If there is a disparity between the two arm readings, the arm with higher pressure should be used. Normal difference between two arms can be 3-5 mmHg. The BP should be taken twice on each visit, with the readings separated by 1-2 minutes to allow the release of trapped blood. If the second value is >5 mmHg different from the first, continued measurements should be made until a stable value is attained. The correct value is average of the last two measurements. There are occasional patients in whom the BP needs to be measured in the legs. The classic example is in cases of suspected coarctation of the aorta in which there is an arm-to-leg gradient.
BP should be taken in the leg among women with breast cancer with bilateral axillary lymph node dissection. In unilateral axillary node dissection, BP should be taken in the opposite arm. The tourniquet effect may damage the lymphatics and exacerbate the arm edema. No precaution is needed if there has not been axillary node dissection. The systolic upper pressure in the leg is 10-20% higher than that in the brachial (elbow) artery. Values >10% lower than brachial measurements are used to screen for significant peripheral vascular disease.
Measurement of BP at the wrist may be more practical in obese people, since wrist diameter is not significantly affected. Systolic upper BP rises and diastolic lower BP falls, in more distal arteries. In the wrist, the hydrostatic pressure related to the lower position of the wrist relative to the heart can result in a further false elevation of BP. This can be minimized by taking the BP with the wrist kept at the level of the heart. Errors can occur when the BP is taken at home or work by the patient or spouse, even when the instrument is accurate. The BP varies throughout the day. For monitoring therapy, the BP should be measured at roughly the same time each day and the relation to meals and medications noted. The patient should be instructed to wait to measure the BP if they have recently eaten a meal or exercised. Cuff inflation hypertension: A problem with selfmeasurement of BP is that the muscular activity used to inflate the cuff can acutely raise the BP by as much as 12/9 mmHg. This dissipates within 5-20 seconds. Inflating the cuff to at least 30 mmHg above supper BP and then allowing the mercury column to fall no >2‑3 mmHg/heartbeat is indicated both for accurate measurement and to permit this effect to disappear. One should take multiple BP measurements. In the absence of end-organ damage, the diagnosis of mild hypertension should not be made until the BP has been measured on at least two additional visits, spaced over a period of one week or more. BP drops by an average of 10-15 mmHg between the first and third visits in newly diagnosed patients, with a stable value not being achieved until more than six visits in some cases. Thus, many patients considered to be having high BP at the first visit may in fact be normal. If the BP is taken at home to diagnose or monitor treatment, at least 12-14 measurements should be obtained, with both morning and evening measurements taken over seven workdays. n
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Clinical Practice
Detection of Atypical Bacterial Infections in Asthma Patients by IgM ELISA Sunita D Deshpande*, Kirti S Kulkarni**, Manish S Pathak**, Sangeeta J Pednekar†, Shekhar T Nabar‡
Abstract Asthma is a chronic inflammatory disorder of the airways. Mycoplasma and Chlamydia spps. can play an important role in frequent exacerbations of asthma. This study was undertaken in order to find out the incidence of IgM antibodies against atypical bacteria (Mycoplasma pneumoniae and Chlamydia pneumoniae) in patients presenting with acute infective exacerbation of asthma. Total 111 (81 test and 30 control) patients were selected. Detailed notes regarding pulmonary function tests, eosinophilia, exacerbation were recorded; blood samples were collected for enzyme-linked immunosorbent assay (ELISA) for C. pneumoniae immunoglobulin M (IgM) and M. pneumoniae IgM. Out of 81 ‘asthma group’ patients, 24 (29.63%) showed C. pneumoniae ELISA IgM test positivity and 22 (27.16%) showed M. pneumoniae ELISA IgM test positivity indicating recent infection. Remaining 35 (43.21%) ‘Asthma group’ patients showed no evidence of IgM ELISA for M. pneumoniae and C. pneumoniae. None of the patients showed simultaneous occurrence of M. pneumoniae and C. pneumoniae infections. ELISA for IgM antibodies against C. pneumoniae and M. pneumoniae were negative in all ‘control group’ subjects. In the present study, incidence of atypical bacterial infections such as C. pneumoniae and M. pneumoniae in asthma patients was more or less similar i.e. 28.4%. Key words: Chlamydia pneumoniae, Mycoplasma pneumoniae, ELISA, asthma
A
sthma is a chronic inflammatory disorder of the airways, which in susceptible individuals causes recurrent episodes of wheezing, breathlessness, chest tightness and cough. These symptoms are usually associated with widespread but variable airflow limitation that is at least partly reversible either spontaneously or with treatment. The inflammation also causes an associated increase in airway hyperresponsiveness.1 Among triggering factors for asthma, respiratory tract infections, mainly viral, play an important role followed by bacteria including atypical organisms which include Mycoplasma and Chlamydia.2 The relationship between asthma and respiratory infections is an important one. Infection with respiratory syncitial virus (RSV) and bacteria such as Mycoplasma and Chlamydia spps frequently cause exacerbation of asthma.3 Mycoplasma pneumoniae classically causes dry cough and fever in school-aged *Professor **PhD Student, Dept. of Microbiology †Professor ‡Professor and Head, Dept. of Medicine TN Medical College and BYL Nair Charitable Hospital, Mumbai Address for correspondence Dr Sunita D Deshpande 2/39, Government Colony, KK Marg, Haji Ali, Mumbai - 400 034 E-mail: sunita_dd@yahoo.com Source: Indian Journal of Clinical Practice 2010;20(9):660-62.
Indian Journal of Clinical Practice, Vol. 21, No. 8, January 2011
children (≥5 years old). Serological studies have suggested a possible role for Chlamydia pneumoniae in the pathogenesis of severe asthma.3 The diagnosis of mycoplasma, infection is problematic. Culture method is time consuming. Serum immunoglobulin M (IgM) is a sensitive indicator of infection, but as it persists upto 12 months it is not specific.3 It is known that some respiratory pathogens provoke asthma attacks, such as RSV and Chlamydia but much is still unknown about the mechanisms involved and as to why some pathogens are more potent inducers of wheeze than others.3 Antibiotic therapy, for persons with asthma along with the documentation of coexisting M. pneumoniae infection or infections that caused by other organisms may prove useful. However, it should be emphasized that antibiotic administration should ideally be reserved for those asthmatic patients who are actually shown to harbor the organism.4 Studies done till now suggest that atypical bacterial pneumonia confers a risk of asthma similar to that seen with nonatypical bacterial pneumonia and prospective studies are warranted to evaluate the importance of atypical bacterial pneumonia as a risk factor for asthma.3 Methods In the present study, 111 subjects were studied; of these, 81 were test group patients who had acute 445
Clinical Practice asthma as per GINA guidelines5 and 30 formed the control group. Patients were screened and selected by applying stringent inclusion and exclusion criteria at Asthma OPD, BYL Nair Charitable Hospital. Further testing was carried out at Dept. of Microbiology, TN Medical College and BYL Nair Charitable Hospital. Study protocol was approved by the Institutional Ethics Committee before commencement of the study. Male and female patients of age groups viz. upto 18, 19-60 and above 60, attending the Asthma OPD, diagnosed cases of bronchial asthma on the basis of clinical symptoms, signs and PFTs (pulmonary function tests) were included in the study. Clinically infective exacerbation was diagnosed on the basis of history of increased symptoms of breathlessness, purulence of sputum and/or fever. Nonasthmatic healthy subjects served as control group. From each patient detailed history and routine investigation findings such as blood counts, ESR, Hb, PFT were recorded and blood sample in a sterile tube was collected for enzyme-linked immunosorbent assay (ELISA) test for C. pneumoniae and M. pneumoniae IgM. A doxycycline course for seven days in a dose of 100 mg twice-daily was given to each patient. ELISA was carried out using NOVATEC® C. pneumoniae IgM and NOVATEC® M. pneumoniae IgM kits. The results were compiled and correlated with history and were statistically analyzed by Chi-square test. Results
and PFT findings, history and allergic asthma with present infective exacerbation. In the control group (n = 30), five males and five females belonged to each of the three age groups viz. upto 18, 19-60, above 60 years. All control group subjects were normal, healthy adults devoid of any asthma symptoms and with no past history of pulmonary tuberculosis. Investigations of test and control group patients are as shown in Table 1. All the patients from asthma group showed baseline moderate-to-severe obstruction according to PFT. Differential eosinophil count of test group subjects ranged from 8 to 10% (normal range: <6%). Eosinophil count and PFT of control subjects were within normal limits. Twenty-two test group subjects showed raised IgM for M. pneumoniae and 24 test group subjects showed raised IgM for C. pneumoniae. In the present study, incidences of atypical bacterial infections due to C. pneumoniae and M. pneumoniae in asthma patients were more or less similar. None of the patients showed simultaneous M. pneumoniae and C. pneumoniae infections. ELISA for IgM antibodies against C. pneumoniae and M. pneumoniae were negative in all control group subjects. The results of ELISA for IgM antibodies against C. pneumoniae and M. pneumoniae in test subjects were found to be statistically significant (Table 2). Discussion
In the asthma group (test group), the male population was more i.e., 53 (65.43%) and female population was 28 (34.57%). Taking into consideration the age group pattern, four (4.94%) were upto 18 years of age, 68 (83.95%) were from 18 to 60 years of age and nine (11.11%) were above 60 years of age, respectively. All test group patients were selected on the basis of clinical
In the present study, 81 patients with chronic asthma were studied with respect to the role of C. pneumoniae and M. pneumoniae as etiological agents in causing infective exacerbation. Healthy subjects without any past and present symptoms of respiratory infections were selected as controls. Microbial infections associated with allergic respiratory disorder increase the
Table 1. Investigations of Test and Control Group Patients History of past tuberculosis
Exacerbation
Eosinophilia
C. pneumoniae IgM positive
M. pneumoniae IgM positive
20 (24.69)
61 (75.31)
77 (95.04)
24 (29.63)
22 (27.16)
Control (N2 = 30)
Nil
Nil
Nil
Nil
Nil
Total (N = N1 + N2 = 111)
20
61
77
24
22
Test (N1 = 81)
()=%
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Clinical Practice Table 2. Statistical Analysis of IgM-ELISA Test Control
Test
Total
p value
Mycoplasma pneumoniae IgM-ELISA IgM positive
0
22
22
IgM negative
30
59
89
Total
30
81
111
0.0035
Chlamydia pneumoniae IgM-ELISA IgM positive
0
24
24
IgM negative
30
57
87
Total
30
81
111
0.0019
severity and duration of the disease besides themselves acting as an allergen. Presence of these infective agents can exacerbate the asthmatic condition in the patient due to additional allergic phenomenon. Treatment with antimicrobial agents can improve patient’s condition and helps in fast recovery which can reduce corticosteroid consumption by patients.6,7 M. pneumoniae and C. pneumoniae act as a cofactor in severe respiratory tract infections. It can lead to secondary bacterial lower respiratory tract infections. This may lead to subsequent bronchiectasis or other pulmonary abnormalities. There is strong evidence which suggests that there is a colonization of airways in significant number of asthmatics by M. pneumoniae resulting in pathogenic sequence of events of varied clinical significance.1,8 Number of studies have supported an association between C. pneumoniae infection and asthma. A population-based study showed significant association between C. pneumoniae seropositivity and atopy in young children.8 In the present study, 27.16% cases were positive for M. pneumoniae IgM antibody, whereas 29.63% cases were positive for C. pneumoniae IgM antibody when tested by ELISA. Kraft et al1 detected M. pneumoniae by polymerase chain reaction (PCR) in respiratory secretions of 10 out of 18 i.e., 56% stable adult asthmatics and in only one out of 11 healthy controls. Arora and Daga et al9 reported 20% cases with M. pneumoniae in acute exacerbations of chronic obstructive pulmonary diseases (COPD). IgM seropositivity of M. pneumoniae and C. pneumoniae should be considered as an evidence of recent infection and focused treatment will result in early improvement of patient’s condition. The same recommendations were suggested by different researchers.1,8 Outcome of
the present study highlights that C. pneumoniae and M. pneumoniae can act as a co-factor in severe respiratory tract infections. This may lead to subsequent bronchitis or other pulmonary abnormalities. These infectious agents may also act as potential allergens, aggravating the symptoms. Hence, while treating the patients with asthma or respiratory allergy with exacerbation, presence of C. pneumoniae and M. pneumoniae in respiratory tract should be considered so that focused treatment can be given to clear the organisms which may result in early improvement of patients’ condition. Since culture of such organisms is difficult and time-consuming, carrying out IgM-ELISA test for this kind of diagnosis appears promising. This also highlights the need and importance of empirical simple antibiotic therapy in treating infective exacerbations of acute asthma in the absence of elaborate testing. References 1. Acharya V, Sahoo R, Shenoy S, Sheony SM, Antony S, Anand R. Study of isolation of M. pneumoniae in asthmatics by sputum culture. Lung India 2005;22: 50‑3. 2. Broide DH. The role of bacterial infections in allergy. A clinical paradox review from 57th Annual Meeting of the American Academy of Allergy, Asthma and Immunology. New Orleans, Louisiana 2001:16-21. 3. Isaacs D, Joshi P. Respiratory infections and asthma. MJA 2002;177(6 Suppl):550-1. 4. Waites KB, Talkington DF. M. pneumoniae and its role as a human pathogen. Clin Microbiol Rev 2004; 697-728. 5. Diagnosis and Classification In: Global strategy for asthma management and prevention. Global initiative for asthma 2008;2:16-25. 6. Nagayama Y, Tsubaki T. Role of bacterial infection in the exacerbation of acute or prolonged asthma attack in children. Allergol Int 1999;48(2):137‑44. 7. Varghese A. Immune profile in respiratory viral infections in asthmatics. Indian J Allerg Immunol 2001;15(2):87‑92. 8. Sebastian LJ, Martin RJ. Chlamydia pneumoniae and Mycoplasma pneumoniae: a role in asthma pathogenesis. Am J Respir Crit Care Med 2005;172:1078-89. 9. Arora N, Daga MK, Mahajan R, Krishna S. Microbial pattern of acute exacerbation of chronic obstructive airway disease in a hospital based study. Indian J Chest Dis Allied Sci 2001;43:55-62.
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Photo Quiz
Adolescent with a Diffuse, Progressive Rash
A
15-year-old boy presented with a diffuse rash that began on his lower extremities and rapidly progressed over the previous two weeks to his upper extremities, chest, and back. A basic metabolic panel and complete blood count were unremarkable. Topical steroids were ineffective. The rash was associated with mild muscle aches, joint pain, and one day of emesis. On physical examination, the patient was nontoxic and had no fever. Skin examination revealed multiple, diffuse, nonblanching purpura scattered on the distal lower extremities, lower abdomen, lower back, and distal upper extremities (Figure 1). In addition, there were several areas of coalescence with a few scattered vesicles that varied in level of progression (Figure 2). Urine dipstick testing was unremarkable.
Figure 1.
Figure 2. Source: Adapted from Am Fam Physician 2010;82(11):1401-1402.
Question Based on the patient’s history and physical examination, which one of the following is the most likely diagnosis? A. Contact dermatitis. B. Henoch-Schönlein purpura. C. Idiopathic thrombocytopenic purpura. D. Meningococcemia. E. Rocky Mountain spotted fever. Discussion The answer is B: Henoch-Schönlein purpura. Henoch-Schönlein purpura is the most common systemic vasculitis of childhood.1 The disease is characterized by a tetrad of clinical manifestations, including palpable purpura without thrombocytopenia or coagulopathy, arthritis and arthralgias, abdominal pain, and renal disease. The rash often begins with erythematous, macular, or urticarial wheals that coalesce into ecchymosis, petechiae, and palpable purpura.2 The purpura are typically located on pressure-dependent areas, often in a symmetric distribution. Henoch-Schönlein purpura is less common in adults, often occurring between three and 15 years of age. The condition appears primarily in the fall, winter, and spring, but rarely in the summer. Approximately 50 percent of cases are preceded by an upper respiratory infection, particularly streptococcal pharyngitis3; however, the underlying cause is unknown. HenochSchönlein purpura is an immune complex–mediated vasculitis associated with immunoglobulin A (IgA) deposition in small vessels. The diagnosis is clinical but may be confirmed with skin or renal biopsies, which demonstrate leukocytoclastic vasculitis with a predominance of IgA deposition. The clinical manifestations may develop over days to weeks and may vary in order of presentation. Henoch-Schönlein purpura is usually self-limited. Treatment includes supportive care and symptomatic Cont’d on page 453...
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Photo Quiz ...Cont’d from page 448
Summary Table Condition
Characteristics
Contact dermatitis
Pruritic papules and vesicles on an erythematous base that typically do not coalesce; distribution related to exposure (e.g., poison ivy, nickel)
Henoch-Schönlein purpura
Immune complex–mediated vasculitis associated with immunoglobulin A deposition in small vessels; characterized by palpable purpura without thrombocytopenia or coagulopathy, arthritis and arthralgias, abdominal pain, and renal disease; usually occurs between three and 15 years of age
Idiopathic thrombocytopenic purpura
Nonpalpable petechia; associated with thrombocytopenia and coagulopathy; lesions do not coalesce
Meningococcemia
Fever and malaise in severely ill patients; petechiae, purpura, ecchymosis; associated with neurologic symptoms
Rocky Mountain spotted fever
Rickettsial infection; blanching maculopapular eruption; may be pruritic; lesions start distally and spread centripetally to the trunk and extremities
therapy for arthralgias, abdominal pain, and skin irritation. Acetaminophen and nonsteroidal antiinflammatory drugs are the mainstays of treatment. Hospitalization may be required in patients who cannot maintain hydration and in those with severe abdominal pain, gastrointestinal bleeding, mental status changes, or renal disease. Early, aggressive oral prednisone is recommended for patients with severe renal involvement.1 Contact dermatitis is characterized by pruritic papules and vesicles on an erythematous base that typically do not coalesce.4 A causative exposure typically can be identified, such as poison ivy or nickel, and distribution of the rash is usually related to exposure. Idiopathic thrombocytopenic purpura is characterized by nonpalpable petechiae, which occur mostly in areas that are subject to pressure, such as the lower extremities, belt line, and buttocks.5 The lesions do not coalesce. The condition is associated with thrombocytopenia and coagulopathy. Meningococcemia is a severe systemic infection that usually causes fever and malaise. The condition can occur at any age.4 The rash appears as petechiae, purpura, and ecchymosis. Patients often have
neurologic symptoms (e.g., mental status changes) at presentation. Rocky Mountain spotted fever is a rickettsial infection that appears as a classic blanching, maculopapular eruption on the wrists and ankles, then spreads centripetally to involve the trunk and extremities.6 References 1. Reamy BV, Williams PM, Lindsay TJ. Henoch-Schönlein purpura. Am Fam Physician. 2009;80(7):697-704. 2. Roane DW, Griger DR. An approach to diagnosis and intial management of systemic vasculitis. Am Fam Physician. 1999;60(5):1421-1430. 3. Masuda M, Nakanishi K, Yoshizawa N, Iijima K, Yoshikawa N. Group A streptococcal antigen in the glomeruli of children with Henoch-Schönlein nephritis. Am J Kidney Dis. 2003;41(2):366-370. 4. Ely JW, Seabury Stone M. The generalized rash: part I. Differential diagnosis. Am Fam Physician. 2010;81(6):726-734. 5. Blanchette V, Bolton-Maggs P. Childhood immune thrombocytopenic purpura: diagnosis and management. Hematol Oncol Clin North Am. 2010;24(1):249-273. 6. Elston DM. Tick bites and skin rashes. Curr Opin Infect Dis. 2010;23(2):132-138.
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case report
Hemoglobin 2 gm%: A Common Occurrence in India KK Aggarwal*, Archna Gupta
Abstract Iron deficiency anemia is the leading cause of nutritional anemia globally. Although significant progress has been made in improving health indicators in India, there has been a lack of progress in the improvement of nutritional status. This case report highlights the severity by which iron deficiency anemia can exist in the general population, hoping to highlight the need for more aggressive public health intervention to address this issue. Key words: Anemia, nutritional anemia, severe anemia, iron deficiency anemia
A
nemia is a major problem worldwide; approximately 30% of the worldâ&#x20AC;&#x2122;s population are affected by anemia, and the majority of them are in the developing world. There are numerous causes of anemia, but iron deficiency is the most significant cause of nutritional anemia around the world. It is reported that 56% of pregnant women in developing countries and 18% in developed countries are anemic. In nonpregnant women, the estimated prevalence is 43% and 12% in developing and developed countries, respectively. Several countries have policies to provide iron in a supplement form, but despite this, maternal anemia prevalence has not declined significantly where large-scale programs have been evaluated. Case Report In March 2009, a 35-year-old woman presented to the emergency department with generalized weakness, dizziness, exhaustion, abdominal pain and decreased appetite. She felt weak for the past year, but her symptoms became progressively worse over the last month. The patient was a G5P5 whose first three deliveries occurred at home, while the last two were in hospital. The patient denied any history of intrapartum or postpartum hemorrhage. The patient recalled being told that her hemoglobin was low at her last delivery *Senior Physician and Cardiologist, Moolchand Medcity, New Delhi Address for correspondence Dr KK Aggarwal E-mail: emedinews@gmail.com
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but did not report taking medications for it. The patient has been breastfeeding her youngest child since her last delivery one-year prior to presentation. She has not had her menses for the past year. The patient denied any past medical problems, surgical history and family medical history. She denied taking any medications on a daily basis. The patient was an uneducated housewife who cares for her five children. Her husband was a guard. She does not consume alcohol, nor smoke. On examination, the patient was malnourished and had marked pallor. She was however able to walk into the emergency department unaided. Her height was 157 cm and she weighed 33 kg (body mass index [BMI]: 13.4). She had pallor in her mucous membranes and conjunctiva. She was tachycardic with bounding radial pulses. Laboratory analysis at admission showed a severely low hemoglobin of 2.1 g/dl (ref: 11.516.5). The packed cellular volume was only 7.9% (ref: 36-45). The mean corpuscular volume measured 84 Âľm3 (ref: 80.0-96.1). The erythrocyte sedimentation rate (ESR) was elevated at 105 mm (0-20). The mean corpuscular hemoglobin measured 22.3 pg/cell (ref: 27.5-33.2) and mean corpuscular hemoglobin concentration measured 26.6% (ref: 33.4-35.5), slightly below physiological levels. Both total leukocyte count (6,800/cm2) and platelets (2.68 Ă&#x2014; 105/mm3) were within normal limits. Blood film showed sparsely distributed microcytic to normocytic anisopoikilocytosis. Indian Journal of Clinical Practice, Vol. 21, No. 8, January 2011
Case Report Iron studies showed a low iron value at 24 µg/dl (ref: 65-150) and total iron binding capacity of 306 µg/dl (ref: 250-420). Other nutritional status laboratory investigations showed vitamin B12 of 474 pg/ml (ref: 211-911) and folic acid of 26.76 mg/ml (ref: 75-138). Serum ferritin was 20 ng/ml (ref: 30-300). She was treated with two packed cells blood transfusion, intravenous iron followed by oral iron. At discharge her hemoglobin was 8 g/dl. Discussion National studies done in India have highlighted the association between the level of anemia and biosocial factors. It has been shown that educational level of women and the standard of living of households play a large role in the degree of anemia in women. Illiterate women suffer more from anemia (54.5%) than those who studied upto primary, secondary and higher secondary levels. Higher prevalence of anemia has also been noticed in women with low standard of living index (59.5%). As of 2004, 34.3% of the population was living below the poverty line (% living n <US$1 per day) in India. One in three women 15-49 years of age has a BMI below 18.5 indicating severe nutritional deficiency and malnutrition. There have been improvements in most health indicators in India, including a reduction of infant mortality from 82 in 1990 to 57 in 2006 and a drop in the total fertility rate from 4.0 to 2.9 in the same period of time. However, improvements in nutritional status have been subpar, and improvements are necessary to help defer disease processes such as iron deficiency anemia. The consequences of anemia in women are vast, including risk of low birth weight and prematurity,
perinatal and neonatal mortality, inadequate iron stores for the newborn and lowered physical activity, mental concentration and productivity. Anemia is attributed to be the cause of approximately 26% of maternal deaths in India. Given the number and severity of consequences of anemia in women, and the high prevalence of it in India, more aggressive and effective public health interventions are needed to address this issue. Suggested Reading 1. Bentley ME, Griffiths PL. The burden of anemia among women in India. Eur J Clin Nutr 2003;57(1):52‑60. 2. Bharati P, Som S, Chakrabarty S, Bharati S, Pal M. Prevalence of anemia and its determinants among nonpregnant and pregnant women in India. Asia Pac J Public Health 2008;20(4):347-59. 3. DeMaeyer EM, Adiels-Tegman M. The prevalence of anemia in the world. World Health Stat Q 1985;38(3):302-16. 4. DeMaeyer EM, Dallman P, Gurney JM, Hallberg L, Sood SK, Srikantia SK. Preventing and controlling iron deficiency anemia through primary health care. Geneva: WHO;1989. 5. Galloway R, Dusch E, Elder L, Achadi E, Grajeda R, Hurtado E, et al. Women’s perceptions of iron deficiency and anemia prevention and control in eight developing countries. Soc Sci Med 2002;55(4):529-44. 6. National Family Health Survey (NFHS 3), 2005-06, India: Volume I, and National Fact Sheet, International Institute for Population Sciences, Mumbai, September; 2007. 7. World Health Organization (WHO). The prevalence of anemia in women: A tabulation of available information. Geneva, Switzerland: WHO;1992. 8. World Health Organization-Core Health Indicators. WHOSIS Statistical Information System. Available at: < http://www.who.int/whosis/en/>.
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Case Report
Adenocarcinoma of the Jejunum: A Rare Cause of Intestinal Obstruction in Young Adults Jyotsna Madan*, S Mitra**, U Madanâ&#x20AC;
Abstract Primary malignant neoplasms of the jejunum and ileum are rare lesions and have high mortality and morbidity. Documented rarity, low index of suspicion, vague clinical presentation and diagnostic difficulty in this segment of bowel lead to delayed or erroneous diagnosis resulting in poor outcome. We report a case of primary adenocarcinoma in the jejunoileal segment in a young adult that presented with features of intestinal obstruction and with a clinical diagnosis of intestinal tuberculosis. Key words: Small bowel, primary malignant tumors, adenocarcinoma
A
lthough the small intestine constitutes 75% of the total length of gastrointestinal tract and >90% of the mucosal surface, the malignant neoplasms of small bowel are among the most rare types of cancer and account for 1-2% of total gastrointestinal malignancies.1 Primary adenocarcinoma is the most common histologic type. Clinical features of jejunoileal neoplasms are nonspecific and late. Moreover, such neoplasms are inaccessible to conventional endoscopy, hence, the diagnosis is often missed or delayed. As the clinical stage of the neoplasm is one of the important prognostic factors, early diagnosis may give better results and favorable outcome. Case History A 31-year-old male patient presented to surgical emergency unit with a history of abdominal pain, nausea, vomiting and inability to pass flatus and stool for 48 hours. Patient had history of anemia and weight loss for six months and was taking treatment for tuberculosis. At the time of admission, patient had tachycardia, abdominal distension; rest of the systemic examination was within normal limits. His hemoglobin was 7.0 g/dl; abdominal ultrasonography *Professor **Associate Professor Dept. of Pathology, Santosh Medical College and Hospital, Ghaziabad â&#x20AC; Senior Consultant, Dept. of General and Laparoscopic Surgery Ganesh Hospital, Ghaziabad Address for correspondence Dr Jyotsna Madan Sector 16-A, House No.-1530, Vasundhra, Ghaziabad, UP - 201 012 E-mail: drjyotsnamadan@yahoo.co.in Source: Indian Journal of Clinical Practice 2010;21(2):94-95, 98.
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and X-ray findings were consistent with acute intestinal obstruction. Considering the age of the patient, the rarity of malignancy in small bowel and clinical features, a preoperative diagnosis of tubercular intestine was considered. Emergency exploratory laparotomy was performed to relieve the symptoms of complete intestinal obstruction. Surgery revealed stricture of jejunum and a small growth, 10 cm distal to duodenojejunal junction. Segment of small intestine showing the above lesion was resected and end-to-end anastomosis was done. There was no evidence of spread of tumor to lymph nodes, peritoneum and liver. Resected segment was sent for histopathological examination and a diagnosis of welldifferentiated adenocarcinoma was established. Grossly, the resected segment of small intestine measured 10 cm in length; showing stricture encircling the bowel wall and a small growth measuring 1 Ă&#x2014; 1 cm and 5 cm away from the resected margins (Fig. 1). No other gross abnormality was seen. Microscopic examination revealed neoplastic glands or acini of widely varying sizes, lined by tall columnar cells. Nuclei were pleomorphic with tendency to layering. Mitotic activity was moderate among tumor cells (Fig. 2A). Neoplastic glands were invading deep in the muscle layer (Fig. 2B), though the serosa was not invaded. Thus, a diagnosis of well-differentiated adenocarcinoma was made (T2). Resected margins were free from malignancy. Indian Journal of Clinical Practice, Vol. 21, No. 8, January 2011
Case Report adenocarcinoma is the most frequent histologic type of carcinoma of small bowel accounting for 40% of cases followed by carcinoid tumor (36%).2 Recently published data from the Connecticut Tumor Registry has shown the carcinoid tumor as the most common intestinal tumor followed by adenocarcinoma.3 Anatomically, duodenum is the most common location for adenocarcinoma (52%) followed by jejunum (25%) and ileum (13%).4
Figure 1. Gross photograph of the resected segment of bowel showing stricture and a small growth (arrow).
(A)
(B)
Figure 2. Photomicrograph showing malignant glands lined by columnar epithelium with pleomorphic nuclei and mitotic activity (A), malignant glands invading deep into the muscle layer (B), hematoxylin eosin, x400.
Discussion Primary jejunoileal malignancies are unusual and constitute about 1-2% of total gastrointestinal cancers.1 Several theories have been proposed to explain this low prevalence like rapid transit of luminal contents; the high turn over rate of small bowel epithelial cells, which may minimize the carcinogenic exposure; alkalinity of small bowel contents; high level of IgA and low bacterial count of small intestinal luminal contents, etc. but precise reasons are not clear. The research into the natural history and prognosis of patients has been limited because of small number of cases and heterogeneity of tumor type, like adenocarcinoma, carcinoids, sarcoma and lymphoma. Primary Indian Journal of Clinical Practice, Vol. 21, No. 8, January 2011
The mean age at the time of diagnosis is 55 years,4 although our patient was 29-years-old. Clinical presentation of these malignancies is often nonspecific and vague like insidious abdominal pain, anemia and weight loss. Some patients may present as surgical emergencies including intestinal obstruction, hemorrhage or perforation.5 Our patient also presented with clinical features of obstruction and showed classical features of obstruction in the plain abdominal films. Because of the rarity of lesion and young age of the patient, the stricture was initially thought to be tuberculous in nature. Diagnostic modalities available for small bowel tumors include plain X‑ray abdomen to reveal small bowel obstruction. Small bowel enteroclysis with double contrast barium enema, which has a sensitivity of 95%. Upper gastrointestinal endoscopy with small bowel enteroscopy ‘push enteroscopy’ is a useful procedure to identify and take biopsy of lesions in the duodenum and jejunum, although the procedure is time-consuming and difficult to perform. ‘Capsule endoscopy’ is another newer technique which has better sensitivity and specificity.6 Sometimes diagnostic laparoscopy or exploratory laparotomy is indicated for definitive diagnosis and treatment. Surgical resection is the treatment of choice for patients with small bowel adenocarcinoma but in one-third patients, disease is unresectable because of extensive local disease or distant metastasis.7 The overall 5-year survival rate is 30%. The prognostic factors influencing the survival include histological grade, nodal involvement, distant metastasis and vascular invasion, etc. Stage of the tumor at the time of diagnosis is one of the significant prognostic factor.8 So, the emphasis is on early diagnosis. Conclusion Jejunoileal malignancies should always be in mind despite their rarity, nonspecific presentation and 457
Case Report difficulty in diagnosis with conventional diagnostic tools. Prediction of malignancy before surgery enables us to design adequate therapeutic strategies for better results in terms of survival. References 1. Howe JR, Karnell LH, Menck HR, Scott-Connerc C. The American College of Surgeons Commission on Cancer and the American Cancer Society. Adenocarcinoma of the small bowel: review of the National Cancer Data Base, 1985-1995. Cancer 1999;86(12): 2693-706. 2. Chow JS, Chen CC, Ahsan H, Neugut AI. A population based study of the incidence of malignant small bowel tumors: SEER, 1973-1990. Int J Epidemiol 1996; 25(4):722-8. 3. Hatzaras I, Palesty JA, Abir F, Sullivan P, Kozol RA, Dudrick SJ, et al. Small-bowel tumors: epidemiologic and clinical characteristics of 1260 cases from the Connecticut Tumor Registry. Arch Surg 2007; 142(3):229‑35.
4. Dabaja BS, Suki D, Pro B, Bonnen M, Ajani J. Adenocarcinoma of the small bowel: presentation, prognostic factors, and outcome of 217 patients. Cancer 2004;101(3):518-26. 5. Catena F, Ansaloni L, Gazzotti F, Gagliardi S, Dé Saverio S, De Cataldis A, et al. Small bowel tumors in emergency surgery: specificity of clinical presentation. ANZ J Surg 2005;75(11):997-9. 6. Appleyard M, Fireman Z, Glukhovsky A, Jacob H, Shreiner R, Kadirkamanathan S, et al. A randomized trial comparing wireless capsule endoscopy with push enteroscopy for detection of small-bowel lesions. Gastroenterology 2000;119(6):1431-8. 7. Cunningham JD, Aleali R, Aleali M, Brower ST, Aufses AH. Malignant small bowel neoplasms: histopathologic determinants of recurrence and survival. Ann Surg 1997;225(3):300-6. 8. Chaiyasate K, Jain AK, Cheung LY, Jacobs MJ, Mittal VK. Prognostic factors in primary adenocarcinoma of the small intestine: 13-year single institution experience. World J Surg Oncol 2008;6:12.
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Case Report
Disseminated Intravascular Coagulation: A Rare Complication of Enteric Fever Vikas R Pandey*, Sandip Shah*, Nilay Thakore**, Ilesh Mehta†
Abstract Enteric fever, better known as ‘Typhoid Fever’, in our country has been one of the common causes of fever since ages throughout the world. Enteric fever along with its prolonged fever is very well-known for its complications like intestinal perforation and gastrointestinal bleeding. We hereby present a case where disseminated intravascular coagulation (DIC), a very rare complication of enteric fever, was the presenting feature. Key words: Leukopenia, Salmonella typhi, ceftriaxone, azithromycin
Case History
Case Highlight and Investigations
We hereby report a case of 20-year-old male who was transferred to our hospital from a private nursing home where he was admitted with history of fever of 10 days, abdominal pain seven days and headache two days and bloody diarrhea two days. The fever was high-grade, intermittent, in nature, not associated with chill and rigors and not responding to antipyretics. In the three days of admission in private hospital he underwent routine investigations, which just showed leukopenia. He was treated with injectable artesunate and ceftriaxone. On the third day, patient developed complications in the form of bleeding per rectum and gum bleeding. In our hospital, the initial investigations showed patient to be having low hemoglobin and low platelet counts along with altered coagulation profile. Patient was transfused with PCV, PRC and FFP. Patient’s complications continued; he was investigated for fever. All reports were normal apart from his Widal test which was strongly positive. Other investigations showed that the patient had disseminated intravascular coagulation (DIC). Suspecting it to be a multidrugresistant enteric fever, azithromycin 1 g was added for seven days to which patient responded well and his complications resolved.
Before presenting to us, the patient had a normal hematological profile with hemoglobin (Hb) 12 g/dl and platelet count of one lac per cu.mm. Within two days of hospitalization, his Hb reduced to 4 g/dl and platelets to 16,000/dl along with prolonged prothrombin time (PT), activated tissue thromboplastin time (aPTT), increased fibrinogen degradation product (FDP) and positive D-dimer. Patient was negative for malarial parasite, dengue IgM, urinary tract infection and blood culture report. Patient had already been treated with ceftriaxone and did not respond to it. He was treated with azithromycin for seven days along with ceftriaxone and he recovered well with resolution of symptoms and signs of DIC.
*Senior Resident **Associate Professor †Professor, Dept. of Medicine, Smt. NHL MMC, Sheth VS Hospital KM School of Post Graduation, Ahmedabad Address for correspondence Dr Vikas R Pandey C/o: Dr Sandip Shah M 6/70, Parasnagar - I, Sola Road, Naranpura, Ahmedabad - 16 Source: Indian Journal of Clinical Practice 2010;20(8):629-30.
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Discussion Typhoid fever, also known as enteric fever, is a potentially fatal multisystem illness caused primarily by Salmonella typhi. The classic presentation includes fever, malaise, diffuse abdominal pain and constipation. The development of severe disease (which occurs in 10-15% of patients) depends on host factors, virulence of the strain and choice of antibiotic therapy. Complications like gastrointestinal bleeding (10-20%) and intestinal perforation (1-3%) most commonly occur in the third and fourth weeks of illness and require immediate surgical intervention.1 Other rare complications, whose incidences are reduced by prompt antibiotic treatment, include DIC, hematophagocytic syndrome, pancreatitis, hepatic and splenic abscesses and granulomas, endocarditis, pericarditis, myocarditis, orchitis, hepatitis, glomerulonephritis, pyelonephritis 459
Case Report and hemolytic uremic syndrome, severe pneumonia, arthritis, osteomyelitis and parotitis.2 DIC is characterized by a systemic activation of the blood coagulation system, which results in the generation and deposition of fibrin, leading to microvascular thrombi in various organs and contributing to the development of multiorgan failure.3 Consumption and subsequent exhaustion of coagulation proteins and platelets, due to ongoing activation of coagulation system, may induce severe bleeding complications.4 Several disease states may lead to the development of DIC of which septicemia and release of procoagulant material in blood (e.g., in cancer, pregnancy) are commonest. Treatment of underlying disease states with infusion of blood components improves survival. DIC is a rare manifestation of enteric fever, but its incidence is significantly increased in infection with multidrug-resistant strain of salmonella.5 Thus therapy with appropriate antibiotic, if initiated early, will improve outcome. The discovery of chloramphenicol for the treatment of enteric fever in 1948 resulted in dramatic change in outcomes. But the appearance of multi-resistant strain of salmonella in 1990, which was resistant to chloramphenicol, ampicillin and cotrimoxazole was a major setback.6 The introduction of ciprofloxacin in 1987 was a major breakthrough but recently fluoroquinolone-resistant strains have been reported from Vietnam (44%) Pakistan (59%) and India (7%).7 The possible alternatives are third-generation cephalosporins, azides and newer 8-methoxyquinolones (gatifloxacin). Three large randomized controlled trials on the treatment of nalidixic acid-resistant S. typhi infections have been completed recently. From these trials it emerges that
High dose ofloxacin (20 mg/kg/day for seven days) is inferior to oral azithromycin (10 mg/kg/day for 10 days).8 Oral cefixime, even when used in doses of 20 mg/kg/day for seven days, is far inferior to gatifloxacin (10 mg/kg/day for × 10 days).9 Azithromycin (20 mg/kg/day for seven days) and gatifloxacin (10 mg/kg/day for seven days) are similar in efficacy, achieving fever clearance in about 80% of patients by day seven of treatment.10
Short course of ceftriaxone (7 days) is associated with high rates of relapse, but extension of regime for 14 days can be used in complicated/severe typhoid
fever. Recently, an increasing trend in the MICs of third-generation cephalosporins has been reported from northern India.11 Thus, appropriate treatment according to resistant profile in community if initiated within the first few days of full-blown illness causes the disease liable to remit after about two days, and the patient’s condition markedly improves within 4-5 days. Any delay in treatment increases the likelihood of complications and recovery time. References 1. Khanna AK, Tiwary SK, Khanna R. Surgical complications of enteric fever in children. J Ped Infect Dis 2007; 2(2):59-66. 2. Cohen JI, Bartlett JA, Corey GR. Extra-intestinal manifestations of salmonella infection. Medicine (Baltimore) 1987;66:349-88. 3. Vincent JL, De Backer D. Does disseminated intravascular coagulation lead to multiple organ failure. Crit Care Clin 2005;21(3):469-77. 4. Levi M, Ten Cate H. Disseminated intravascular coagulation. N Engl J Med 1999;341(8):586-92. 5. Koul PA, Quadri MJ, Wani JI, Wahid A, Shaban M. Hemostatic abnormalities in multidrug-resistant enteric fever. Acta Haematol 1995;93(1):13-9. 6. Rowe B, Ward LR, Therefall EJ. Multidrug-resistant Salmonella typhi: a worldwide epidemic. Clin Infect Dis 1997;24(Supp 1):S106-9. 7. Ochiai RL, Acosta CJ, Danovaro-Holliday MC, Baiqing D, Bhattacharya SK, Agtini MD, et al. A study of typhoid fever in five Asian countries diseases burden and implication for control. Bull World Health Organ 2008;86(4):260-8. 8. Parry CM, Ho VA, Phuong le T, Bay PV, Lanh MN, Tung le T, et al. Randomized controlled comparison of ofloxacin, azithromycin and an ofloxacinazithromycin combination for treatment of multidrugresistant and nalidixic acid-resistant typhoid fever. Antimicrob Agents Chemother 2007;51(3):819-25. 9. Pandit A, Arjyal A, Day JN, Paudyal B, Dangol S, Zimmeraman MD, et al. An open randomized comparison of gatifloxacin versus cefixime for the treatment of uncomplicated enteric fever. PLoS One 2007;2(6):e542. 10. Doleceke C, Tran TP, Nguyen NR, Le TP, Ha V, Phung QT, et al. A multicenter randomized controlled trial of gatifloxacin versus azithromycin for the treatment of uncomplicated typhoid fever in children and adults in Vietnam. PLoS One 2008;3(5): e2188. 11. Capoor MR, Nair D, Deb M, Aggarwal P. Enteric fever perspective in India: emergence of high-level ciprofloxacin resistance and rising MIC to cephalosporins. J Med Microb 2007;56:1131-2.
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Symposium on Child Health
Update on Some Common Problems in Neonatology Anjali Kulkarni
Abstract It is imperative that neonatal intensive care units (NICUs) caring for large number of very low birth weight (VLBW) infants must maintain high standards of neonatal care with a continuous audit of the care to salvage more of these VLBW infants. Key words: Very low birth weight, neonatal intensive care units, Apgar scores, alveolar-arterial oxygen gradient, systemic vascular resistance, pulmonary vascular resistance
Risk Factors for Predicting Mortality in Very Low Birth Weight Babies Survival of very low birth weight (VLBW) babies admitted to neonatal intensive care units (NICUs) in India is generally lower than in the developed world with wide variations in the performances of different NICUs within the country itself. This situation has been attributed to the intrinsic limitations of a poor infrastructure and limited resources. The purpose of having an outcome assessment score is to identify patients who are at a higher mortality risk and to optimize the health resource distribution. A number of antenatal and intrapartum factors have been reported to be significantly associated with perinatal and neonatal mortality.1-5 Various authors have elucidated the significant role of prematurity and low birth weight (LBW) in contributing to neonatal mortality.3,6,7 In a recently published study, multivariate analysis was used for risk factors associated with early neonatal mortality.8 The variables selected for multivariate analysis included birth weight, gestation, Apgar scores at 1, 5 and 10 minutes, need for resuscitation at birth, shock, need for supplemental oxygen and mechanical ventilation, pH and the alveolar arterial oxygen gradient. The initial modeling did not include mechanical ventilation as its effect was Address for correspondence Dr Anjali Kulkarni Consultant Neonatologist Indraprastha Apollo Hospitals, New Delhi Source: Indian Journal of Clinical Practice 2010;20(8):601-6.
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expected to be dependent on the skills of the care providers. The independent predictors of mortality were shock, LBW, low pH and large high alveolararterial oxygen gradient (A-aDO2). Since shock, acidosis and hypoxia were indications of ventilation, another model was used wherein shock, pH and AaDO2 were replaced by mechanical ventilation, the other variables being the same. It was observed that birth weight and mechanical ventilation were the only significant risk factors for mortality. However, the odds of mortality due to ventilation was far greater than the combined odds of shock, low pH and large A-aDO2, suggesting that iatrogenesis could possibly be a confounder in ventilated babies.8 Therefore, it can be said that VLBW neonates, especially those with a birth weight <1,200 g, who are critically ill due to disturbances in the pulmonary and circulatory physiology have a very high risk of mortality. Interventions such as the need for ventilation may increase the burden of mortality contributed to by severe illness. It is therefore imperative that NICUs caring for large number of VLBW infants must maintain high standards of neonatal care with a continuous audit of the care provided in order to salvage more of these VLBW infants. Persistent Pulmonary Hypertension of the Newborn Perinatal Adaptations
Cardiovascular and pulmonary changes occur as the fetus adapts to an extrauterine environment. In the fetus, systemic vascular resistance (SVR) normally is low due to low-resistance placental vessels. Pulmonary 461
Symposium on Child health vascular resistance (PVR) is high, resulting in diversion of blood from the pulmonary artery through the ductus arteriosus away from the lungs. After birth, SVR increases when the umbilical cord is clamped along with exposure to cold environmental temperature (as compared to intrauterine temperature) and PVR decreases with the onset of regular breathing and increased alveolar oxygenation. The fetal lung is filled with fluid that must be cleared in order to facilitate adequate gas exchange afterbirth. In late gestation and as labor ensues, the production of lung fluid decreases and transporters in the lung that increase lung fluid clearance are induced so that lung fluid can be cleared rapidly. In the latter part of gestation, synthesis of surfactant and antioxidant enzymes increase to prepare the lungs for air breathing. Failure of these perinatal adaptations results in respiratory distress and arterial hypoxemia. Persistent pulmonary hypertension of the newborn (PPHN) is one of the causes of respiratory distress soon after birth. It is caused by persistently elevated PVR that leads to right-to-left shunting through the foramen ovale and the ductus arteriosus, resulting in hypoxemia. PPHN results from three types of abnormalities of the pulmonary vasculature: Underdevelopment, maldevelopment and maladaptation.9-11 Clinical Features
Infants with PPHN are typically born at term or nearterm gestation. Common clinical features are severe cyanosis and tachypnea. There may be a significant difference in pre and postductal saturations if the shunt is at the level of ductus arteriosus. Other clinical signs depend upon the associated respiratory disease, if any. Some infants have a heart murmur consistent with tricuspid insufficiency. The appearance of the chest radiograph in PPHN depends upon the presence of associated lung disease. In infants without lung disease, the lung fields may appear clear with decreased pulmonary vascularity. The heart size may be normal or increased. A cardiac evaluation should be performed in infants with severe hypoxemia to exclude structural heart diseases as a cause. In infants with PPHN, echocardiography shows a structurally normal heart with signs of 462
elevated right ventricular pressure and right-to-left shunting through the foramen ovale and/or the ductus arteriosus. The right ventricular pressure can often be estimated from a jet of tricuspid insufficiency. Management
Treatment strategies for PPHN are directed at reducing PVR. Mechanical ventilation typically is needed early in the course. High-frequency ventilation or surfactant may be beneficial in infants with parenchymal lung disease. Cardiac output should be supported with vasopressors and fluid administration. Traditionally, alkalosis induced by administration of base or by hyperventilation, was used to improve oxygenation in infants with PPHN. However, induced alkalosis has not been shown to improve the outcomes of infants with PPHN. In addition, intentional hyperventilation increases the risk of lung injury. Thus, induced alkalosis currently has little role in the treatment of infants with PPHN. Infants with severe hypoxemia should be treated with inhaled nitric oxide, a selective pulmonary vasodilator. Inhaled nitric oxide decreases the need for extracorporeal membrane oxygenation in infants with PPHN, although it does not reduce mortality.12,13 Inhaled nitric oxide does not significantly decrease the need for extracorporeal membrane oxygenation in infants with congenital diaphragmatic hernia.12 Evaluation of a Newborn for Fluid and Electrolyte Imbalance The principles of fluid and electrolyte balancing include the following points: Total body water equals intracellular fluid (ICF) plus extracellular fluid (ECF). ECF equals ICF (plasma and lymph in the vessels) plus interstitial fluid (between cells). Characteristics of fluid changes: n Neonates are born with an excess of total body water, primarily ECF, which needs to be removed. n Term neonate bodies are 75% water (40% ECF, 35% ICF), and term neonates usually lose 5-10% of their weight in the first week. n Preterm neonates have more water (at 23 weeks’ gestation, 90% water composed of Indian Journal of Clinical Practice, Vol. 21, No. 8, January 2011
Symposium on child health
60% ECF and 30% ICF) and they may lose 5-15% of their weight in the first week. Characteristics of insensible water loss (IWL): n IWL is water loss that is not readily measured. It is water lost via evaporation through the skin (two-thirds) or respiratory tract (one-third). n IWL depends on gestational age; the earlier the gestational age of the preterm infant, the greater the IWL. n The magnitude of IWL also depends on the postnatal age. Since skin thickens with age, IWL also decreases as neonates age. n All other measurable sources of fluid and electrolyte losses need to be considered as well. Sources include stool (e.g., diarrhea and ostomy), nasogastric or orogastric drainage and cerebrospinal fluid, including ventricular drainage. Renal function changes: Neonates have a decreased capacity to concentrate or dilute urine in response to changes in intravascular fluid status, and they are at risk for dehydration or fluid overload. The normal maturation of renal function that occurs with increasing gestational and postnatal age also plays a role in determining fluid requirements.
Clinical Evaluation
Cardiovascular Signs
Sudden changes in an infant’s weight do not necessarily correlate with changes in intravascular volume. An infant’s weight rises significantly for a number of reasons while intravascular volume has decreased. Examples include the long-term use of paralytic agents and peritonitis, both of which can lead to increased interstitial fluid volume and increased body weight but decreased intravascular volume. While growth charts are valuable in following growth parameters and nutritional status over time, they play little role in the daily management of fluid and electrolyte balances.
Skin and Mucosa Manifestations
Altered skin turgor, a sunken anterior fontanela and dry mucous membranes are not sensitive indicators of dehydration in babies. It is important to remember that premature infants have poorly keratinized skin that leads to a marked elevation in IWL. Indian Journal of Clinical Practice, Vol. 21, No. 8, January 2011
Although delayed capillary refill occurs in low cardiac output states, it can also be seen in infants with peripheral vasoconstriction resulting from cold stress. Hepatomegaly can occur in neonates with ECF excess, especially in congestive heart failure. As a result of an infant’s compensatory mechanisms, blood pressure readings usually are normal, with mild or moderate hypovolemia. With severe hypovolemia, hypotension is almost invariably present.
Laboratory Evaluation
Depending on the clinical situation and the suspected etiology of fluid and electrolyte derangements, some or all of the following tests may be warranted:
Weight Factors
Tachycardia can result either from too much ECF (as can be seen in congestive heart failure or from too little ECF (as can be seen in hypovolemia).
Serum electrolyte, urea nitrogen, creatinine and plasma osmolality levels: Keep in mind that over the first 12-24 hours, results of these tests may still reflect maternal values Accurate total urine output and total fluid intake Urine electrolytes and specific gravity: If the infant is being treated with diuretics, results of these tests are difficult to interpret Calculation of the fractional urinary excretion of sodium in relation to creatinine (FENa).
Persistent Jaundice: Common Causes Persistent neonatal jaundice is defined as visible jaundice that persists beyond 14 days of life in a term infant or 21 days in a preterm infant.14,15 The urgency to investigate a baby with prolonged neonatal jaundice is to rule out treatable causes for a favorable long-term outcome. Physiologic jaundice (unconjugated hyperbilirubinemia) typically resolves by 14 days of age. Nonetheless, between 2.4 and 5% of newborns are jaundiced at two weeks of age.14,16 The majority of these infants have breast milk jaundice. Even though it is estimated that between 60 and 375 jaundiced infants will need 463
Symposium on Child health to be tested at two weeks of age to detect one case of neonatal cholestasis,17 such testing is recommended because it is possible that some of these infants may not have another healthcare visit until they are two months old (an important prognostic threshold for infants with biliary atresia). Tables 1 and 2 depict the causes of persistent jaundice. Table 1. Causes of Unconjugated Hyperbilirubinemia
Current Recommendations for Evaluation and Management of Cholestatic Jaundice The NASPGHAN guidelines for the evaluation of cholestatic jaundice in infants between 2-8 weeks of age makes the following recommendations regarding the evaluation:17
Breast milk jaundice Hemolysis Blood group incompatibilities (ABO and Rhesus) Polycythemia Extravasated blood Increased enterohepatic circulation Pyloric stenosis
Bowel obstruction Endocrine/metabolic (also cause conjugated hyperbilirubinemia) Hypothyroidism Hypopituitarism Hypoadrenalism Galactosemia
Any infant who is noted to be jaundiced at two weeks of age should be evaluated for cholestasis by measuring total serum bilirubin and conjugated (direct) bilirubin. The evaluation of breastfed infants who have a normal physical examination, normally colored stools and urine, and can be closely monitored may be delayed until they are three weeks of age. Conjugated hyperbilirubinemia is defined as conjugated bilirubin concentration >1.0 mg/dl (17.1 µmol/l), if the total bilirubin is <5.0 mg/dl (85.5 µmol/l) or >20% of the total bilirubin, if the total bilirubin is >5.0 mg/dl (85.5 µmol/l). Infants in whom a treatable condition is diagnosed (e.g., urinary tract infection [UTI], galactosemia) and in whom jaundice fails to resolve should be re-evaluated.
Table 2. Causes of Conjugated Hyperbilirubinemia Idiopathic neonatal hepatitis (infection)
Metabolic diseases
Viral (CMV, rubella, herpes, HIV, parvovirus B19, ECHO, adenovirus)
a1-antitrypsin deficiency
Bacterial (UTI, sepsis, syphilis)
Cystic fibrosis
Bile duct obstruction
Tyrosinemia
Extrahepatic biliary duct atresia
Gaucher disease
Choledochal cyst
Niemann-Pick disease
Nonsyndromic paucity of intrahepatic biliary ducts
Wolman disease
Inspissated bile/mucus plug
Arginase deficiency
Cholelithiasis/biliary sludge
Galactosemia
Tumors/masses (intrinsic and extrinsic)
Fructosemia
Neonatal sclerosing cholangitis
Type 4 glycogen storage disease
Congenital hepatic fibrosis or Caroli’s disease
Peroxisomal disorders
Cholestatic syndromes
Zellweger syndrome
Arteriohepatic dysplasia (Alagille syndrome)
Hypopituitarism
Byler syndrome
Hypothyroidism
Progressive familial intrahepatic cholestasis type 1-3
Neonatal hemochromatosis
Bile acid synthesis defects
Miscellaneous: Shock, hypoperfusion, intestinal obstruction, erythrophagocytic lymphohistiocytosis, neonatal lupus
Toxins Drugs Total parenteral nutrition
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Symposium on child health Table 3. General Management Clinical impairment
Management
Malnutrition related to malabsorption of dietary long chain fatty acids
Replace with dietary formula or supplements containing mediumchain fatty acids
Fat soluble vitamin malabsorption:
Vitamin A deficiency
Replace with 10,000-15,000 IU/day as Aquasol A
Vitamin E deficiency
Replace with 50-400 IU/day as oral α-tocopherol
Vitamin D deficiency
Replace with 5,000-8,000 IU/day of vitamin D2 or 3-5 µg/kg/day of 25-hydroxy cholecalciferol
Vitamin K deficiency
Replace with 2.5-5 mg of parenteral vitamin K alternate day
Micronutrient deficiency
Supplement calcium, phosphate and zinc
Water soluble vitamin deficiency
Supplement with twice the recommended dietary allowances
Retention of biliary constituents e.g. cholesterol (leading to itching and xanthomas)
Administer choleretic bile salts and ursodeoxycholic acid, 15-20 mg/kg/day
Progressive liver disease; portal hypertension, spontaneous bacterial peritonitis
Control bleeding, salt restriction, spironolactone, appropriate management with antibiotics and supportive care
End-stage liver disease
Liver transplantation
Referral to a pediatric gastroenterologist is recommended for all infants with cholestasis. Ultrasound and liver biopsy is recommended for most infants with cholestasis.
2. Knobloch H, Malone A, Ellison PH, Stevens F, Zdeb M. Considerations in evaluation of changes in outcome for infants weighing less than 1650 grams. Pediatrics 1982;69:285-95.
MRCP and ERCP are not routinely recommended, although ERCP may be useful in experienced hands.
3. Mavalankar DV, Trivedi CR, Gray RH. Levels and risk factors for perinatal mortality in Ahmedabad, India. Bull WHO 1991;69:435-43.
The first step in management is to treat the underlying cause. Biliary atresia and choledochal cyst: Early surgical management before irreversible cirrhosis sets in.
Galactosemia: Lactose-free diet.
Hypothyroidism: Thyroxine replacement.
Sepsis and UTI: Treat with antibiotics.
Congenital infections: Treat appropriately.
1. Rees JM, Lederman SA, Kiely JL. Birth weight associated with lowest neonatal mortality: infants of adoloscent and adult mothers. Pediatrics 1996;98:1161-6.
Scintigraphy and duodenal aspirate are not routinely recommended but may be useful in situations in which other tests are not readily available.
Management
References
Panhypopituitarism: To provide required hormone replacements.
This should be followed by management of clinical impairment as shown in Table 3. Indian Journal of Clinical Practice, Vol. 21, No. 8, January 2011
4. Cibils LA, Karrison T, Brown L. Factors influencing neonatal outcomes in the very low birth weight fetus (<1500 grams) with a breech presentation. Am J Obstet Gynecol 1994;171:35-42. 5. Spinillo A, Fazzi E, Stronati M, Ometto A, Capuzzo E, Guaschino S. Early morbidity and neurodevelopmental outcome in low birth weight infants born after third trimester bleeding. Am J Perinatol 1994;11:85-90. 6. Lubchenko LO, Searls DT, Brazie JV. Neonatal mortality rate: relationship to birth weight and gestational age. J Pediatr 1972;81:814-22. 7. Phelps DL, Brown DR, Tung B, Cassady G. 28 days survival rates of 6676 neonates with birth weights of 1250 grams or less. Pediatrics 1991;87:7-17. 8. Gera T, Ramji S. Early predictors of mortality in very low birth weight neonates. Indian Pediatrics 2001;38: 596-602.
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Symposium on Child health 9. Hansen T, Corbet A. Disorders of transition. In: Averyâ&#x20AC;&#x2122;s Diseases of the Newborn. 7th edition, WB Saunders, Philadelphia 1998:603. 10. Geggel RL, Reid LM. Structural basis of PPHN. Clin Perinatol 1984;11:525. 11. Murphy JD, Rabinovitch M, Goldstein JD, Reid LM.The structural basis of PPHN infant. J Pediatr 1981;98: 962-7. 12. Finer NN, Barrington KJ. NO for respiratory failure in infants born at or near term. Cochrane Database Syst Rev 2001;4:CD000399. 13. Kinsella JP, Abman SH. Inhaled NO. Current and future uses in neonates. Semin Perinatol 2000;24:387. 14. Ives NK. Neonatal jaundice. Current Paediatrics 1997; 7:67-72.
15. Kelly DA. Hepatology In: Investigations in Paediatrics Addy and Douglas (Eds.), WB Saunders 1994:123-30. 16. Kelly DA, Stanton A. Jaundice in babies: implications for community screening for biliary atresia. BMJ 1995;310:1172. 17. Moyer V, Freese DK, Whitington PF, Olson AD, Brewer F, Colletti RB, et al; North American Society for Pediatric Gastroenterology Hepatology and Nutrition. Guideline for the evaluation of cholestatic jaundice in infants: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2004;39(2):115-28.
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Symposium on Neurology
Diagnostic Tools for DPNP Alejandra Gonzalez-Duarte, David M Simpson
Abstract Diabetic peripheral neuropathic pain (DPNP) is a debilitating complication of diabetes, DPNP can dramatically impact quality of life early diagnosis and treatment are essential to the care of patients with DPNP. Key words: Diabetic peripheral neuropathic pain, hyperglycemia, pins and needles sensation, stocking and glove pattern
D
iabetic peripheral neuropathic pain (DPNP) is a debilitating complication of diabetes, affecting 10% to 20% of patients with this disease.1 The prevalence of peripheral neuropathy approaches 50% in patients who have had diabetes for more than 25 years.2,3 Neuropathic pain is often described as aching, burning, stabbing, or shooting sensations in the feet.1,4 It is variable in severity and is often worst at night.1,4,5 DPNP can dramatically impact quality of life.5 Painful symptoms have been linked to worsening physical and psychosocial functioning.5 DPNP also predisposes patients to foot ulceration, burns, infections, gangrene, and Charcot’s neuroarthropathy.6 Thus, early diagnosis and treatment are essential to the care of patients with DPNP. Key questions in the diagnosis of DPNP are listed in Table 1. Features of DPNP Neuropathic pain is defined as spontaneous pain or hypersensitivity to sensory stimuli in association with damage to or a lesion of the nervous system.7 It is often chronic and unrelenting, and it does not respond to treatment with common analgesics.8 Neuropathic pain can be diagnosed clinically on the basis of distinct features that help differentiate it from other types of pain (Table 2).1,6,8 Alejandra Gonzalez-Duarte, MD, Neurologist, Mount Sinai School of Medicine, New York City David M. Simpson, MD, Professor of Neurology, Director, Clinical Neurophysiology Laboratories, Director, Neuro-AIDS Program, Mount Sinai School of Medicine, New York City Source: Adapted from McMahon Publications, Pain Medicine News, June 2007 (IJCP 2010;20(9):664-7).
Indian Journal of Clinical Practice, Vol. 21, No. 8, January 2011
The pathogenesis of diabetic neuropathy is complex. In hyperglycemia, elevated intracellular levels of glucose drive secondary pathologic mechanisms, such as oxidative stress and protein glycation, in vascular and nervous tissues.9 Diabetic neuropathy can affect both large and small nerve fibers to varying degrees, resulting in mixed symptoms and sensory loss.10,11 More commonly, small-fiber neuropathy predominates over large-fiber neuropathy. Large afferent nerve fibers transmit propioception (i.e. spatial limb location) and sensations of cold and vibration.10,12 Small afferent fibers conduct nociceptive stimuli and sensations of touch and warmth.10,12,13 The diagnosis of DPNP is usually made based on the patient’s history and results of a physical and neurologic examination. Neuropathic symptoms are often difficult for patients to describe. They may consist of severe burning pain, paresthesias, and numbness and can fluctuate in intensity from mild discomfort to severe pain. The classic presentation of DPNP is pain in Table 1. Key Questions for the Diagnosis of DPNP
Is the patient diabetic?
Does the patient have burning pain in his or her feet?
Is the pain associated with tingling, pinprick sensations, or numbness? Are the symptoms distributed symmetrically? Are the examination findings consistent with distal peripheral neuropathy (i.e. decreased or absent ankle reflexes, decreased sensation of temperature or vibration, decreased propioception)? Have other, nondiabetic causes of neuropathy been ruled out (e.g. neoplasm, infection, toxic substance abuse)?
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Symposium on neurology Table 2. Features of Neuropathic and Nociceptive Pain1,6,8 Neuropathic pain
Nociceptive pain
Time course
Chronic, unrelenting, and not self-limited; can persist for years
Usually acute and self-limited
Symptoms
Sensations of burning or of electric, tingling, or shooting pain
Sharp, aching, throbbing, or gnawing pain
Treatment response Poor response to NSAIDs; usually responds to anticonvulsants, antidepressants, opioids and topical agents
Usually responds to nonspecific analgesics, NSAIDS, and opioids
Pathophysiology
Produced by damage to or pathologic changes in the peripheral or central nervous system
Caused by the stimulation of A-δ and C-polymodal pain receptors and by algogenic substances (e.g. histamine, bradykinin, substance P)
Source of pain
Injury or malfunction in the peripheral or central nervous system
Protective biological function to warn of ongoing tissue damage
Examples
Radiculopathy, trigeminal neuralgia, postherpetic neuralgia, phantom limb pain, complex regional pain syndrome, polyneuropathies (i.e. DPNP HIV infection)
Postoperative pain, pain associated with trauma or arthritis
DPNP = Diabetic peripheral neuropathic pain; HIV = Human immunodeficiency virus; NSAIDs = Nonsteroidal anti-inflammatory drugs.
the feet, often described as ‘burning,’ ‘shooting,’ or ‘throbbing.’ The pain may be spontaneous or stimulusevoked and may be associated with allodynia (pain resulting from a stimulus that ordinarily does not elicit a painful response, such as contact with bedclothes, shoes, and socks) or with hyperalgesia (increased sensitivity to a painful stimulus, such as pinprick).8,12 Tingling or ‘pins and needles’ sensations are common. In addition to the painful (positive) symptoms of neuropathy, patients may experience nonpainful (negative) symptoms. These include numbness, often described as an area that is ‘dead’ or ‘asleep.’ Other negative symptoms include gait unsteadiness (ataxia) and, in late stages, distal muscle weakness.1,12,14 Patients often compare this sensation to one of walking through sponges that make it impossible to feel the ground normally. Excruciating pain is the most common identified symptom of diabetic neuropathy; however, the damage typically develops insidiously as loss or changes of sensation that may be detected only by clinical tests.1,4 Typically, DPNP first affects the feet and lower limbs symmetrically and affects the upper extremities only in late stages.1,12 The distribution resembles a ‘stocking and glove’ pattern.12,15 Proximal motor weakness or an asymmetric distribution should suggest other types of neuropathy.1,16 470
Clinical Examination Neurologic examination in DPNP reveals absent or depressed ankle reflexes relative to knee reflexes. Because of the anatomic position of the Achilles tendon, assessment of the ankle reflex (S1 innervation) is at times difficult to perform correctly. To obtain the Achilles tendon reflex, the foot should be flexed upward to stretch the tendon. The tendon on the back of the leg at the height of the ankle bone is tapped, and if the reflex is present, the foot will extend. Most physicians have experience with the knee reflex (L3 innervation) because it is accessible and easily palpated. However, to obtain this reflex, it is necessary to bend the knee to stretch the patellar tendon and ensure that the leg is relaxed. The tendon must be palpated to verify the location. When reflexes are present, the leg will extend when tapped. Normal reflexes are usually graded as 2+. Hyperactive reflexes are graded 3+ and 4+, depending on the presence of clonus (the rhythmic contraction and relaxation of a muscle group). Hypoactive reflexes are graded 1+ and absent reflexes 0. Results of sensory examination are commonly abnormal in patients with DPNP. Proprioception and sensations of light touch, vibration, and temperature are decreased or absent. A relative loss of discrimination of sharp touch is noted over the distal lower extremities, and an area of gradual transition where normal sensation returns. A broken tongue depressor is commonly used to test for sharp sensation,8 although more specific Indian Journal of Clinical Practice, Vol. 21, No. 8, January 2011
Symposium on neurology commercial sterile examination pins and nylon monofilaments are available. Vibratory sensation is assessed by placing a 128-Hz tuning fork over the bony surface of the malleolus or first distal phalanx. The threshold to vibratory sensation is usually elevated in the feet compared with that in the knees. Data from one study suggest that the predictive value of testing with a 128-Hz tuning fork in the diagnosis of DPNP is similar to that of national and international scoring systems.17 The study authors concluded that the tuning fork should play a central role in the diagnosis of DPNP.17 Temperature sensation may be assessed with a cool tuning fork or with test tubes that contain warm or cold water.8 Like the thresholds to vibratory sensation, altered thresholds to thermal sensation have been well documented in patients with DPNP, and their elevation has been associated with progression of neuropathy.1,18 Loss of proprioception can impair gait and balance.1,14 Because the diagnosis of DPNP is usually evident based on results of the bedside examination, further neurologic testing is unnecessary in most patients.8,19 However, other diagnostic tests may be helpful in patients with atypical clinical presentations, or in the research setting. Several methods to assess peripheral nerve function are available (Table 3). • Nerve conduction studies (NCS) and electromyography (EMG) have long been considered the gold standard for the assessment of peripheral neuropathy. However, in DPNP, which may affect predominantly small nerve fibers, NCS and EMG may yield normal results or show only minor abnormalities. NCS may differentiate DPNP from other neuropathies.4,8,20 Abnormal NCS results frequently indicate more severe involvement, a less benign course, and a less favorable diagnosis. The progressive loss of distal axons is the pathologic hallmark of peripheral neuropathies. This loss is reflected in NCS by
prolonged distal latencies, reduction in evoked potential amplitudes, and secondary slowing of conduction velocity. • Quantitative sensory tests (QSTs) are used mostly for research purposes, although they may also be applied in the clinical setting. They are performed with devices, often computer-assisted, that make it possible to assess somatosensory function, including the perception of vibration, temperature, light touch, and pain.8,12,20 QSTs can be used to identify the sensory modalities affected and to estimate the magnitude of the deficit. In patients with diabetes, QSTs have proved valuable in the detection of subclinical neuropathy.1,12
Skin biopsy is a newer technique that is sensitive in the detection of small-fiber neuropathies.12,21 A skin biopsy is a procedure in which a small piece of the patient’s skin is removed for examination under a microscope. It is a useful tool that requires basic medical skills and is easy to learn. Specimens are obtained by performing skin-punch biopsies at various sites in the leg, usually in the distal portion of the leg above the ankle and in the thigh. Full-thickness skin specimens are needed. After sterilizing and numbing the area, a circular blade is rotated down through the epidermis and dermis and into the subcutaneous fat, yielding a 3 to 4 mm cylindrical core of tissue. Samples are fixed and sent to the pathology laboratory, where morphometric and immunohistochemical methods are used to examine the thinly myelinated and unmyelinated nerve fibers. Integrity, density, and distribution of these fibers is assessed. Skin biopsy is the most sensitive measure of neuropathic changes. Significant inverse correlations between the density of nerve fibers and the severity of neuropathy have been documented.2 Moreover, changes in nerve fiber density over time correlates with decreased neuropathic pain.22
Table 3. Diagnostic Tests for Diabetic Peripheral Neuropathic Pain NCS/EMG
Measures the speed and amplitude of sensory and motor conduction
Objective, parametric, noninvasive, and reproducible
QST
Detects sensory thresholds for vibration, heat, and pain
Useful in tracking the progression of neuropathy in large cohorts and efficacy of treatment endpoints in multicenter clinical trials
Skin biopsy
Measures density of intraepidermal nerve fiber at various sites in the leg
Loss of nerve fibers is associated with increased neuropathic pain
Insensitive in acute and small-fiber neuropathy
Although test is invasive, it requires only a 3-mm skin biopsy specimen and enables a direct study of small nerve fibers
NCS/EMG = Nerve conduction studies/electromyography; QST = Quantitative sensory tests.
Indian Journal of Clinical Practice, Vol. 21, No. 8, January 2011
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Symposium on neurology The first step in the approach to diabetic patients with pain is to establish the diagnosis of neuropathic pain and determine the form of neuropathy. A simple key question to ask patients with diabetes might be, “Do you feel burning pain, tingling, or numbness on your feet?”8 If the answer is positive, the distribution may differentiate DPNP from other conditions. A distal and symmetric distribution of symptoms and signs is suggestive of DPNP.1,8 A nerve root distribution suggests radiculopathy whereas a nerve trunk distribution may indicate mononeuropathy simplex or multiplex. Sensory function should be assessed on both sides of the feet and hands to distinguish DPNP from entrapment syndromes (e.g. carpal or tarsal tunnel syndrome). Additional symptoms such as weakness are more suggestive of large-fiber dysfunction, such as diabetic amyotrophy or motor neuropathies. The diagnostic studies previously discussed provide valuable data in differentiating these forms of neuropathy.
6. Aring AM, Jones DE, Falko JM. Evaluation and prevention of diabetic neuropathy. Am Fam Physician 2005;71:2123-8.
Conclusion
13. Vinik AI, Holland MT, LeBeau JM, Liuzzi FJ, Stansberry KB, Colen LB. Diabetic neuropathies. Diabetes Care 1992;15:1926-75.
DPNP is predominantly a clinical diagnosis. Patients usually present with burning pain, tingling, and numbness in a symmetrical distribution over the feet and occasionally the hands. Physical examination reveals decreased or absent ankle reflexes, sensations of pinprick and vibration, and propioception. NCS, QSTs, and skin biopsy are helpful in differentiating DPNP from other forms of neuropathy and in assessing the progression of neuropathy over time. References 1. Boulton AJ, Malik RA, Arezzo JC, Sosenko JM. Diabetic somatic neuropathies. Diabetes Care 2004;27:1458-86. 2. Pirart J. Diabetes mellitus and its degenerative complications: a prospective study of 4,400 patients observed between 1947 and 1973 (3rd and last part). Diabetes Metab 1977;3:245-56. 3. Cabezas-Cerrato J. The prevalence of clinical diabetic polyneuropathy in Spain: a study in primary care and hospital clinic groups. Neuropathy Spanish Study Group of the Spanish Diabetes Society (SDS). Diabetologia 1998;41:1263-9. 4. Boulton AJ, Vinik AI, Arezzo JC, et al. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care 2005;28:956-62. 5. Schmader KE. Epidemiology and impact on quality of life of postherpetic neuralgia and painful diabetic neuropathy. Clin J Pain 2006;18:350-4.
7. Merskey H, Bogduk N (Eds.). Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms, Second Edition. Seattle, Wash: IASP Press; 1994:209-14. 8. Argoff CE, Cole BE, Fishbain DA, Irving GA. Diabetic peripheral neuropathic pain: clinical and quality-of-life issues. Mayo Clin Proc 2006;81:S3-S11. 9. Duby JJ, Campbell RK, Setter SM, White JR, Rasmussen KA. Diabetic neuropathy: an intensive review. Am J Health Syst Pharm 2004;61:160-76. 10. Vinik AI, Park TS, Stansberry KB, Pittenger GL. Diabetic neuropathies. Diabetologia 2000;43:957-73. 11. Bird SJ, Brown MJ. The clinical spectrum of diabetic neuropathy. Semin Neurol 1996;16:115-22. 12. Barbano R, Hart-Gouleau S, Pennella-Vaughan J, Dworkin RH. Pharmacotherapy of painful diabetic neuropathy. Curr Pain Headache Rep 2003;7:169-77.
14. van Deursen RW, Sanchez MM, Ulbrecht JS, Cavanagh PR. The role of muscle spindles in ankle movement perception in human subjects with diabetic neuropathy. Exp Brain Res 1998;120:1-8. 15. Wulff EA, Simpson DM. HIV-associated peripheral nervous system complications. NeuroAIDS 1999;2. 16. Dyck PJ, Karnes JL, O’Brien PC, Litchy WJ, Low PA, Meltton LJ. The Rochester Diabetic Neuropathy Study: Reassessment of tests and criteria for diagnosis and staged severity. Neurology 1992;42:1164-70. 17. Meijer JW, Smit AJ, Lefrandt JD, van der Hoeven JH, Hoogenberg K, Links TP. Back to basics in diagnosing diabetic polyneuropathy with the tuning fork! Diabetes Care 2005;28:2201-5. 18. Sosenko JM, Kato M, Soto R, Bild DE. Comparison of quantitative sensory-threshold measures for their association with foot ulceration in diabetic patients. Diabetes Care 1990;13:1057-61. 19. Pascuzzi RM. Peripheral neuropathies in clinical practice. Med Clin North Am 2003;87:697-724. 20. Vinik AI, Mehrabyan A. Diabetic neuropathies. Med Clin North Am 2004;88:947-99. 21. Sorensen L, Molyneaux L, Yue DK. The relationship among pain, sensory loss, and small nerve fibers in diabetes. Diabetes Care 2006;29:883-7. 22. Boulton AJ. Clinical trials report. Curr Diab Rep 2006;6:415-6.
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Emedinews Section
From eMedinewS Botox may Relieve Postherpetic Neuralgia
Heavy Internet Usage Associated with Depression
Subcutaneous injection of botulinum toxin A significantly reduced postherpetic neuralgia compared with lidocaine and saline placebo in a small randomized clinical study. Preliminary data suggest that Botox may be useful for the treatment of refractory postherpetic neuralgia.
According to a study of more than 1,300 people to be published in the journal Psychopathology, British researchers found that people who compulsively browse, chat and play online have higher rates of moderate-tosevere depression than people who aren’t compulsively driven to use the Internet.
—Dr Lizu Xiao, Nanshan Hospital, Shenzhen, China
Most Deviations from Guidelines may be Correct According to an observational study published in the journal Annals of Internal Medicine, physician-recorded medical exceptions are correct most of the time. In the setting of a large internal medicine practice, physicians recorded 650 standardized medical exceptions i.e., documenting medical reasons for deviating from recommendations put forth by guidelines, during a period of seven months. The reporting tool was used without any medical reason 36 times (5.5%). Of the remaining 614 exceptions, a peer-review panel classified 93.6% as medically appropriate, 3.1% as inappropriate and 3.3% as having uncertain appropriateness. After physicians received direct feedback about inappropriate exceptions, eight of 19 (42%) changed management. Source: Ann Intern Med 2010;152:225-31.
Third-hand Smoke: New Term Tobacco smoke contamination lingering on furniture, clothes and other surfaces, is dubbed third-hand smoke. It may react with indoor air chemicals to form potential cancer-causing substances, according to a study in the Proceedings of the National Academy of Sciences: After exposing a piece of paper to smoke, researchers at the Lawrence Berkeley National Laboratory found the sheet had levels of newly formed carcinogens that were 10 times higher after three hours in the presence of an indoor air chemical called nitrous acid (HONO) commonly emitted by household appliances or cigarette smoke. Nicotine reacted with the indoor air pollutant to form carcinogenic compounds called tobacco-specific nitrosamines (TSNAs). They found substantial levels of TSNAs on surfaces inside the smoker’s truck that was used in the study. More than half of the cancer-causing compounds remained more than two hours after the cigarette smoke had cleared.
Milestones in Gastroenterology
eMedinewS Try this it Works
1785-1850: William Prout, a British Chemist and Physiologist, identified hydrochloric acid in stomach secretions or gastric juice. He presented a paper to the Royal Society of London, entitled ‘Nature of Acid and Saline Matters usually existing in the Stomachs of Animals’, in which he quantified the concentration of free and total hydrochloric acid, including chlorides in gastric secretion.
Check the Pulse in Suspected Paradoxus
Indian Journal of Clinical Practice, Vol. 21, No. 8, January 2011
A quick bedside test to check for presence of pulses paradoxus consists of feeling the pulse and noting whether or not it changes with respiration. The test is positive if you can feel the pulse diminish in amplitude and even disappear during inspiration. On the other hand, a normal-volume pulse during inspiration rules out significant pulsus paradoxus.
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emedinews Section International Medical Science Academy Update
Mnemonic of the Day Management of renal failure (acute)
Clinical and Prognostic Subforms of New Daily-persistent Headache
Remember your vowels .... AEIOU Anemia/Acidosis Electrolyte and fluids Infections Other measures (e.g., nutrition, vomiting) Uremia
New daily-persistent headache (NDPH) is a type of daily headache that is unremitting from onset or very soon after onset. A new study that used modified criteria for the diagnosis found that 56% of patients with NDPH had prominent migraine features. Source: Robbins MS, Grosberg BM, Napchan U, et al. Neurology 2010;74:1358-64.
FDA Issues Safety Notice for Sibutramine On January 21, 2010, the US FDA issued a statement about sibutramine (Meridia) to follow-up regarding earlier concerns that use of the drug may elevate the risk of adverse cardiovascular events. Meridia is FDAapproved for the management of obesity, including weight loss and maintenance of weight loss, along with a reduced-calorie diet. The notification was based on data from the Sibutramine Cardiovascular Morbidity/ Mortality Outcomes in Overweight or Obese Subjects at Risk of a Cardiovascular Event (SCOUT) study. A new contraindication is being added to the sibutramine product label stating that sibutramine is
nausea,
—Dr Maj Prachi Garg
not to be used for patients with CVD, including those with the following:
History of coronary artery disease (e.g., myocardial infarction, angina)
History of stroke or transient ischemic attack
History of cardiac arrhythmias
History of congestive heart failure
History of peripheral arterial disease
Uncontrolled hypertension >145/90 mmHg)
(e.g.
with
BP
Effective Antibiotic Prescribing: Top 10 Tips 1. Start antibiotic treatment immediately in patient with life-threatening infection. 2. Prescribe in accordance with local policies and guidance avoiding broad-spectrum agents. 3. Document, in clinical notes, indication(s) for prescribing antibiotics. 4. Send appropriate specimens to the microbiology lab draining pus and removing foreign bodies if indicated. 5. Use antimicrobial susceptibility data to de-escalate/substitute/add agents and to switch from intravenous to oral therapy 6. Prescribe the shortest antibiotic course likely to be effective 7. Always select agents minimize collateral damage (i.e., selection of multi-resistant bacteria/Clostridium difficile). 8. Monitor antibiotic drug levels when relevant (e.g., vancomycin). 9. Use single dose antibiotic prophylaxis wherever possible. 10. Consult your local infection experts. — Dr GM Singh
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Indian Journal of
Clinical Practice
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departments and institutions where the work was performed, name of the corresponding authors, acknowledgment of financial support and abbreviations used. – The title should be of no more than 80 characters and should represent the major theme of the manuscript. A subtitle can be added if necessary. – A short title of not more than 50 characters (including inter-word spaces) for use as a running head should be included. – The name, telephone and fax numbers, e-mail and postal addresses of the author to whom communications are to be sent should be typed in the lower right corner of the title page. – A list of abbreviations used in the paper should be included. In general, the use of abbreviations is discouraged unless they are essential for improving the readability of the text. Summary – The summary of not more than 200 words. It must convey the essential features of the paper. – It should not contain abbreviations, footnotes or references. Introduction – The introduction should state why the study was carried out and what were its specific aims/objectives. Methods – These should be described in sufficient detail to permit evaluation and duplication of the work by others. – Ethical guidelines followed by the investigations should be described. Statistics The following information should be given: – The statistical universe i.e., the population from which the sample for the study is selected. – Method of selecting the sample (cases, subjects, etc. from the statistical universe). – Method of allocating the subjects into different groups. – Statistical methods used for presentation and analysis of data i.e., in terms of mean and standard deviation values or percentages and statistical tests such as Student’s ‘t’ test, Chi-square test and analysis of variance or non-parametric tests and multivariate techniques.
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.
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Title page Should contain the title, short title, names of all the authors (without degrees or diplomas), names and full location of the
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Indian Journal of Clinical Practice, Vol. 21, No. 8, January 2011
Confidence intervals for the measurements should be provided wherever appropriate.
Results These should be concise and include only the tables and figures necessary to enhance the understanding of the text.
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Discussion –
This should consist of a review of the literature and relate the major findings of the article to other publications on the subject. The particular relevance of the results to healthcare in India should be stressed, e.g., practicality and cost.
References These should conform to the Vancouver style. References should be numbered in the order in which they appear in the texts and these numbers should be inserted above the lines on each occasion the author is cited (Sinha12 confirmed other reports13,14...). References cited only in tables or in legends to figures should be numbered in the text of the particular table or illustration. Include among the references papers accepted but not yet published; designate the journal and add ‘in press’ (in parentheses). Information from manuscripts submitted but not yet accepted should be cited in the text as ‘unpublished observations’ (in parentheses). At the end of the article the full list of references should include the names of all authors if there are fewer than seven or if there are more, the first six followed by et al., the full title of the journal article or book chapters; the title of journals abbreviated according to the style of the Index Medicus and the first and final page numbers of the article or chapter. The authors should check that the references are accurate. If they are not this may result in the rejection of an otherwise adequate contribution. Examples of common forms of references are: Articles
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Do not use clips/staples on photographs and artwork.
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Illustrations must be drawn neatly by an artist and photographs must be sent on glossy paper. No captions should be written directly on the photographs or illustration. Legends to all photographs and illustrations should be typed on a separate sheet of paper. All illustrations and figures must be referred to in the text and abbreviated as “Fig.”.
Please complete the following checklist and attach to the manuscript: 1. Classification (e.g. original article, review, selected
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.
2. Total number of pages ________________________
Books
5. Special requests _____________________________
Stansfield AG. Lymph Node Biopsy Interpretation Churchill Livingstone, New York 1985.
6. Suggestions for reviewers (name and postal address)
Articles in Books
2.____________
2._ _______________
Strong MS. Recurrent respiratory papillomatosis. In: Scott Brown’s Otolaryngology. Paediatric Otolaryngology Evans JNG (Ed.), Butterworths, London 1987;6:466-470.
3.____________
3._ _______________
4.____________
4._ _______________
Tables –
These should be typed double spaced on separate sheets with the table number (in Roman Arabic numerals) and title above the table and explanatory notes below the table.
Legends – These should be typed double spaces on a separate sheet and figure numbers (in Arabic numerals) corresponding with the order in which the figures are presented in the text. –
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Figures – Two complete sets of glossy prints of high quality should be submitted. The labelling must be clear and neat. – All photomicrographs should indicate the magnification of the print. – Special features should be indicated by arrows or letters which contrast with the background. – The back of each illustration should bear the first author’s last name, figure number and an arrow indicating the top. This should be written lightly in pencil only. Please do not use a hard pencil, ball point or felt pen. – Color illustrations will be accepted if they make a contribution to the understanding of the article.
The legend must include enough information to permit interpretation of the figure without reference to the text.
summary, etc.)_______________________________ 3. Number of tables ____________________________ 4. Number of figures ___________________________
Indian 1.____________Foreign 1._ _______________
7. All authors’ signatures________________________ 8. Corresponding author’s name, current postal and e-mail address and telephone and fax numbers __________________________________________
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igh doses or long-term use of PPIs or proton-pump inhibitors can lead to an increased risk of bone fractures. This holds especially true for those over the age of 50, and for people on the high dose. The latest warning is based on a FDA review of several studies of the treatment. These epidemiologic studies revealed an elevated fracture risk at the hip, wrist and spine. But the studies do not, definitively prove that PPIs are the cause of the fractures.
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FDA has instructed the manufacturers of the drugs to change the labels for both the prescription and the over-the-counter versions of the PPIs. The FDA said they should only be taken for 14 days to help ease frequent heartburn and under no circumstances should over-the-counter PPIs be taken for more than three 14-day periods in a year.
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Most researchers believe that more fractures are due to decreased calcium absorption from the diet because of the reduced stomach acid. But, it’s also possible that these drugs interfere with bone maintenance. Notably, PPIs have previously been linked to an increased risk of contracting pneumonia and the troublesome bacterium Clostridium difficile, as well as to an increased risk of dementia.
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iddle-aged women who move around more in their daily life have lower levels of intra-abdominal fat, a risk factor for heart disease. Minor modifications in daily routine such as reducing the time watching TV or increasing the walk time to work, can make a difference in the long-term health. Visceral fat is a hot topic because of metabolic syndrome, which predisposes people to disease. Intra-abdominal fat, or the fat that wraps around the organs in the abdomen and chest, tends to accumulate at midlife and can contribute to developing diabetes, hypertension and heart disease. The fat around the organs is known to be more related to heart disease and diabetes. A woman does not need to appear outwardly heavy to have a potentially troublesome extra ‘tire’ around her organs. Exercise for long has been known to reduce the amount of intra-abdominal fat.
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Make sure that good nursing care and maintenance of skin hygiene is advised first to patients with bed sores, along with topical antibiotics. KK Aggarwal
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