Critical Care January-March 2014

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Volume 9, Number 4

January-March 2014

Attitude, Knowledge and Practices of Medical Professionals About ADR and Their Reporting in a Teaching Hospital A Comparative Analysis of Commercial Metformin Tablets Role of Atorvastatin in Dyslipidemia: A Clinical Study Echocardiographic Findings in Submassive Pulmonary Embolism Anaphylactic Shock: A Rare Presentation of Phenytoin Drug Reaction Unusual Presentation of Angioimmunoblastic T-cell Lymphoma As a Solitary Lymph Node A Case of Biotinidase Deficiency Presenting as Quadriparesis ACP Releases Best Practice Advice on Colorectal Cancer Screening More...

Asian Journal of

Critical Care Volume 9, Number 4, January-March 2014

An IJCP Group Publication Dr Sanjiv Chopra Prof. of Medicine & Faculty Dean Harvard Medical School Group Consultant Editor Dr Deepak Chopra Chief Editorial Advisor Padma Shri and Dr BC Roy National Awardee

Dr KK Aggarwal Group Editor-in-Chief Dr Veena Aggarwal MD, Group Executive Editor

CONTENTS Contents FROM THE DESK OF GROUP EDITOR-IN-CHIEF

Off-Hours Myocardial Infarction, Air Pollution and Acute Coronary Syndromes KK Aggarwal

Critical Care Editorial Board Dr MM Pandit Rao Prof. Anesthesia, BJ Medical College, Pune Dr Vijay Langer Head, Dept. of Anesthesia, Moolchand Medcity, New Delhi Dr Rajesh Chauhan Sr. Anesthetist, Escorts Heart Institute, New Delhi Dr A Kale Prof. Anesthesia, AIIMS, New Delhi Dr Manju Mani Director-Critical Care, Delhi Heart and Lung Institute New Delhi Dr Tarlika Doctor Associate Professor Anesthesia, BJ Medical College, Ahmedabad

5

CLINICAL STUDY

Attitude, Knowledge and Practices of Medical Professionals About ADR and Their Reporting in a Teaching Hospital

6

Manoj Goyal, Monika Bansal, Shailesh Yadav, Varnika Grover, Preetkanwal

A Comparative Analysis of Commercial Metformin Tablets

10

P Elango, Ramesh, S Shanmuganathan IJCP Editorial Board

Obstetrics and Gynaecology Dr Alka Kriplani, Dr Thankam Verma, Dr Kamala Selvaraj Cardiology Dr Praveen Chandra, Dr SK Parashar Paediatrics Dr Swati Y Bhave Diabetology Dr CR Anand Moses, Dr Sidhartha Das Dr A Ramachandran, Dr Samith A Shetty ENT Dr Jasveer Singh, Dr Chanchal Pal Dentistry Dr KMK Masthan, Dr Rajesh Chandna Gastroenterology Dr Ajay Kumar, Dr Rajiv Khosla Dermatology Dr Hasmukh J Shroff, Dr Pasricha, Dr Koushik Lahiri Nephrology Dr Georgi Abraham Neurology Dr V Nagarajan, Dr Vineet Suri Journal of Applied Medicine & Surgery Dr SM Rajendran, Dr Jayakar Thomas Orthopedics Dr J Maheshwari Anand Gopal Bhatnagar Editorial Anchor

Advisory Bodies

Heart Care Foundation of India Non-Resident Indians Chamber of Commerce & Industry AdvisoryofBody World Fellowship Religions

Role of Atorvastatin in Dyslipidemia: A Clinical Study

16

Pooja BA, S Bhatted, N Chaturvedi, S Deekshit, MK Bhojani

IMAGING

Echocardiographic Findings in Submassive Pulmonary Embolism

19

SR Mittal

CASE REPORT

Anaphylactic Shock: A Rare Presentation of Phenytoin Drug Reaction

22

Amit D Bhatt, Anjali N Joshi, AP Jain

Unusual Presentation of Angioimmunoblastic T-cell Lymphoma As a Solitary Lymph Node

23

N Ashalatha, BN Kumarguru, BS Dayananda, AH Nagarajappa

Asian Journal of

Critical Care Volume 10, Number 4, January-February 2014

CONTENTS

Published, Printed and Edited by Dr KK Aggarwal, on behalf of IJCP Publications Ltd. and Published at E - 219, Greater Kailash, Part - 1 New Delhi - 110 048 E-mail: editorial@ijcp.com

CASE REPORT

A Case of Biotinidase Deficiency Presenting as Quadriparesis 28

Printed at Entire Printers Nampally, Hyderabad

Rajeev Thapar, K Venkatnarayan

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PRACTICE GUIDELINES

ACP Releases Best Practice Advice on Colorectal Cancer Screening

32

MEDILAW

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Medicolegal Cases in Injury Patients and Indian Law

Note: Asian Journal of Critical Care does not guarantee, directly or indirectly, the quality or efficacy of any product or service described in the advertisements or other material which is commercial in nature in this issue.

Lighter Side of Medicine

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KK Aggarwal

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Need for a Will or Power of Attorney

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FROM THE DESK OF GROUP EDITOR-IN-CHIEF XXXXXXXXXXX CLINICAL PRACTICE

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Off-Hours Myocardial Infarction, Air Pollution and Acute Coronary Syndromes

S

tudies have suggested that patients with acute myocardial infarction (MI) have poorer outcomes when they arrive at night or on the weekend, possibly related to delays in treatment or staffing issues. Henry Ting, MD, of the Mayo Clinic in Rochester, Minn., and colleagues set out to get a better idea of the magnitude of the relationship by pooling data from 48 studies with a total of nearly 1.9 million patients. Off-hours presentation was associated with a significant increase in the likelihood of dying either in the hospital or within 30 days of the event. Although the relative increase was small, the authors calculated that one out of every 27 in-hospital deaths and one out of every 29 deaths within 30 days could be avoided if the issue with off-hours presentation could be resolved. Part of the association could be related to treatment delay, as the likelihood of receiving percutaneous coronary intervention within the recommended 90 minutes was significantly lower at night and on the weekend.

Air Pollution and Risk of Acute Coronary Syndromes Giulia Cesaroni, MSc, of the Lazio Regional Health Service in Rome and colleagues turned to the European study of cohorts for air pollution effects (ESCAPE) project to examine whether long-term exposure to different types of air pollution is associated with greater risks of acute coronary syndromes. They performed a meta-analysis of 11 European cohorts from five countries that included a total of 1,00,166 people who did not have a history of coronary disease at baseline. Through an average follow-up of 11.5 years, 5.1% had an acute MI or developed unstable angina. In the fully adjusted model, only one type of air pollution– particulate matter measuring < 10 µm (PM10) – was associated with a risk of events. For every 5 μg/m3 increase in the estimated annual exposure, there was a 12% greater risk of having an acute coronary syndrome. Particulate matter measuring < 2.5 μm (PM2.5) and PM10 were both associated with greater risks of acute events in analyses limited to exposures below the annual European limits for the two pollutants of 25 and 40 μg/m3, respectively.

Asian Journal of Critical Care Vol. 9, No. 4, January-March 2014

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CLINICAL STUDY CLINICAL PRACTICE

Attitude, Knowledge and Practices of Medical Professionals About ADR and Their Reporting in a Teaching Hospital Manoj Goyal*, Monika Bansal**, Shailesh Yadav†, Varnika Grover‡, Preetkanwal‡

ABSTRACT Adverse drug reactions (ADRs) are one of the leading causes of morbidity and represent a substantial burden on healthcare resources. It has been reported that 2.4-6.5% of the total admissions in the hospitals are due to the adverse reactions, many of which are preventable. Voluntary ADR reporting is fundamental to medical drug safety surveillance; however, substantial under-reporting is the main limitation of the system. It is estimated that only 6-10% of all ADRs are reported. Therefore, the present study has been designed to assess the knowledge, attitude and practices of the medical professionals towards the ADRs and their reporting in our Institute. Aim and objectives: This study is aimed at investigating the knowledge and attitude and practices of medical professionals in a teaching hospital. Material and methods: The present study was a questionnaire based study. A structured validated questionnaire was used consisting of open ended and closed ended questions to collect the information after approval from the Institutional Ethics Committee (IEC). The study population consisted of all the medical teachers of the institute. Results: The response rate was 85%. Eighty percent of the respondents identified ADR as one of the major causes for mortality and morbidity in patients. ADR reporting was considered important by 87.5% respondents.

More than 85% wrote that they did not have enough knowledge about how to report an ADR. One hundred percent of the participants believed that there should be a system of ADRs reporting and monitoring in the institute. Interestingly, all the respondents believed that if the teachers from allied streams (dental, nursing, physiotherapy, pharmacy) are sensitized, it can be useful. Conclusion: There are gaps between knowledge and ADRs reporting among doctors working in a teaching hospital.

These gaps need to be filled by improved training and awareness in pharmacovigilance at various levels of healthcare system.

Key words: Adverse drug reactions, attitude, knowledge and practices of medical professionals

A

dverse drug reactions (ADRs) are one of the leading causes of morbidity and represent a substantial economic burden on healthcare resources.1 It has been reported that 2.4-6.5% of the total admissions in the hospitals are due to the adverse reactions, many of which are preventable.2 The incidence of serious ADRs is 6.7% in India.3 Spontaneous ADR reporting is fundamental to medical drug safety surveillance. Though, this system

*Associate Professor Dept. of Pharmacology **Associate Professor Dept. of Physiology † Professor Dept. of Pharmacology

‡ MBBS Student Maharishi Markandeshwar Institute of Medical Sciences and Research Mullana, Ambala, Haryana Address for correspondence Dr Manoj Goyal Associate Professor Dept. of Pharmacology Maharishi Markandeshwar Institute of Medical Sciences and Research Mullana, Ambala, Haryana -133 207 E-mail: dr_manojgoyal@yahoo.co.in

6

is inexpensive and easy to operate and encompasses all drugs and patient populations, including special groups but substantial under-reporting and inability to calculate the incidence of ADRs are the inherent disadvantages of this system.3,4 Under-reporting can lead to long delays between marketing and detection/ regulatory action of an adverse reaction. Almost seven million patients were exposed to fenfluramine before the association with valvular heart disease led to its withdrawal from the market.5 In one of the studies, 72% of surgical specialists and 81% of medical specialists had diagnosed an ADR but did not report, due to multiple reasons.6 It is estimated that only 6-10% of all ADRs are reported.7 Therefore, the present study was contemplated and done to assess the knowledge, attitude and practices of the medical professionals working in a teaching hospital in North India regarding ADRs and reporting to get an insight into the reasons for nonreporting and to suggest possible ways of improving spontaneous reporting based on our findings.

Asian Journal of Critical Care Vol. 9, No. 4, January-March 2014

CLINICAL STUDY Material and Methods The present survey was carried out at Maharishi Markandeshwar Institute of Medical Sciences and Research (MMIMSR), Mullana, Ambala, Haryana, a teaching postgraduate medical institute in North India. The study participants comprised of the medical teachers working in various preclinical, paraclinical and clinical specialties of the institute involved in imparting medical education to the undergraduate and postgraduate students. A structured validated questionnaire was used to collect the information from the study participants (n = 150) after approval from the Institutional Ethics Committee (IEC) using a Paper-and-pencil questionnaire administration mode.8 A verbal consent was taken and objective of the survey was clearly explained to them before administering the questionnaire.

Results and Observations The filled up questionnaires were collected and analyzed. The response rate was 85%. Eighty percent of the respondents said that ADR is one of the major causes for mortality and morbidity in patients.

ADR reporting was considered important by 87.5% respondents. Morbidity can be decreased, will help in identifying and banning the drug, and will increase awareness about particular ADRs, were some of the reasons quoted by the participants for the importance of reporting. 27.5% said all types of ADRs should be reported; whereas, 50% believed that only severe ADRs should be reported. 28.5% were aware about the country’s Pharmacovigilance program and 22% of the respondents wrote that ADRs can be reported using ADR reporting forms of which only 10% had reported an ADR to an ADR reporting and monitoring center.

67.5%, 95% and 100% had written that natural Table 1. Factors which would Influence them to Report ADRs Factors

Percentage (%)

Seriousness of an ADR

17.5

Certainty of ADR due to drug

2.5

Unusual ADR

2.5

Serious + Unusual ADR

7.5

Serious + Certain

2.5

Unusual + Certain

2.5

Serious + Certain + Unusual

65

Asian Journal of Critical Care Vol. 9, No. 4, January-March 2014

Table 2. Factors Influencing the Respondents not to report an ADR Factors

Percentage of respondents

1

42.5%

2

5%

3

7.5%

1&2

10%

1&3

5%

1, 2 & 3

7.5%

1, 2, 3 & 4

22.5%

1. Not enough knowledge, 2. Reporting forms not available, 3.

ADR already well known, 4. Others; no time to report, no incentive for reporting etc

health products, medical devices and equipment and vaccines, respectively can also produce ADRs. No one could write the four essential components of an ADR report, whereas 30% mentioned atleast one component of an ADR report. Majority believed that it is the seriousness, certainty and unusual nature of an ADR, which influences them to report an ADR (Table 1).

More than 85% wrote that they did not have enough knowledge about how to report an ADR (Table 2).

Others reasons; reporting forms not available, ADR already well-known, no incentive is given for reporting, no time to report, were also answered by few of the respondents (Table 2).

One hundred percent of the participants believed that there should be a system of ADRs reporting and monitoring in their institute and all of them opined that this kind of system would be useful for their patients and for them to be better healthcare professionals.

Pharmacologists’ and clinical pharmacists’ assistance will be useful in detection, reporting and management of ADRs was agreed upon by 87.55 and 57.5%, respectively. Interestingly, all the respondents believed that if the teachers from allied streams (dental, nursing, physiotherapy, pharmacy) are sensitized, can be useful.

All of them said were of the view point that if the medical students and the students from the allied fields are sensitized and trained, may prove useful.

Discussion During the developmental phase of a drug a good deal is known about its therapeutic activity but rather less about its safety because the clinical trials are conducted in a controlled environment in a lesser number of 7

CLINICAL STUDY patients and subjects. Once a drug gains entry into the market it will be prescribed by hundreds of doctors to thousands of patients belonging to different age groups. The scenario is complicated when there are ethnic variations, presence of co-morbid conditions and concomitant medications. During this phase only unusual and rare ADRs are encountered. So, if we have a system which can help us determine any new information available in relation to their safety profile can be critically useful. And since there are considerable social and economic consequences of ADRs, there is a need to engage healthcare professionals, in a well structured program to build synergies for monitoring ADRs. As ADR reporting is of prime importance in the success of any pharmacovigilance program, so the present survey was conducted with the intention of assessing the outlook of prescribers towards this.

Studies identify ADRs as important factors leading to hospital admissions.9 Our respondents felt that ADRs contribute to excessive healthcare costs through increased patient morbidity and mortality. It has been reported that the ADRs come as 4th-6th largest cause for mortality in the USA, including one million deaths and 2.2 million hospitalizations.10 Sixteen percent of hospital admissions in UK are due to ADRs.11 Some countries spend upto 15-20% of their hospital budget dealing with drug complications.12 Majority of our respondents felt that ADR reporting was important for the reason that it will bring down the mortality and morbidity and will decrease the healthcare cost. In one of the studies it was reported that 49.3% of ADRs leading to hospital admissions are avoidable13 and direct cost of managing drug-related morbidity and mortality in ambulatory setting was exorbitant at USD 76.6 billion/year.14 There is a considerable degree of under-reporting, which might partly be explained by lack of knowledge and misconceptions about spontaneous reporting of ADRs. More than 85% of the respondents in our survey admitted not having enough information on how to report ADRs as one of the reasons for not reporting, along with other reasons. Similar observations are made in other studies as well.6 Ignorance was admitted as a reason for not reporting ADRs in one of the studies by the respondents.15 Almost everyone admitted that if there is such kind of system in place then it would be useful for patients and them as well. The reasons for 8

under-reporting of ADRs have been summarized by Inman16 as the â&#x20AC;&#x2DC;seven deadly sinsâ&#x20AC;&#x2122;. This includes financial incentives (rewards for reporting), legal aspects (fear of litigation), complacency (belief that the serious ADRs are already documented when a drug is introduced in the market), diffidence (belief that reporting should be done when there is certainty that the reaction is caused by the use of a particular drug), indifference (belief that a single report would make no difference), ignorance (that only serious ADRs are to be reported), lethargy (excuses about lack of time or disinterestedness). In our study, a major reason observed was ignorance about the reporting system, while the financial and other aspects were given less importance. This suggests that an intervention to generate awareness on how to report ADRs may be necessary.

Available data indicate that the introduction of nurse and pharmacist reporting is proving to be very useful.17 Our respondents have also suggested sensitizing the members of allied streams including the paramedical staff about this issue. Continuous medical education (CME), training and workshops were the most cited means of improving ADR reporting in the suggestions.

This certainly shows that the doctors are willing to improve their knowledge of ADR reporting and increase their participation in the pharmacovigilance program of the country if education and awareness on the reporting scheme is instituted in the hospital.

The objective of this study was to evaluate the attitudes and knowledge of doctors in our teaching hospital to spontaneous ADR reporting. It would be logical to extend this study to other teaching hospitals, private practitioners, members of allied fields, students of medical and associated streams to enable us generalize our findings.

Conclusion There are gaps between knowledge and ADRs reporting among doctors working in a teaching hospital. These gaps need to be filled by improved training and awareness in pharmacovigilance at various levels of healthcare system. Attitudinal changes would be critical for a long-term improvement of ADR reporting. This may have important implications in terms of public health, if knowledge and attitudes are viewed as potentially modifiable factors.

Asian Journal of Critical Care Vol. 9, No. 4, January-March 2014

CLINICAL STUDY Possible Interventions and Suggestions by the Authors

Regular CMEs and workshops for all levels of healthcare system at institutional level and in the private sector. Faculty from the allied fields should be incorporated in the program to strengthen the system and improve the reporting culture. Students of medical, dental, nursing and physiotherapy should also be sensitized in order to spread the awareness about it. Increased educational efforts are needed to up-skill undergraduates and postgraduates in drug safety and pharmacovigilance. Mass media including the social media can be brought into use to spread the awareness about ADRs. ADR reporting is critical for drug safety monitoring and should be considered more of a professional responsibility by all the stakeholders in healthcare system in order to contribute optimally to the well-being of the society.

References 1. Kohn LT, Corrigan JM, Donaldson MS. To err is Human: Building a Safer Health System. Institute of Medicine: Washington DC; 2000.

2. Carrasco-Garrido P, de Andrés LA, Barrera VH, Ángel de Miguel G, Jiménez-García R. Trends of adverse drug reactions related-hospitalizations in Spain (2001-2006).

BMC Health Services Research 2010;10:28.

3. Desai CK, Iyer G, Panchal J, Shah S, Dikshit RK. An evaluation of knowledge, attitude, and practice of adverse drug reaction reporting among prescribers at a tertiary care hospital. Perspect Clin Res 2011;2(4):129-36.

4. Herdeiro MT, Figueiras A, Polónia J, Gestal-Otero JJ. Physicians’ attitudes and adverse drug reaction reporting: a case-control study in Portugal. Drug Saf 2005;28(9):825-33.

5. Pillans PI. Clinical perspectives in drug safety and adverse drug reactions. Expert Revof Clinical Pharmacol 2008;1(5):695-705.

6. Eland IA, Belton KJ, van Grootheest AC, Meiners AP, Rawlins MD, Stricker BH. Attitudinal survey of

voluntary reporting of adverse drug reactions. Br J Clin Pharmacol 1999;48(4):623-7.

7. Oshikoya KA, Awobusuyi JO. Perceptions of Doctors to Adverse Drug Reaction Reporting in a Teaching Hospital in Lagos, Nigeria. BMC Clin Pharmacol 2009;9:15.

8. Mellenbergh GJ.Tests and Questionnaires: Construction and administration. In: Advising on Research Methods: A Consultant’s Companion. Adèr HJ, Mellenbergh GJ (Eds.) Johannes van Kessel Publishing: Huizen, The Netherlands 2008p.211-36.

9. Rehan HS, Vasudev K, Tripathi CD. Adverse drug reaction monitoring: knowledge, attitude and practices of medical students and prescribers. Natl Med J India 2002;15(1):24-6.

10. Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 1998;279(15):1200-5.

11. Moore N, Lecointre D, Noblet C, Mabille M. Frequency and cost of serious adverse drug reactions in a department of general medicine. Br J Clin Pharmacol 1998;45(3):301-8.

12. White TJ, Arakelian A, Rho JP. Counting the costs of drug-related adverse events. Pharmacoeconomics 1999;15(5):445-58.

13. Nelson KM, Talbert RL. Drug-related hospital admissions. Pharmacotherapy 1996;16(4):701-7.

14. Lassetter JH, Warnick ML. Medical errors, drug-related problems, and medication errors: a literature review on quality of care and cost issues. J Nurs Care Qual 2003;18(3):175-81; quiz 182-3.

15. Lopez-Gonzalez E, Herdeiro MT, Figueiras A. Determinants of under-reporting of adverse drug reactions: a systematic review. Drug Saf 2009;32(1): 19-31.

16. Inman WH. Attitudes to adverse drug-reaction reporting.

Br J Clin Pharmacol 1996;41:433-5.

17. van Grootheest K, Olsson S, Couper M, de Jongvan den Berg L. Pharmacists’ role in reporting adverse drug reactions in an international perspective.

Pharmacoepidemiol Drug Saf 2004;13(7):457-64.

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Asian Journal of Critical Care Vol. 9, No. 4, January-March 2014

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CLINICAL STUDY CLINICAL PRACTICE

A Comparative Analysis of Commercial Metformin Tablets P Elango*, Ramesh**, S Shanmuganathan†

ABSTRACT Objective: Five commercial brands were analyzed with respect to their physical characters, chemical content and drug release.

Methods: The brands of metformin were randomly selected. All the groups were coded and analyzed. The tablets were examined for their shape, size, weight and color and the tablets were tested for their friability, disintegration, drug content, and purity using standard procedures. Results and discussion: On physical inspection, Brand C 500 was is the smallest and Brand D 500 SR was the largest in size. Brand C 500 was lesser in weight while Brand E XR 500 weighed more. On purity test, all other brands passed the standard for purity. All the brands had loss in weight less than 1% after the friability test.

On chemical content examination, variation was seen between the batches as well as the brands. The brands such as Brand A XL 500 and Brand D 500 SR contained the required content. But the brands like Brand C 500 and Brand E XR 500 had only lesser content and failed in the validity test. Conclusion: The physical properties of the five brands of metformin tablets were analyzed. Sustained release dosage form was mainly designed for maintaining therapeutic blood or tissue levels of the drug for extended period of time. Apart from the color and shape, the weight and size are very important to improve patients’ compliance. It is the duty of the pharmaceutical company to manufacture proper dosage forms to achieve the therapeutic goal.

Key words: Metformin, physical aspects, sustained release, content, disintegration time

M

etformin hydrochloride (MET) is chemically N, N-dimethylimidodicarbonimidic diamide hydrochloride (1, 1-dimethylbiguanide hydrochloride) that acts by decreasing intestinal absorption of glucose, reducing hepatic glucose production and increasing insulin sensitivity (Fig. 1). Metformin is considered as the first-line oral hypoglycemic agent in the treatment of type 2 diabetes mellitus. MET is the drug of choice in obese patients.1–3 Metformin activates adenosine monophosphateactivated protein kinase (AMPK), a liver enzyme that plays an important role in insulin signaling, whole body energy balance and metabolism of glucose and

*Associate Professor Dept. of Pharmacology Sri Ramachandra Medical College and Research Institute, Porur, Chennai **Lecturer † Professor Dept. of Pharmaceutics Sri Ramachandra College of Pharmacy, Sri Ramachandra University, Porur, Chennai Address for correspondence Dr P Elango Dept. of Pharmacology Sri Ramachandra Medical College and Research Institute Sri Ramachandra University Porur, Chennai - 600 116 E-mail: drpelango@yahoo.com

10

H 3C H3C

N

C NH

C

NH

NH2 HCI

NH

Figure 1. Chemical structure of MET.

fats. Activation of AMPK is required for metformin’s inhibitory effect on the production of glucose by liver cells. It is an official drug in Indian Pharmacopoeia,4 British Pharmacopoeia,5 European Pharmacopoeia,6 and United States Pharmacopoeia BP.7 Many brands are available for metformin generic in the market. This study was committed to evaluate the quality of the five brands of metformin. The brands having high quality should be equivalent not only in their basic chemical structure and dosage forms but also in their content, purity, friability and dissolution rates.8 Objective The study was a single-blind comparative analysis of five brands of metformin tablets and this study intended: zz To evaluate the physical quality in their appearance, purity in their substance, friability on handling, and the content in their preparations.

Asian Journal of Critical Care Vol. 9, No. 4, January-March 2014

CLINICAL STUDY zz

zz

To evaluate the time taken for their dissolution/ release.

To analyze the observations and make a comparison of the brands.

Methodology Five commercial brands of metformin were randomly selected. Metformin brands having label strength of 500 mg were purchased from a retail pharmacy in Chennai. Three batches were taken from each brand.

All tests were performed within product expiration dates. The brands were coded (Table 1) and analyzed in the following procedures. The analysts were kept blinded.

The tablets were visually examined for their shape, size, weight and color; the tablets were tested for their purity, friability and content, and dissolution rates were estimated using standard procedures.

Physical Inspection

The shape and color of the different brands of tablets were examined visually. The size was examined with the help of Vernier caliper. Tablets of each brand were weighed individually using a digital analytical balance (Ohaus Adventure, China).

Coding

Expiry date

No of tablets

GF01

FEB 2014

25

GF02

APR 2014

25

GF03

APR 2014

25

XM01

FEB 2014

25

XM02

JAN 2014

25

BRAND - B 500

XM03

NOV 2014

25

BRAND - C 500

GP01

MAY 2015

25

GP02

JAN 2015

25

GP03

APR 2015

25

GM01

MAR 2014

25

GM02

MAR 2014

25

GM03

MAY 2014

25

CP01

JULY 2014

25

CP02

AUG 2014

25

CP03

MAR 2012

25

BRAND - A XL 500

BRAND - B SR 500

BRAND - D SR

BRAND - E XR 500

Assay to estimate the purity of metformin of the given five brands was carried out using ultraviolet (UV) spectrophotometer method at specific absorbance (232 nm) as per Indian Pharmacopoeia.8 Friability Test

It is the tendency of the tablets to powder, chip, or fragment and this can affect the elegance appearance and consumer acceptance of the tablet, and can also add to the tablet’s weight variation or content uniformity problems. Friability is a property that is related to the hardness of the tablet. An instrument called friabilator is used to evaluate the ability of the tablet to withstand rattling in packaging, handling and shipping.

Procedure

Twenty tablets were weighed and subjected to abrasion using a tablet friability tester (Veego Instruments Corporation, Mumbai, India) at 25 revolutions per minute (rpm). zz zz

Weigh 20 tablets altogether = W1 Put these tablets in the friabilator and adjust the instrument at 100 rpm (i.e., 25 rpm for 4 min)

zz

Weigh 20 tablets (after friability) = W2

zz

Friability (% loss) = W1 − W2 % W1 × 100

Chemical Content Determination

Table 1. Coding of Tablets Brand

Purity

Asian Journal of Critical Care Vol. 9, No. 4, January-March 2014

This is used to determine whether the individual content of the tablets are within the limits set with reference to the average content of the sample.

Metformin powder is weighed in amounts of 0.1, 0.2, 0.3, 0.4, 0.5 and 0.75 mg. Each sample was dissolved separately in 1 mL of 0.2 M HCl and shaken up for 5 minutes. Five milliliters of 10−5 M KMnO4 was then added, warmed in a water bath at 50°C for 10 minutes and cooled for 3 minutes before 2 mL of 10−4 M methylene blue and 100 mL of distilled water was added. Five milliliters aliquot of the final volume was taken for each weight. The absorbance of the resulting solutions was determined at 663 nm. The procedure was applied to the five brands of metformin employed in the study.

Dissolution Rate Determination

In vitro dissolution rate is an important tool to predict the in vivo bioavailability and bioequivalence and to 11

CLINICAL STUDY decide on interchangeability.9 As per Food and Drug Administration guidance for highly soluble drugs, a single-point dissolution test specification of 85% in 60 minutes or less is sufficient as a quality control test for uniformity between different batches.10 Similarly, as per the European Medicines Agency (EMA) guidance, when more than 85% of the active substances are dissolved within 15 minutes, it is sufficient as a quality control test for uniformity between different batches.11,12 For this reason, dissolution testing of solid oral drug products has emerged as one of the most important control tests for assuring product uniformity and batch-to-batch equivalence.13 Therefore, any dosage forms having good dissolution rate is considered to be having good quality and is an important part of good manufacturing practice.14 Before performing dissolution test, six serially diluted solutions of pure metformin with the concentration of 0.3125 to 10 µg/mL were prepared from a stock solution and a standard curve was drawn. The curve was linear between 0.3125 and 10 µg/mL. The dissolution test was undertaken using USP apparatus II (Erweka DT6R, Gemini BV, The Netherlands) with the rate of 100 rpm at 37°C on six tablets of each brand. The dissolution medium was 900 mL phosphate buffer (pH = 6.8). To draw dissolution profile, 5 mL of dissolution samples were withdrawn at different time intervals up to 60 min and replaced with the same volume of prewarmed dissolution medium. Subsequently, samples after 100-fold dilution were assayed by UV spectrophotometer at an absorbance wavelength of 232 nm. The concentration of each sample was determined from a calibration curve (Fig. 2).

Medium: pH 6.8 phosphate buffer prepared by dissolving 6.8 g of monobasic potassium phosphate in 1,000 mL of water and adjusting with 0.2 N sodium hydroxide to a pH of 6.8 in 0.1; 1,000 mL. Apparatus II: 100 rpm, for tablets labeled to contain 500 mg.

Time: 1, 3, and 10 hours.

Procedure: Determine the amount of MET (C4H11N5·HCl) dissolved by UV absorption at the wavelength of maximum absorbance at about 232 nm on portions of the solution under test passed through a 0.45-m hydrophilic polyethylene filter and suitably diluted with Medium. Calculate the amount of MET, 12

A B S O R B A N C E

Series 1

1.2

Linear (Series 1)

y = 0.0193 x -0.0128

1

R2 = 0.9967

0.8 0.6 0.4 0.2 0 -0.2

0

10

20

30

40

50

60

CONCENTRATION Figure 2. Calibration curve.

in percentage, released at each time point by the formula as follows: C × (Au / As ) × (V - Vs ) + (C60 × Vs ) + (C180 × Vs )] × 100 L where C is the concentration of the standard solution in mg/mL; Au and As are the absorbances of the solution under test and the standard solution, respectively; V is the initial volume of medium in the vessel, in mL; Vs is the volume withdrawn from the vessel for previous samplings, in mL; C60 is the concentration of MET in the medium determined at 1 hour, in mg/mL; C180 is the concentration of MET in the medium determined at 3 hours, in mg/mL; 100 is the conversion to percentage; and L is the tablet label claim in mg.

Results and Discussion Physical Inspection

The different brands of metformin tablets were examined in their physical aspects, namely, shape, size, weight and color, and the details are given in table 2.

Size of the Tablets

The size of the tablets is above 0.50 cm in all the brands except Brand C 500 having only the size around 0.323 ± 0.003 cm, being the smallest. The size of the Brand D 500 SR is 0.71 cm, being the largest of the brands examined. There is no significant difference between batches of the brands. The size of dosage forms determines the compliance of the patients.

Weight of the Tablets

The weight of the tablets are in the range of 0.75-0.85 g except the Brand C 500 having only 0.55 g and being lesser in weight, while the Brand E XR 500 weighs more (0.85 g) among the brands examined. There is no significant difference between batches of the brands.

Asian Journal of Critical Care Vol. 9, No. 4, January-March 2014

CLINICAL STUDY Table 2. Physical Aspects Brand

Coding

Shape

Size Avg (cm)

Weight

Color

Friability %

Drug Purity content (%w/w) (mg)

Purity result

Brand A XL 500

GF01

Capsule shape with convex face

0.62

0.75

White

0.133

550

110

PASS

GF02

Capsule shape with convex face

0.61

0.75

White

0.133

540

108

PASS

GF03

Capsule shape with convex face

0.615

0.756

White

0.133

501

100

PASS

XM01

Capsule shape with flat face and bevel edges

0.50

0.75

White

0.133

425

85

FAIL

XM02

Capsule shape with flat face and bevel edges

0.506

0.75

White

0.136

550

110

PASS

Brand B 500

XM03

Capsule shape with convex face

0.52

0.75

White

0.268

474

95

PASS

Brand C 500

GP01

Capsule shape with concave face and bevel edges

0.32

0.55

White

0.225

431

86

FAIL

GP02

Capsule shape with concave face and bevel edges

0.323

0.55

White

0.256

511

102

PASS

GP03

Capsule shape with concave face and bevel edges

0.326

0.55

White

0.133

469

94

PASS

GM01

Oval shape

0.64

0.71

White

0

512

102

PASS

GM02

Oval shape

0.653

0.70

White

0

519

104

PASS

GM03

Oval shape

0.653

0.70

White

0

484

97

PASS

CP01

Capsule shape with convex face

0.536

0.85

White

0.618

550

110

PASS

CP02

Capsule shape with convex face

0.53

0.85

White

0.458

426

85

FAIL

CP03

Capsule shape with convex face

0.533

0.85

White

0.133

462

92

PASS

Brand B SR 500

Brand D 500 SR

Brand E XR 500

Purity

A tablet will usually contain active ingredient and vehicle matter. This study is conducted to identify the actual percentage of concentration of active ingredient of a single tablet of these five brands.

The purity assay showed that the five different brands contained different concentrations of the pure chemical and are found to be chemically not equivalent (Table 2). One of the batches of Brand B SR 500 (XM01), another one of Brand C 500 (GP01), and one more of Brand E XR 500 (CP02) contained only 85%, 86% and 85% of the ingredient, respectively and these Asian Journal of Critical Care Vol. 9, No. 4, January-March 2014

batches failed the validity test of 90% concentration.

All other brands passed the validity test.

Friability Test

The difference in weight loss before and after the friability test is analyzed. If it is to be declared as stable preparation for handling and transport, it must be less than or equal to 1%. The friability is expressed as the loss of mass and it is calculated as a percentage of loss of weight in the initial weight.15 All the brands are having the weight loss less than 1% after the friability test. But among the batches of the brands examined, Brand A 13

CLINICAL STUDY XL 500 have no significant difference within their three batches. The batch of Brand B SR 500 coded as XM03 has higher friability. It is because of being conventional or short-acting dosage form. The brand, Brand D 500 SR, has no weight loss in friability test and it is a very stable dosage form of the brands examined. The batches of Brand E XR 500 coded as CP01 and CP02 have got higher friability than code CP03.

Chemical Content

We examined only the tablets having concentration of 500 mg of metformin. A wide range of variations is seen in the contents of the tablets. The variation is seen between the batches as well as the brands. A brand should contain 90% of the substance (450-550 mg) to clear the validity test. The brands such as Brand A XL 500 and Brand D 500 SR contain the required content.

But the brands like Brand C 500 and Brand E XR 500 had only lesser content and failed the validity test. The content is also not uniform among batches (Fig. 3).

Batch 01

Batch 02

Dissolution Rate

Dissolution or release of the contents is more than 10 hour in all brands of sustained dosage forms. But the release in case of Brand B 500, batch XM03 and all the batches of Brand C 500 is in 60 minutes because of their conventional or short-acting dosage forms. Brand A XL 500 released more than 90% of their contents in 10 hour and it is sustained release dosage form as shown in (Fig. 4). Two batches (XM01, XM02) of Brand B SR 500 took 10 hour to release 83%-100% of its contents, but one batch (XM03) being short acting had taken 60 minutes to release more than 90%. This shows that the long-acting forms are suitable for less frequency in administration of drugs and improves patientsâ&#x20AC;&#x2122; compliance (Fig. 5). Brand C 500 had taken only 60 minutes for 94%-97% release as a short-acting form (Fig. 6).

Brand D 500 SR being sustained release form released 86%-92% 10 hour (Fig. 7). Brand E XR 500 had release time of 10 hour for 80%-99% of their contents (Fig. 8).

Batch 03

Series 1

600 120

400

100

% Drug Release

500 300 200 100 0 Brand B SR 500

Brand C 500

Brand D 500 SR

In vitro Drug Release for GF 01,02,03

60 40 20

Brand E XR 500

0

200

Series 2

Series 2

Series 3

800

Series 3

Series 4

120

100

% Drug Release

% Drug Release

120 80 60 40 20 0

200

400

600

800

100 80 60 40 20 0

0

15

Time in Min Figure 5. Release of Brand B.

14

600

In vitro Drug Release for GP 01,02,03

In vitro Drug Release for XM 01,02,03

0

400 Time in Min

Figure 4. Release of Brand A.

Figure 3. Drug content in milligrams per tablet.

Series 1

Series 3

80

0 Brand A XL 500

Series 2

30

45

60

Time in Min Figure 6. Release of Brand C.

Asian Journal of Critical Care Vol. 9, No. 4, January-March 2014

CLINICAL STUDY Series 1

Series 2

References

Series 3

1. Clinical Guidelines Task Force, International Diabetes Federation. Glucose control: oral therapy. In: Global Guideline for Type 2 Diabetes. Brussels: International Diabetes Federation 2005:35-8.

In vitro Drug Release for CP 01,02,03

% Drug Release

120 100

2. National Collaborating Centre for Chronic Conditions.

Type 2 diabetes: National Clinical Guideline for Management in Primary and Secondary Care (update).

London: Royal College of Physicians 2008:86.

80 60 40 20 0

0

200

400 Time in Min

600

3. American Diabetes Association. Standards of medical care in diabetes—2009. Diabetes Care 2009;32(Suppl 1): S13-61.

800

Figure 7. Release of Brand E.

4. Indian Pharmacopoeia, Government of India, Ghaziabad.

The Indian Pharmacopoeia Commission 2007;2:1358.

Main Limitations of the Study

5. British Pharmacopoeia, Her Majesty’s Stationary Office.

London, UK 2009;1 and 2:3813.

Dissolution test in vitro will preconceive the in vivo behavior of a drug. But the real bioavailability and bioequivalence of the products can be concluded only in vivo studies. The human gastrointestinal tract with its own nature and various other factors affect its activity, the generalization of dissolution conditions, and thus results of this study is not aptly applied. In vivo and in vitro comparison studies are required to confirm findings in this study.9 Conclusion The physical properties of five brands of metformin tablets were analyzed and results were presented.

Sustained release dosage form is mainly designed for maintaining therapeutic blood or tissue levels of the drug for extended period of time with minimized local or systemic adverse effects. Economy and greater patient compliance are other advantages of sustained release preparations. Apart from the color and shape, the weight and size are very important to improve patients’ compliance. It is the duty of the pharmaceutical company to manufacture the dosage forms sustaining more rattling in handling, to have more shelf life, and to supply the drugs in pure form with recommended content. This only will achieve the therapeutic goal.

6. European Pharmacopoeia. Council of Europe, France.

3rd edition. 1997;55 and United States Pharmacopoeia BP (The United States Pharmacopoeia).

7. The United States Pharmacopoeia. US Pharmacopoeial Convention, Inc.: Rockville, MD. 31st Revision.

2008;2640.

8. United States Pharmacopoeia and National Formulary USP 24–NF 19; The United States Pharmacopoeial Convention, Inc.: Rockville, MD, 2000;1882-3.

9. Al Ameri MN, et al. The differences between the branded and generic medicines using solid dosage forms: in-vitro dissolution testing. Results Pharma Sci 2012;2:1-8.

10. Food and Drug Administration (FDA). Guidance for industry: dissolution testing of immediate release solid oral dosage forms, August 1997, May 5, 2011.

11. European Medicines Agency (EMA). Note for guidance on the investigation of bioavailability and bioequivalence, July 16, 2001, January 26, 2010.

12. Voegele D. Drug release in vitro: an aid in clinical trials?

Met Find Exp Clin Pharmacol 1992;21(1):55-62.

13. Moore, JW, Flanner HH. Mathematical comparison of dissolution profiles. Pharm Technol 1996;20:64-74.

14. Quo Jh, et al. Validation of tablet dissolution method by high-performance liquid chromatography. Drug Develop Industr Pharmacy 2000;26(3):337-42.

15. European Pharmacopoeia 5.0, p. 234.

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15

CLINICAL STUDY CLINICAL PRACTICE

Role of Atorvastatin in Dyslipidemia: A Clinical Study Pooja BA*, S Bhatted**, N Chaturvedi†, S Deekshit†, MK Bhojani‡

ABSTRACT This clinical study aimed to see the efficacy of atorvastatin in the management of dyslipidemia. It was a randomized observational clinical study involving 30 patients diagnosed with dyslipidemia. The patients were administered atorvastatin 10 mg tablet once-daily at bedtime and followed up for 12 weeks. This drug achieved the desired lipid profile at the end of the 12th week. Statistically strongly significant results were obtained in all the lipid profile levels. Thus, the present study showed this drug to be effective in the treatment of dyslipidemia.

Key words: Dyslipidemia, atorvastatin

D

yslipidemia, defined as an abnormal amount of lipids (e.g., cholesterol and/or fat) in the blood,1 is an important risk factor for coronary heart disease and stroke (cerebrovascular disease). In developed countries, most dyslipidemias are hyperlipidemias often due to faulty diet and lifestyle. Dyslipidemia can be caused due to prolonged elevation of insulin levels and also due to increased levels of O-linked N-acetylglucosamine (O-GlcNAc) transferase.

The data from the US National Health and Nutrition Examination Survey conducted from 1999 to 2000 reported that 25% of adults either had total cholesterol greater than 239.4 mg/dL or were taking a lipidlowering medication.2 According to the World Health Report 1999, ischemic heart disease was the leading single cause of death in the world, the leading single cause of death in high-income countries, and second only to lower respiratory tract infections in low- and

*PhD Scholar **Associate Professor Dept. of Panchakarma National Institute of Ayurveda, Jaipur, Rajasthan † Assistant Professor Dept. of Cardiology SMS Medical College and Hospital, Jaipur, Rajasthan ‡ Professor Government Ayurvedic Medical College, Junagadh, Gujarat Address for correspondence Dr Pooja BA Dept. of Panchakarma National Institute of Ayurveda, Jaipur, Rajasthan E-mail: drpoojaba@gmail.com

16

middle-income countries. In 1998, it was the leading cause of death, with nearly 7.4 million estimated deaths per year in member states of the World Health Organization and caused the eighth highest burden of disease in low and middle-income countries (30.7 million disability-adjusted life years).

Lifestyle modifications should always be part of the treatment regimen for patients with dyslipidemia, regardless of pharmacologic intervention. There are four main classes of lipid-lowering drugs: The bile acid sequestrants (resins), niacin/nicotinic acid, fibric acid derivatives (fibrates) and the 3-hydroxy-3methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins).

The statins, or HMG-CoA reductase inhibitors, have taken a major role in the management of dyslipidemia.

More specifically, this family of agents is considered first-line for the treatment of hypercholesterolemia in patients who have failed to adequately respond to dietary therapy.3 The statins are well-tolerated and there does not appear to be major differences in toxicity or adverse effect profiles.4,5 Hence, this study was undertaken to see the efficacy and tolerability of atorvastatin (a statin) in the treatment of dyslipidemia.

Methods The present study was a randomized observational clinical trial carried out at the Sawai Mansingh Medical College and Hospital, Jaipur, Rajasthan, over a period of 6 months. The study protocol was approved by the Ethical Committee of the National Asian Journal of Critical Care Vol. 9, No. 4, January-March 2014

CLINICAL STUDY Institute of Ayurveda, Jaipur. After obtaining written informed consent, 30 patients of either sex in the age group of 20-60 years with newly detected dyslipidemia were selected for the study. Patients with the following conditions were excluded from the study: pregnant and lactating women and patients with history or evidence of systemic disorders like cardiac, hepatic, renal, or neurological diseases. A detailed medical history, clinical examination, anthropometric measurements, and baseline laboratory investigations were carried out.

Patients fulfilling the study criteria were administered with atorvastatin 10 mg tablet once daily at bedtime for 90 days (12 weeks). The lipid profile was recorded at baseline and after the 12th week. The patients were monitored for adverse events throughout the study period.

Laboratory investigations like Hb%, fasting blood sugar, lipid profile, renal function tests, liver function tests, urine analysis and electrocardiography were done at baseline and at the end of the 12th week.

The data were expressed in percentages and mean ± standard deviation (SD). ANOVA was used to find the significance of treatment on the lipid profile.

Results Out of 30 patients, 24 were men and 6 were women.

The mean age was 45 ± 8.0 years. Ninety-two percent of patients were from urban and the remaining 8% were from rural areas.

The most comorbid condition, obesity (BMI ≥ 25 kg/m2) was observed in 26.66% (n = 8) of patients. Table 1 reveals that the mean cholesterol level was 303.33 ± 26.31 at baseline and 223.33 ± 34.77 after 12th week with p < 0.001**, which is statistically strongly significant. Mean triglyceride (TG) level was 232.00 ± 23.98 at baseline that reduced to 159.67 ± 23.27 at Table 1. Lipid Profile Analysis Between Basal and 12th Week Values Lipid profile Basal value in mean ± SD

12th week value in mean ± SD

p value

Serum cholesterol

303.33 ± 26.31

223.33 ± 34.77

< 0.001**

Serum TG

232.00 ± 23.98

159.67 ± 23.27

< 0.001**

Serum HDL

50.37 ± 6.24

49.70 ± 5.86

0.094†

Serum LDL

206.57 ± 24.71

142.03 ± 32.74

< 0.001**

31.93 ± 4.65

< 0.001**

Serum VLDL 46.40 ± 4.80

Asian Journal of Critical Care Vol. 9, No. 4, January-March 2014

Table 2. Adverse Events During Study Symptoms

Number of patients

Constipation

3

Fatigue

2

Abdominal discomfort

4

Myalgia

3

12th week with p < 0.001**, which is strongly significant.

The mean high-density lipoprotein (HDL) level was 50.37 ± 6.24 at baseline and 49.70 ± 5.86 at 12th week with p = 0.094†, which is significant. At the baseline, mean low-density lipoprotein (LDL) was 206.57 ± 24.71 and at 12th week it was 142.03 ± 32.74 with p < 0.001** showing statistically strongly significant result. The mean very-lowdensity lipoprotein (VLDL) level was 46.40 ± 4.80 at baseline and 31.93 ± 4.65 after 12th week with p < 0.001**, which is statistically strongly significant.

All other laboratory parameters, both at baseline and at the end of 12th week, were within normal limits.

Adverse events like constipation and myalgia were encountered in three patients; abdominal discomfort and fatigue was observed in four and two patients, respectively (Table 2). All these symptoms were mild, transient, and did not require any treatment, discontinuation of medication, or withdrawal from the study.

Discussion In this study, reduction in cholesterol level by 26.37%, TGs level by 31.17%, HDL level by 1.33%, LDL level by 31.24% and VLDL level by 31.18% was achieved at 12th week when compared with baseline values. Statistically, the results were showed strongly significant.

Atorvastatin calcium is a synthetic lipid-lowering agent and is an inhibitor of HMG-CoA reductase, which catalyzes the conversion of HMG-CoA to mevalonate. Inhibition of HMG-CoA reductase leads to upregulation of LDL cholesterol (LDL-C) receptors in the liver,6 mediated by activation of sterol regulatory element-binding proteins resulting in enhanced clearance of LDL from the circulation, thus playing an important role in preventing atherosclerosis.

In the present study, mild adverse events like constipation and fatigue were observed in few patients, which are considered as the common adverse reactions 17

CLINICAL STUDY of atorvastatin. The patients did not require any medication to treat the same.

Conclusion Dyslipidemia is a common high-risk factor of cardiovascular disease. Despite the widespread availability of safe and efficacious medications, the management of this condition is far from optimal.

Indeed, epidemiological studies have indicated that 90% of patients with dyslipidemia fail to achieve their therapeutic targets. Moreover, the optimal goal in patients with risk factors has been steadily declining, necessitating the treatment of bigger population subsets.

Statin group of drugs have excellent efficacy and safety profiles for the treatment of dyslipidemia. The present study also suggested that atorvastatin is effective in controlling the lipid profile at the end of 12th week and is tolerated with few minor adverse symptoms.

2. Rosamond W, Flegal K, Furie K, et al. Heart disease and stroke statistics – 2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2008;117(4):e25-e146.

3. Heart Protection Study Collaborative Group. MRC/ BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360(9326):7-22.

4. Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-thanaverage cholesterol concentrations, in the AngloScandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003;361(9364):1149-58.

References

5. Pearson TA, Laurora I, Chu H, Kafonek S. The lipid treatment assessment project (L-TAP): a multicenter survey to evaluate the percentages of dyslipidemic patients receiving lipid-lowering therapy and achieving low-density lipoprotein cholesterol goals. Arch Intern Med 2000;160(4):459-67.

1. Harrison TR. Harrison’s Principles of Internal Medicines, 12th International Edition. In: Braunwald E, Fanci AS, Hauser SL, Kasper DL, Longo DL, Jameson JL (editors).

New York: McGraw-Hill Medical Publishing Division, Vol. I, 2002.

6. Delsing DJ, Jukema JW, van de Wiel MA, et al.

Differential effects of amlodipine and atorvastatin treatment and their combination on atherosclerosis in Apo E* 3-Leiden transgenic mice. J Cardiovasc Pharmacol 2003;42(1):63-70.

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Asian Journal of Critical Care Vol. 9, No. 4, January-March 2014

Echocardiographic Findings in Submassive Pulmonary Embolism

IMAGING CLINICAL PRACTICE

SR Mittal

ABSTRACT Echocardiography provides important clues for diagnosis of submassive pulmonary embolism in a high-risk patient.

Disproportionate right ventricular dilatation and dysfunction with apical sparing in the setting of mild-to-moderate pulmonary artery hypertension should raise suspicion. Absence of any regional wall motion abnormality of left ventricle is an important negative finding.

Key words: Echocardiography, pulmonary embolism, right ventricle

E

chocardiographic findings in a case of pulmonary embolism depend on: Cardiorespiratory status prior to embolism and size of embolus-massive, submassive, small.

Massive emboli usually present as sudden death. Small emboli present as chronic pulmonary hypertension.

In a case of submassive pulmonary embolism in a case with normal cardiorespiratory system, echocardiography reveals following findings.

Normal size of pulmonary artery (Fig. 1) inspite of pulmonary artery hypertension. This occurs because in acute embolism, pulmonary artery does not have time to dilate.

Pulsed Doppler evaluation of pulmonary artery flow shows acceleration time < 100 m-sec (Fig. 2) and midsystolic reduction in flow (Fig. 2) suggestive of pulmonary artery hypertension.1 Dilatation of right atrium and right ventricle (RV) due to RV dysfunction (Fig. 3).2 Normal size of left ventricle (LV) with no regional wall motion abnormality of LV (Fig. 4).2 Hypokinesia of proximal and mid part of free wall of RV with sparing (normal contractility) of RV apex (McConnell sign) (Fig. 5).1

Ex-Senior Professor and Head Dept. of Cardiology Jawaharlal Nehru Medical College, Ajmer, Rajasthan Address for correspondence Dr SR Mittal XI/101, Brahampuri Ajmer - 305 001, Rajasthan E-mail: sarweshwar_mittal@reddifmail.com

Asian Journal of Critical Care Vol. 9, No. 4, January-March 2014

Figure 1. Short-axis view at the level of aortic root showing normalsized pulmonary artery.

Figure 2. Pulsed Doppler evaluation of pulmonary artery flow showing acceleration time <100 m-sec and midsystolic reduction in flow.

19

IMAGING

20

Figure 3. Apical four chamber view showing dilatation of right atrium and right ventricle.

Figure 6. M-mode of lateral tricuspid annulus showing systolic excursion < 18 mm.

Figure 4. End-diastolic (ED) and end-systolic (ES) frames of shortaxis view showing normal size and contractility of LV.

Figure 7. Tissue Doppler imaging of medial tricuspid annulus showing Aa velocity more than Ea velocity and MPI >0.3.

Figure 5. End-diastolic (ED) and end-systolic (ES) frames of apical four chamber view showing hypokinesia of proximal and mid-portion of RV free wall (double arrow) with normal contractility of RV apex (single arrow).

Figure 8. Tissue Doppler imaging of medial mitral annulus showing Aa velocity more than Ea velocity.

Asian Journal of Critical Care Vol. 9, No. 4, January-March 2014

IMAGING

Figure 9. Pulsed Doppler evaluation of tricuspid regurgitation jet showing calculated pulmonary artery systolic pressure < 60 mmHg.

Figure 10. Apical four chamber view showing increased right atrial volume and shifting of interatrial septum to left.

Impairment of overall RV systolic function: Lateral tricuspid annulus systolic excursion (TAPSE) <18 mm (Fig. 6).2 Impaired relaxation (Aa > Ea) and decreased contractility (myocardial performance index [MPI] >0.3) of RV on tissue Doppler imaging of medial and lateral tricuspid annulus (Fig. 7).

Decreased filling of LV as evidenced from decreased Ea velocity in tissue Doppler imaging of medial and lateral mitral annulus (Fig. 8).2 Tricuspid regurgitation with calculated pulmonary artery systolic pressure of < 60 mmHg (Fig. 9).2

Dilatation of right atrium due to increased right atrial pressure (Fig. 10).2 Shifting of interatrial septum to left due to raised right atrial pressure (Fig. 10).2 References 1. Forfia PR, Wiegers SE. Echocardiographic findings in acute and chronic respiratory disease. In: The Practice of Clinical Echocardiography. 3rd edition, Otto CM (Ed.), Saunders: Philadelphia 2007:p.848-76.

2. Armstrong WF, Ryan T. Echocardiographic in systemic disease and clinical problem solving. In: Fergenbaum’s Echocardiography. 7th edition, Armstrong WF, Ryan T (Ed.), Wolters Kluwer, Philadelphia 2010:p.741-74.

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Asian Journal of Critical Care Vol. 9, No. 4, January-March 2014

21

CASE REPORT CLINICAL PRACTICE

Anaphylactic Shock: A Rare Presentation of Phenytoin Drug Reaction Amit D Bhatt*, Anjali N Joshi**, AP Jain†

ABSTRACT The adverse effects of phenytoin are well-documented in literature. We describe a case of severe anaphylactic shock following intravenous administration of phenytoin, a rarely described and known entity.

Key words: Severe anaphylactic shock, phenytoin toxicity

P

henytoin is a very commonly used drug in medical practice. However, it is not adverse to side effects due to hypersensitivity some of which are well-documented in literature as Stevens-Johnson syndrome, cerebellar toxicity and Drug Reaction with Eosinophilia and Systemic Symptom (DRESS) syndrome.1-3 We describe a case of severe anaphylactic shock following intravenous (IV) administration of phenytoin, a rarely described and known entity.

Our patient, 40-year-old male presented with generalized tonic clonic seizures (6 episodes in 1 day). He was managed with IV lorazepam followed by intravenous loading dose of phenytoin 600 mg (15 mg/kg in 100 ml of 0.9% sodium chloride injection) over 30 minutes (20 mg/min). The patient developed erythematous rash all over his body within 15 minutes of the infusion followed by respiratory distress and wheeze. This was followed by profound hypotension (BP 60 systolic mmHg). A diagnosis of anaphylactic shock was made based on clinical picture and was managed as per standard protocol with IV infusion of fluids, adrenaline and steroids. The patient’s blood sugar levels, serum electrolytes and ECG were found to be normal. Patient recovered well from the episode in three days without after effects.

*Lecturer **Resident Postgraduate † Director Professor and Head Dept. of Medicine, Mahatma Gandhi Medical Sciences, Sewagram, Wardha, Maharashtra Address for correspondence Dr Amit D Bhatt Dept. of Medicine, Mahatma Gandhi Medical Sciences, Sewagram Wardha - 442 102, Maharashtra E-mail: amitbhtt.md@gmail.com

22

Literature search for probable cause of such manifestation revealed an interesting point. Such shock may be due to rapid loading rates of phenytoin in excess of 50 mg/min, the anaphylaxis being due to propylene glycol.

It is known fact that IV phenytoin precipitates if diluted with IV fluids such as 5% dextrose and can only be diluted with 0.9% sodium chloride. To augment its solubility, IV phenytoin is formulated with 40% propylene glycol, a diluent. Propylene glycol has been attributed in literature to be cardiotoxic leading to hypotension and arrhythmias.4,5 This may be proposed as a likely explanation to the episode. It, however fails to explain the dermatological and respiratory manifestations. Wisdom to be learnt from the episode is to know the spectrum of phenytoin toxicity and especially to control the infusion rates so as to prevent shock and cardiotoxicity.

References 1. Rzany B, Correia O, Kelly JP, Naldi L, Auquier A, Stern R. Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis during first weeks of antiepileptic therapy: a case-control study. Study Group of the International Case Control Study on Severe Cutaneous Adverse Reactions. Lancet 1999;353(9171):2190-4.

2. O’Brien TJ, Meara FM, Matthews H, Vajda FJ. Prospective study of local cutaneous reactions in patients receiving IV phenytoin. Neurology 2001;57(8):1508-10.

3. Allam JP, Paus T, Reichel C, Bieber T, Novak N. DRESS syndrome associated with carbamazepine and phenytoin.

Eur J Dermatol 2004;14(5):339-42.

4. Wheless JW. Pediatric use of intravenous and intramuscular phenytoin: lessons learned. J Child Neurol 1998;13 Suppl 1:S11-4; discussion S30-2.

5. Ramsay RE, DeToledo J. Intravenous administration of fosphenytoin: options for the management of seizures.

Neurology 1996;46(6 Suppl 1):S17-9.

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CASE REPORT CLINICAL PRACTICE

Unusual Presentation of Angioimmunoblastic T-cell Lymphoma As a Solitary Lymph Node N Ashalatha*, BN Kumarguru**, BS Dayananda†, AH Nagarajappa‡

ABSTRACT Introduction: Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive subtype of peripheral T-cell lymphoma (PTCL) characterized by systemic disease. It is a rare subtype of non-Hodgkins lymphomas. However, it forms a major subset of PTCL. Lymph node is the primary site of disease and virtually all patients present with generalized lymphadenopathy. Case report: A 42-year-old male presented with fever of short duration and a solitary axillary lymph node swelling on the right side.

Systemic examination revealed moderate ascites and hepatosplenomegaly. Hematological investigations showed pancytopenia and abnormal liver function. Axillary lymph node showed histological features suggesting AITL and was confirmed by a panel of immunohistochemistry (IHC). Conclusion: AITL presenting as solitary axillary lymph node enlargement is unusual. Such atypical presentation mandates careful clinical and laboratory evaluation. IHC is an effective ancillary tool for confirmation of diagnosis of this distinct clinicopathological entity.

Key words: Angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, non-Hodgkin’s lymphoma, solitary axillary lymph node enlargement, pancytopenia, immunohistochemistry

A

ngioimmunoblastic T-cell lymphoma (AITL) is a peripheral T-cell lymphoma (PTCL) characterized by systemic disease, a polymorphous infiltrate involving lymph nodes with a prominent proliferation of endothelial venules and follicular dendritic cells (FDC). Spleen, liver, skin and bone marrow are also frequently involved.1 Though, it is one of the more common specific subtypes of PTCL, accounting for approximately 20% of cases, it constitutes only 1-2% of all non-Hodgkins lymphoma.1,2 It occurs in the middle-aged and elderly with an equal incidence in males and females.1 Originally described in 1974 as 'immunoblastic lymphadenopathy' by Rappaport and Lukes, AITL is recognized in the current World Health Organization (WHO) classification as a PTCL

*Assistant Professor **Tutor † Professor ‡ Professor and Head Dept. of Pathology Bangalore Medical College and Research Institute, Bangalore Address for correspondence Dr N Ashalatha Assistant Professor Dept. of Pathology Victoria Hospital, Bangalore Medical College and Research Institute Fort, Bangalore- 560 002, Karnataka E-mail: drbnkg007@hotmail.com

Asian Journal of Critical Care Vol. 9, No. 4, January-March 2014

with distinct clinicopathologic features.3 The postulated normal counterpart is CD4+ follicular helper T-cell (TFH).1 This subset of T-cell is located at the boundary between the mantle zone and germinal center light zone and is supposed to provide help to germinal center B-cells during their terminal differentiation.4 The patients present with generalized lymphadenopathy (up to 90%), hepatoslpenomegaly (50-79%), cutaneous rash (50%), hypergammaglobulinemia (50%), pleural effusion (37%) and autoimmune phenomena (20%).5 The laboratory findings include circulating immune complexes, cold agglutinins with hemolytic anemia, positive rheumatoid factor and antismooth muscle antibodies.

Epstein-Barr virus (EBV)-positive cells are nearly always present. Characteristically, the neoplastic cells show phenotype of normal TFH expressing CD10, CXCL13 and PD1 in 60-100% of cases.1 Cytogenetic and molecular studies have consistently shown clonal chromosomal abnormalities and monoclonal or oligoclonal T-cell populations in most cases, which strongly supports a T-cell neoplasm.6 Patients with AITL have a poor prognosis with conventional treatment, with a median overall survival of less than 3 years. Patients achieving a good clinical response seem to benefit from a consolidation with high-dose therapy and autologous stem cell transplantation.2 23

CASE REPORT

A 42-year-old male presented with fever of 4 days duration and easy fatigability. General physical examination revealed a solitary lymph node in the right axilla measuring 4 Ă&#x2014; 2.5 Ă&#x2014; 2 cm. No other lymph nodes were enlarged. Abdominal examination revealed moderate ascites, hepatomegaly and massive splenomegaly. Blood investigations were done.

Hemoglobin was decreased (5.4 g/dL), leukocyte count was reduced (2,300 cells/mm3), platelet count

was reduced (62,000/mm3). Peripheral smear also suggested pancytopenia. Coombs test was negative. Bone marrow examination did not reveal any pathological findings. Human immunodeficiency virus (HIV) was negative and hepatitis B surface antigen (HBsAg) was nonreactive. Biochemical investigations showed increased levels of postprandial glucose (150 mg/dL), total proteins (11 g/dL), alkaline phosphatase (207 U/L) and lactate dehydrogenase (LDH) (693 U/L).

Serum albumin was reduced (3.3 g/dL). Ultrasonography of abdomen showed moderate ascites mild hepatomegaly

Figure 1. Photomicrograph of tissue section showing effacement of lymph node architecture (H&E, x40).

Figure 2. Photomicrograph of lymph node section showing postcapillary venules lined by plump endothelial cells (arrows) (H&E, x400).

Figure 3. Photomicrograph of lymph node section showing tumor cells having convoluted nuclear borders and prominent nucleoli and good number of mitotic figures (arrows) (H&E, x400).

Figure 4. Photomicrograph of lymph node section showing background of reactive lymphocytes, eosinophils, plasma cells and histiocytes (H&E, x400).

Case Report

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Asian Journal of Critical Care Vol. 9, No. 4, January-March 2014

CASE REPORT

Figure 5. Photomicrograph of lymph node section showing diffuse immunopositivity for CD3 neoplastic cells (IHC, x400).

Figure 6. Photomicrograph of lymph node section showing diffuse immunopositivity for CD10 neoplastic cells (IHC, x200).

Figure 7. Photomicrograph of lymph node section showing scattered immunopositivity for CD30 neoplastic cells (IHC, x400).

Figure 8. Photomicrograph of lymph node section showing CD20+ reactive residual B-cells (IHC, x200).

and massive splenomegaly. Considering these features the present case corresponds to Ann Arbor Stage III ES, International Prognostic Index (IPI) score of four and prognostic index for PTCL/unspecified (PIT) score of 2.

The axillary node was excised and sent for histopathological examination. Grossly the lymph node measured 3.5 Ă&#x2014; 2.5 Ă&#x2014; 1.5 cm. Cut section showed homogeneous grey-white appearance. Sections from the lymph node showed effacement of architecture and follicular depletion (Fig. 1). Prominent arborising postcapillary venules lined by plump endothelial cells

were seen (Fig. 2). Clusters of tumor cells having vesicular nuclei and prominent nucleoli, showed vaguely convoluted borders, clear to pale cytoplasm and mitotic figures (Fig. 3). Mature lymphocytes, plasma cells, histiocytes and significant number of eosinophils were also seen in the background of patchy hyaline material (Fig. 4). Immunohistochemistry (IHC) was performed, which showed neoplastic cells as diffusely distributed CD3 positive cells (Fig. 5) and CD10 positive cells (Fig. 6). CD30 positive cells were scattered and comparatively scant (Fig. 7). Residual

Asian Journal of Critical Care Vol. 9, No. 4, January-March 2014

25

CASE REPORT reactive B lymphocytes were CD20 positive (Fig. 8).

These findings confirmed the histological diagnosis of AITL. Discussion AITL is a rare and complex lymphoproliferative disorder, clinically characterized by widespread lymphadenopathy, extranodal disease, immune-mediated hemolysis and polyclonal hypergammaglobulinemia.3 It represents a distinct clinicopathological entity among nodal PTCLs.4 AITL is a systemic disease involving lymph nodes, spleen and bone marrow.6 AITL was first described by Ree et al who reported progression of two such cases into typical AITL.6 It is an aggressive PTCL whose natural history is poorly understood.5 Mourad et al4 recorded the median age of 62 years while Cho et al7 recorded the median age of 58.5 years in their studies. AITL occurs in middle-aged and elderly with an equal incidence in males and females.1 Rodriguez-Justo et al5 and Attygalle et al6 observed occurrence of AITL in middle-aged and elderly with male preponderance. Lymph node is the primary site of disease and virtually all patients present with generalized lymphadenopathy.1,3,5,6 Cho et al7 recorded generalized lymphadenopathy as commonest presentation (91%) in their study. In contrast, the middle-aged patient in the present case presented with solitary right axillary lymph node. Lymph node enlargement was accompanied by an episode of fever and easy fatigability. Rodriguez-Justo et al5 observed organomegaly (hepatomegaly or splenomegaly) in 33% of cases. Attygalle et al6 and Cho et al7 also observed hepatosplenomegaly in their studies. Mourad et al4 observed pleural effusion or ascities or edema in 16% of cases in their study. Even in the present case, the patient had hepatosplenomegaly, deranged liver function and ascities. Most of the cases present at an advanced stage (III-IV).2,4,5 Peripheral blood picture suggested pancytopenia.

However, bone marrow did not show tumor infiltration and Coomb's test was negative. Thirty-three percent of cases had hemolytic autoimmune anemia in study conducted by Rodriguez-Justo et al5. Mourad et al4 recorded anemia in 65% of cases and positive Coomb's test in 33% of cases. Rodriguez-Justo et al5 and Cho et al7 observed bone marrow involvement in 22% cases and 70% cases in their studies. Mourad et al4 observed 26

bone marrow involvement in 38% of anemic patients.

Serum LDH level was elevated in the present case.

Similar elevations of serum LDH were noted in studies conducted by Mourad et al4 and Cho et al.7 Mourad et al4 considered five criteria for histological diagnosis: Partial or diffuse effacement of the nodal architecture, vascular proliferation with prominent arborization of high endothelial venules, extrafollicular meshwork of FDCs, atypical population of CD3+ T-cells and large CD20+ B-cells. Similar criteria were considered in the present case. But CD20+ B-cells were present as reactive residual component of the lesion.

The constellation of microscopic features of this case corresponded with pattern II of AITL described by Attygalle et al6. In the present case, neoplastic cells were diffusely positive for CD3 and CD10. CD30+ cells showed scattered positivity and were comparatively scant. CD20+ cells represented reactive residual B-cells.

Mourad et al4 observed that neoplastic cells were CD3 in 100% cases and CD10 in 71% cases in their study.

Cho et al7 noted that CD3 and CD5 were strongly positive and aberrant expression of CD10 was observed in 65% of cases. Attygalle et al6 observed that CD10 identified the tumor cells in 90% of AITL. In contrast, Rodriguez-Justo et al5 observed that only small proportion of neoplastic cells (5-10%) expressed CD10. CD30 staining was done in only three cases and was positive in all the three cases.5 The etiology and pathogenesis of AITL are unknown.

In a high percentage of cases the diagnosis is preceded by allergic reactions, infections and/or exposure to drugs, particularly antibiotics.2 EBV and Human herpes virus (HHV6 and HHV8) may play a role in pathogenesis of AITL and this might explain its response to antiviral therapy with valacyclovir.5 Although, it has not been thoroughly investigated, it was suggested that the increase in T-cell immunoblasts would indicate transformation into a PTCL/unspecified. An increase in EBV infected B-cells may also occur and in rare cases, an overt diffuse large B-cell lymphoma develops.4 The physiologic role of CD10 is thought to involve hydrolysis of polypeptides such as inflammatory mediators in the extracellular milieu. Expression of CD10 may regulate apoptosis by interfering with negative or positive signals present in the Asian Journal of Critical Care Vol. 9, No. 4, January-March 2014

CASE REPORT extracellular environment. It is possible that aberrant CD10 expression in neoplastic T-cells in AITL may be an indicator of disturbed apoptotic cell death.6 Interestingly, it has been suggested that production of interleukin-21 by TFH is responsible for B-cell activation and hypergammaglobulinemia seen in AITL.5 It has been recently shown that CXCL13, a chemokine critically involved in B-cell migration into germinal centers, was highly upregulated in the TFH subset.4 It was hypothesized that the clinical effects of AITL are due to marked dysregulation of the immune system rather than to direct complications of tumor growth.4 Peculiar histologic features of AITL, where tumor cells are greatly outnumbered by the surrounding reactive cells and found in intimate contact with the expanding meshwork of FDCs. Hence, AITL can be considered as an immunologically functional disease in which the clinical behavior is determined by the resultant cross-talk between the malignant cells and the immunologic microenvironment.4 T-cell receptor genes show clonal rearrangement in 75-90% of cases. Clonal immunoglobulin gene rearrangement may be found in 25-30% cases. Trisomy 3 and 5 and an additional X-chromosome are the most frequent cytogenetic abnormalities detected in AITL.1,2 Conclusion Solitary axillary lymph node enlargement is an unusual presentation of AITL. In view of such atypical presentation and taking into consideration the aggressive nature of this distinct clinicopathological entity, careful clinical and laboratory evaluation is necessary. Immunophenotyping serves as an effective auxiliary weapon for the confirmation of diagnosis.

Acknowledgment We sincerely thank Dr Clementina Ramarao, Professor of Pathology, Kidwai Institute of Medical Oncology, Bangalore for the kind cooperation extended to us for diagnosing this rare entity.

References 1. Dogan A, Gaulard P, Jaffe ES, et al. Angioimmunoblastic T-cell lymphoma. In: World Health Organization Classification of Tumors of Haematopoietic and Lymphoid Tissues. 4th edition, Campo E, Harris NL, Jaffe ES, et al (Eds.). Swerdlow SJ. IARC Press: Lyon 2008:p.309-11.

2. Iannitto E, Ferrari AJM, Minardi V, et al. Angioimmunoblastic T-cell lymphoma. Crit Rev Oncol Hematol 2008;68:264-71.

3. Alizadeh AA, Advani RH. Evaluation and management of angioimmunoblastic T-cell lymphoma: a review of current approaches and future strategies. Clin Adv Hematol Oncol 2008;6(12):899-909.

4. Mourad N, Mounier N, Brière J, Raffoux E, Delmer A, Feller A, et al; Groupe d'Etude des Lymphomes de l'Adulte.

Clinical, biologic, and pathologic features in 157 patients with angioimmunoblastic T-cell lymphoma treated within the Groupe d'Etude des Lymphomes de l'Adulte (GELA) trials. Blood 2008;111(9):4463-70.

5. Rodriguez-Justo M, Attygalle AD, Munson P, Roncador G, Marafioti T, Piris MA. Angioimmunoblastic T-cell lymphoma with hyperplastic germinal centres: a neoplasia with origin in the outer zone of the germinal centre?

Clinicopathological and immunohistochemical study of 10 cases with follicular T-cell markers. Mod Pathol 2009;22(6):753-61.

6. Attygalle A, Al-Jehani R, Diss TC, Munson P, Liu H, Du MQ, et al. Neoplastic T cells in angioimmunoblastic T-cell lymphoma express CD10. Blood 2002;99(2):627-33.

7. Cho YU, Chi HS, Park CJ, Jang S, Seo EJ, Huh J. Distinct features of angioimmunoblastic T-cell lymphoma with bone marrow involvement. Am J Clin Pathol 2009;131(5):640-6.

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CASE REPORT CLINICAL PRACTICE

A Case of Biotinidase Deficiency Presenting as Quadriparesis Rajeev Thapar*, K Venkatnarayan†

ABSTRACT Biotinidase deficiency is a rare disorder with a wide-spectrum of neurological, dermatological and immunological dysfunction.

Identification of this disorder is important as it is easily treatable and the patients show dramatic response to therapy, besides the fact that it can prove fatal if not diagnosed. We report a case of biotinidase deficiency who presented with quadriparesis, highlighting all these issues.

Key words: Biotin, biotinidase

B

iotinidase deficiency is a rare metabolic disease with estimated incidence of approximately 1:60,089.1 This enzyme is required for the restoration of free biotin from biocytin after it has activated various carboxylases in the biotin cycle.2,3 Absence of biotinidase results in biotin deficiency, which results in a wide spectrum of neurological, dermatological and immunological abnormalities.4 Case Report A 3 year 10-month-old girl child was referred to our hospital with complaints of episodes of rapid breathing and progressive weakness of all four limbs. Her complaints had started about 3 months prior when she was admitted for a “lower respiratory tract infection” with predominant complaints of rapid breathing.

Subsequent to this, she continued to have episodes of rapid breathing, for which she received treatment on OPD basis.

Over a period of time, she developed weakness of all four limbs, predominantly of the proximal muscle group, manifesting as unsteady gait and inability to selffeed. The weakness progressed and she was bedridden

*Professor and HOD † Assistant Professor Dept. of Pediatrics, Command Hospital (Eastern Command), Alipore, Kolkata Address for correspondence Dr Rajeev Thapar Dept. of Pediatrics Command Hospital (Eastern Command) Kolkata 700 027 E-mail: rajeevrenuthapar@gmail.com

28

at the time of admission (Fig. 1). There was also history of one episode of generalized clonic-tonic seizures 2 weeks prior. She was a product of a nonconsanguineous marriage, with no remarkable delay in attaining the target developmental milestones. Her elder brother had died following similar clinical manifestations of progressive weakness at 4 years of age. In fact, this heightened the parental anxiety to seek medical help.

Clinically, she was alert and had silent tachypnea. Skin manifestations in form of candidal lesions of the axilla (Fig. 2) and the toe clefts (Fig. 3) along with alopecia were present (Fig. 4). The bilateral plantars were extensor with gross hypotonia and the power in the proximal muscles of both limbs was Grade II (as per Medical Research Council Grading System of United Kingdom). Baseline investigations revealed partially compensated metabolic acidosis. Magnetic resonance imaging (MRI) studies showed mild cerebral atrophy with hypoplasia of cerebellar vermis. MRI of spine was suggestive of myelopathy (Fig. 5). Cerebrospinal fluid (CSF) study and ophthalmologic and audiological evaluations were normal.

In view of family history and the episodic nature of respiratory complaints suggestive of metabolic acidosis, along with the skin manifestations, possibility of neurometabolic syndrome was considered. Serum lactate was elevated (31 mg/dL [4.5-19.8 mg/dL]) and the biotinidase activity was 0 nmol/min/mL. The child was started on daily oral biotin 20 mg and made significant recovery. Hyperventilation subsided in 12 hours; the child could sit without support in 2 days and started walking in the second week of treatment.

Asian Journal of Critical Care Vol. 9, No. 4, January-March 2014

CASE REPORT

Figure 1. Patient presenting with hypotonia and quadriparesis (left panel) and improvement following biotin replacement therapy (right panel).

Figure 2. Axillary candidal skin lesions before (left panel) and after treatment (right panel).

Skin lesions healed in the third week and there was hair growth.

Discussion Biotinidase is an essential enzyme required for recycling biotin by lysing lysine moiety from biocytin, as elucidated in the biotin cycle.2,3 Deficiency of biotinidase results in the deficiency of biotin, which Asian Journal of Critical Care Vol. 9, No. 4, January-March 2014

is required as a catalyst for the carboxylase systems in the body. The four main carboxylase systems being: (1) Pyruvate carboxylase (required for glucose production; inactivity lowers blood sugar resulting in hypoglycemia and lactic acidosis); (2) acetyl-CoA carboxylase (required for biosynthesis of fatty acids by liver and fat cells; inactivity results in reduced availability of stored fatty acids for exercise resulting in hypotonia); (3) 29

CASE REPORT

Figure 3. Candidiasis of toe clefts before (left panel) and after treatment (right panel).

Figure 4. Note the degree of alopecia in a 4-year-old girl child.

Figure 5. MRI cervical spine showing hyperintensities suggestive of myelopathy.

propionyl-CoA carboxylase (required for breakdown of amino acids with an odd number of carbons; inactivity results in propionic academia and reduced activity of citric acid cycle resulting in reduced energy production in the brain, resulting in developmental delays); and (4) methylcrotonyl-CoA carboxylase (required for breakdown of leucine; inactivity results in lowered carnitine levels and methylcrotonylglycinuria).4

The clinical presentation of repeated episodes of hyperventilation, progressive neurological deterioration with skin lesions and corroborating with laboratory features of lactic acidosis suggested the diagnosis of biotinidase deficiency in this case.

Although individual deficiencies of all four carboxylases have been reported, the clinical spectrum varies widely from a severe form presenting early (multiple carboxylase deficiency, holocarboxylase synthase deficiency) to milder varieties presenting late (biotinidase deficiency).5,6 30

The clinical spectrum of biotinidase deficiency depends on the severity of the defect. The clinical manifestations predominantly include neurological and skin and respiratory manifestations. The neurological spectrum includes seizures, hypotonia and developmental delay in the early period. Some older children present with progressive spastic quadriparesis and hearing and visual impairment.7 Asian Journal of Critical Care Vol. 9, No. 4, January-March 2014

CASE REPORT The present case had muscle weakness. In view of the clinical presentation and previous case reports of recurrent myelopathy,7 MRI of spine was done, which was suggestive of myelopathy (Fig. 5). Seborrheic dermatitis, alopecia and candidal infections due to immunological dysfunction are the predominant skin manifestations and our patient had most of these features. Metabolic acidosis resulting in hyperventilation often masquerades as a primary respiratory illness, as in this patient.

Identification of this disorder is important as it can be treated with supplementation of biotin. Lifelong supplementation upto 40 mg/day is needed that results in both clinical and radiological improvement.

References 1. Wolf B. Worldwide survey of neonatal screening for biotinidase deficiency. J Inherit Metab Dis 1991;14(6):923-7.

2. Frank Y, Ashwal S. Neurologic disorders associated with gastrointestinal diseases, nutritional deficiencies

and fluid-electrolyte disorders. In: Pediatric Neurology: Principles and Practice. 4th edition, Swaiman K, Ashwal S, Ferriero D (Eds.), Elsevier: Philadelphia 2006:p.2317.

3. Enns G, Cowan T, Klein O, Packman S. Aminoacidemias and organic acidemias. In: Pediatric Neurology: Principles and Practice. 4th edition, Swaiman K, Ashwal S, Ferriero D (Eds.). Elsevier: Philadelphia 2006:p.590e1.

4. Wolf B. Disorders of biotin metabolism. In: The Metabolic and Molecular Basis of Inherited Disease.

8th edition, Scriver CR, Beaudet AL, Sly WS, Valle D (Eds.). McGraw-Hill: New York 2001:p.3935-62.

5. Burri BJ, Sweetman L, Nyhan WL. Mutant holocarboxylase synthetase. Evidence for the enzyme defect in early infantile biotin responsive multiple carboxylase deficiency. J Clin Invest 1981;68(6):1491-5.

6. Dahiphale R, Jain S, Agarwal M. Biotinidase deficiency.

Indian Pediatr 2008;45:777-9.

7. Raha S, Udani V. Biotinidase deficiency presenting as recurrent myelopathy in a 7-year-old boy and a review of the literature. Pediatr Neurol 2011;45(4):261-4.

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PRACTICE GUIDELINES CLINICAL PRACTICE

ACP Releases Best Practice Advice on Colorectal Cancer Screening

A

lthough the incidence of colorectal cancer in the United States has been declining by 2 to 3 percent per year over the past 15 years, it is the second leading cause of cancer-related death in the country. The disease is rare before 40 years of age, with 90 percent of cases occurring in those older than 50 years. Appropriate screening is important because detection and removal of premalignant adenomas or localized cancer can prevent the development of cancer.

The American College of Physicians (ACP) recently reviewed available guidelines from the American Cancer Society/U.S. Multi-Society Task Force on Colorectal Cancer/American College of Radiology, Institute for Clinical Systems Improvement, U.S. Preventive Services Task Force, and the American College of Radiology. Based on the evidence from these guidelines, the ACP has published best practice advice, which is summarized in Table 1.

Guidance Statements Clinicians should perform individualized assessment of risk for colorectal cancer in adults.

This assessment can help determine when screen足 ing should begin. Risks include age, race, and family history (e.g., history of colorectal cancer, especially in a first-degree relative diagnosed before 50 years of age; hereditary nonpolyposis; or familial adenomatous polyposis). Blacks have the highest incidence of cancer compared with other races.

Clinicians should screen for colorectal cancer in averagerisk adults starting at 50 years of age, and in high-risk adults at 40 years of age or at 10 years younger than the age at which colorectal cancer was diagnosed in the youngest affected relative.

Evidence shows that screening identifies premalig足 nant lesions, allowing for early treatment and reduced mortality. The benefits of screening outweigh the risks in these adults.

Source: Adapted from Am Fam Physician. 2012;86(12):1153-1154

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Table 1. American College of Physicians Best Practice Advice on Colorectal Cancer Screening Indications for screening Average-risk adults starting at 50 years of age High-risk adults starting at 40 years of age, or at 10 years younger than the age at which colorectal cancer was diagnosed in the youngest affected relative Black adults starting at 40 years of age See Table 2 for screening intervals of the different testing options Harms of unnecessary screening Endoscopic and radiologic tests Optical colonoscopy: costly and limited availability (facilities and clinicians), postpolypectomy bleeding, perforation/ bleeding, cardiopulmonary complications, diverticulitis, severe abdominal pain, death, false-negative results Flexible sigmoidoscopy: perforation/bleeding, false-negative results Double-contrast barium enema: perforation/bleeding (low risk), false-positive results, false-negative results Computed tomography colonography: low-dose radiation exposure, additional diagnostic testing and procedures for lesions that might not be clinically significant, false-negative results Stool-based tests: few known harms other than false-positive results, false-negative results High-value, cost-conscious care Clinicians should not screen adults who are older than 75 years or who have a life expectancy of less than 10 years (e.g., those with significant comorbid conditions such as diabetes mellitus, cardiopulmonary diseases, or stroke); harms of screening seem to outweigh the benefits in most of these patients 10 years is usually regarded as a safe interval for optical colonoscopy screening

Stool-based tests, flexible sigmoidoscopy, or optical colo足 noscopy should be used for screening average-risk adults.

Test selection should be based on benefits versus harms, availability, and patient preference.

Because colorectal cancer screening tests have similar effectiveness, the patient should be counseled about Asian Journal of Critical Care Vol. 9, No. 4, January-March 2014

PRACTICE GUIDELINES Table 2. Screening Tests for Colorectal Cancer Test

Sensitivity

Specificity Cost

Interval

Requirements

Computed tomography colonography

Medium

Medium

5 years

Complete bowel preparation

High

Double-contrast barium enema

Low

Low

Low

5 years

Complete bowel preparation

Flexible sigmoidoscopy*

Medium

Medium

High

5 years

Complete bowel preparation

Guaiac-based fecal occult blood test*

Variable

Variable

Low

Annual

Two samples from three consecutive stools at home

Immunochemical-based fecal occult blood test*

Variable

Variable

Medium

Annual

Stool sample Complete bowel preparation

Optical colonoscopy

High

High

High

10 years

Stool DNA panel*

Variable

High

High

Uncertain Adequate stool sample (30-g minimum)

Note: Positive results from noncolonoscopic tests require follow-up with colonoscopy. Specific risks of the tests are listed in Table 1. *Low-risk test.

the benefits, harms, effectiveness data, and costs of the different options (Table 2).

Optical colonoscopy is generally considered the preferred screening test; however, it has a false-negative rate of 10 to 20 per­cent, and evidence on the optimal frequency of the screening is unclear. Although colonoscopy screening every 10 years is regarded as safe in average-risk per­sons, high-risk persons should be screened every five years. If a noncolonoscopic test is used, patients with a positive result should receive

follow-up colonoscopy screening. Although computed tomography colonog­raphy is an option for averagerisk patients older than 50 years, the U.S. Preventive Services Task Force found insufficient evidence to determine the benefits and harms of the test.

Screening should end after 75 years of age or if the patient’s life expectancy is less than 10 years.

The harms of screening seem to outweigh the benefits in these patients.

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MEDILAW CLINICAL PRACTICE

Medicolegal Cases in Injury Patients and Indian Law KK Aggarwal

Section 324 of IPC in Medical Practice Section 324: Voluntarily causing hurt by dangerous weapons or means: “Whoever, except in the case provided for by Section 334, voluntarily causes hurt by means of any instrument for shooting, stabbing or cutting, or any instrument which, used as weapon of offence, is likely to cause death, or by means of fire or any heated substance, or by means of any poison or any corrosive substance, or by means of any explosive substance or by means of any substance which it is deleterious to the human body to inhale, to swallow, or to receive into the blood, or by means of any animal, shall be punished with imprisonment of either description for a term which may extend to 3 years, or with fine, or with both”.

It is the duty of the attending doctor to record all injuries, their dimensions as much as possible, and the body parts where the injuries are located; the nature of injury, whether simple or grievous; whether caused by sharp/blunt object; age or duration of injury and vital parameters like blood pressure, pulse respiration along with the mental status of the patient. When an investing officer comes to the hospital he needs some specific answers for his legal investigation and to book a case under the law of land. zz Are the injuries present, self-inflicted or fabricated?

If yes, please mention the forensic justification. zz Are there any signs/symptoms or smell of alcohol or any drug intoxication? If yes, please opine about the mental status due the influence of intoxication.

Also, preserve the sample of blood. zz Please opine if the injured or intoxicated patient is fit to give statement? If no, please give due reasons and an approximate time interval for medical reevaluation for his/her fitness for statement. zz Is the condition of patient critical, severe or serious?

If so, the dying declaration must be recorded by attending doctor before one or two witnesses.

Senior Physician and Cardiologist Moolchand Medcity, New Delhi

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Grievous Hurt As Per IPC S 320 IPC defines grievous hurt and lists eight kinds of hurt which it lables as “grievous”. These clauses are not mutually exclusive for there can be injuries which may fall in more than one clause. However, the list is exhaustive in the sense that, the framers of the Code have used the term “only”, while listing the type of hurts which they designated as “grievous”.

This positively shows that the list is exhaustive and no hurt outside the list given in S. 320 can be termed as ‘grievous hurt’.

The following kinds of hurt only are designated as “grievous”: First: Emasculation; Secondly: Permanent privation of the sight of either eye; Thirdly: Permanent privation of the hearing of either ear; Fourthly: Privation of any member or joint; Fifthly: Destruction or permanent impairing of the powers of any member or joint; Sixthly: Permanent disfiguration of the head or face; Seventhly: Fracture or dislocation of a bone or tooth; Eighthly: Any hurt which endangers life or which causes the sufferer to be during the space of twenty days in severe bodily pain or unable to follow his ordinary pursuits.

Explanation: To make out the offence of causing grievous hurt, there must be a specific hurt, coming within any of the eight kinds enumerated in this section. A simple hurt cannot be designated as grievous simply because it was on a vital part of the body, unless the dimensions or the nature of the injury or its effects are such that (in the opinion of the doctor) it actually endangers life. For the courts to determine whether the hurt caused is grievous, the extent of the hurt and the intention of the offender have to be taken in to account. Further, it has to be proved that the offender intended to cause or had the knowledge that his act was likely to cause grievous hurt. Intention to cause grievous hurt is inferable from the circumstances of the case and the nature of the injury caused. The medical person, however, must confine himself to only opining whether a given hurt is grievous or otherwise, as per the 8 Clauses of S 320 IPC, and leave the “intention/ knowledge” part to the courts to decide. “Grievous bodily harm, which is defined in the book, is not necessarily either permanent or dangerous, but harm that seriously interferes with health or comfort. That is sufficient”. An injury is not grievous per se unless the Asian Journal of Critical Care Vol. 9, No. 4, January-March 2014

MEDILAW nature, extent and effects of the said injury are such as to endanger the life of the victim, as per the opinion of the doctor, formed in good faith.

Medical Testimony of Doctor in the Court of Law (Do not misrepresent documents/medical literature in the Court of Law) When evidence is read into the record of a trial, only that portion of the document, which validates the information being discussed needs to be read aloud.

One paragraph or even one part of a paragraph may be all that is necessary to substantiate the point you are making. Documents must be presented in the words of the author. When you paraphrase evidence, you argue in a circle. Reading the remainder of the document, even if it establishes a context for the evidence, is unnecessary and time窶田onsuming. When a document is cut in a manner, which lends the quoted passage a meaning other than what would be derived from a more complete reading, you are misrepresenting the document. This does not mean, however, that you are responsible for drawing the same conclusions from information as the author of the document. Drawing a contrary conclusion from passages accurately interpreted does not constitute misrepresentation.

The fact that the author of the document reached a different conclusion from the information argues perhaps persuasively against your conclusion. However, you have not misused the evidence.

Medicolegal Cases and Injury, Assault and Hurt in Indian Law The words injury, assault and hurt are invariably used by doctors in hospital practice and are used as synonyms.

But all three have a different meaning as per law. It is defined by the Indian Penal Code as below: zz Injury: Section 44 of IPC defines injury as any harm whatever illegally caused to any person in body, mind, reputation or property. zz Assault: Section 351 of IPC defines assault as an offer or threat or attempt to apply force on body of another in a hostile manner. It may be a common/ simple assault or an intention to murder. zz Hurt: Section 319 of IPC defines hurt as whoever causes bodily pain, disease or infirmity to any person is said to cause hurt.

When we as doctors deal with cases of hurt/body injury, it means bodily pain, wound, disease or infirmity voluntarily caused to any person in medicolegal cases.

These would include abrasions, contusions, lacerations, stab wounds, electric shock, firearm, or ligatures, etc.

Asian Journal of Critical Care Vol. 9, No. 4, January-March 2014

resulting in injury to the human body. The doctor who is certifying an injury report should keep in mind the Penal provisions (as below) required by police to book the case. zz Simple injury: IPC Section 323. zz Simple injury caused by dangerous weapons: IPC Section 324. zz Grievous injury: IPC Section 325. zz Grievous injury caused by dangerous weapons: IPC Section 326. zz Dangerous injury: IPC Section 307. zz Injury likely to cause death: IPC Section 304. zz Injury sufficient to cause death: IPC Section 302. zz Causing hurt by means of poison: IPC Section 328.

Preparation of MLC in Injury Cases by the Attending Doctor zz Injuries produced by a blunt weapon on tense skin covering the bones, as on scalp, eyebrow, iliac crest, shin, perineum, knee or elbow look like incised wounds. During the preparation of medicolegal cases (MLC) report the doctors should keep in mind that he has to provide a clue about the weapon used, whether sharp-edged one or otherwise, the direction of the force, the duration of injury and the location of the wound, which may suggest mode of production i.e., suicide, accident, homicides along with whether the injury is fabricated or otherwise. zz Wounds produced by a blunt weapon or by a fall on the hard surface, object, on tense structures/ skin covering the bones, such as the scalp, eyebrow, iliac crest, shin, perineum, knee or elbow when the limb is flexed look like incised wounds; but, they are lacerated wounds, also called split lacerations.

These wounds may mislead the doctor and the investigating authorities about a sharp weapon. zz When incised-looking wounds are examined by doctor under magnifying lens, the edges of such wounds are found to be irregular with bruising and wounds are produced by blunt weapon. zz An incised wound, cut, slash and slice is a clean cut through the skin, it may or may not involve underlying tissues and structures. It is caused by a sharp-edged instrument, which is longer than the depth of wound. It is produced by infliction of an object having a sharp-cutting edge such as knife, razor, blade, scalpel, sword over the body.

35

MEDIFINANCE CLINICAL PRACTICE

Need for a Will or Power of Attorney

W

ill a personâ&#x20AC;&#x2122;s family know what to do when one dies? Will all the members affected know how to respond if one becomes disabled? Is a person prepared to deal with a disabilityrelated early retirement? If not, it will not be the plans that fail. The problem will be the failure to plan!

Common Pitfalls Every family, every year, should be sure to train itself to be prepared for the worst of circumstances. Yet, most people do not bother to take the essential measures.

Many do not have adequate amounts of life insurance.

Others neglect their wills. Many people with complex needs have only a simplistic will when a carefully drawn trust is really needed. Some haphazardly purchase financial products and have no overall financial plan.

Every estate is planned, either actively or passively.

Either you maintain control, or the government does it for you. If one does not bother, his family may suffer undue duress and expense due to protracted court proceedings. You can avoid all this by planning ahead.

Reasons to Plan In the case of a minor child or elderly parent. For example; one would not think of leaving them alone without a baby sitter. Nor would one allow someone else to decide who that baby sitter should be. It is important for a doctor to specify a guardian (and alternate guardians) in his will.

A doctorâ&#x20AC;&#x2122;s spouse or family members cannot be expected to know all his financial arrangements. He can save them a lot of anguish by keeping records current, including bank account numbers, insurance policies, real estate deeds and records, stocks, bonds and other investments, wills, trust agreements, employee benefit records, birth certificates, marriage license, military service records and Social Security information.

Employee benefit accounts and beneficiary arrangements change frequently, and often it is appropriate to change prior elections. It is essential for a doctor to keep an inventory of all his property, mortgage 36

information and an informal letter of instructions regarding estate administration.

It is also important for the doctor to make sure he is doing everything possible to assure adequate income at retirement. He should take full advantage of savings, investments, insurance, individual retirement accounts and all the products and services available to him.

His professional financial advisor must help him understand the advantages and disadvantages of each.

Special Arrangements May be Needed A doctor owes it to himself and his loved ones to become informed, and to teach his survivors now, how to make decisions and handle money. Maintaining oneâ&#x20AC;&#x2122;s financial safety often means that, if a doctor is not well, he or his wife may not be able to handle money, run a business or manage an investment portfolio. It would be unfair and unwise to thrust these burdens on the wrong people.

If a doctor has a mentally challenged, learning disabled or physically handicapped child, he must plan ahead.

Such children may never be able to care for themselves.

The same might apply to a parent or dependent sibling. Such cases call for special legal arrangements, and frequently require special funding efforts to be effective.

Every closely held business owner should consider what will happen if a business associate dies or becomes disabled. What will happen to his survivors if he meets with an accident? Could his spouse or children take over if they had to? Would he want them to? If there are no written, binding plans, could the wrong employees take control?

Suppose he is single. Who will act for him later, if he does not act for himself now?

A doctor may have important charitable objectives.

Government cutbacks have shifted some responsibility for social services back to the public, and many worthwhile organizations have a great need for funds.

He may be contributing time and money now - what about a legacy after his death?

Asian Journal of Critical Care Vol. 9, No. 4, January-March 2014

MEDIFINANCE Benefits of Planning Controlled estate planning will systematically uncover problems and gaps in his estate and provide solutions.

For example, he can plan against: ÂÂ Excessive transfer costs: The improper plan or group of documents might cause too much tax, payable too soon. ÂÂ Lack of liquidity: Or not enough cash to pay taxes and other predictable expenses could result in the forced sale of his liquid assets or other income producing property. This is an especially critical factor for owners of closely held businesses or investment real estate. ÂÂ Improper disposition of assets: This could result in the estate being disposed of in equal but inequitable shares among his children, even if their needs vary greatly. It may also be an improper disposition of assets to leave 40 or 50 lakhs in life insurance to a 21-year-old child or to a spouse - without the benefit of a trust arrangements to prioritize for proper investment - or to preclude wild spending. ÂÂ Inadequate income if disability occurs: Electing the maximum benefits from his employersponsored plans, and filling in the gaps with

ÂÂ

personal disability coverage and insurance waivers of premium.

Inadequate income for his family at his death: To maintain the same standard of living, the family will typically need 80% of his present gross income. This must be adjusted periodically for inflation, additional debts incurred, education funding needs and special family circumstances.

How to Proceed Consult with a professional financial advisor to check all his insurance. Review his will and trust, making sure these documents will do, what he wants them to do in the most effective manner?

Inform his heirs, before they become heirs, where his personal and financial documents are located especially a durable power of attorney. If he is married, he should measure his needs annually, establish his priorities and then develop and put into effect plans to make sure that his financial future is sound.

It is not necessary to cancel and entirely redraw his legal instrument. A will can be modified by a codicil (amendment), and some forms of trust agreements are also subject to alteration. Of course, his attorney will be familiar with the correct procedures.

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Asian Journal of Critical Care Vol. 9, No. 4, January-March 2014

37

LIGHTER READING CLINICAL PRACTICE

Lighter Side of Medicine

Should you have a bad day at work, think of the man who has been out of work for many months struggling to feed his family.

Should you notice a new gray hair in the mirror, think of the cancer patient in chemo who wishes she had hair to examine. Should you find yourself at a loss and pondering what is life all about, asking, “What is my purpose?”, be thankful, there are those who didn’t live long enough to get the opportunity.

“Success is not measured by what you accomplish but by the opposition you have encountered and the courage with which you have maintained the struggle against overwhelming odds”.

—Orison Swett Marden

Dr. Good and Dr. Bad SITUATION: A type 1 diabetic wanted to observe

Ramadan fast.

Go ahead

Avoid it

©IJCP Academy

AN INSPIRATIONAL STORY

38

Should you find yourself stuck in traffic, don’t despair; there are people in this world for whom driving is an unheard of privilege.

QUOTE

T

wo traveling angels stopped to spend the night in the home of a wealthy family.

The family was rude and refused to let the angels stay in the mansion’s guest room.

Instead the angels were given a small space in the cold basement.

As they made their bed on the hard floor, the older angel saw a hole in the wall and repaired it. When the younger angel asked why, the older angel replied, “Things aren’t always what they seem.” The next night the pair came to rest at the house of a very poor, but very hospitable farmer and his wife.

After sharing what little food they had, the couple let the angels sleep in their bed where they could have a good night’s rest. When the sun came-up the next morning, the angels found the farmer and his wife in tears.

Their only cow, whose milk had been their sole income, lay dead in the field. The younger angel was infuriated and asked the older angel, “How could you have let this happen? The first man had everything, yet you helped him,” she accused. “The second family had little but was willing to share everything and you let the cow die.” “Things aren’t always what they seem,” the older angel replied.

“When we stayed in the basement of the mansion, I noticed there was gold stored in that hole in the wall. Since the owner was so obsessed with greed and unwilling to share his good fortune, I sealed the wall so he wouldn’t find it. Then last night as we slept in the farmer’s bed, the angel of death came for his wife.

I gave him the cow instead. Things aren’t always what they seem.”

Sometimes that is exactly what happens when things don’t turn out the way they should. If you have faith, you just need to trust that every outcome is always to your advantage. You might not know it until sometime later.

Should you find it hard to get to sleep tonight, remember the homeless family who has no bed to lie in.

LESSON: Fasting is especially risky for those with

type 1 diabetes.

KK Aggarwal

Asian Journal of Critical Care Vol. 9, No. 4, January-March 2014