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JIMIJOURNAL OF INTERNAL MEDICINE OF INDIA

Associate Editors Prof. (Dr.) Sarita Bajaj • Prof. (Dr.) Om Kumari Gupta

Assistant Editors Prof. (Dr.) Madhukar Rai • Prof. (Dr.) Kauser Usman

Editorial Secretary Dr. S.K. Plaha • Dr. A.K. Shukla • Dr. Meenakshi Jain

Editor-in-Chief: Dr. S. Chakravorty

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Dr. Anuj Maheshwari Dr. N.K. SoniDr. Virendra AtamDr. Arvind MishraDr. K.K. SawlaniDr. Praveen Kumar BassDr. R.R. SinghDr. K.C. LohaniDr. Jalees FatimaDr. Veerendra SinghDr. Mahim Mittal

Dr. Balvir Singh

Dr. Sudhir Agarwal

Editorial Board

Dr. Sanjay Singh

Dr. A.K. Singh

Dr. Subodh Chandra

Dr. Abha Gupta

Dr. Amitesh Aggarwal

Dr. Saurabh Shrivastava

Dr. S.K. Sahoo

Dr. Atul Mehrotra

Dr. G.C. Vaishnava

Dr. R.K. Gattani

Dr. Sanjay Mahajan

JOURNAL OF INTERNAL MEDICINE OF INDIA • APRIL 2017 • VOL. 11 • NO. 3 • RNI No. 69152/98

JIMI • APRIL 2017 • VOL. 11

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Subscription InformationUttar Pradesh Journal of Internal Medicine of India (ISSN: 0972-1096). For 2017, Volume 11(2 issue) is scheduled for publication. Subscription prices are available upon request from the publisher or from UP Journal of Internal Medicine of India or from this Journal website (www.upjimi.org), or contact UP JIMI Customer Service Centre: T-21, Sector-11, Noida-201301 (UP) India.Tel. (0120-2538432, +91 9810210479)E-mail: [email protected]

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JIMI • APRIL 2017 • VOL. 112 JIMI • APRIL 2017 • VOL. 11 3

Chairman Dr. Sarita Bajaj Chairman-Elect Dr. Virendra atam Vice-Chairman Dr. Kauser Usman Dr. Veerendra Singh Hon.Seceretary Dr. D. Himanshu Treasurer Dr. S. Chaudhary JointSecretaries Dr. Anupam Wakhlu Dr. S. Chakravorty

Governing Body Members

Dr. Jalees FatimaDr. Sanjay TandonDr. Anuj MaheshwariDr. Abha GuptaDr. Anjum ParvejDr. Jaya Chakravorty

Co-opted Members

Dr. R.R. GuptaDr. K.K. SawlaniDr. Kailash Kumar GuptaDr. A.K. SinghDr. Manoj MathurDr. N.K. SoniDr. Om Kumari GuptaDr. Sudhir Agarwal

Governing Body ASSOCIATION OF PHYSICIANS OF INDIA

NOIDA CHAPTER

Governing Body ASSOCIATION OF PHYSICIANS OF INDIA

UP CHAPTER

PatronDr. (Prof.) B.C. BansalDr. (Prof.) Om Kumari GuptaDr. S.K. Plaha

FormerChairmanDr. B. GandhiDr. K.C. SoodDr. Subodh ChandraDr. G.C. Vaishnava

ChairmanDr. S. Chakravorty

ViceChairmanDr. Kunal Das

SecretaryDr. A.K. Shukla

JointSecretaryDr. Amitesh AggarwalDr. Saurabh Srivastava

TreasurerDr. Meenakshi Jain

ScientificAdvisorDr. Rakesh PrasadDr. L.K. JhaDr. Amitabh Yaduvanshi

CoreCommitteeMemberDr. Gulab GuptaDr. Ajay AgarwalDr. S.K. SahooDr. Yogesh ValechaDr. N.K. SharmaDr. Kiran SethDr. Amit GuptaDr. Vandana Garg


JIMI • APRIL 2017 • VOL. 112 JIMI • APRIL 2017 • VOL. 11 3

“The art of medicine consists of amusing the patient while nature cures the disease.”

—VoltaireDear All,

India is facing biggest scourge on the medical community and medical services. Almost every other day we come

to hear about the medical atrocities and violence faced by the doctors all over the country. Lack of adequate infrastructure, dismal doctor–patient population ratio, poor administrative efforts all contribute to patient’s dissatisfaction and improper reach of healthcare to the remotest corner of the society. The atrocities faced by the budding doctors dishearten them in treating their patients with love, care and compassion and the same being translated as they mature to become a money spinning machine. Commercialization of healthcare in Tier one & Tier two cities has led to unsatisfactory reach of healthcare to the patients below poverty line. An inadequate effort to reach out medical service to the villages has also led to the migration of population from village to the cities. The quest for a better healthcare does not appear to have an immediate solution. The least a doctor can do is to communicate with the patients and attendant regarding the disease, its outcome, diagnosis and prognosis and deal the situation with compassion.

The training for medical communication must start at college level, infact at school may be appropriate.

The art of communication must be embedded in the regular curriculum with usual clinical posting. The delivery of the message in a layman’s language to convince the patients about disease activity and its outcome is the key to success in clinical practice.

To deliver a high quality healthcare effective doctor-patient communication is essential to build up a therapeutic doctor-patient’s relationship. Much patient’s dissatisfaction, complaint and violence at work place is due to ineffective communication causing breakdown in doctor-patients relationship.1-3-8 Many of the doctors may be highly qualified with super specialist degree but show poor communicating ability which leads to patient dissatisfaction.

Barriers to Effective Communications• In adequate time devotion on each patients.• Burden of work (clinical + administrative).• Fear of litigation.• Improper match between patient and doctors level

of understanding and communication.• Fear of physical or verbal abuse.• Unrealistic patient’s expectations.In older days most physicians considered it detrimental

to patients to disclose adverse news regarding the poor

outcome of certain life threatening diseases such as cancer, tuberculosis and many other chronic diseases with less available treatment. However with advent of consumerism, shared decision making and information exchange has become the current approach of doctor-patients communication. Nowadays patients have recognized that they are not passive recipients and are able to resist the power and expert authority that society grants doctors.2-7

Patients receiving effective information regarding the disease are strongly associated with speedy recovery.

Fig. 1: Holistic Approach of an Effective Doctor-Patients Communication

“The patient will never care how much you know, until they know how much you care.” (Terry Canale in his American Academy of Orthopaedic Surgeons Vice Presidential Address).

Most atrocities and violence against doctors are related to poor communication rather than clinical competency.8

Patients want doctors who can skilfully diagnose and treat their sicknesses as well as communicate with them effectively.

Doctors use a scientific and a biomedical model to understand the disease whereas patient’s beliefs and values are influenced by social, behavioural as well as ill conceived biology. Diversion of beliefs can negatively affect treatment decisions by bringing distrust of prescribing therapies.10 Doctors should try to overcome such barriers and understand the patient’s perspective and deliver the message accordingly.

“Cure sometimes, treat often and comfort always.”—Hippocrates

Editorial


JIMI • APRIL 2017 • VOL. 114 JIMI • APRIL 2017 • VOL. 11 PB

References1. Fong, Jennifer Ha, Anat, Dip Surg and Longnecker, Nancy

(2010), “Doctor-Patient Communication: A Review”, The Ochsner Journal, Vol. 10, pp. 38–43.

2. Hall, J.A., Roter, D.L. and Rand, C.S. (1981), “Communication of Affect Between Patient and Physician”, J. Health Soc Behav., Vol. 22(1), pp. 18–30.

3. Duffy, F.D., Gordon, G.H. and Whelan, G. et al. (2004), “Assessing Competence in Communication and Interpersonal Skills: The Kalamazoo II Report”, Acad Med., Vol. 79(6), pp. 495–507.

4. van Zanten, M., Boulet, J.R., McKinley, D.W., DeChamplain, A. and Jobe, A.C. (2007), “Assessing the Communication and Interpersonal Skills of Graduates of International Medical Schools as Part of the United States Medical Licensing Exam (USMLE) Step 2 Clinical Skills (CS) Exam”, Acad Med., Vol. 82(10 Suppl), pp. S65–S68.

5. Bre´ dart, A., Bouleuc, C. and Dolbeault, S. (2005), “Doctor-patient Communication and Satisfaction with Care in Oncology”, Curr Opin Oncol., Vol. 17(14), pp. 351–354.

6. Brinkman, W.B., Geraghty, S.R. and Lanphear, B.P. et al. (2007), “Effect of Multisource Feedback on Resident Communication Skills and Professionalism: A Randomized Controlled Trial”, Arch Pediatr Adolesc., Vol. 161(1), pp. 44–49.

7. Lee, R.G. and Garvin, T. (2003), “Moving from Information Transfer to Information Exchange in Health and Health Care”, Soc Sci Med., Vol. 56(3), pp. 449–464.

8. Arora, N. (2003), “Interacting with Cancer Patients: The Significance of Physicians’ Communication Behavior”, Soc Sci Med., Vol. 57(5), pp. 791–806.

9. Platt, F.W. and Keating, K.N. (2007), “Differences in Physician and Patient Perceptions of Uncomplicated UTI Symptom Severity: Understanding the Communication Gap”, Int. J. Clin. Prac., Vol. 61(2), pp. 303–308.

DISCLAIMERThe content and context of the papers are written by authors and compiled in this volume. The originality and authenticity of the papers and the interpretation of information and views expressed therein are the sole responsibility of the authors. The publishers or editors do not take any responsibility for the same in any manner. Although every care has been taken to avoid errors and omissions, JIMI is being published on the condition and undertaking that the information given in this Journal is merely for reference and must not be taken having authority of, or binding in any manner on the editors or publisher.

JIMI


JIMI • APRIL 2017 • VOL. 11PB JIMI • APRIL 2017 • VOL. 11 5

Contents

ORIGINAL ARTICLE

1. Observational Study to Evaluate the Safety and Efficacy of Saroglitazar in Diabeticdyslipidemia Patients with and without Coronary Artery Disease (CAD)Minal Mohit, Jayanta Kumar Panda and Jugal Kishor Sharma 7

2. Study of Cardiometabolic Risk Factors and their Perception in Patients Attending Tertiary Care Hospital in GhaziabadRajaram Aggarwal, Rakesh Kumar Jagdish, M.K. Bhatnagar and Pradeep Kumar 12

REVIEW ARTICLE

3. Smoking and Recurrent Ischemic EpisodesShridhar Dwivedi, Amitesh Aggarwal and Vivek Suman 18

4. Brain Death: Medical, Legal, Social & Ethical IssuesBhupendra Chaudhary, Puneet Bhasin and Gagandeep Singh Bajaj 22

5. How to Approach a Patient who has Consumed Unknown PoisonR.R. Singh, N.S. Sengar, Ankit Singh, Wasim Farooqi and Namrata Singh 27

6. Prevention of Drug Resistant TuberculosisRajendra Prasad, Nikhil Gupta and Amitabh Banka 36

7. Pancreas, Islet Cell and Stem Cell Transplantation: Current ScenarioVeerendra Singh 41

8. Posterior Reversible Encephalopathy Syndrome (PRES): From a Nephrologist EyePrashant Bendre and Bhupendra Chaudhary 44



CASE REPORT

9. Acute Onset Facial Nerve Palsy Associated with Lyme DiseaseArvind Kumar Mishra, Shubham Agarwal, Rohit Anand and K.K. Gupta 49

10. Medical History-Stethoscope 51

11. Knowledge Forum-RPN 53

JOURNAL OF INTERNAL MEDICINE OF INDIA APRIL 2017 VOL. 11

JIMI APRIL 2017 VOL. 11 7

Introduction

Coronary heart disease (CHD) is currently the leading cause of death worldwide and together with diabetes,

poses a serious health threat, particularly in the Indian

Asian population. Cardiovascular diseases (CVD), comprising coronary heart (CHD) and cerebro-vascular diseases, are currently the leading causes of death globally. Of the risk factors, diabetes, and its predominant form, type 2 diabetes mellitus (T2D), has a distinctive association with CHD. Those with diabetes have two- to four-fold higher risk of developing coronary disease than people without diabetes1, and CVD accounts for an overwhelming 65-75 per cent of deaths in people with diabetes 2, 3.Type 2 Diabetes Mellitus (T2D) is a very common metabolic disorder that has detrimental cardiovascular consequences.4High morbidity and mortality in T2D could also be the result of a complex interplay of several comorbidities like chronic hyperglycemia, dyslipidemia

1Consultant, Department of Endocrinology, Manipal Hospital, Jaipur-3020132Associate Professor, PG Department of Medicine, SCB Medical College, Cuttack–7530073Medical Director & Senior Consultant, Central Delhi Diabetes Centre 34/34, Old Rajinder Nagar, New Delhi–110 060 (INDIA)E-m ail: [email protected], [email protected], [email protected], [email protected]

ABSTRACT

Patients with type 2 diabetes (T2D) have a unique pattern of dyslipidemia characterized by triad of increased triglyceride levels (TG), lower High Density Lipoprotein cholesterol (HDL-C) and higher proportion of small dense Low Density Lipoprotein cholesterol (LDL-C). Management approach to this type of diabetes dyslipidemia (DD), perhaps requires a multi-pronged approach involving the reduction of triglycerides as well as a simultaneous control of insulin resistance. Recently, the introduction of Saroglitazar, a dual PPAR agonist that addresses both these aspects of controlling high triglycerides and improving insulin sensitivity has raised hopes of a better and more pragmatic management of dyslipidemia in T2D.

Aim: The objective of this study was toevaluate the effect of addition of saroglitazar to statins on triglycerides and other lipid parameters in diabetic dyslipidemia patients, with or without coronary artery disease(CAD).

Methods: This was an observational, multicenter, single-arm,open label post marketing study in Indian diabetic dyslipidemia (DD) patientswith or without history of CAD.Saroglitazar 4 mg was prescribed once dailyto patients with type 2 diabetes (with on-going antidiabetic and statin medication), age above 18 years, and triglycerides >200 mg/dL.The data werecollected and analyzed from the treating physicians who had prescribed saroglitazar during routine care at inclusion (visit 1), then at 3 months (visit 2) and 6 months (visit 3).

Results: A total 50 patients (25 with CAD)with a mean duration of diabetes10.88 years were included in this analysis. The baseline demographic profi le was: mean age of 58.5 years, mean body weight 74.16 kg and 58% patients were male. All patients were on antidiabetic and statin medications. Meanbaseline TG was 212.96 mg/dL vs. 101.64 mg/dL at 6 months follow-up,there was a signifi cant reduction of 111.32mg/dL from baseline. Statistically signifi cant improvements in all other lipid parameters were also noted (a mean reduction of 81.48 mg/dL in LDL-C levels, 81.06 mg/dL in total cholesterol levels and mean increase of 1.98 mg/dL in HDL-C levels).Addition of saroglitazar to baseline antidiabetic medications showed a signifi cant 1.9% absolute reduction in HbA1c at the end of 6 months. No serious adverse events or increase in weight gain were reported. Saroglitazar 4 mg treatment resulted in similar improvements in lipid parameters and Hb1Ac at 6 months follow-up in patients with and without CAD.

Conclusion: Saroglitazar is equally effective in improving lipid and glycemic parameters in patients with diabetic dyslipidemia with or without CAD.

Observational Study to Evaluate the Safety and Effi cacy of Saroglitazar in Diabeticdyslipidemia Patients with

and without Coronary Artery Disease (CAD)Minal Mohit1, Jayanta Kumar Panda2 and Jugal Kishor Sharma3

Original Article


JIMI APRIL 2017 VOL. 118

and hypertension.5 Dyslipidemia, a major cardiovascular risk, is one of the most common co-morbidity associated with T2D.6 Diabetic dyslipidemia, is defi ned by the presence of an altered lipid profi le in a diabetic patient and characterized by elevated serum triglyceride (TG) levels (>150 mg/dL), reduced high-density lipoprotein (HDL) cholesterol levels (<40 mg/dL in males and <50 mg/dL in females) and normal or elevated levels of low-density lipoprotein (LDL) cholesterol (>100 mg/dL).7 Several studies have shown that intensive glycemic control has little or no effect on preventing macrovascular complications.8 Therefore, a lot of emphasis has been laid to control diabetic and associated comorbidities like dyslipidemia simultaneously, in order to reduce the macrovascular complications and eventually, to reduce the mortality rates in T2D.Statins are the fi rst recommended therapy for dyslipidemia to reduce not only low-density lipoprotein cholesterol (LDL-C) levels but also the risk of cardiovascular disease (CVD) in patients with or without Diabetes.9 Intensive statin therapy as compared with moderate-dose statin therapy incrementally lowers LDL cholesterol levels and rates of nonfatal cardiovascular events.10 The magnitude of CVD risk reduction as a consequence of LDL-C lowering mostly ranges between 25% and 35%.11 This statistically signifi cant but clinically inadequate control of CVD risk is in part due to a lipid treatment focus on LDL-C alone with a resultant neglect of other important aspects of lipoprotein metabolism.12 Statin therapy may not eliminate CVD Risk associated with high triglycerides and low HDL which are common lipid abnormalities seen in Diabetes.13,14 Statin therapy alone doesn’t eliminate CVD Risk (residual risk) associated with high triglycerides, therefore Triglyceride-rich lipoproteins may be an important additional target for therapy. Studies have also shown that in comparison to Caucasians, Indians have higher TG levels and an associated low HDL-C.15,16 High TG has been long debated to be a major risk factor for CVD and today there is growing evidence which associating higher TG levels with increased CVD disease. Patients who have hypertriglyceridemia are at signifi cant risk for CVD even if patients are on statins and LDL-C levels are at goal.17A study analyzed the results of two trials, dal-OUTCOME and MIRACL, to predict long and short term effects of fasting TGs on recurrent ischemic evens in Acute coronary syndrome (ACS) patients already on statins. Results showed that high TG (>175 mg/dL on long term and >195mg/dL on short term) inspite of statin therapy in post-acute coronary artery syndrome (ACS) patients leads to 60% (Hazard ratio 1.6) and 50% (Hazard ratio 1.5) higher cardiovascular risk compared to those with lower TG (≤ 80 mg/dL on long term and ≤135/dL on short term).18 This relationship of triglycerides to CVD risk was independent of LDL-C in both studies.18

Saroglitazar is one novel dual PPAR α/γ agonist, with a predominant PPAR α agonistic activity approved in 2013 by drug controller general of India (DCGI) for management of Diabetic Dyslipidemia and Hypertriglyceridemia in

T2D patients not controlled by statins alone. It has been found to have an excellent pre-clinical and clinical safety profi le together with a higher effi cacy in optimizing lipids (especially high triglycerides and Non-HDL-C) and glycemic targets.19,20 It could be suitable and safe option to add over and above statins for comprehensive management of dyslipidemia.In this phase 4, post marketing study of saroglitazar we wish to evaluate the effect of addition of saroglitazar to statins on lipid parameters and goals achievement in diabetic dyslipidemia patients. This study was designed to refl ect the optimal treatment of diabetic dyslipidemia in the clinical setting, in that saroglitazar was added to on-going statin therapy to enable patients to achieve lipid goals.

MethodologyStudy DesignThis was an observational, multicenter, single-arm, open label post marketing study of saroglitazar 4mg in Indian diabetic dyslipidemia (DD) patients with or without history of CAD to evaluate effi cacy and safety of saroglitazar as an add on to statins on lipid parameters. The data of Diabetic Dyslipidemic patients who were prescribed saroglitazar and statins both were collected and analysed. Saroglitazar 4 mg was prescribed once daily as per the approved indication (diabetic dyslipidemia and hypertriglyceridemia in type 2 diabetes not controlled with statin). Only patients who qualifi ed for saroglitazar treatment as per treating physician’s clinical judgment (as per prescribing information of saroglitazar) in outpatient settings were included in this analysis. There was no experimental intervention done. The data were collected from the treating physicians who had prescribed saroglitazar during routine care at inclusion (visit 1), then at approximately 3 months (visit 2), 6 months (visit 3).

PatientsPatients who had diabetes dyslipidemia with or without history of CAD (with on-going antidiabetic medication), age above 18 years and triglycerides 200 mg/dL were included. The exclusion criteria were pregnancy, lactating mothers, active liver disease, NYHA class III or IV heart failure, malignancy, or patients with history of hypersensitivity to saroglitazar or any of the excipients used in the formulation.

Outcome MeasuresThe objective of this analysis was to evaluate the effi cacy and safety of saroglitazar in patients of type 2 diabetes with or without coronary artery disease(CAD). This is a retrospective analysis of total 50 patients (25 patients with stable CAD) who have been prescribed saroglitazar 4 mg once daily. All patients were on anti-hyperglycemic medication and statin therapy at baseline. The dose of on-going anti-hyperglycemic medication was modifi ed depending on the baseline glycemic control. The mean



duration of follow up was 6 months. All these 50 patients were prescribed tablet saroglitazar 4 mg once daily before breakfast. Baseline and 6 month follow up glycemic parameters (HbA1c, Fasting plasma glucose, post-prandial plasma glucose), lipid parameters (total cholesterol, LDL-C, HDL-C, TG, non-HDL-C) and adverse event if any reported were recorded. The laboratory tests were conducted at centers recommended by treating physicians. The LDL-C values are direct, not calculated from Friedewald’s equation. Non-HDL-C was calculated by subtracting HDL-C value from total cholesterol value.

Results: Demographic Profi leAll were type 2 diabetes patients with average duration of diabetes of 10.88 years. The mean age of the patients was 58.5 years. Out of the total subjects, 58% (29) of the patients were male and 42% (21) were females. The number of males with disease was more compared to females. The patients had a mean weight of 74.16 kgs. Out of these 50 patients, 25 of them had history of CAD. (Refer Table 1)

Table 1: Demographic Profile

N=50 Baseline Age(year) 58.58±14.00Male 29(58%)Female 21(42%)Weight (kg) 74.16±13.60Average duration of Diabetes(years) 10.88±5.82Patients with CAD 25(50%)

Effi cacyAt 6 months follow-up, there were signifi cant improvements in Lipid parameters (total cholesterol, triglycerides, LDL-C and HDL-C) and HbA1c in entire cohort (Table 2). Saroglitazar in addition to oral antidiabetic medication and statin showed signifi cant improvement in all lipid and glycemic parameters at 6 month follow-up. The mean baseline TG was 212.96 mg/dL vs. 101.64 mg/dL at 6 months follow-up, a signifi cant reduction of 111.32mg/dL from baseline. A statistically signifi cant improvement in all other lipid parameters was also noted (a mean reduction of 81.48 mg/dL in LDL-C levels, 81.06mg/dL in total cholesterol levels and mean increase of 1.98mg/dL in HDL-C levels). Analysis of glycemic parameters revealed a statistically signifi cant 1.9% absolute reduction in HbA1c from baseline value of 8.7% to 6.8% at 6 months follow-up. No serious adverse events or increase in weight gain were reported.

DiscussionStatins have been recommended as the primary therapy for the management of dyslipidemia in diabetes by various guidelines,21,22 however residual cardiovascular risk remains a major concern despite statin therapy and atherogenic diabetic dyslipidemia is postulated to be a major factor contributing to it. Studies have shown that in comparison to Caucasians, Indians have higher TG levels and an associated low HDL-C.23,24 High TG has been long debated to be a major risk factor for CVD and today there is growing evidence associating higher TG levels with

Table 2: Entire Cohort: Change in Lipid and Glycemic Parameters after 6 Months of Treatment with Saroglitazar 4mg Once Daily (N =50)

Parameter Baseline After 6 Months Absolute Difference P ValueLipid Parameters (mg/dl)Total Cholesterol 224.60±28.11 143.54±33.84 -81.06(69.24-92.88) 0.0001TG 212.96±47.59 101.64±24.76 -111.32(95.90-126.74) 0.0001HDL 48.96±12.73 50.94±7.68 1.98(6.54-2.58) 0.3869LDL 157.08±75.60 75.60±25.89 -81.48(75.28-87.68) 0.0001Total Cholesterol 224.60±28.11 143.54±33.84 -81.06(69.24-92.88) 0.0001Glycemic Parameters (%)HbA1c 8.78±0.50 6.80±0.25 -1.98(1.808-2.152) 0.0001All values in Mean ± SD. Abbreviations: N= number of subjects in specifi ed treatment baseline and post-baseline visits. p-values are calculated from paired t - test.

Saroglitazar 4 mg treatment resulted in similar improvements in lipid parameters and Hb1Ac at 6 months follow-up in patients with and without CAD (Table 3).

Table 3: Subgroup Analysis between with and without CAD Patients

Lab Parameters Mean Absolute Reduction in Patients with CAD(N=25)

Mean Absolute Reduction in Patients without CAD(N=25)

P-Value

TC(mg/dl) -72.88±8.82 -89.24±7.61 0.16

TG(mg/dl) -116.16±10.34 -106.48±11.47 0.53

HDL(mg/dl) 2.80±3.22 1.16±3.24 0.72

LDL(mg/dl) -78.92±4.71 -84.04±4.01 0.41

Hb1Ac(%) -1.96±0.10 -1.99±0.14 0.89

All values in Mean ± SED. Abbreviations: N= number of subjects in specifi ed treatment baseline and post-baseline visits. P - values are calculated from unpaired t-test.



increased CVD disease. A recent observational study showed that elevated triglyceride level is independently associated with increased all-cause mortality in patients with established coronary heart disease. In 15,355 patients with proven CHD who were screened between 1990 and 1992 for the Bezafi brate Infarction Prevention (BIP) trial, a secondary-prevention trial. The 22-year mortality risk for patients with severe hypertriglyceridemia was increased by 68% when compared with patients with low-normal triglycerides (P<0.001)25. Another recent observational study in more than 75,000 subjects from general population, followed up for 34 years has revealed that lower TG level was associated with lower CV risk. It was observed that the group with TG <90 mg/dL had 60% lower risk (statistically signifi cant) of ischemic heart diseases than those with TG >360 mg/dL.26 Another meta-analysis published in 2014 revealed that non-fasting TG of 600 mg/dL versus 72 mg/dL was associated with hazard ratio of 5.1 (95% CI 3.5-7.2) for myocardial infarction, 3.2 (2.5–4.1) for ischemic heart disease, 3.2 (2.2–4.7) for ischemic stroke, and 2.2 (1.8–2.7) for all-cause mortality.27 Thus, higher TG level is found to be associated with increased cardiovascular risk. The latest American Association of Clinical Endocrinology (AACE) dyslipidemia guidelines also recommend a non-HDLC calculation rather than LDL-C calculation alone when TG is above 200 mg/dL but <500 mg/dL for better risk assessment especially in patients with insulin resistance.28 The AACE diabetes guidelines suggest that non-HDL-C goal is to be achieved with TG lowering therapy after achievement of desirable LDL-C level.29 The European Society of Cardiology 2016 dyslipidemia guidelines recommend TG lowering therapy to be considered in subjects with TG more than 2.3 mmol/L (more than 200 mg/dL) despite being on lifestyle measures and statins.30 Lipid association of India 2016 guidelines recommends if TG<500 mg/dL – fi rst achieve LDL target with statin; if TG is still above 200 mg/dL calculate non-HDL-C level, if it is above goal, add a non-statin drug to achieve the non-HDL-C goal. If TG>500 mg/dL – TG lowering is fi rst line to reduce the risk of pancreatitis. In patients with diabetes, saroglitazar is also an option for high TG. Meta-analysis of the fi ve major fi brate trials has shown 35% statistically signifi cant decrease in coronary heart disease with fi brates in the group with baseline TG - 204 mg/ dL and HDL-C - 34 mg/dL.31 Thus there is increasing evidences bolstered by guidelines supporting the control of TG to manage non-HDL-C and cardiovascular risk. Unfortunately, the currently available options for the treatment of high TG, fi brates and niacin, are associated with several side effects which limits their use. The use of fi brates is associated with higher risk of muscle symptoms when given in conjunction with statins, increased risk of cholelithiasis, and alteration in renal and liver parameters.32 Niacin is associated with decreased patient compliance due to skin fl ushes, and also manifests glucose intolerance.33 In this context, saroglitazar, a novel molecule, is a dual PPAR-a/g agonist, approved for the use in diabetes dyslipidemia (DD). The present study

shows that saroglitazar in addition to statins led to a signifi cant improvement in lipid parameters in patients with or without history CAD. At 6 months there was a signifi cant reduction in TG, LDL-C, total cholesterol and non- HDL-C (Table 2 & 3). Further, in patients on existing baseline antidiabetic medications, the addition of saroglitazar, showed a signifi cant reduction in HbA1c Finally, there were no serious adverse events or alteration in liver or renal enzymes and edema or weight gain reported in this study.

Limitations of the StudyThis observational study consists of data from real time clinical practice and is not a randomized, controlled, blinded trial.

ConclusionThe results of this retrospective analysis indicate that Saroglitazar is equally effective in improving biochemical parameters in patients with CAD and without CAD having diabetic dyslipidemia.

References1. Kannel, W.B. and McGee, D.L. (1979), “Diabetes and

Cardiovascular Disease: The Framingham Study”, JAMA, Vol. 241, pp. 2035–8.

2. Moss, S.E., Klein, R. and Klein, B.E. (1991), “Cause-specifi c Mortality in a Population-based Study of Diabetes”, Am J Public Health, Vol. 81, pp. 1158–62.

3. Geiss, L.S., Herman, W.M. and Smith, P.J. (1995), Diabetes in America, 2nd ed. Bethesda, M.D.: NIH & NIDDK: National Diabetes Information Clearing House; “Mortality in Non-insulin-dependent Diabetes”, pp. 233–55, In: National Diabetes Data Group, Editor.

4. “Diagnosis and Classifi cation of Diabetes Mellitus”, American Diabetes Association, Diabetes Care, Vol. 31, Supplement 1: January 2008, pp. S62–S67.

5. Ghatrif, M., Kuo, Y.F., Snih, S., Raji, M.A., Ray, L.A. and Markides, K.S. (2011), “Trends in Hypertension Prevalence, Awareness, Treatment and Control in Older Mexican Americans, 1993–2005”, Annals of Epidemiology, Vol. 21, No. 1, pp. 15–25.

6. Taskinen, M.R. (2002), “Diabetic Dyslipidemia”, Atheroscler Suppl., 2002 May, Vol. 3(1), pp. 47–51.

7. The ADVANCE Collaborative Group, “Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes”, N. Engl. J. Med., Vol. 358, pp. 2560–2572.

8. Gaede, P., Vedel, P., Larsen, N., Jensen, G.V., Parving, H.H. and Pedersen, O. (2003), “Multifactorial Intervention and Cardiovascular Disease in Patients with Type 2 Diabetes”, N. Engl. J. Med., Vol. 348, pp. 383–393.

9. Baigent, C., Keech, A. and Kearney, P.M. (2005), “Cholesterol Treatment Trialists’ (CTT) Collaborators, Effi cacy and Safety of Cholesterol Lowering Treatment: Prospective Meta-analysis of Data from 90,056 Participants in 14 Randomised Trials of Statins”, Lancet, Vol. 366, pp. 1267–78.



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IntroductionThe concept of cardiovascular risk factors was fi rst introduced in 1961 from the Framingham Heart Study, linking the presence of specifi c parameters like elevated cholesterol, hypertension (HTN), diabetes mellitus (DM) and tobacco use. Asian Indian lineage accounts for over one-fi fth of the world population[1]. Later on INTERHEART study and INTERSTROKE study have revealed the

signifi cance of various risk factors in pathogenesis of Atherosclerotic coronary vascular disease (ASCVD). Asian Indian phenotype is marked by combination of clinical (larger waist-to-hip and waist-to-height ratios signalling excess visceral adiposity), biochemical [insulin resistance, lower adiponectin and higher C-reactive protein levels], and metabolic aberrations [raised triglycerides (TGs), low-and high-density lipoprotein-cholesterol (HDL-c)][2]. An Indian Council of Medical Research (ICMR) study in the 1990s evaluated risk factors in Delhi in north India and Vellore in south India and reported a signifi cantly greater prevalence of risk factors in north India compared to south India[3]. The government of India sponsored the National family health Survey (NFHS)[4,5], NFHS-2 and NFHS-3 reporting on differences in prevalence of overweight and obesity among men and women in different Indian states[4]. Prevalence of overweight and obesity was the highest in southern and northern Indian states and the lowest in central Indian states[6]. This study

1Resident Medicine,Santosh Medical College and Hospital, Ghaziabad, U.P.2*Assistant Professor Medicine,Santosh Medical College and Hospital, Ghaziabad, U.P.3Professor Medicine,Santosh Medical College and Hospital Ghaziabad,Ex Director Professor,Lady Hardinge Medical College, New Delhi4Professor, Biochemistry Department,Santosh Medical College and Hospital Ghaziabad

ABSTRACT

Aims and Objectives: Asian Indian phenotype is more prone to develop various cardiometabolic risk factors, both modifi able and non-modifi able than the rest of the world population. We therefore planned this study to evaluate various cardiometabolic risk factors in adults attending the OPD and IPD of Santosh Hospital, Ghaziabad, Uttar Pradesh, India.

Methodology: This is a cross sectional hospital based study comprising 350 patients aged 18–70 years. All patients were randomly selected for the study and was evaluated via face to face interviews to gather data on a predesigned performa. The performa included details on demographics, presence of comorbid conditions. All participants in study were subjected to measurement of height, weight, BMI, waist circumference, routine investigations such as fasting and post prandial blood glucose levels, glycosylated hemoglobin and complete lipid profi le. NCEP guidelines were used to identify subjects having various cardiometabolic risk factors. Data was analyzed using SPSS software V.17 and reported as mean with standard deviation using group and descriptive statistics. p values of <0.05 was considered signifi cant. All values were considered keeping 95% of CIs (Confi dence Intervals).

Result: Maximum number of patients having cardiometabolic risk factors were from 40–49 years age group with 99 patients (n= 350) at 28.29%. All risk factors were studied among male and female group. Overall prevalence of Metabolic Syndrome (n=245, 70%) was highest, followed by other risk factors among all patients (Obesity 56.9%, n=199; Dyslipidemia 51.1%, n=179; Diabetes 45.1%, n=158; Hypertension 44.9%, n=157; Smoking 4.3%, n=15). In female prevalence of Obesity (BMI ≥ 30 Kg/m2) and smoking was high (p<0.05). None of the other risk factors were statistically signifi cant however female group had higher cases of hypercholesterolemia (Tc>200 mg/dl) along with Hypertension. In male diabetes and metabolic syndrome were more prevalent.

Conclusion: All Cardiometabolic risk factors except diabetes and metabolic syndrome was more prevalent in the female study group. It is probably due to physical inactivity coupled with unhealthy diet leading to unhealthy lifestyles. For this reason all Indians are at high risk for ASCVD and their predisposition.

Keywords: Obesity, Hypertension (HTN), Diabetes Mellitus (DM), Dyslipidemia, Metabolic Syndrome, Smoking

Study of Cardiometabolic Risk Factors and their Perception in Patients Attending Tertiary

Care Hospital in GhaziabadDr. Rajaram Aggarwal1, Dr. Rakesh Kumar Jagdish2*, Dr. M.K. Bhatnagar3 and Dr. Pradeep Kumar4

Original Article



was planned to study prevalence of major modifi able and non-modifi able risk factors in general population, attending our hospital outpatient department (OPD) and inpatient department (IPD) in Ghaziabad city UP, India. The awareness of cardiometabol ic risk factors and its grave implications are not there in our society due to various factors involved like lower educational status, false beliefs, unhealthy diet, apathy of government on spreading awareness about the risk factors and its socioeconomic implications, poverty etc.

Subjects and MethodsThe study was designed as cross sectional hospital based study. 350 patients (Men:Women, 171:179) aged 18–70 years (mean 46.75 ± 12.75 years) were randomly selected for the study and was evaluated via face to face interviews to gather data on a predesigned Performa. The screening procedures were similar in both (i.e., male and female) study groups. Demography, medical history, smoking and alcohol habits, family history of diabetes and/family history of cardiovascular diseases were recorded. Standard oral glucose tolerance test was done for non-diabetic subjects. Fasting and 2h post prandial blood glucose was done for known cases of diabetes. History of hypertension and treatment details were noted. Average of two blood pressure readings in sitting position was recorded. Values ≥ 130/≥85 mm Hg was considered to be abnormal[7]. Fasting serum total cholesterol, triglycerides (TG) and high density lipoprotein–cholesterol (HDLC) were estimated and low density lipoprotein–cholesterol (LDLC) was calculated using Friedwald’s formula and very low density lipoprotein–cholesterol (VLDLC) was also calculated using Friedewald’s WT formula = TG/5. Height and weight were measured, body mass index (BMI, kg/m2) was calculated. Waist circumference was measured as the minimum girth between the iliac crest and lower costal margin. BMI ≥ 25kg/m2 and waist circumference > 90cms for men and >80cms for women were considered abnormal[8]. Cut off values for lipids were: cholesterol ≥ 200mg/dl, TG ≥ 150mg/dl, HDLC < 40mg/dl for men; < 50mg/dl for women and LDLC ≥ 130mg/dl[8]. Diagnosis of diabetes was made if the fasting plasma glucose was ≥126mg/dl and/or 2 hr. post glucose plasma glucose was ≥200mg/dl[9]. Metabolic syndrome was diagnosed as per Asian specifi c harmonized criteria[7]. Metabolic syndrome was diagnosed if any three or more of the following were present: hyperglycemia (fasting glucose ≥ 100 mg/dl or diabetes), elevated blood pressure (Systolic ≥130 and/or diastolic ≥85 mm Hg) or on treatment for hypertension, waist circumference >90cms for men and >80cms for women, Elevated Triglycerides (TG ≥ 150 mg/dl) or on specifi c treatment for hypertriglyceridemia, Reduced HDLC (HDL < 40mg/dl in men ; < 50mg/dl in women) or on drug treatment

for reduced high density lipoprotein cholesterol (HDLC). Plasma glucose was estimated by glucose peroxidase enzymatic colorimetric method both in fasting and post-prandial state and lipids by standard enzymatic method.

Statistical AnalysisThe study group of 350 patients were subdivided into male and female group. The collected data was entered into the statistical package for social science (SPSS) database (V.17.0, SPSS Inc, Chicago, Illinois, USA). All data were analyzed and reported as mean with standard deviation using group and descriptive statistics. Independent sample T test was done to fi nd out the signifi cance (p value) between the data of male and female test group. Crosstab analysis was done of the study group’s perception towards various cardiometabolic risk factors and their signifi cance was evaluated using chi square test. p Values of <0.05 was considered signifi cant. All values were considered keeping 95% of CIs (Confi dence Intervals).

ResultsThis study is comprised of 350 subjects. All subjects were randomly selected from medicine OPD and IPD. Informed consent was obtained from all subjects eligible for the study.

Table 1: Age and Sex Specific Distribution of the Study Population (N=350)

Age Group (in Years)

No. of Subjects

Percentage (%)

Male Female

10–19 3 0.86 2 120–29 39 11.14 30 930–39 58 16.57 28 3040–49 99 28.29 42 5750–59 81 23.14 35 4660–70 70 20 34 36Total 350 100 171 179

Out of 350 subjects included in study, maximum number and percentage of subjects were from age group of 40–49 years at 28.29%. The study population consisted of 171 males at 48.86% and 179 females at 51.14%. Among them 42 and 57 number of males and females respectively were from 40–49 years of age and were the largest representation of the studied population.

Fig. 1: Prevalence of Various Cardiometabolic Risk Factors Observed



Table 2: (N=350)

Variables No. of Subjects (n) Percentage of Subjects (%)

Obesity 199 56.9%Diabetes 158 45.1%Hypertension 157 44.9%Dyslipidemia 179 51.1%Metabolic Syndrome 245 70%Smoker 15 4.3%

In Table 2 it is shown that metabolic syndrome is affecting 245 out of 350 subjects and is the most prevalent risk factor at 70%. The next commonest prevailing risk factor is obesity at 56.9% affecting 199 out of 350 people, then dyslipidemia (51.1%) followed by diabetes (45.1%) and hypertension at 44.9% affecting 157 out of 350 study subjects. The least prevailing risk factor among them is smoking (4.3%), done by 15 out of 350 study subjects.The trend of all the prevailing risk factors are represented as a graphical representation in Figure 3. It can be noted that the trend line is dipping as we go from obesity to hypertension but it pics up on reaching dyslipidemia and metabolic syndrome. The trend line again declined on approaching smoking. Also with 245 cases metabolic syndrome is the most commonly occurring risk factor and with 15 cases smoking is the least common risk factor encountered among the test subjects.

Fig. 2: Comparative Analysis of Various Cardiometabolic Risk Factors in Men and Women

Table 3 illustrates the various risk factors as Variables which were studied among 350 subjects. The analyzed variables were studied in two group viz. men and women. Their prevalence was computed as means ± S.D. Their signifi cance (p<0.05) was studied among men and women. We found that the most commonly encountered risk factor among the study subjects was raised total cholesterol at 247.8 ± 57.89 in women and 247.3 ± 58.82 among men. The difference between the two group was not statistically signifi cant (p = 0.957). All other components

Patient’s Belief Concerning Obesity/ Weight Gain and other Cardiometabolic Risk Factors

Table 3 (N=350)

Variables Total (n= 350) Women (n= 179) Men (n= 171) P valueMean S.D Mean S.D Mean S.D

Overweight [BMI ≥ 25 Kg/m2 and < 30 Kg/m2] 27.18 1.33 27.22 1.23 27.14 1.42 0.701Obesity [BMI ≥ 30 Kg/m2] 35.04 4.02 35.63 4.17 34.32 3.72 0.023Abdominal obesity [W:H Ratio (men>0.9cm; Women>0.8cm)]

0.99 0.53 1 0.05 0.99 0.05 0.337

Diabetes [Known Diabetics/ FBS≥100 mg/dl] 164 72.02 161.1 72 167.4 72.3 0.538HTN [Known Hypertensive/ systolic B.P.≥130mmhg and/or diastolic B.P.≥ 85mmhg]

147.2 80.12 148.1 19.5 146.2 16.6 0.458

Dyslipidemia [Total Cholesterol ≥200 mg/dl] 247.6 58.11 247.8 57.9 247.3 58.8 0.957[TGL ≥ 150mg/dl] 224.4 87.94 221.5 77.3 227.5 98.5 0.656[LDL ≥ 130mg/dl] 168.6 33.44 171.2 36.8 165.3 28.6 0.318[HDL Men<40mg/dl; Women<50mg/dl] 47.15 10.12 39.01 5.92 34.33 4.41 0.631Metabolic Syndrome 1.3 0.459 1.26 0.44 1.34 0.48 0.119Smokers 1.96 0.2 1.99 0.11 1.92 0.27 0.003

Table No. 4

Patient’s Belief Total (n= 350) Male (n= 171) Female (n= 179)Agreed Declined Agreed Declined Agreed Declined

Obesity is due to family history 164 (47%) 186 (53%) 81 (47%) 90 (53%) 83 (46%) 96 (54%)Obesity is due to drugs used, illness or disease in the past 261 (56%) 89 (25%) 127 (74%) 44 (26%) 134 (75%) 45 (25%)Obesity is due to lifestyle related factors. 339 (97%) 11 (3%) 164 (92%) 7 (8%) 175 (98%) 4 (2%)Does HTN poses any risk of developing ASCVD in future 147 (42%) 203 (58%) 72 (42%) 99 (58%) 75 (42%) 104 (58%)Does DM poses any risk of developing ASCVD in future 232 (66%) 118 (34%) 119 (70%) 52 (30%) 113 (63%) 66 (37%)Does Dyslipidemia poses any risk of developing ASCVD in future

207 (59%) 143 (41%) 107 (63%) 64 (37%) 100 (56%) 79 (46%)



of dyslipidemia was more common in women. Prevalence of diabetes (p= 0.538) and metabolic syndrome (p= 0.119) was more common in men. Hypertension in women (148.1 ± 19.5) was more common than in men (146.2 ± 16.6). The difference in its prevalence among the two groups was not signifi cant with p= 0.458. Among other variables, obesity (BMI>30 kg/m2) and smoking was more commonly present in women than men having signifi cant difference of prevalence with p value of 0.023 and 0.003 respectively.Table 4 shows patient‘s perception towards various risk factors. As many as 97% of study population believe that obesity is due to lifestyle related factors such as unhealthy diet (73%), due to physical inactivity (67%), due to cultural infl uences (42%), due to stress (32%), due to advancing age (63%), obesity being a marker of good health (43%) and obesity is considered as normal weight (39%). 56% (n =261) and 47% (n =164) out of 350 study subjects think that obesity is due to drug used, illness/disease in the past, and due to the family history respectively. 66% (n =232), 59% (n =207) and 42% (n =147) out of 350 study subjects think diabetes, dyslipidemia and hypertension respectively is a marker of ASCVD in future life.

DiscussionThe concept of cardiovascular risk factors was fi rst introduced in 1961 from the Framingham Heart Study, linking the presence of specifi c parameters like elevated cholesterol, hypertension, diabetes mellitus, and tobacco use. Asian Indian lineage accounts for over one-fi fth of the world population[1]. Asian Indian phenotype is marked by combination of clinical (larger waist-to-hip and waist-to-height ratios signalling excess visceral adiposits), biochemical [insulin resistance, lower adiponectin and higher C-reactive protein levels], and metabolic aberrations [raised triglycerides (TGs), low- and high-density lipoprotein-cholesterol (HDL-c)][2]. This study was planned to study prevalence of major modifi able and non-modifi able risk factors in general population, attending our hospital O.P.D in Ghaziabad city. In the present study we included 350 subjects of 18–70 years of age, out of whom the largest representation were from the age group of 40-49 years. The representation progressively declined on either side of them [Table 1]. Male: Female ratio was 171:179 having following mean age; Female 47.72±11.13 years; Male: 44.58±14.04 years. An important focus of recent studies is the changing trends in cardiovascular risk factors. Reviews show that all major risk factors are increasing in India[10]. In the last 30 years, the prevalence of hypertension and hypercholesterolemia has doubled while that of diabetes has trebled. In our study we found the prevalence of hypertension, dyslipidemia and diabetes to be 44.9%, 51.1% and 45.1% respectively. The values we got are higher than the Jaipur Heart Watch-6 study which reported prevalence of hypertension, dyslipidemia (TC≥200 mg/dl) and diabetes to be 36%, 25.8% and 19.2% respectively[11], in our study this was 44.1%, 51.1% and

45.1% respectively. We analyzed the data and plotted individual risk factors as per male and female group, we found that more number of females are having raised total cholesterol as compared to males [Table 3]. This can be noted across all the parameters of dyslipidemia. Incidence of hypercholesterolemia in our study is consistent with India Migration Study (n=1983),[12] Indian Council of Medical Research (ICMR) Integrated Disease Surveillance Project (urban N=15223, rural N=13517, slum/periurban N=15751),[13] in view that prevalence of raised Tc≥200mg/dl is more in female subjects. Obesity, in our study, was considered as patient having BMI ≥30 Kg/m2 as per WHO defi ned criteria for obesity[14]. The mean with S.D of total study group of 350 patients having BMI≥30 Kg/m2 was 35.04±4.02 [Table 3]. When the difference in their means and S.D. assessed in between the male and female group (female>male), it was found to be statistically signifi cant (p=0.023). On plotting difference in mean and S.D., between male and female group across other parameters of obesity viz. BMI ≥25 Kg/m2 but <30 Kg/m2 and Waist to Hip Ratio (men>0.9cm; Women>0.8cm), it was found that female group had higher values than male group for the risk factor considered. The difference in their prevalence was, however, not statistically signifi cant (p>0.05). In our study we noted that incidence of diabetes was more in men (167.4±72.3) than in women (161.1±72). The difference in their prevalence in either of the sexes was not signifi cant (p =0.538) [Table 4]. It was noted that prevalence of hypertension was more in women (n =179) than in men (n =171) [Table 4]. The difference in its prevalence in either of the sexes was not signifi cant (p>0.05). Hypertension is a major risk factor for CVDs, including stroke and myocardial infarction, and its burden is increasing disproportionately in developing countries as they undergo demographic shift. For every 20 mmHg systolic or 10 mmHg diastolic increase in resting blood pressure there is a two-fold increase in risk of death from ischemic heart disease or stroke [15]. Out of 350 study subjects included in our study, 70% was having metabolic syndrome [Table 4]. Its prevalence in our study is extremely high. A high prevalence of metabolic syndrome and associated cardiovascular risk factors have also been observed in other studies done within rural to urban migrant population belonging to lower socioeconomic population groups residing in urban slums[16,17]. The main drivers are related to rapid nutritional changes, lifestyle and socioeconomic transitions, consequent to increasing affl uence, urbanization, mechanization, and rural-to-urban migration[17,18]. Metabolic syndrome and cardiovascular risk in Asian Indians/ South Asians are also heightened by their relative increase in body fat mass, truncal subcutaneous fat mass, intra-abdominal fat mass, and also in ectopic fat deposition. Smoking is considered to be the most important risk factor for CAD in young subjects. The free radicals alter the lipid metabolism and form oxidized and cytotoxic LDL, which is considerably more atherogenic than native LDL. In our study the prevalence of smoking is still very less at 4.3% (15/350 smokers) [Table 3]. When we assessed its mean



of prevalence in between the men and women group we found that its difference in between them was signifi cant (p =0.003) [Table 4] in females. All study subjects were asked few questions in order to fi nd out their perception towards obesity and weight loss regime in general as well as their perception towards the risk factors like hypertension, diabetes and dyslipidemia for developing ASCVD in future. Their responses are stated in a tabulated form in Table 4. As many as 97% of study population believe that obesity is due to lifestyle related factors such as unhealthy diet (73%), due to physical inactivity (67%), due to cultural infl uences(42%), due to stress (32%), due to advancing age (63%), obesity being a marker of good health (43%) and obesity is considered as normal weight (39%). 261 (56%) and164 (47%) out of 350 study subjects think that obesity is due drug used, illness/disease in the past, and, obesity is due to the family history (genetic in origin) respectively. 232 (66%), 207 (59%) and 147 (42%) out of 350 study subjects think diabetes, dyslipidemia and hypertension respectively is a marker of ASCVD in future life. Physical inactivity is responsible for almost 12% of the global burden of myocardial infarction[19]. The relative risk of CVD is reduced in regular physical activity[20-25].

ConclusionThe prevalence of cardiometabolic risk factors in our study was maximum for metabolic syndrome 70% (n=245), followed by obesity (56.9%) n=199 then dyslipidemia (51.1%) followed by diabetes (45.1%) and hypertension at 44.9% affecting 157. The least prevailing risk factor among them is smoking (4.3%), done by 15 out of 350 study subjects. Association of atleast one of the components of dyslipidemia was present along with smoking, hypertension, diabetes and one of the components of obesity. Also dyslipidemia was present in all subjects having metabolic syndrome. Females are more commonly affected than male by dyslipidemia and obesity, probably due to physical inactivity coupled with unhealthy diet leading to unhealthy lifestyles. For this reason Indians are at high risk for ASCVD and their predisposition. Therefore early identifi cation of cardiometabolic risk factors and appropriate intervention may be of primary importance in population. 43% patients think obesity is a sign of good health and 39% patients considers it as a normal body weight indicating false perception towards obesity. We suggest that awareness campaign towards cardiometabolic risk factors should be done on large scale so that false belief of population and unhealthy lifestyle practices can be addressed.

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16. Mohan, V. and Rao, G.H.R. (2007), Type 2 Diabetes in South Asains, 1st ed., New Delhi: South Asian Society on Atherosclerosis and Thrombosis, 2007.

17. Prasad, D.S., Kabir, Z., Dash, A.K. and Das, B.C. (2011), “Abdominal Obesity, An Independent Cardiovascular Risk Factor in Indian Subcontinent: A Clinico Epidemiological Evidence Summary”, J. Cardiovasc Dis. Res., Vol. 2, pp. 199–205.

18. Misra, A., Pandey, R.M., Devi, J. Rama, Sharma, R., Vikram, N.K. and Khanna, N. (2001), “High Prevalence of Diabetes, Obesity and Dyslipidemia in Urban Slum Population in Northern India”, Int. J. Obes. Relat. Metab Disord., Vol. 25, pp. 1722–9.

19. Yusuf, S., Hawken, S., Ounpuu, S., Dans, T., Avezum, A. and Lanas, F. et al. (2004), “Effect of Potentially Modifi able Risk Factors Associated with Myocardial Infarction in 52 Countries (the INTERHEART Study): Case-control Study”, Lancet, Vol. 364(9438), pp. 937–952.

20. Sattelmair, J., Pertman, J., Ding, E.L., Kohl, H.W., Haskell, W. and Lee, I.M. (2011), “Dose Response Between Physical Activity and Risk of Coronary Heart Disease: A Meta-analysis”, Circulation, doi: 10.1161/ Circulation AHA.110.010710.

21. Mansikkaniemi, K., Juonala, M., Taimela, S., Hirvensalo, M., Telama, R. and Huupponen, R. et al. (2011), “Cross-sectional Associations Between Physical Activity and Selected Coronary Heart Disease Risk Factors in Young Adults, The Cardiovascular Risk in Young Finns Study”, Ann Med., Vol. 44(7), pp. 733–744.

22. Moholdt, T., Wisloff, U., Nilsen, T.I. and Slordahl, S.A. (2008), “Physical Activity and Mortality in Men and Women with Coronary Heart Disease: A Prospective Population-based Cohort Study in Norway (the HUNT Study)”, Eur. J. Cardiovasc. Prev. Rehabilit, Vol. 15(6), pp. 639–645.

23. Church, T. (2011), “Exercise in Obesity, Metabolic Syndrome, and Diabetes”, Prog. Cardiovasc Dis., Vol. 53(6), pp. 412–418.

24. Carroll, S. and Dudfi eld, M. (2004), “What is the Relationship Between Exercise and Metabolic Abnormalities? A Review of the Metabolic Syndrome”, Sports Med., Vol. 34(6), pp. 371–418.

25. Long, A.N. and Dagogo-Jack, S. (2011), “Comorbidities of Diabetes and Hypertension: Mechanisms and Approach to Target Organ Protection”, J. Clin. Hypertens, Vol. 13(4), pp. 244–251.



Introduction

Western studies have revealed that patients diagnosed to be having stroke, coronary artery disease,

diabetes and/ or lung disease are more likely to quit smoking rather than those not receiving such a diagnosis.[1] However in South Asian countries this does not seem to be happening that often despite the well known fact that chronic smoking leads to accelerated atherosclerosis and premature coronary artery disease (CAD) more so when combined with concurrent diabetes. It has been often observed that in spite of recurrent ischemic episodes patients keep smoking to the detriment of their vascular health.[2] We present here with the clinical discussion in question answer form related to two middle aged patients, who had recurrent vascular episodes on account of their smoking habits, family history, waist circumference and vascular disease (coronary artery disease, type 2 diabetes mellitus (T2DM), hypertension). We intend to discuss the important issues which have bearing on presentation, therapy and prevention in such clinical scenario.

Clinical DetailsTwo 50 year, old males, belonging to lower middle income group, both chronic smokers and known case of CAD, presented with history of recurrent acute chest pain on same day, which turned out to be acute coronary syndrome (ACS). Both had left anti-ischemic and appropriate anti-diabetic and anti-hypertensive treatment. Case 1 left the treatment about a month back while case 2 left it 9 months back. Further clinical details of both the cases have been summarized in Table 1 and following questions need to be addressed.

Abbreviations• ACS: Acute Coronary Syndrome• AWMI: Anterior Wall Myocardial Infarction• CCA: Common Carotid Artery• CIMT: Carotid Intima Media Thickness• DM: Diabetes Mellitus• FBS: Fasting Blood Sugar• HTN: Hypertension• IWMI: Inferior Wall Myocardial Infarction• LAH: Left Atrial Hypertrophy• LVEF: Left Ventricular Ejection Fraction• LVF: Left Ventricular Failure• LVH: Left Ventricular Hypertrophy• NSTEMI: Non ST Elevation Myocardial Infarction• PPBS: Post Prandial Blood Sugar.

1MD, FRCP (London), Ph.D (Cardiology), Ean & Principal, Professor of Medicine/ Preventive Cardiology, Hamdard Institute of Medical Sciences and Research, Associated, Hakeem Abdul Hameed Centenary Hospital, Jamia Hamdard (Hamdard University),New Delhi, India2MD, PGCC (Clinical Cardiology),Assistant Professor, Department of Medicine, University College of Medical Sciences, University of Delhi,GTB Hospital, Delhi, India3MD, Senior Resident,Department of Medicine, University College of Medical Sciences, University of Delhi, GTB Hospital, Delhi, IndiaE-mail: [email protected], [email protected], [email protected]

ABSTRACT

Western studies have revealed that patients receiving diagnosis of stroke, coronary artery disease, diabetes and/or lung disease are likely to quit smoking rather than those not receiving such a diagnosis. However in South Asian countries this does not seem to be happening that often. Patients often fail to follow therapeutic life style measures and quit smoking despite the recurrent ischemic episodes to the detriment of their vascular health. We present here with clinical scenario of two middle-aged patients, who had sharp differences on many counts like their smoking profi le, family history, waist circumference and evolutionary pattern of vascular disease (coronary artery disease, type 2 diabetes mellitus, and hypertension), but continued smoking despite recurrent ischemic episodes. We try to discuss the important issues which have immense therapeutic and preventive implications in such a clinical scenario in question answer form. The aim is to sensitize the readers to emphasize smoking cessation and adoption of appropriate lifestyle measures which is sadly neglected in crowded and busy practice.

Keywords: Smoking, Premature Coronary Artery Disease, Diabetes Mellitus, Accelerated Atherosclerosis

Smoking and Recurrent Ischemic EpisodesShridhar Dwivedi1, Amitesh Aggarwal2 and Vivek Suman3

Review Article



Q1. What are the Common Risk Factors for Coronary Artery Disease?A. Risk factors for coronary artery disease are:

1. Smoking2. High blood pressure3. Raised cholesterol4. Obesity–central/ metabolic syndrome5. Diabetes mellitus6. Mental stress7. Family h/o vascular disease (CAD, hypertension,

type-2-diabetes mellitus, cerebrovascular accident)

8. Novel risk factors

• Homocysteine

• High sensitive–C reactive protein (hs-CRP)

• Lipoprotein (a)

• Fibrinogen

Table 1: Short History and Clinical Features of Cases

Parameters Case 1 Case 2Age (yrs)/Sex/Religion

50, male, Hindu 50, male, Hindu

Presentation Acute chest pain Acute chest pain > 3 days

Smoking-TypeNumber x yearsSmoking indexPresent status

Bidi5 × 30yrs150Continuing

Bidi20 × 35yrs700left – 1 year

Socioeconomic status (Kuppuswamy scale)

Lower middle income

Lower middle income

1st episode of chest pain

ACS/DM 2004 3yrs back at age 47

IWMI/HTN – 1yr backat age 49

Recurrence 6 months back Unstable angina 5 months back and angina 10 days back

Drugs Left oral hypoglycemic agents / left anti-ischemic treatment 1 month back

Left anti-hypertensive and anti-ischemic treatment 9 months back.

Family history Father – T2 DMMother – hypertensive

No family history of HTN/T2 DM

Blood pressure (mmHg)

140/80 (HTN 1 month)

130/80 (HTN 1 year)

Waist circumference (cms)

102 78

Obstructive sleep apnoea

Present Absent

FBS/PPBS (mg/dl) Known diabetic 3yrs

FBS- 153, PPBS-177

Lipids: HDL (mg/dL) TG (mg/dL)

27226

39129

ECG ST-T changesLAHLVH

AWMI + IWMI

Echo Inf wall hypokinesiaRV dilatation/hypokinesiaLVEF – 45 %

Ant wall hypokinesiaLVEF – 46 %

CIMT (mm) Rt CCA - 0.64Lt CCA – 0.57No plaque/thrombus

Rt CCA – 0.63Lt CCA – 0.67No plaque/thrombus

Evolution of disease ACS/T2DM-3yearsACS-6 monthsNSTEMI/HTN

Ac IWMI/HTN 1 yearUnstable angina-5months Unstable angina-10 days backWMI+IWMI+ LVF+DM

Q2. What is the Reason for Recurrence of Acute Ischemic Episode in two Cases?A. Plausible reasons for recurrent ischemic episode in case-1 were as follows:Case 1

1. Continued smoking but left anti-diabetic and anti-ischemic treatment

2. Non-adherence to therapeutic life style changes including diet

3. Associated diabetes4. Metabolic syndrome and obstructive sleep apnea

(Syndrome Z)5. Dyslipidemia characterized by low high density

lipoprotein (HDL)/ raised triglycerideCase 2 suffered from repeated chest pain on account of

following reasons:1. Left smoking recently, about a year back2. Left antihypertensive and anti-ischemic treatment

9 months back3. Concurrent diabetes4. Non-adherence to therapeutic life style changes

including diet5. Low HDL

Q 3. Case 2 Left Smoking about a Year Back, Even Then he Suffered Repeated Episodes of Acute Coronary Events. Do you have any Explanation for the Same?A. There are studies which favors the hypothesis that in ex-smokers risk of a coronary event defi nitely declines after quitting but the risk is similar to that of non-smokers only after a time period of 2–3 years.[3] Convincing evidence has come from INTERHEART study, which says that the risk of acute myocardial infarction (AMI) in smokers is more than non-smokers even 20 years after quitting smoking [Table 2].[4]



Table 2: Smoking and Tobacco Use and AMI Risk (INTERHEART Study)

Smoking Status OR (95% CI)Current smoking 2.95Beedi smoking 2.89Chewing tobacco 2.23Smokers and tobacco chewers 4.09Former smoking <3yrs of cessation 1.87Former smoking >20yrs of cessation 1.22Second hand smoking (1-7hr/wk) 1.24Second hand smoking (>21hr/wk) 1.62

Q4. How the Intensity of Smoking Does Determines the Age of Onset of Acute CAD?A. Smoking has direct adverse effect on heart. The more the number smoked, the more is the nicotine level in blood which adversely increases the myocardial workload.[5] Smoking affects atherothrombosis by many mechanisms in addition to accelerated atherosclerotic progression. Prolonged smoking may enhance oxidation of low density lipoprotein cholesterol and impairs endothelium dependent coronary artery vasodilatation. This latter effect has now been linked directly to dysfunctional endothelial nitric oxide biosynthesis following chronic as well as acute cigarette consumption. In addition smoking has adverse hemostatic and infl ammatory effects including increased level of hs-CRP, soluble intracellular adhesion molecule-1, fi brinogen and homocysteine. Additionally smoking is associated with spontaneous platelet aggregation, increased monocyte adhesion to endothelial cells and adverse alteration in endothelial derived fi brinolytic and antithrombotic factors including tissue type plasminogen activator and tissue pathway factor inhibitor. Smoking affecting atherosclerosis in so many ways is precisely the reason why low socioeconomic group of people who smoke heavily develop premature CAD.

Q5. How the Family History Does Plays Role in CAD?A. Among men having low risk for CAD by risk-factor profi le (i.e., non-smoking, non hypertensive persons, thin), who experience CAD, more than two thirds have a positive parental history. There is adequate clinical evidence to suggest that CAD among persons at low risk (by standard risk factors) may have a substantial genetic component. Risk associated with parental history may not be reduced by modifi cation of this factors.[6]

Q6. Case 1 Had Type 2 Diabetes Mellitus. What is the Most Important Risk Factor for Type 2 Diabetes Mellitus?A. The most common risk factor for type 2 diabetes mellitus is central obesity. This patient also had acanthosis nigricans, skin tags and obstructive sleep apnea. These conditions are features of associated insulin resistance and hyperinsulinemia. The pathophysiologic basis for the importance of central obesity relate to higher rates of lipolysis in visceral adipocytes, which are relatively resistant to insulin induced suppression of

lipolysis following meals; thus, portal-vein free fatty acid concentrations are increased in central obesity.

Q.7 What is Syndrome Z?A. Syndrome Z is a combination of metabolic syndrome and obstructive sleep apnea (OSA). Central obesity and OSA often coexist. OSA has also been linked to cardiovascular disease. OSA may contribute to the cardiovascular consequences of obesity. OSA may emphasize the potential implications for understanding that only a subgroup of obese patients develops cardiovascular disease.[7]

Q8. What is Stress Hyperglycemia? What are its Implications?A. Stress hyperglycemia is a term referring to transient increase in the blood glucose due to the stress of illness. The positive correlation between hyperglycemia and the severity of illness has been reported in association with surgery, trauma, shock state, stroke, and myocardial infarction (MI). It results from combination of the increased hepatic glucose production with the decrease in glucose utilization. It usually does not require specifi c treatment and resolves spontaneously. Howeverm it must be distinguished from various forms of diabetes mellitus. It has been associated with increased mortality in patients with MI.[8]

According to a randomized control trial (RCT) of over 1500 surgical intensive care unit (ICU) patients, controlling patients’ blood glucose level below 110 mg/dL (6.1 mmol/L) signifi cantly decreased the mortality to 4.6% versus 8% with conventional treatment.[9]

Q9. How Diabetes Accelerates Coronary Atherosclerosis?A. Diabetes accelerated coronary artery disease in several ways:By producing endothelial dysfunction and thus causes basement membrane thickening, decrease release of nitric oxide and increased expression of adhesion molecule, by inducing lipoprotein abnormality and thus causing oxidation of lipoprotein enhanced in presence of hyperglycemia and hypertriglyceridemia and by causing coagulation abnormalities. Diabetics have higher level of plasminogen activator inhibitor-1 (PAI-1) than non-diabetics which inhibits fi brinolysis.

Q10. How Does Smoking is Related to Diabetes?A. Recent data from annals of family medicine suggest that smoking is independently associated with insulin resistance, dyslipidemia and endothelial dysfunction.[10]

Q11. What is the Implication of Left Ventricular Hypertrophy (LVH) in case 1?A. LVH on electrocardiography (ECG) has consistently been shown to be a strong independent risk factor for cardiovascular (CV) mortality.[11] Multiple studies have consistently demonstrated an association between ECG



evidence of LVH and CV mortality.[12] LVH defi ned by the presence of a left ventricular strain pattern on the ECG confers a worse prognosis than LVH by an increased voltage pattern alone.[13]

Q12. What should be the Ideal Management of Case 1?A. Ideal management of case 1 will consist of:

1. Appropriate therapeutic life style changes (cessation of smoking and diabetic diet)

2. Control of blood sugar & blood pressure (BP) (Goal BP <130/80 for diabetics and <120/80 for patients with left ventricular dysfunction).

3. Low molecular weight heparin, aspirin, clopidogrel, β-blockers, angiotensin-converting-enzyme inhibitor and statins.

4. Revascularization strategy– percutaneous coronary intervention/coronary artery bypass grafting.

Q13. How would you Manage Diabetes in Case 1?A. Such a patient should receive intensive glucose control after MI (DIGAMI-2). This can be accomplished by alternative and possibly more convenient oral hypoglycemic.[14] However, insulin administration is often necessary due to therapeutic considerations like:

• Contraindication of metformin in cardiac insuffi ciency or congestive heart failure (CHF),

• Potential side effects of pioglitazone increasing CHF,

• Sulfonylureas, particularly glibenclamide, may disrupt endogenous cardioprotective mechanisms.

Q14. How would you Plan Management Strategy for Case 2?A. Case 2 deserves to be counseled for reinforcing smoking abstinence and diet control. Medical therapy includes streptokinase, aspirin, clopidogrel, β-blockers, angiotensin-converting-enzyme inhibitor, statins, control of BP and differentiating stress hyperglycemia from actual T2DM undetected previously and its appropriate management.

Q15. What Advice would you Give to Their Progeny?A. Children of both these cases need to be counseled regarding avoidance of smoking, central obesity and necessity to do regular exercise. They also need to be impressed regarding regular check up for hypertension and diabetes.

References1. Pagoto, S. and Judith, O. (2009), “Windows of Opportunity

Foe Smoking and Weight Loss Counseling”, Archive Intern. Med., Vol. 169, pp. 217–218.

2. Dwivedi, S., Aggarwal, R. and Aggarwal, A. (2009), “Tobacco Continues Despite Manifest Cardiovascular Disorders: Tobacco Cessation Clinics-Crying need of the Hour”, International Symposium on Atherosclerosis, Atherosclerosis Supplements, Vol. 10(2), p. 914.

3. Dobson, A.J., Alexander, H.M., Heller, R.F. and Lloyd, D.M. (1991), “How Soon After Quitting Smoking Does Risk of Heart Attack Decline”, J. Clin. Epidemiol., Vol. 44, pp. 1247–1253.

4. Teo, K.K., Ounpuu, S., Hawken, S., Pandey, M.R., Valentin, V. and Hunt, D. et al. (2006), “Tobacco Use and Risk of Myocardial Infarction in 52 Countries in the INTERHEART Study: A Case Control Study”, Lancet, Vol. 368, pp. 647–58.

5. Koch, A., Hoffmann, K., Steck, W., Horsch, A., Hengen, N. and Morl, H. et al. (1980), “Acute Cardiovascular Reactions After Cigarette Smoking”, Atherosclerosis, Vol. 35, pp. 67–75.

6. Myers, R.H., Kiely, D.K., Cupples, L.A. and Kannel, W.B. (1990), “Parental History is an Independent Risk Factor for Coronary Artery Disease: The Framingham Study”, Am Heart J., Vol. 120, pp. 963–969.

7. Wolk, R. and Somers, V.K. (2006), “Obesity-related Cardiovascular Disease: Implications of Obstructive Sleep Apnoea”, Diabetes, Obesity & Metabolism, Vol. 8, pp. 250–260.

8. Marfella, R., Siniscalchi, M., Esposito, K., Sellitto, A., De Fanis, U. and Romano, C. et al. (2003), “Effects of Stress Hyperglycemia on Acute Myocardial Infarction: Role of Infl ammatory Immune Process in Functional Cardiac Outcome”, Diabetes Care, Vol. 26, pp. 3129–3135.

9. Van den Berghe, G., Wouters, P., Weekers, F., Verwaest, C., Bruyninckx, F. and Schetz, M. et al. (2001), “Intensive Insulin Therapy in the Critically Ill Patients”, N. Engl. J. Med., Vol. 345, pp. 1359–67.

10. Solberg, L., Desai, J., O’Connor, P., Bishop, D. and Devlin, H. (2004), “Diabetic Patients Who Smoke: Are They Different?”, Ann Fam Med., Vol. 2, pp. 26–32.

11. Kannel, W.B. and Cobb, J. (1992), “Left Ventricular Hypertrophy and Mortality: Results from the Framingham Study”, Cardiology, Vol. 81, pp. 291–298.

12. Sullivan, J.M., Vander Zwaag, R.V. and el-Zeky, F. (1993), “Left Ventricular Hypertrophy: Effect on Survival”, J. Am. Coll. Cardiol., Vol. 22, pp. 508–513.

13. Larsen, C.T., Dahlin, J. and Blackburn, H. (2002), “Electrocardiographic Findings and Global Coronary Assessment”, Eur Heart J., Vol. 23, pp. 315–324.

14. Malmberg, K., Ryden, L., Wedel, H., Birkeland, K., Bootsma, A. and Dickstein, K. et al. (2005), “Intense Metabolic Control by Means of Insulin in Patients with Diabetes Mellitus and Acute Myocardial Infarction (DIGAMI 2): Effects on Mortality and Morbidity”, Eur Heart J., Vol. 26, pp. 650–661.



Introduction

In present era of critical care, ‘the care of a severely brain injured patient’ is one of the toughest challenges

for a critical care physician. Initial therapy provided for patients with severe brain injury or insult, is directed towards preservation and restoration of neuronal function. When this primary treatment is unsuccessful and the patient’s condition evolves to brain death, the critical care physician has the responsibility to diagnose brain death with certainty and to offer the patient’s family the opportunity to donate organs and/or tissues.Physicians, health care workers and even the laypeople throughout the world have well accepted that a person is dead when his or her brain is dead. Although the widespread use of mechanical ventilators and other advanced critical care services have transformed the course of terminal neurologic disorders. Vital functions can now be maintained artifi cially for a long period of time after the brain has ceased to function. There is a need to diagnose brain death with utmost accuracy and urgency because of an increased awareness amongst the masses for an early diagnosis of brain death and the requirements of organ retrieval for transplantation.

Physicians need not be, or consult with, a neurologist or neurosurgeon in order to determine brain death.

Concept of Brain DeathBrain death is a clinical diagnosis in which there are absences of cerebral and brain stem functions and irreversibility of the state. Confi rmatory tests are not mandatory in all cases, but a repeat evaluation is generally recommended. Physicians are entrusted to apply accepted standards and practices when making the diagnosis or brain death, and should exhibit patience and provide emotional support of the family. The concept of brain death emerged during the 1950s when, as a consequence of developments in critical care, clinicians were faced for the fi rst time with the prospect of an apparently alive’ patient sustained by mechanical ventilation long after brain function had ceased. The development of organ transplantation and the associated need to determine death before organ retrieval led to the publication of the fi rst widely accepted standard for the confi rmation of brain death by an ad hoc Committee of the Harvard Medical School in 1968. Although this early link with organ donation might give the impression that brain death was a construct designed only to facilitate donation, this is incorrect. Most importantly, the confi rmation of brain death allows the withdrawal of therapies that can no longer conceivably benefi t an individual who has died.In 1981, the report of the medical consultants on the diagnosis of death to the US President’s Commission recommended that the criteria for diagnosis of brain death should be seen as synonymous with the defi nition of death of the organism as a whole. Brain death is declared when brain stem refl exes, motor responses and respiratory drive are absent in a normothermic, non-

1FRCP (Glasgow), FRCP (Ireland), FACP (Philadelphia), FAAN (USA), DM (Neurology), MD (Medicine), MBBS, Senior Consultant Neurologist, Director and Head, Deptt. of Neurosciences, Jaswant Rai Speciality Hospital, Meerut (U.P.)2MD (Medicine), FCCP, Senior Consultant Physician & Critical Care Specialist, Jaswant Rai Speciality Hospital, Meerut (U.P.)3MD (Anesthesia)-AIIMS, Senior Consultant Anesthetist & ICU Specialist, Jaswant Rai Speciality HospitalE-mail: [email protected], [email protected], [email protected]

ABSTRACT

Brain death is a clinical diagnosis with a irreversible absence of cerebral and brain stem functions. In all cases the confi rmatory tests are not mandatory but a repeat evaluation is generally recommended. The diagnosis and confi rmation largely remains a complex clinical, ethical and social issue for physicians, family members and society at a large. The concept of the “dead-donar rule” closely linked to the increasing need for organ transplantation has created confl icts of interests between the demand for organs and the need for a scientifi cally and philosophically valid defi nition of human death. Finally, physicians are entrusted to apply accepted standards and practices while making the diagnosis and confi rmation of brain death and should exhibit patience and provide emotional support to the family.

Keywords: Brain Death, Brain Stem Refl exes, Apnoea Test, Dead-donor Rule

Brain Death: Medical, Legal, Social & Ethical IssuesDr. (Prof.) Bhupendra Chaudhary1, Dr. Puneet Bhasin2 and Dr. Gagandeep Singh Bajaj3

Review Article



drugged comatose patient with a known irreversible massive brain lesion and no contributing metabolic derangements.The absence of brain stem function is judged by lack of spontaneous eye movements, mid-position of the pupils of the eyes and lack of response to oculocephalic and caloric tests; paralysis of bulbar musculature, gag movement and cough and corneal function; and absence of decelebrate response to noxious stimuli. Occasionally, extensor or fl exor posturing can be seen as a transitional phenomenon just after brain death becomes evident. Spinal refl exes may persist in some cases, and the toes often fl ex slowly in response to plantar stimulation; a well-developed Babinski’s sign is unusual.[1-2]

Defi nitionBrain death is defi ned as the irreversible loss of all functions of the brain, including the brainstem. The three essential fi ndings in brain death are coma, absence of brainstem refl exes, and apnoea. An evaluation for brain death should be considered in patients who have suffered a massive, irreversible brain injury of identifi able cause. The common clinical condition that produces irreversible loss of brain stem functions includes severe head injury, hypertensive intracerebral hemorrhage, aneurysmal subarachnoid hemorrhage, severe hypoxic ischemic brain insults and fulminant hepathic failure. The evaluation of a potentially reversible, should include clinical and neuro-imaging evidence of an acute CNS catastrophe that is compatible with the clinical diagnosis of brain death. A patient determined to be brain dead is legally and clinically dead.

The Confounders of Brain DeathBefore making a diagnosis of brain death it is mandatory to exclude any condition that might confound the subsequent examination of cortical or brain stem function. The condition that may confound the clinical diagnosis of brain death are :

1. Shock/hypotension2. Hypothermia (temperature < 32°C)3. Drugs known to alter neurologic, neuromuscular

function and electroencephalographic testing like anesthetic agents, neuroparalytic drugs, methaqualone, barbiturates, benzadiazepines, high dose bretylium, amitryptiline, meprobamate, trichloroethylene, alcohols.

4. Brain stem encephalitis.5. Guillain-Barre’ syndrome.6. Encephalopathy associated with hepatic failure,

uremia and hyperosmolar coma.7. Severe hypophosphatemia.

Persistent Vegetative State (PVS) A separate condition, refers to a vegetative state lasting longer than 1 month. In contrast to brain death, patients with PVS have preservation of brain stem and hypothalamic functions and may exhibit arousal or wakefulness.In the United States, the Uniform Determination of Death Act mandates irreversible cessation of all functions of the entire brain and brain stem.

Diagnosis of Brain DeathThe American Academy of Neurology published practice parameters to standardize the criteria for the diagnosis of brain death in adults. The guidelines for children have some unique features, dealing specifi cally with the age group from full-term newborn to 5 years old. These features are mainly focused on the changing periods of recommended observations relative to the patient’s age.In general, confi rmatory tests for the diagnosis of brain death are not required in adults and children over 1 year of age, but are recommended in children <1 year of age or in situations where the neurologic examination cannot be adequately performed.[2-3]

C onfi rmatory Tests of Brain Death1. The assessment of electrical activity by EEG or

somatosensory evoked potentials (SSEP).2. Assessment of cerebral blood fl ow by radionuclide

studies, transcranial Doppler ultrasound or angiography.

It should be emphasized that any or the suggested confi rmatory tests many produce similar results in patients with catastrophic brain damage, who do not as yet fulfi ll the clinical criteria of brain death, the EEG provides confi rmation of brain death. Most institutions prefer this corroboration of the clinical features, by the demonstration of electrocerebral silence when there is no electrical potential of more than 2 V, during atleast a 30-minute recording that adheres to the minimal technical criteria adopted by the American Electroencephalographic Society. Cerebral unresponsiveness and a fl at (isoelectric) EEG do not always signify brain death, and both fi ndings may occur in some reversible conditions - e.g., profound hypothermia or intoxication with sedative or hypnotic drugs, and immediately following cardiac arrest. Although in the United States a fl at EEG test is not required to certify death, it is considered to have confi rmatory value. In the UK it is not considered to be of value because any continuing activity it might reveal in parts of the brain above the brain stem is held to be irrelevant to the diagnosis of death on the Code of Practice criteria. The diagnosis of brain death needs to be rigorous, in order to be certain that the condition is irreversible. Legal



criteria vary, but in general they require neurological examinations by two independent physicians. The exams must show complete and irreversible absence of brain function (brain stem function in UK), and may include two isoelectric (fl at-line) EEGs 24 hours apart (less in other countries where it is accepted that if the cause of the dysfunction is a clear physical trauma there is no need to wait that long to establish irreversibility). The patient should have a normal temperature and be free of drugs that can suppress brain activity if the diagnosis is to be made on EEG criteria.In addition, the brain death signifi cance of isoelectric EEG in children (especially infants) has not been validated, and there have been a number of case reports showing the recovery of brain function and EEG activity following a period of isoelectric EEG.During SSEP measurements, the bilateral absence of N20–P22 response with median nerve stimulation is supportive of the diagnosis. Some centers have utilized radionuclide scan, cerebral angiography or transcrania Doppler ultrasound, although there are technical pitfalls in these methods.A radionuclide cerebral blood fl ow scan that shows complete absence of intracranial blood fl ow must be considered with other exams–temporary swelling of the brain, particularly within the fi rst 72 hours, can lead to a false positive test on a patient that may recover with more time. CT angiography is neither required nor suffi cient test to make the diagnosis.

G uidelines for Determining Brain Death in C hildren

The brain of infants and young children have increased resistance to damage and may recover substantial functions even after exhibiting unresponsiveness on neurological examination for longer periods as compared to adults. When applying neurological criteria to determine death in children younger than one year, longer observation periods are required. The guidelines to determine brain death in children include :

1. Concurrent coma and apnoea2. Absence of brain stem function3. Pupils unreactive to light (mid-position or dilated)4. Absence of spontaneous eye movement, or no

response to oculocephalic and oculovestibular tests5. Absence of movement of bulbar musculature,

including facial and oropharyngeal muscles (corneal, gag cough, sucking and rooting refl exes)

6. Absent respiratory movements with patient off the ventilator.

7. Apnoea test using “standardized methods”8. Absence of hypotension (for age) or hypothermia

9. Flaccid muscle tone, absence of spontaneous movements (excluding spinal refl exes)

10. Examination consistent with brain death throughout the period of testing and observation

11. Observation and testing according to age:• Reliable criteria have not been established of

brain death in children less than 7 days old.• 7 days to 2 months: Two examinations and

EEGs separated by 48 hours• 2 months to 1 year: Two examinations and

EEGs separated by 24 hours• Older than 1 year: With an irreversible

cause, laboratory tests not required and an observation period of atleast 12 hours recommended; atleast 24 hours of observation recommended if it is diffi cult to assess the extent and reversibility of brain damage (e.g., following a hypoxic ischemic event). The observation period may be reduced if EEG demonstrates electrocerebral silence or the cerebral radionuclide and angiographic study does not visualize cerebral arteries.

Guideline for Determining Brain Death in Adults

Brain dea th is the absence of clinical brain function when the proximate cause is known and demonstrably irreversible.

Pre-requi sites1. Clinical or neuroimaging evidence of an acute

CNS catastrophe that is compatible with clinical diagnosis

2. No drug intoxication or poisoning3. Core temperature 32°C

The three cardinal fi ndings in brain death are coma or unresponsiveness, absence of brain stem refl exes and apnoea.[3-4]

(A) Coma o r UnresponsivenessNo cerebral or motor response to pain in all extremities (nailbed pressure and supraorbital pressure)

(B) Absenc e of Brain Stem Refl exesPupils (Cranial nerve II & III):

• Absent Pupillary Refl ex• No response to direct and consensual bright light• Size: Mid-position (4 mm) to dilated (9 mm)

Ocular movement (Cranial nerve III, IV & VI)• Absent oculocephalic refl ex (testing only when no

fracture or instability of the cervical spine or skull base is apparent)



• Absent oculovestibular refl ex so no deviation of the eyes to irrigation in each ear with intact tympanic membrane with 50 ml of cold water (allow 1 minute after injection and atleast 5 minutes between tests on each side)

Facial Sen sation and Facial Motor Response (Cranial Nerve V, VII & IX):

• No facial sensation and facial motor response• Absent corneal refl ex to touch with a throat swab• Absent jaw refl ex• No grimacing to deep pressure on nail bed,

supraorbital ridge or temporo-mandibular jointPhyaryngea l and tracheal refl exes (Cranial Nerve IX & X):

• Absent Gag refl ex so no response to stimulation of the posterior pharynx with tongue blade

• Absent cough refl ex so no cough response to tracheo-bronchial suctioning

(C) Apnoea Test (Absent Respiratory Efforts in Presence of Hypercarbia)Generally the apnoea is performed after the second examination of brain stem refl exes. The apnoea test need only to be performed once when it its results are conclusive.[5] Before performing the apnoea test, the physician must determine that the patient meets the following conditions :

• Core temperature ≥ 36.5°C or 97.7°F• Systolic blood pressure 90 mmHg• Euvolemia (option: positive fl uid balance in

previous 6 hrs)• Normal PCO2 (option: Arterial PCO2 ≥ 40 mmHg)• Normal PO2 (option: Preoxygenation to obtain

arterial PO2 ≥ 200 mmHg)Procedure to per form Apnoea Test:

• Connect a pulse oximeter and disconnect the ventilator.

• Deliver 100% oxygen (O2), 6 l/min, into the trachea (option: Place a cannula at the level of the carina)

• Look closely for respiratory movements (abdominal or chest excursions that produces adequate tidal volume)

• Measure arterial PO2 and PCO2, and pH, after approximately 8 minutes and reconnect the ventilator

• If respiratory movements are absent and arterial PCO2 is ≥ 60 mmHg (option: 20 mmHg increase in PCO2 over a base line normal PCO2), the apnea test is positive i.e. it supports the diagnosis of brain death

• If respiratory movements are observed, the apnea test is negative i.e. it does not supports the diagnosis of brain death and the test should be repeated

• Connect the ventilator if, during testing, the systolic blood pressure becomes 90 mmHg or the pulse oximeter indicates signifi cant oxygen desaturation and cardiac arrhythmias are present; immediately draw an arterial blood sample and analyze arterial blood gas.

• If PCO2 is 60 mmHg or PCO2 increase is 20 mmHg over baseline normal PCO2, the apnea test is positive.

• If PCO2 is <60 mmHg or PCO2 increase is <20 mmHg over baseline normal PCO2, the test result is indeterminate, and an additional confi rmatory test can be considered.[6-8]

Certifi cation of Brain DeathThe diagnosis of brain death is primarily clinical. No other tests arc required if the full clinical examination, including each of two assessments of brain stem refl exes and a single apnoea test, are conclusively performed.Brain death can be certifi ed by a single physician privileged to make brain death determinations. However, before a patient can become an organ donor, in USA the New York State law requires that the time of brain death must be certifi ed by the physician who attends the donor at his death and one other physician, neither of whom shall participate in the process of transplantation. This requirement ensures that all evaluations meet accepted medical standards, and that all participants can have confi dence that brain death determination has not been infl uenced by extraneous factors, including the needs of potential organ recipients.When two physicians are required to certify the time of death, i.e., when organ donation is planned, both physicians should affi rm that the clinical evaluation meets accepted medical standards, and that the data fully support the determination of brain death. Generally, both physicians should observe the patient, review the medical record, and note whether any additional information is required to make a defi nitive determination. Neither physician should certify brain death unless all aspects of the determination have been completed.

Clinical Observations Compatible with the Diagnosis of Brain Death

The following manifestations are occasionally seen and should not be misinterpreted as evidence for brainstem function:

1. Spontaneous movements of limbs other than pathologic fl exion or extension response (It is very important for family members and health care professionals to be aware of natural movements also known as Lazarus sign or Lazarus refl ex that can



occur on a brain-dead person whose organs have been kept functioning by life support. The living cells that can cause these movements are not living cells from the brain or brain stem, these cells come from the spinal cord. Sometimes these body movements can cause false hope for the family members.)

2. respiratory-like movements (shoulder elevation and adduction, back arching, intercostal expansion without signifi cant tidal volumes)

3. sweating, fl ushing, tachycardia4. normal blood pressure without pharmacologic

support or sudden increases in blood pressure5. absence of diabetes insipidus6. deep tendon refl exes; superfi cial abdominal

refl exes; triple fl exion response7. Babinski refl ex

Responsibility of Physician Determining Brain Death & Medical Record

DocumentationAll phases of the determination of brain death should be clearly documented in the medical record; The medical record must indicate:

• Etiology and irreversibility of coma/ unresponsiveness

• Absence of motor response to pain• Absence of brainstem refl exes during two separate

examinations separated by at least 6 hours• Absence of respiration with pCO2 > 60 mm hg• Justifi cation for, and result of confi rmatory tests if

used.

Withdrawl of Cardiorespiratory Support & the Dead-donar Rule of Organ Donation

When a patient is certifi ed as brain dead and the ventilator is to be disconnected, the family should be treated with sensitivity and respect. If family members wish, they may be offered the opportunity to attend while the ventilator is disconnected. However, family members should be prepared for the possibly disturbing clinical activity that they may witness when organ donation is contemplated, ventilatory support will conclude in the operating room and family attendance is not appropriate.The major diffi culties that arise in relation to brain death are those involving the sensitive relationship with the patient’s family and other medical professionals. The task of dealing with these matters often falls to the neurologist. In addition to imparting bad news to the family, the major impetus for medical, community and legal acceptance of brain death is the need for organ donation from “beating-heart” donors.The “dead-donor rule” requires patients to be declared dead before the removal of life-sustaining organs for

transplantation. Therefore, brain death is essential to current practices of organs retrieval, because it legitimizes organ removal from bodies that continue to have circulation and respiration, thereby avoiding ischemic injuries to the organs. The physicians involved in the patient’s care should be in close communication with the family during the process of determining brain death. The interpretation of clinical examination as well as fi ndings should be clearly explained. The issue of organs transplantation should be raised after adequate time has passed for them to absorb the shock of the circumstances (and the physicians should be aware of whether family members perceive “brain death” as tantamount to death). It is important to clarify that the diagnosis of brain death is not required in patients with overwhelming brain injuries, for medical supports to be withdrawn.

ConclusionBrain death is the complete and irreversible loss of cerebral and brain stem function. In most countries and in most situations, brain death is considered to be equivalent to cardiopulmonary death. The diagnosis of brain death is usually made by neurological examination, provided certain prerequisites are met; the underlying cause is understood; the etiology is capable of producing neuronal death and confounding from drug intoxication or poisoning, metabolic derangements, and hypothermia have been ruled out. The neurological examination must demonstrate coma, no brain-generated response to external stimuli and absent brain stem refl exes. The potential for organ donation offers comfort to the bereaved and should be offered to the families, but it should not be the impetus for the diagnosis of brain death.

References1. "Guidelines for the Determination of Death: Report of

the Medical Consultants on the Diagnosis of Death to the President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioural Research", JAMA, 1981, Vol. 246, pp. 2184–6.

2. Guidelines for the Determination of Brain Death in Children", Padiatrics, 1987, Vol. 80, pp. 298–300.

3. "Practice Parameters for Determining Brain Death in Adults", Neurology, 1995, Vol. 45, pp. 1012–1014.

4. Wijdicks, E.F. (1995), "Determining Brain Death in Adults", Neurology, Vol. 45, pp. 1003–1011.

5. Willatts, S.M. and Drummond, G. (2000), "Brain Death and Ventilator Trigger Settings", Anesthesia, Vol. 55, pp. 676–7.

6. Ruiz-Garcia, M., Gonzalez-Astiazaran, A., Collado-Corona, M.A. et al. (2000), "Brain Death in Children: Clinical Neurophysiology and Radioisotopic Angiographic Findings in 125 Patients", Child Syst., Vol. 16, pp. 40–45.

7. Banasiak, K.J. and Lister, G. (2003), "Brain Death Children", Cuur. Opin. Pediatr., Vol. 15, pp. 288–293.

8. Sapsosnik, G., Rizzo, G., Vega, A., Sabbatiello, R. and Deluca, J.L. (2004), "Problems Associated with the Apnea Test in the Diagnosis of Brain Death", Neuro India, Vol. 52, pp. 352–5.



What is it that is not a poison? All things are poison and nothing is without poison. Solely, the dose determines

that a thing is not a poison.—Paracelsus (1493–1541), the Renaissance Father of Toxicology, in his Third Defence

Poisoning is caused by exposure to a harmful substance. This can be due to swallowing, injecting, breathing in, or other means. Most poisonings occur by accident.

First AidImmediate fi rst aid is very important in a poisoning emergency. The fi rst aid you give before getting medical help can save a person’s life.It is important to note that just because a package does not have a warning label does not mean a substance is safe. You should consider poisoning if someone suddenly becomes sick for no apparent reason. Poisoning should also be considered if the person is found near a furnace, car, fi re, or in an area that is not well ventilated.A brief physical assessment should be performed immediately in all patients to determine the effects of toxin(s) and other conditions that might be present. Particular attention should be directed to adequacy of the airway and ventilation, level of mental status and cardiac function. Unstable patients should be placed on a cardiac monitor, with measurement of vital signs every fi ve to 15 minutes until the patient is stabilized to the point that monitoring is no longer necessary.Toxic overdose can present with various clinical symptoms, including abdominal pain, vomiting, tremor, altered mental status, seizures, cardiac dysrhythmias, and respiratory depression. These may be the only clues to diagnosis when the cause of toxicity is unknown at the time of initial assessment and management. The diagnosis may be complicated by the possibility of a multiple-drug ingestion.Stabilization of the patient is the fi rst priority in managing toxic ingestions and is performed simultaneously with the initial physical assessment. Treatment should address the “ABCs” (airway, breathing, circulation) without delay. Also, the potential for rapid changes in the patient’s

condition should be considered in making decisions about airway and ventilatory support.

ToxicokineticsThe prognosis and clinical course of recovery of a patient poisoned by a specifi c agent depends largely on the quality of care delivered within the fi rst few hours in the emergency setting. Fortunately, in most instances, the drug or toxin can be quickly identifi ed by a careful history, a directed physical examination, and commonly available laboratory tests. Attempts to identify the poison should never delay life-saving supportive care, however.Once the patient has been stabilised, the physician needs to consider how to minimise the bioavailability of toxin not yet absorbed, which antidotes (if any) to administer, and if other measures to enhance elimination are necessary.The initial evaluation and management of poisoned patients should be comprehensive and include an accurate history whenever possible, stabilization of the patient’s condition, a physical assessment to evaluate the extent of poisoning and the presence of concurrent conditions, decontamination of the gastrointestinal tract using activated charcoal, gastric lavage, administration of ipecac or irrigation, poison-specifi c treatment with administration of antidotes when indicated and proper disposition. Consultation with a poison control center is often helpful in assessing and treating these patients.Apart from basic stabilization measures (such as oxygen administration, cardiac monitoring, and venous access establishment), emergency medical system (EMS) personnel need to do little in the fi eld with the overdosed patient, especially when the transport time to the nearest hospital is short. EMS personnel should avoid giving ipecac because of the possibility of delaying defi nitive therapy and the potential for aspiration in the comatose or combative patient. Some clinical trials have studied the effi cacy of prehospital charcoal administration documenting some clinical effi cacy.There is still a lack of defi nitive evidence to advocate the administration of charcoal in the prehospital setting, however. In the patient who has a depressed mental status EMS personnel should check a rapid serum glucose and administer intravenous dextrose when necessary. Small doses of naloxone may be required if opioids are highly suspected and the patient is hypoxic or suffering airway compromise. Benzodiazepines can be given for toxin-induced seizures. Prehospital intravenous sodium bicarbonate administration for known overdoses of cardiac sodium channel blocking

1Consultant Physician,Diabetologist & Cardiologist,Raghvendra Hospital & Heart Centre, Jhansi.2Professor & Head of Medicine,Principal, M.L.B. Medical College, Jhansi3DNB Final Year Resident,Care Hospital Banjara Hills, Hyderabad4Junior Resident Medicine, M.L.B Medical College, Jhansi5MBBS (STD), Dr. D.Y. Patil Medical College, Pimpri, Pune

How to Approach a Patient who has Consumed Unknown Poison

Dr. R.R. Singh1, Dr. N.S. Sengar2, Dr. Ankit Singh3, Dr. Wasim Farooqi4 and Namrata Singh5

Review Article



agents (ie, cyclic antidepressants, propoxyphene, and cocaine) demonstrating a widened QRS complex on the cardiac monitor may also be considered.

HistoryHistorical facts should include the type of toxin or toxins, time of exposure (acute versus chronic), amount taken, and route of administration (ie, ingestion, intravenous, inhalation). It is also important to understand why the exposure occurred (accidental, suicide attempt, euphoria, therapeutic misadventure) and whether there is history of psychiatric illness or previous suicide attempts. Furthermore, it is important to inquire about all drugs taken, including prescription, over-the-counter medications, vitamins, and herbal preparations. Patients may incorrectly name the drugs they have ingested; for example, they may refer to ibuprofen as acetaminophen or vice versa. Poisoned patients can be unreliable historians, particularly if suicidal, psychotic, presenting with altered mental status, or under the infl uence of recreational drugs. If unavailable from the patient, information solicited from family and friends may also prove helpful. Although issues of confi dentiality may arise, it is advisable to err on the side of acting in the patient’s best interest. Paramedics or emergency medical technicians are also good sources of information because they may be able to furnish details, such as the presence of empty pill bottles or drug paraphernalia that were at the scene.

Physical ExaminationIn the emergency setting, performing an overly detailed physical examination is a low priority compared with patient stabilization. Even a directed examination can yield important diagnostic clues, however. Once the patient is stable, a more comprehensive physical examination can reveal additional signs suggesting a specifi c poison. Additionally, a dynamic change in clinical appearance over time may be a more important clue than fi ndings on a single examination. There are classic presentations that occur with specifi c drug classes. Even these classic presentations may not always be seen, however, and their appearance depends on the dose that the patient has ingested, the patient’s premorbid condition, other substances that may have been taken, and complications that may occur in the course of the poisoning (ie, aspiration pneumonia, rhabdomyolysis, and anoxic brain injury). Emergency physicians should be aware of the classic drug syndromes that may occur, but also realize the limitations depending on other confounding factors.

SkinA careful examination of the skin should be performed. The patient’s clothing should be removed and the skin

assessed for color, temperature, and the presence of dryness or diaphoresis. The absence of diaphoresis is an important clinical distinction between anticholinergic and sympathomimetic poisoning. The presence of bites or similar marks may suggest spider or snake envenomations. The presence of a rash or bullae may also help provide a diagnosis. Although uncommon, bullous lesions are typically located on dependent portions of the body, such as between the fi ngers, knees, axilla, and back, as a result of prolonged immobility. They may be associated with any sedative hypnotic drug-induced coma, but are classically described with barbiturate poisoning. Such lesions could also be indications of rhabdomyolysis or the development of compartment syndrome. A common skin fi nding is the presence of track marks, suggesting intravenous or subcutaneous opiate or cocaine abuse. Blue skin indicates methemoglobinemia or hypoxia; red skin may suggest niacin or boric acid exposure. The skin examination should also include a search for pharmaceutic patches, such as opioids like fentanyl. In cases of drug abuse, these patches may be present in unusual locations, such as the vagina and scrotum.

Neurological Examination Neurological examination is of utmost importance in patients with altered sensorium or coma due to metabolic toxicity. An intracranial insult can be suspected if the patient has loss of mid brain puppilary functions, decerebrate, or decorticate posture. The Glasgow Coma Scale (GCS) commonly used in head trauma patients has limited role in predicting the prognosis of poisoned patient (6, 7). Some other studies have used Alert/Verbal/Painful/Unresponsive Scale (AVPU) to assess consciousness in poisoning patients (8). Both the scales are commonly used in emergency department but, neither of them is suitable to predict outcome.Seizures, a common presentation in emergency can be caused by various drugs and toxins.

Agents that Cause Seizures • Organophosphates, oral hypoglycemics

• Tricyclic antidepressants

• Isoniazid, insulin

• Sympathomimetics, strychnine, salicylates

• Camphor, cocaine, carbon monoxide, cyanide, chlorinated hydrocarbons

• Amphetamines, anticholinergics

• Methylxanthines (theophylline, caffeine), methanol

• Phencyclidine (PCP), propranolol



• Benzodiazepine withdrawal, botanicals (water hemlock, nicotine), bupropion, GHB

• Ethanol withdrawal, ethylene glycol

• Lithium, lidocaine

• Lead, lindane

Pupillary signs, namely miosis and mydriasis are important indicators to ascertain the class of toxin and direct patient management.

Agents that Affect Pupil Size

Miosis

• Clonidine, carbamates

• Opiates, organophosphates

• Phenothiazines (antipsychotics), pilocarpine, pontine hemorrhage

• Sedative-hypnotics

Mydriasis

• Sympathomimetics

• Anti-cholinergics

• Other neurological signs which may be used to guide the diagnosis are:

• Nystagmus: phenytion, PCP, carbamazapine, ethanol, lithium, and sedative-hypnotics.

• Ophthalmoplegia: thiamine defi ciency in chronic alcoholics .

• Optic Neuritis: methanol poisoning, denatured spirit.

Vision Loss

• Fasciculations: organophosphorus compound poisoning.

• Rigidity: strychnine poisoning.

• Tremors: methyl-xanthine and phenytoin.

• Dystonic Posturing: neuroleptic agents.

SkinA keen skin examination is of paramount importance in suspected poisoning. Color, temperature, diaphoresis, or dryness, rash or bullous lesions should be looked for as they may provide important clues. Presence of bite marks might suggest spider/snake envenomation. Finding track

marks or pharmaceutical patches in poisoning patients may suggest drug abuse.

Agents that Cause Skin Signs

Diaphoretic Skin• Sympathomimetics• Organophosphates• Acetylsalicylic acid or other salicylates• Phencyclidine

Dry Skin• Antihistamines, anticholinergics, atropine, dhatura

Bullae• Barbiturates and other sedative-hypnotics,• Snakes and spiders bites

Acneiform Rash• Bromides• Chlorinated aromatic hydrocarbons (dioxin)

Flushed or Red Appearance• Anticholinergics, niacin• Boric acid• Carbon monoxide (rare)• Cyanide (rare)

Cyanosis• Ergotamine• Nitrates• Nitrites• Aniline dyes• Phenazopyridine• Dapsone• Any agent causing hypoxemia, hypotension, or

methemoglobinemia.

OdorsCertain poisons produce odors which are highly characteristic; such as garlic like smell (organo-phosphate poisoning, insecticides, arsenic). Bitter almond smell of cyanide is so subtle that it may not be noticed by 30% of the population (9), while others such as rotten egg smell of sulphur dioxide and hydrogen sulphide are easily noticed.



Table 1: Odors that Suggest the Diagnosis

Odor Possible Source

BitterCarrots FruityGarlic

Gasoline Mothballs Pears Pungent aromatic Oil of wintergreenRotten eggs Freshly mowed hay

Almonds CyanideCicutoxin (water hemlock)Diabetic ketoacidosis, isopropanolOrganophosphorus compds, arsenic, dimethyl sulfoxide (DMSO), seleniumPetroleum distillates, keroseneNaphthalene, camphorChloral hydrateEthchlorvynolMethylsalicylateSulfur dioxide, hydrogen sulfi dePhosgene, aluminium phosphide compds.

Laboratory Tests A regional poison centre should be consulted with to narrow down the range of tests to be ordered in order to save time and resources.

Routine Tests

These tests provide important information which may guide the diagnosis; e.g. serum electrolytes, random blood sugar, arterial blood gas analysis etc.

Anion gap should be considered as increased anion gap with metabolic acidosis may be present in numerous poisons.

Conditions/Agents Causing an Elevated Anion Gap

• Diabetic ketoacidosis

• Methanol, metformin

• Alcoholic ketoacidosis

• Ethylene glycol

• Acetaminophen (large overdoses)

• Lactic acidosis

• Cyanide, carbon monoxide, colchicine

• Isoniazid, iron, ibuprofen

• Generalized seizure-producing toxins

• Acetylsalicylic acid or other salicylates

• Paraldehyde, phenformin

If no reason of metabolic acidosis is found, serum osmolality is measured and osmolal gap is calculated. The osmolal gap the difference between measured serum osmolality and calculated serum osmolality. Normal Osmolal gap is approximately in the range of -15 to +10 (10).

Agents Increasing the Osmolar Gap• Methanol• Ethylene glycol• Diuretics (mannitol), Diabetic ketoacidosis

(acetone)• Isopropyl alcohol• Ethanol

Toxicology ScreensIt is used to measure the presence and level of a toxic agent or its metabolites in blood or urine samples; although it is of limited value in clinical scenarios as it has various practical limitations. Qualitative screening should be used only if it can guide patient management whereas quantitative tests are important for agents in which blood levels are necessary to predict toxicity and guide specifi c therapy e.g. acetaminophen, theophylline, lithium, alcohol, digoxin etc.

Urine TestingDetailed urine analysis is important both for diagnostic purpose and monitoring treatment in specifi c circumstances, such as the presence of calcium oxalate crystals may be diagnostic of ethylene glycol poisoning. Moreover, monitoring urine pH is important in bicarbonate therapy for salicylate poisoning. Urine color may also hint towards a diagnosis:

• Orange to Orange Red: rifampicin, mercury, chronic lead poisoning

• Pink: Ampicillin, cephalosporins• Brown: Chloroquine, carbon terrachloride• Greenish Blue: Methylene blue, copper sulphate

ABCsMost poisoned patients are awake and have stable vital signs. Some patients may present with an altered state of consciousness, hemodynamic instability, or active convulsions. The fi rst priority is to stabilize the ABCs and manage life-threatening complications. When intubation is necessary, rapid sequence induction is indicated with a preference toward using short-acting paralytic agents. The emphasis should be placed on short-acting paralytics for fear of masking toxin-induced seizures. For cases in which hyperkalemia or poisoning with cholinesterase inhibitors is suspected, nondepolarizing agents are preferred. A patient’s oxygenation status can be monitored with a bedside pulse oximeter. Certain toxins, however, may demonstrate a normal pulse oximetry reading despite severe poisoning. This observation is particularly true in carbon monoxide poisoning, in which the pulse oximeter is unreliable in detecting carboxyhemoglobin. The pulse oximeter only provides information regarding oxygen saturation and does not assess acid–base status. It should



not be used as a substitute for obtaining an arterial blood gas or serum bicarbonate level when such information is clinically warranted.Intravenous access should be considered in all potentially poisoned patients. This practice should be maintained even when the patient seems stable and asymptomatic. Many toxins produce delayed effects, such as hypotension or seizures, that could make obtaining intravenous access diffi cult.The poisoned patient should be kept under close observation with frequent evaluations of the level of consciousness, oxygenation status, and vital signs.This observation is important, particularly with the patient who presents in a stable condition, because continued absorption of an ingested substance may lead to delayed clinical evidence of poisoning. An electrocardiogram and continuous cardiac monitoring are indicated for any agent with potential cardiac toxicity. Examples include sympathomimetic agents, cyclic antidepressants, cardiac glycosides, beta-blockers, calcium channel antagonists, antihypertensive agents, arsenic, cyanide, carbon monoxide, antidysrhythmics, citalopram, diphenhydramine, venlafaxine, chloral hydrate, methylxanthines, propoxyphene, phenothiazines, and quinine. An electrocardiogram should also be routinely obtained in patients who have polysubstance ingestions and in cases of unknown suicidal ingestions. Unlike patients who have chronic cardiopulmonary diseases whose condition worsens progressively, the poisoned patient may unexpectedly become unstable.The patient who has an unknown poisoning may present convulsing or with a history of seizure activity. Toxin-induced seizures tend to be global central nervous system (CNS) processes as opposed to focal processes like those seen in patients who have epilepsy or CNS structural lesions.Benzodiazepines, barbiturates, and valproic acid, therefore, are considered the fi rst-and second-line therapies for toxin-induced seizures. Phenytoin is generally not effective in treating toxin-induced seizures or seizures from alcohol or sedative-hypnotic withdrawal.

Laboratory EvaluationLaboratory evaluation is indicated in most symptomatic patients, when ingested substances are unknown, if the poison has the potential to produce moderate to severe toxicity and if the ingestion was intentional. Routine studies should include a complete blood cell count, determination of serum electrolyte and glucose levels, a chemical screen with hepatic and renal function studies (e.g., calcium, aspartate aminotransferase, alanine aminotransferase, bilirubin, alkaline phosphatase, lactate dehydrogenase, prothrombin time, blood urea nitrogen, creatinine) and urinalysis. Measurement of serum osmolarity may be helpful if poisoning with methanol, ethylene glycol or isopropanol is suspected.

Ancillary TestsAn electrocardiogram should be performed in patients with arrhythmias and/or suspected ingestion of cardiotoxic drugs. Chest radiographs should be obtained in patients with suspected aspiration, coma or ingestion of medications (salicylates, narcotics, paraquat, sedative-hypnotics) that can produce non-cardiogenic pulmonary edema. Abdominal radiographs may detect abnormal densities in patients who have ingested drug packets, salicylates, calcium salts, heavy metals (e.g., iron tablets) or radiopaque foreign bodies. Ingested hydrocarbons may be visualized as a “layer” between gastric fl uid and the gastric air bubble.Ancillary tests such as electrocardiograms, chest radiographs and plain abdominal fi lms need not be routinely ordered but, when appropriate, can provide the clinician with additional useful information.

Radiologic StudiesAbdominal FilmsA plain abdominal radiograph (KUB) can reveal radiopaque pills, drug- fi lled packets, or other toxic material. Drugs or toxins that are likely to be visible on fi lms can be recalled by the mnemonic COINS. In some cases, the vehicle in which the drug is contained, such as an enteric coating or latex, is more radiopaque than the drug itself. For this reason, a KUB may be useful in cases of body packers (drug smugglers). On the other hand, body stuffers who quickly swallow the evidence to evade the authorities typically have abdominal fi lms that are negative for foreign body detection. For many slightly radiodense drugs, such as neuroleptics and salicylates, visibility depends on the time of ingestion. A patient presenting several hours after the ingestion rarely has a positive radiograph. In practice, the KUB is probably most useful to determine the presence of a heavy metal foreign body in the gastrointestinal tract and to monitor the progress of gastrointestinaldecontamination (such as whole bowel irrigation).

Chest FilmsPatients who have tachypnea, hypoxia, obtundation, or coma should have a chest radiograph performed to search for potential causes of hypoxemia: chemical or aspiration pneumonitis, cardiogenic or noncardiogenic pulmonary edema (acute lung injury), and atelectasis. Drugs that can cause noncardiogenic pulmonary edema can be remembered by the mnemonic MOPS. Chest fi lms are also useful for detecting occasional pneumothorax or pneumomediastinum seen in patients abusing cocaine or other sympathomimetic agents.

DecontaminationFollowing evaluation and stabilization of the poisoned patient, attention is directed toward decontamination, i.e., decreasing absorption of the ingested poison from



the gastrointestinal tract. This can be accomplished by emptying the stomach via gastric lavage, administration of activated charcoal within the gut lumen and use of methods for increasing transit of the toxic substances through the gastrointestinal tract.Gastric emptying should not routinely be used in all oral poisoning cases because it is ineffective when used at a late stage, may delay more effective interventions and can cause needless complications, such as aspiration. However, it is often benefi cial when used early in the treatment of potentially severe poisonings. Gastric emptying is most effective when used within one hour of the ingestion and cannot be justifi ed beyond four hours following the ingestion except in patients with concretions, massive ingestions or ingestions of substances that markedly decrease gastric motility. The stomach may be emptied by gastric lavage or by inducing emesis with syrup of ipecac.

Gastric LavageIn most situations, gastric lavage is preferable to administration of ipecac, particularly in emergency departments where prolonged ipecac-induced vomiting may delay treatment with activated charcoal. Indications for lavage include ingestions of highly toxic substances (large ingestions or substances associated with high morbidity and/or mortality); substances not well adsorbed by activated charcoal (i.e., lithium, iron, lead, methanol) and in patients with the potential for a jeopardized airway (e.g., altered alertness).Contraindications to gastric lavage include ingestion of corrosives and most hydrocarbons (gastric emptying is indicated after ingestions of hydrocarbon products containing benzene, toluene, camphor, halogenated hydrocarbons, pesticides or heavy metals, or if the ingestion was greater than 4 to 5 mL per kg); patients with depressed gag refl exes who are not intubated and clinically insignifi cant ingestions. Complications include aspiration, and perforation of the esophagus or bronchus. A 28- to 36-in French tube is suitable for use in children; a 36- to 40-in French tube is suitable for use in adults.8,12Gastric lavage is accomplished in children using normal saline or tap water in 15 mL per kg aliquots until clear.3 Lavage in adults uses 300 mL aliquots until clear, up to 10 to 20 L, if necessary. Administration of activated charcoal through the lavage tube before and after lavage may be benefi cial in patients with potentially fatal ingestions.

IPECACIpecac continues to be useful in the telephone management of alert patients unable to travel to a health care facility within one hour of the ingestion. It has been shown that ipecac used at home by experienced hospital staff treating pediatric poisonings following ingestions identifi ed as not being “high-risk” decreases pediatric emergency department visits without jeopardizing safety.14

Syrup of ipecac is administered in the following dosages: in infants six months to one year of age, 10 mL; in children one to 12 years of age, 15 mL; in adolescents over 12 years of age, 30 mL. Water is given immediately after the ipecac to enhance the effi cacy of gastric emptying with emesis; adults should receive 8 to 16 oz; children should receive 4 to 8 oz; children less than one year of age should receive 5 to 15 mL per kg body weight.Ipecac should not be given to children who are less than six months of age, patients who are already vomiting, patients with altered mental status or impaired gag refl exes, and patients who have ingested medications that cause seizures or decreased responsiveness. Use of ipecac should be avoided following ingestion of corrosives (acids or alkalis), sharp objects, most hydrocarbons (similar to gastric lavage) or when treatment with activated charcoal is anticipated within 60 to 90 minutes.

Activated CharcoalActivated charcoal forms the mainstay of gastric decontamination and is effective for most oral poisonings when given alone or following gastric emptying. Exceptions include ingestions of caustic acids and alkalis, alcohols, lithium and heavy metals (e.g., iron, arsenic). Activated charcoal is inert and remains within the gastrointestinal tract, offering a large surface area for adsorption of ingested toxins. In addition, activated charcoal may decrease the absorption of drugs that undergo enterogastric or enterohepatic circulation.The usual dosage is 1 to 2 g per kg for children and adults, usually given as a single dose combined with a cathartic. The charcoal is mixed with water in a ratio of 1:4 to 1:8 (1 part charcoal to 4 or 8 parts water) to form a slurry; small quantities of fruit juice or chocolate powder can improve the taste. Multiple dosing (1 g per kg every two to six hours) has been shown to be effective for poisonings with phenobarbital, phenytoin (Dilantin), carbamazepine (Tegretol), salicylates, digitalis, theophylline and dapsone.12,15–17 When multiple dosing is used, a cathartic can be given with the fi rst dose but should not be administered with subsequent doses because of the potential for serious fl uid and electrolyte abnormalites. Contraindications to activated charcoal use include mechanical bowel obstruction and ileus.

Whole Bowel IrrigationWhole bowel irrigation uses isosmotic cathartic solutions to fl ush and cleanse the bowel. It is potentially benefi cial in patients who have ingested substances that are not well-absorbed by activated charcoal and/or are not amenable to lavage. Examples of such substances include iron, lithium and slow-release potassium, and packets or vials containing cocaine and other drugs. Commonly used irrigants (Golytely, Colyte) contain a polyethylene glycol electrolyte solution that is not absorbed from the



gastrointestinal tract and does not cause signifi cant fl uid or electrolyte imbalances. The solution is administered orally or through a nasogastric tube at the rate of 2 L per hour in adults and 0.5 L per hour (or 25 to 40 mL per kg per hour) in children until the rectal effl uent is clear.8,12,13 Patients tolerate the procedure best when alert and sitting on a commode; supine patients are best managed by placing a rectal tube. Contraindications to whole bowel irrigation include mechanical obstruction, ileus, perforation and gastrointestinal bleeding.

AntidotesAntidotes are typically given once the patient has been stabilized, usually within a few hours of the ingestion. Unless clinicians are familiar with the use of an antidote, it is probably wise to contact a certifi ed poison control center regarding the specifi cs of its use. In addition, many antidotes have a short duration of action relative to the effects of the ingested poison, and observation in a specialized hospital unit following administration of the antidote is advisable.

DispositionPeople who have a potentially serious overdose should be observed for several hours before discharge. If signs or symptoms of intoxication develop during that time, the patient should be admitted for further observation and treatment. Some agents may require a more prolonged observation period. Such agents include sustained-release products and agents with known delayed or prolonged onset of action: calcium channel antagonists, theophylline, lithium, methadone, Lomotil, monoamine oxidase inhibitors, and oral hypoglycemic agents. Overdose with these substances may require up to 24 hours of continuous observation [106]. Although some patients admittedrequire observation in an intensive care unit, others can be appropriately managed on the general medical fl oor or in an observation unit. Consultation with a medical toxicologist or regional poison control center can help to determine the appropriate disposition. Because many poisoned patients require less than 24 hours of observation, unnecessary hospitalization may be avoided by the use of observationunits. Such units have already been developed for asthma and chest pain patients. This model may also work well for poisoned patients. All patients presenting with an intentional poisoning should have a psychiatric evaluation and will likely require psychiatric admission. Substance abusers should be considered for drug abuse counseling.

SummaryThe management of the poisoned patient who has an unknown exposure can be diagnostically and

therapeutically challenging. The history and physical examination, along with a small dose of detective work, can often provide the clues to the appropriate diagnosis. The two-pronged approach as outlined in Fig. 1 provides a framework for evaluating poisoned patients.Consultation with a regional poison center or clinical toxicologist early in the care of poisoned patient can have a profound impact on the management and disposition of such patients.

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9. Gonzalez, E.R. (1982), “Cyanide Evades Some Noses, Overpowers Others”, JAMA, Vol. 248, p. 2211.

10. Hoffman, R.S., Smilkstein, M.J. and Howland, M.A. et al. (1993), “Osmol Gaps Revisited: Normal Values and Limitations”, J. Toxicol. Clin. Toxicol., Vol. 31, pp. 81–93.

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12. Wills, B. and Erickson, T. (2005), “Drug-and Toxin-associated Seizures”, Med. Clin. North Am., Vol. 89, pp. 1297–321.

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14. Goldfrank, L., Weisman, R.S. and Errick, J.K. et al. (1986), “A Dosing Nomogram for Continuous Infusion Intravenous Naloxone”, Ann Emerg Med., Vol. 15, pp. 566–70.

15. Stahl, S.M. and Kasser, I.S. (1983), “Pentazocine Overdose”, Ann. Emerg. Med., Vol. 12, pp. 28–31.

16. Wang, D.S., Sternbach, G. and Varon, J. (1998), “Nalmefene: A Long-acting Opioid Antagonist, Clinical Applications in Emergency Medicine”, J. Emerg. Med., Vol. 16, pp. 471–5.

17. Hoffman, R.S. and Goldfrank, L.R. (1995), “The Poisoned Patient with Altered Consciousness. Controversies in the Use of a “coma cocktail”, JAMA, Vol. 274, pp. 562–9.

18. Johri, S., Shetty, S. and Soni, A. et al. (2000), “Anaphylaxis from Intravenous Thiaminedlong Forgotten?”, Am J. Emerg Med., Vol. 18, pp. 642–3.

19. Votey, S.R., Bosse, G.M. and Bayer, M.J. et al. (1991), “Flumazenil: A New Benzodiazepine Antagonist”, Ann Emerg Med., Vol. 20, pp. 181–8.

20. Lheureux, P., Vranckx, M. and Leduc, D. et al. (1992), “Flumazenil in Mixed Benzodiazepine/ Tricyclic Antidepressant Overdose: A Placebo-controlled Study in the Dog”, Am J. Emerg Med., Vol. 10, pp. 184–8.

21. Spivey, W.H., Roberts, J.R. and Derlet, R.W. (1993), “A Clinical Trial of Escalating Doses of Flumazenil for Reversal of Suspected Benzodiazepine Overdose in the Emergency Department”, Ann Emerg Med., Vol. 22, pp. 1813–21.

22. Gueye, P.N., Hoffman, J.R. and Taboulet, P. et al. (1996), “Empiric Use of Flumazenil in Comatose Patients: Limited Applicability of Criteria to Defi ne Low Risk”, Ann Emerg Med., Vol. 27, pp. 730–5.

23. Barnett, R., Grace, M. and Boothe, P. et al. (1999), “Flumazenil in Drug Overdose: Randomized, Placebocontrolled Study to Assess Cost Effectiveness”, Crit Care Med., Vol. 27, pp. 78–81.

24. Kirk, M.A. (2001), “Managing Patients with Hazardous Chemical Contamination”, In: Ford, M., Delaney, K., Ling, L. et al., editors. Clinical Toxicology, Philadelphia: Saunders, p. 115–26.

25. American Academy of Clinical Toxicology (1995), “Clinical Policy for the Initial Approach to Patients Presenting with Acute Toxic Ingestion or Dermal or Inhalation Exposure”, American College of Emergency Physicians. Ann Emerg Med., 25, pp. 570–85.

26. Kulig, K. (1992), “Initial Management of Ingestions of Toxic Substances”, N. Engl. J. Med., Vol. 326, pp. 1677–81.

27. Erickson, T.B., Goldfrank, L.R. and Kulig, K. (1997), “How to Treat the Poisoned Patient”, Patient Care, Vol. 90, pp. 90–113.

28. Nejman, G., Hoekstra, J. and Kelley, M. (1990), “Journal Club: Gastric Emptying in the Poisoned Patient”, Am J. Emerg. Med., Vol. 8, pp. 265–9.

29. “Position Paper: Ipecac Syrup”, J. Toxicol. Clin. Toxicol., 2004, Vol. 42, pp. 133–43.

30. Vale, J.A. and Kulig, K. (2004), “Position Paper: Gastric Lavage”, J. Toxicol. Clin. Toxicol., Vol. 42, pp. 933–43.

31. Glaser, D.S. (1996), “Utility of the Serum Osmol Gap in the Diagnosis of Methanol or Ethylene Glycol Ingestion”, Ann Emerg Med., Vol. 27, pp. 343–6.

32. Moll, J., Kerns, W.N. and Tomaszewski, C. et al. (1999), “Incidence of Aspiration Pneumonia in Intubated Patients Receiving Activated Charcoal”, J. Emerg. Med., Vol. 17, pp. 279–83.

33. Gomez, H.F., Brent, J.A. and Munoz, D.C.T. et al., (1994), “Charcoal Stercolith with Intestinal Perforation in a Patient Treated for Amitriptyline Ingestion”, J. Emerg. Med., Vol. 12, pp. 57–60.

34. American Academy of Clinical Toxicology (2004), “Position Paper: Cathartics”, J. Toxicol. Clin. Toxicol., Vol. 42, pp. 243–53.

35. Nejman, G., Hoekstra, J. and Kelley, M. (1990), “Journal Club: Gastric Emptying in the Poisoned Patient”, Am J. Emerg. Med., Vol. 8, pp. 265–9.

36. American Academy of Clinical Toxicology (2004), “Position Paper: Whole Bowel Irrigation”, J. Toxicol. Clin. Toxicol., Vol. 42, pp. 843–54.

37. Woolf, A.D. and Chrisanthus, K. (1997), “On-site Availability of Selected Antidotes: Results of a Survey of Massachusetts Hospitals”, Am. J. Emerg. Med., Vol. 15, pp. 62–6.

38. Patel, R. and Connor, G. (1985), “A Review of Thirty Cases of Rhabdomyolysis-associated Acute Renal Failure Among Phencyclidine Users”, J. Toxicol. Clin. Toxicol., Vol. 23, pp. 547–56.

39. Brent, J., McMartin, K. and Phillips, S. et al. (2001), “Fomepizole for the Treatment of Methanol Poisoning”, N. Engl. J. Med., Vol. 344, pp. 424–9.

40. Brent, J., McMartin, K. and Phillips, S. et al. (1999), “Fomepizole for the Treatment of Ethylene Glycol Poisoning, Methylpyrazole for Toxic Alcohols Study Group”, N. Engl. J. Med., Vol. 340, pp. 832–8.

41. Megarbane, B., Borron, S.W. and Baud, F.J. (2005), “Current Recommendations for Treatment of Severe Toxic Alcohol Poisonings”, Intensive Care Med., Vol. 31, pp. 189–95.



42. Dart, R.C. and McNally, J. (2001), “Effi cacy, Safety, and Use of Snake Antivenoms in the United States”, Ann Emerg Med., Vol. 37, pp. 181–8.

43. Offerman, S.R., Bush, S.P. and Moynihan, J.A. et al. (2002), “Crotaline Fab Antivenom for the Treatment of Children with Rattle Snake Envenomation”, Pediatrics, Vol. 110, pp. 968–71.

44. Tanen, D.A., Danish, D.C. and Clark, R.F. (2003), “Crotalidae Polyvalent Immune Fab Antivenom Limits the Decrease in Perfusion Pressure of the Anterior Leg Compartment in a Porcine Crotaline Envenomation Model”, Ann Emerg Med., Vol. 41, pp. 384–90.

45. Lavonas, E.J., Gerardo, C.J., O’Malley, G. et al. (2004), “Initial Experience with Crotalidae Polyvalent Immune Fab (ovine) Antivenom in the Treatment of Copperhead Snakebite”, Ann Emerg Med., Vol. 43, pp. 200–6.

46. Lheureux, P.E., Zahir, S. and Gris, M. et al. (2006), “Bench-to-bedside Review: Hyperinsulinaemia/Euglycaemia Therapy in the Management of Overdose of Calcium-channel Blockers”, Crit Care, Vol. 10, p. 212.

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Introduction

Tuberculosis occurs world wide and remains an important cause of morbidity and mortality in many

countries. In 2015 there were an estimated 10.4 million new cases of tuberculosis causing death to 1.8 million people globally. There were an estimated 2.8 million (27% of the total cases) new cases in India and 0.48 million people died in our country due to tuberculosis in 2015. It is a cause for concern as India stands fi rst in terms of absolute number of cases.1 It is a real paradox because pathogenesis, transmission, prevention, diagnosis and specifi c therapy are all well known for tuberculosis.Ideally good treatment of Tuberculosis should achieve 100% sputum conversion provided correct regimens are prescribed and taken. There will be hardly any relapse if duration of treatment has been suffi cient and there will be no emergence of drug resistance. Every treatment failure should be regarded as a failure by the doctor. He has either prescribed a bad or unreliable regimen or he has failed to ensure that the patient takes the regimen as prescribed.2-4 Drug resistant tuberculosis((DR-TB) has been reported since the early days of introduction of anti TB chemotherapy, but multidrug resistant tuberculosis (MDR-TB) defi ned as disease due to Mycobacterium tuberculosis that is resistant to atleast isoniazid and rifampicin, Rifampicin resistant TB (RR-TB) defi ned as resistance to rifampicin detected using genotypic or phenotypic methods with or without resistance to other fi rst line anti TB drugs, Pre extensively drug resistant tuberculosis(pre XDR-TB) is defi ned as MDR-TB and resistance to either fl ouroquinolone or second line anti-TB injectable drugs, extensively drug resistant tuberculosis(XDR-TB) defi ned as resistance to any fl ouroquinolone and atleast one second line injectable anti-TB in addition to MDR-TB and more recently total drug resistant tuberculosis (TDR-TB) defi ned as resistance to all available fi rst and second line Anti-TB drugs has been an area of growing concern, and is posing threat to global efforts of tuberculosis control. Prevalence of DR-TB mirrors the functional state and effi cacy of tuberculosis control programmes and realistic attitude of the community towards implementation of such programmes5. DR-TB in our country is due to inadequate tuberculosis control services, less well trained doctors in modern chemotherapy, wide spread inadequate treatment by private practitioner of various systems of medicine and quacks and inadequate management

of already drug resistant tuberculosis.6-10 DR-TB is one of the important reasons of morbidity and mortality in tuberculosis.The Global Tuberculosis Report 2016 estimated that 3.9% of newly diagnosed and 21% of previously treated Tuberculosis cases had MDR-TB. It has been estimated that 480,000 new cases of MDR-TB and additional 100,000 cases of rifampicin resistant tuberculosis (RR-TB) emerged causing death to 250,000 people globally in 2015. In India, it is estimated that the prevalence of MDR-TB among new and previously treated patients was 2.5% and 16% respectively. It is estimated that 130,000 cases of MDR-TB/RR-TB emerge every year of which 79,000 were among notifi ed cases of TB in 2015. XDR-TB has been reported in all regions of the world and it has become a serious emerging threat to global public health especially in countries with a high prevalence of Human Immunodefi ciency Virus (HIV). 9.5% of MDR-TB cases were found to have XDR-TB. To date, a cumulative total of 117 countries have confi rmed at least one case of XDR-TB.1 According to the data reported on XDR-TB from India, it varied from 1.5% to 11% of MDR-TB cases11-14

.XDR-TB has raised the possibility that the current drug susceptible TB will be replaced with a form of TB with severely restricted treatment options. This would halt the progress made in recent years to control TB globally. Thus it is evident that, drug resistant TB is a human made problem and its emergence can be prevented. Management of drug resistant TB is more diffi cult, complicated, challenging and more costly and so the saying “Prevention is better than cure” holds strength here. The present write up gives an overview of general principles for treatment of tuberculosis for the prevention of drug resistant TB.

General Principles for Treatment for Prevention of Drug Resistant TuberculosisGeneral principles for treatment of Tuberculosis for the prevention of drug resistant TB are as follows:

1. No single drug therapy for treatment of tuberculosis as drug resistance usually follows and is permanent. Never add a single drug to a failing regimen. If he is getting worse, his bacilli may be resistant to all drugs being used. Adding one drug is the same as giving one drug alone. The patient will soon develop resistance to the new drugalso.15

2. All the drugs should be administered in single dose preferably, as serum peak concentration of drug has greater and more prolonged inhibitory effect on tubercle bacilli compared to minimum inhibitory concentration (MIC) in the serum

1Department of Pulmonary Medicine, Era’s Lucknow Medical College and Hospital, Lucknow2Department of Medicine, Era’s Lucknow Medical College and Hospital, Lucknow

Prevention of Drug Resistant TuberculosisRajendra P rasad1, Nikhil Gupta2 and Amitabh Banka1

Review Article



following administration of the same dose in divided doses.16,17

3. Use only standard, time tested drug regimens recommended by various national and international agencies18-21.

4. Use drugs in adequate doses and for adequate duration.

5. Never use unreliable chemotherapy even for a short time.

6. Always prescribe good quality medicines if you are prescribing fi xed dose combinations, make sure that they are of good quality as supported by frequent bioavailability test. 22-24.

7. Be kind and sympathetic to the patient. He is much more likely to come back and complete his treatment if he has confi dence in you and believes that you are his well-wisher.

8. Follow up the patient regularly, motivate and make sure that patient takes full recommended course of treatment for adequate duration. If possible make sure that some one sees the patient taking every dose (directly observed therapy).

9. Always assess adverse effects due to medications and address them quickly and adequately19,21,25,26.

10. Use rifampicin only in tuberculosis or leprosy. Avoid misuse of rifampicin as it is one of the most potent anti tuberculosis drugs available at present.

11. Relapse after good and adequate treatment is rare. If relapse has occurred after good and adequate treatment or after too short duration of regular treatment, such cases can be treated with previously used drug regimens. Five drug (2SHREZ/1HRZE/5HRE) regimen would be much effective and safe.15

12. In the group of previously treated patients with one or several courses of chemotherapy and who remain sputum positive (by smear and/or culture) three sub populations can be observed. (a) Patients existing bacilli still sensitive to all drugs. (b) Patients existing bacilli resistant to atleast isoniazid but sensitive to rifampicin. (c) Patients bacilli resistant to atleast,isoniazid and rifampicin.The respective proportion of the three subpopulations varies according to chemotherapy applied in the community and number of courses of chemotherapy and type of regimens received by the patients.In the patients who have failed after the fi rst course of chemotherapy, the proportion of patients existing bacilli sensitive to all drugs is usually higher than the proportion of two other subpopulations. For such patients WHO retreatment regimens of fi ve drugs (2SHRZE/1HRZE/5HRE) under direct supervision can cure majority of patients having either sensitive bacilli or bacilli resistant to

isoniazid and/or streptomycin but still sensitive to rifampicin.15,27

13. In patients who have failed after several courses of previous treatment perhaps with bad or unreliable drug regimens or after two or more courses of chemotherapy under National Tuberculosis Control Programme (last being the fully supervised standard WHO retreatment regimen of fi ve drugs), the proportion of patients with MDR- TB can be as much as 50–70%. Treatment of such patients requires expertise as planning of treatment is very complex and a mistake at this stage can be fatal. 25-26.

14. Early suspicion, diagnosis and appropriate treatment of MDR-TB/RR-TB is essential to prevent morbidity, mortality and transmission of MDR-TB/RR-TB. An ‘presumptive case of MDR-TB ’ is defi ned as a TB patient who fails an new treatment regimen and retreatment regimens with fi rst-line drugs who is sputum smear positive at the end of the fourth month of treatment or later and Close contacts of drug-resistant TB cases.28,29

Ideally every such patient should be subjected to rapid genotypic and/or phenotypic culture and Drug Sensitivity Testing (DST) for mycobacterium tuberculosis from a quality accredited laboratory before starting a retreatment regimen. Subsequently when the rapid genotypic and/or phenotypic culture and DST report confi rms MDR-TB/RR-TB, an appropriate treatment regimen containing pyrazinamide and atleast 4 new drugs selected from 5 groups of Anti-TB drugs in hierchial order which the patient has not taken previously or to which the bacilli is considered to be sensitive are given25-26.

15. WHO has reclassifi ed the Anti-TB drugs used for MDR TB in 2016 in 4 groups - A, B, C and D30. In patients with MDR-TB/RR-TB, a regimen with at least fi ve effective Anti-TB drugs during the intensive phase is recommended, including pyrazinamide and four core second-line Anti-TB drugs - one chosen from group A (fl ouroquinolones: levofl oxacin, moxifl oxacin and gatifl oxacin), one from group B(Second line injectable drugs: Kanamycin, Amikacin, Capreomycin), and at least two from group C(Other core second-line agents: ethionamide/ prothionamide, cycloserine/terizidone, Linezolid and clofazimine). If the minimum of effective Anti-TB drugs cannot be composed as above, a drug from group D2 (Bedaquiline & Delaminid) and other drugs from D3 (PAS, Imipenem-cilastatin, Meropenem, Amoxicillin-clavulanate & Thioacetazone) may be added to bring the total number of drugs to fi ve. The regimen may be further strengthened with rest of Group D1 drugs (high-dose isoniazid and/



or ethambutol). Thioacetazone should not be used if the patient is HIV seropositive14. Intensive phase including injectables should be given for atleast 8 months for most patients which can be modifi ed depending upon the response of the patient and the total duration of treatment is atleast 20 months which can be extended upto 24 months depending upon the response of the patient. Pyrazinamide is usually continued for the entire treatment especially if there is an extensive disease. If the patient has minimal disease, pyrazinamide can be stopped with injectables at end of intensive phase. Bedaquiline or delamanid are used for 6 months in intensive phase and are presently not recommended for whole treatment duration. All care providers must use proper and appropriate regimens in MDR and XDR-TB patients.

16. A new Shorter regimen for treatment for subset of MDR TB/RR-TB patients have been introduced recently30. In patients with MDR TB/RR-TB who have not been previously treated with second-line drugs and in whom resistance to fl ouroquinolones and second-line injectable agents has been excluded or is considered highly unlikely, a shorter MDR-TB regimen of 9–12 months may be used instead of a conventional regimen of 20–24 months. The intensive phase of 4 months extended to 6 months in case of lack of sputum smear conversion which consists of gatifl oxacin or moxifl oxacin, Kanamycin, prothionamide, clofazimine, high-dose isoniazid, pyrazinamide, and ethambutol. This is followed by a continuation phase of 5 months which consisits of gatifl oxacin or moxifl oxacin, clofazimine, ethambutol, and pyrazinamide

17. For effective regimen to treat XDR-TB 25use pyrazinamide and any other Group 1 anti-TB drugs that may be effective; use an injectable agent to which the bacilli is susceptible and consider an extended duration of use for 12 months or possibly for total duration, if resistant to all injectable drugs, use injectables that the patient has never used before or consider the regimen without an injectable agent, if toxicity is a limiting factor for the use of the injectable agent, consider using inhaled version via a nebulizer; use a Higher-generation fl uoroquinolone such as moxifl oxacin or gatifl oxacin; use all Group 4 anti-TB drugs that have not been used extensively in a previous regimen and which are likely to be effective; add two or more Group 5 anti-TB drugs including bedaquiline or delamanid; consider adding a new investigational drug eligible for use under the compassionate ground; use high-dose isoniazid if low-level resistance or absence of the katG gene is documented. Likelihood of cure is much lower and deaths are higher, especially in

HIV positive patients31. There is limited data of different treatment regimen on the outcomes of XDR-TB patients; treatment success was highest if at least six drugs were used in the intensive phase and four in the continuation phase32. The use of later-generation fl uoroquinolones signifi cantly improved treatment outcomes, even though DST demonstrated resistance to a representative fl uoroquinolone33.

18. Avoid widespread misuse of second line anti-tuberculosis drugs (SLD’s in suspected resistant cases if you are not well trained to manage such cases as these are the only drugs available at present which have some hope of cure. Inappropriately using these valuable drugs might convert a MDR-TB/RR-TB case into XDR-TB and TDR-TB. A preliminary study by the author among sixty MDR suspect patients showed 88.8% of MDR and 72.2% MDR suspect cases had taken SLD’s for more than one month. The most commonly used SLD was fl ouroquinolones (63.36%), ethionamide (47.72%) and kanamycin (40.9%).34

19. Some Physicians feel keeping certain drugs in reserve but this is a serious error. It is a prescription for losing one battle after another. Physicians treating such patient should note that the most powerful drugs available should be used initially and in maximum combination so as to ensure that the fi rst battle is won and won permanently.

20. Treatment of Tuberculosis benefi ts both the community and the patient. Thus any public/private health care provider undertaking to treat a patient with TB is assuming an important public health responsibility that includes not only prescribing an appropriate regimen but also ensuring adherence to the treatment until treatment is completed. Therefore the responsibility for successful treatment of TB is placed primarily on the provider or program initiating therapy, rather than on the patient20-21. All measures should be taken to ensure adherence by persuading and encouraging such patients and their family members not to stop treatment despite all its discomfort as it is the last that stands between the patient and death.

21. Delay in recognition of MDR-TB/ RR-TB, prolonged periods of infectiousness, crowded wards, and mixing TB and HIV patients all contribute to nosocomial transmission. However, in view of its seriousness, every programme or physician attempting to treat MDR-TB/ RR-TB should also undertake a systematic review of current practices and ensure that everything possible is done to prevent transmission among patients and to staff by implementation of adequate infection control precautions35.



Conclusion Emergence of drug resistant tuberculosis is a human-made problem and is always due to medical error. If our tuberculosis control programme is effectively implemented, all doctors can prescribe reliable regimens using reliable drugs and if they can ensure by directly observed treatment and education of the patient and his family that it is taken as prescribed, virtually all patients should be cured without any relapse and no drug resistance should occur. Laboratory services for early diagnosis and adequate and proper treatment of DR-TB must be strengthened. It must be emphasized that optimal treatment of DR-TB alone will not curb the epidemic. Efforts must be focused on the effective use of fi rst line drugs in every new patient so as to prevent the ultimate emergence of DR-TB. The proper use of second-line drugs in every patient of DR-TB must be ensured to cure existing DR TB, to reduce transmission of DR-TB and to prevent further development of drug resistance.

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7. Udwadia, Z.F., Pinto, L.M. and Uplekar, M.W. (2010), “Tuberculosis Management by Private Practioners in Mumbai, India: Has Anything Changed in Two Decades”, Plos one, Vol. 5(8), e12023.doi;10.1371/journal.pone.002023.

8. Prasad, R., Nautiyal, R.G., Mukherji, P.K., Jain, A., Singh, K. and Ahuja, R.C. (2002), “Treatment of New Pulmonary Tuberculosis Patients: What do Allopathic Doctors do in India?”, Int. J. Tuberc Lung Dis., Vol. 6, pp. 895–902.

9. Satyanarayana, S., Subbaraman, R., Sheta, P., Gore, G., Das, J. and Cattamanchi, A. et al. (2015), “Quality of Tuberculosis care in India: A Systematic Review”, Int. J. Tuberc. lung Dis., 23 April 2015, http://dx.doc.org/10-5588/Ijt ld.15.0186

10. Vandan, N., Ali, M., Prasad, R. and Kurriwa, C. (2008), “Physicians Knowledge Regarding the Recommended Anti Tuberculosis Prescribed Medication Regimen: A Crosssectional Survey from Lucknow, India”, SouthEast J. Trop. Med. Public Health., Vol. 39, pp. 1072–75.

11. Jain, A., Dixit, P. and Prasad, R. (2012), “Pre XDR and XDR in MDR and Ofl oxacin and Kanamycin Resistance in Non MDR Mycobacterium Tuberculosis Isolates”, Tuberculosis, Vol. 92, pp. 404–6.

12. Udwadia, Z., Jain, S., Rodrigues, C. and Mehta, A. (2007), “XDR-TB in India: What’s in a Name?”, The Lancet Infectious Diseases, Vol. 7, pp. 441–2.

13. Mondal, R. and Jain, A. (2007), “XDR Mycobacterium Tuberculosis Isolates, India”, (Letter) Emerg. Infect. Dis., Available from http:/www.cdc.gov/EID/content/13/9/ 1429.htm

14. Thomas, A., Ramachandran, R. and Rehman, F. et al. (2007), “Management of Multi Drug Resistant Tuberculosis in the Field: Tuberculosis Research Centre Experience”, Indian J. Tub., Vol. 54, pp. 117–24.

15. Caminero, J.A. (2005), “Management of Multidrug Resistant Tuberculosis and Patients in Retreatment”, Eur. Respir. J., Vol. 25, pp. 928–36.

16. Tuberculosis Research Centre, Indian Council of Medical Research (2001), “Low Rate of Emergence of Drug Resistance in Sputum Positive Patients Treated with Short Course Chemotherapy”, Int. J. Tuberc. Lung Dis., Vol. 5, pp. 40–5.

17. Tuberculosis Chemotherapy Centre Madras (1960), “A Concurrent Comparison of INH and PAS with 3 Regimens of INH alone in the Domiciliary Treatment of Pulmonary Tuberculosis in South India”, Bulletin of the World Health Organisation, Vol. 23, pp. 535–85.

18. Nahid, P. et al. (2016), “Offi cial American Thoracic Society/ Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis”, pp. 1–49, DOI: 10.1093/cid/ciw376

19. Treatment of Tuberculosis, Guidelines for National Programmes, World Health Organisation-Geneva WHO/HTM/TB/2009.420.

20. TB CARE I. International Standards for Tuberculosis Care, Edition 3. TB CARE I, The Hague, 2014.

21. World Health Organisation Standard for TB Care in India, 2014.

22. Acocella, G. (1989), “Studies of Bioavailability in Man”, Bull. Int. Un. Tuberc Lung Dis., Vol. 64, pp. 40–2.

23. Editorial (1988), “Multidrug Formulations”, Ind. J. Tub., Vol. 35, p. 161.



24. Good Manufacturing Practices for Pharmaceutical Products (2014), WHO Expert Committee on Specifi cations for Pharmaceutical Preparations, Forty Eighth Report. Geneva, World Health Organization, (WHO Technical Report Series, No. 986).

25. Guidelines for the Programmatic Management of Drug-resistant Tuberculosis, WHO/HTM/TB/2011.6

26. Companion Handbook to the WHO, Guidelines for the Programmatic Management of Drug Resistant Tuberculosis, WHO/HTM/TB/2014.11

27. Mitchison, D.A. and Nunn, A.J. (1986), “Infl uence of Initial Drug Resistance on the Response to Short Course Chemotherapy of Pulmonary Tuberculosis”, Am. Rev. Respir. Dis., Vol. 133, pp. 423–30.

28. DOTS PLUS Guidelines, Revised National Tuberculosis Control Programme, Central TB Division Directorate General Health Services, Ministry of Health & Family Welfare, Nirman Bhawan, New Delhi, Sep. 2008.

29. Guidelines on Programatic Management of Drug Resistant Tuberculosis (PMDT) in India. Revised National Tuberculosis Control Programme. Central TB Division, Directorate of General Health Services.May 2012.

30. WHO Treatment Guidelines for Drug-resistant Tuberculosis 2016 Update, WHO/HTM/TB/2016.04.

31. Pietersen, E. et al. (2014), “Long-term Outcomes of Patients with Extensively Drug-resistant Tuberculosis in South Africa: A Cohort Study”, Lancet, Vol. 383, pp. 1230–39.

32. Falzon, D. et al. (2013), “Resistance to Fluoroquinolones and Second-line Injectable Drugs: Impact on Multidrugresistant TB Outcomes”, Eur. Respir. J., Vol. 42, pp. 156–68.

33. Jacobson, K.R. et al. (2010), “Treatment Outcomes among Patients with Extensively Drug-resistant Tuberculosis: Systematic Review and Meta-analysis”, Clinical Infectious Diseases, Vol. 5, pp. 6–14.

34. Prasad, R., Hosmane, G., Singh, A., Verma, S.K., Garg, R. and Kushwaha, R.A.S. et al. (2010), “A Study of Prescription of Second Line Drugs in Chronic Tuberculosis Patients Before Confi rmation of Multi Drug Resistance”, Proceedings of European Respiratory Society (ERS) Annual Congress 2010 at Barcelona, Spain on 18th-22nd Sept.2010 (Abstract).

35. Basu, S. et al. (2007), “Prevention of Nosocomial Transmission of Extensively Drug Resistant Tuberculosis in Rural South African District Hospitals: An Epidemiological Modelling Study”, Lancet, Vol. 370, pp. 1500–7.



Introduction

Currently, pancreas transplant is an option for patients undergoing kidney transplantation or less commonly

as a therapy alone. Performed fi rst in 1966 by Kelly and colleagues,¹ it remains a late therapeutic option in advanced disease because it is a major surgery with complications² and patients become lifetime dependent on immunosuppression.Separation of endocrine tissue, which is only 1% of the pancreas from the rest of bulky exocrine tissue, helped develop islet transplantation therapy. Islet replacement therapy has two arms, allogeneic islet transplantation involving harvested islets from deceased organ donors and autotransplantation, using extracted islets from the individual’s own pancreas.The earliest recorded attempt was transplantation of sheep pancreas injected under skin in 1893.³ In 1972 Ballinger and Lacy5 isolated normal islets. Almost a decade later, the fi rst results from a series of type 1 diabetes patients receiving islet transplantation was published from the University of Minnesota.6 Unfortunately, none became insulin independent at the time. But around 1989, clinically successful islet transplantation was achieved.7

The following decade until 2000 witnessed attempts of islet transplantation therapy with less than 10% success of insulin independence.8

The Edmonton protocol published around 2000 by Shapiro and colleagues 9 was a landmark study.

Clinical Islet Transplantation Consortium (CIT) currently has 2 phase III studies, CIT-07 for type 1 diabetes with severe hypoglycemia and glycemic lability and CIT-06, which includes type 1 diabetics with kidney transplantation.10 CITR defi nes insulin independence as no insulin use for 14 or more consecutive days. The review of this public registry results was reported in July 2012. From total of 677 islet recipients, 575 subjects (85%) underwent transplantation as islet alone (with total 1375 infusions, 44% receiving 2 infusions, and 20% more than two.¹² Insulin independence was observed 51% at 1 year and 27% at 3 years for patients transplanted between 1999 and 2002, whereas for the 2007 to 2010 era these numbers were 66% and 44%, respectively.¹³

Primary Endpoints in Pancreaseor Islet Transplant

The fi ve current primary endpoints include insulin independence, occurrence of hypoglycemia, a HbA1c of less than 6.5%, a C-peptide of more than 0.3 and improvements in fasting blood glucose.14 When CITR data are reviewed for the severe hypoglycemia occurrence 90% patients remain free of severe hypoglycemic events. Within this perspective, in the last decade, islet transplantation was transformed into a treatment option for type 1 diabetic patients suffering hypoglycemic unawareness.Recently, outcome data reported15 from a phase III trial were promising as insulin independence was achieved about 55% of recipients at 1 year with 1 or 2 infusions and even without insulin independence hypoglycemic unawareness was treated effectively.16 As reported, insulin independence rates in a single donor islet transplant17 reaches 50% for 5 years as well as observed positive impact of this therapy on complications of diabetes,18,19 islet transplantation as a clinical treatment option is becoming a reality.

GSSM Cardiorespiratory Centre Rekabganj,Faizabad–224001, U.P.E-mail: [email protected]

ABSTRACT

• Pancreas and islet cell transplantation are therapeutic options for type 1 diabetes patients suffering from severe hypoglycemia or worsening complications despite advanced medical therapy.

• The advances and improvements achieved, especially since 2000, brought this therapy much closer to the clinical use.

• Many modifi cations in immunosuppressive regimens allowed islet transplantation to catch up with pancreas transplantation success rates.

• The encapsulation studies in humans with human pluripotent stem cells are underway. Current human trials will give us some answers in the very near future.

Pancreas, Islet Cell and Stem Cell Transplantation: Current Scenario

Veerendra Singh

Review Article



Pancreas Versus Islet TransplantationPancreas transplantation has been performed since 1966, with signifi cant improvements over time. International Pancreas Registry reports more than 42,000 pancreas transplantation worldwide, most commonly performed as SPK. This is a procedure with survival rates at 1 and 5 years of more than 96% and 84%, respectively.20 When a comparison study looked into islet versus pancreas with kidney transplant results demonstrated similar HbA1c levels, although islet recipients were less likely to achieve insulin independence, whereas pancreas recipients had higher procedure related morbidity.²¹Islet transplantation will be an option in cases with high cardiac risk for major surgery and older age, as well as kidney recipients who do not wish to undergo another major surgery.Lifelong exposure to immunosuppression and its impact on the overall health contraindicates these procedures in a larger number of diabetics who could benefi t from tight blood sugar control.

Immunosuppression and New Developing Strategies

The Edmonton protocol using steroid-free immunosuppressive agents such as low-dose tacrolimus, sirolimus, and daclizumab improved the outcome of the procedure. Clinical trials have used alternate protocols such as T-cell–depleting induction therapy.Newer modifi ed protocols used drugs such efalizumab and belatacept, novel monoclonal antibodies.²²The University of San Francisco reported with such modifi cations that 8 out of 8 patients became insulin independent²³ and 50% of them remained so at 5 years, a success close to pancreas transplant.Eliminating or minimizing exposure to immunosuppressive drugs will, without a doubt, revolutionize this fi eld and open this treatment option to possibly all diabetics on insulin therapy.

Islet EncapsulationThe idea of creating an environment protected from immune system but still allowing access to nutrient and product delivery has been considered for more than 40 years. An ideal device would allow selective permeability of smaller molecules such as oxygen, CO2, nutrients and products desired such as insulin pass freely.24 There are 2 forms of encapsulation currently being studied for islet transplantation. Microencapsulation of 1 or 2 islets in 1 semipermeable microcapsule, whereas multiple islets reside in 1 device in macroencapsulation.Currently, there are intravascular or extravascular forms. The intravascular devices have a high risk of thrombosis.25

Macrodevices implanted in an extravascular space such as skin are more attractive.A sheet device by Baxter Health Care (Deerfi eld, IL) called the Encaptra is designed to deliver the cells composed of human pancreatic progenitor cells called PEC-01 TM cells. This system is currently being evaluated in phase I to II clinical trial called STEP ONE (Safety, Tolerability, and Effi cacy of VC-01 Combination Product in Type One Diabetes).Beta-O2, also known as B air alginate macrocapsule seeks to overcome the issue of overcrowded cells and their diffi culty to receive enough oxygen when macroencapsulated. Currently multiple clinical trials are ongoing with microencapsulation with alginate. The encapsulation technique enabled the usage of a new and exciting cell source for beta-cell therapy without compromising the immune system of the host such as xenotransplantation using animal pancreata such as the pig26 and the use of embryonic stem cell lines as an islet source.

Stem Cell StudiesA variety of stem cells studies have been underway. Multiple different types currently exist, for example, human pluripotent stem cells, such as embryonic stem cells and human induced pluripotent stem cells, or mesenchymal stem cells isolated from adult tissues or directly programmed somatic cells.Another source for PSC is reprogramming of somatic cells by episomal vectors based on virus systems. The current trend is toward using human pluripotent stem cell–derived pancreatic progenitors after maturing them into more functional islet like structures in vivo, so they transform into structures with subtypes of cells including alpha, beta, delta, and ghrelin and PP hormone-producing cells. Cells currently being tested in human trial by ViaCYTE undergo this technique.Another interesting result in this fi eld is generating functional beta cells in vitro from partially reprogrammed somatic cells. Recently with two different teams reported achieving in vitro production of beta cell–like structures from embryonic stem cells as well as human induced pluripotent stem cells.27,28

SummaryBoth pancreas and islet cell transplantation are available as therapeutic options for patients with type 1 diabetes who are suffering severe hypoglycemia or worsening complications despite advanced medical therapy. The advances and improvements achieved, especially since 2000, have brought this therapy much closer to clinical use. Many modifi cations in immunosuppressive regimens allowed islet transplantation to catch up with pancreas transplantation success rates. The encapsulation studies in humans with sources such as human pluripotent stem cells are underway and results might open a path for many patients who would benefi t replacement therapy



without the unwanted side effects of immunosuppressive drugs. Current human trials will give us some answers in the very near future.

References1. Kelly, W.D., Lillehei, R.C. and Merkel, F.K. et al. (1967),

“Allotransplantation of the Pancreas and Duodenum along with the Kidney in Diabetic Nephropathy”, Surgery, Vol. 61(6), pp. 827–37.

2. Farney, A.C., Rogers, J. and Stratta, R.J. (2012), “Pancreas Graft Thrombosis: Causes, Prevention, Diagnosis and Intervention”, Curr Opin Organ Transplant, Vol. 17(1), pp. 87–92.

3. Williams, P. (1894), “Notes in Diabetes”, BMJ, Vol. 2, pp. 1303–4.

4. Moskalewski, S. (1965), “Isolation and Culture of the Islets of Langerhans of the Guinea Pig”, Gen Comp Endocrinol., Vol. 5, pp. 342–53.

5. Ballinger, W.F. and Lacy, P.E. (1972), “Transplantation of Intact Pancreatic Islets in Rats”, Surgery, Vol. 72(2), pp. 175–86.

6. Sutherland, D.E., Matas, A.J. and Goetz, F.C. et al. (1980), “Transplantation of Dispersed Pancreatic Islet Tissue in Humans: Autografts and Allografts”, Diabetes, Vol. 29(Suppl 1), pp. 31–44.

7. Scharp, D.W., Lacy, P.E. and Santiago, J.V. et al. (1990), “Insulin Independence After Islet Transplantation into Type I Diabetic Patient”, Diabetes, Vol. 39(4), pp. 515–518.

8. Bretzel, R.G., Brendel, M. and Eckhard, M. et al. (2001), “Islet Transplantation: Present Clinical Situation and Future Aspects”, Exp Clin Endocrinol Diabetes, Vol. 109(Suppl 2), pp. S384–99.

9. Shapiro, A.M., Lakey, J.R. and Ryan, E.A. et al. (2000), “Islet Transplantation in Seven Patients with Type 1 Diabetes Mellitus using a Glucocorticoid-free Immunosuppressive Regimen”, N. Engl. J. Med., Vol. 343(4), pp. 230–8.13.

10. Available at: www.citisletstudy.org. Accessed March 2016.

11. Shapiro, A.M., Ricordi, C. and Hering, B.J. et al. (2006), “International Trial of the Edmonton Protocol for Islet Transplantation”, N. Engl. J. Med., Vol. 355(13), pp. 1318–30.

12. “Collaborative Islet Transplantation Registry (CITR)”, CITR 8th Annual Report, 2014.

13. Barton, F.B., Rickels, M.R. and Alejandro, R. et al., (2012), “Improvement in Outcomes of Clinical Islet Transplantation: 1999–2010”, Diabetes Care, Vol. 35(7), pp. 1436–45.

14. Gruessner, R.W. and Gruessner, A.C. (2014), “What Defi nes Success in Pancreas and Islet Transplantation-insulin Independence or Prevention of Hypoglycemia? A Review”, Transplant Proc., Vol. 46(6), pp. 1898–9.

15. Bartlett, S.T., Markmann, J.F. and Johnson, P. et al. (2016), “Report from IPITA-TTS Opinion Leaders Meeting on the Future of Beta-cell Replacement”, Transplantation, Vol. 100(Suppl 2), pp. S1–44.

16. Hering, B.J., Clarke, W.R. and Bridges, N. et al. (2016), “Phase 3 Trial Transplantation of Human Islets in Type 1 Diabetes Complicated by Severe Hypoglycemia”, Diabetes Care, Vol. 39(7), pp. 1230–40.

17. Hering, B.J., Kandaswamy, R. and Ansite, J.D. et al. (2005), “Single-donor, Marginal-dose Islet Transplantation in Patients with Type 1 Diabetes”, JAMA, Vol. 293(7), pp. 830–5.

18. Danielson, K.K., Hatipoglu, B. and Kinzer, K. et al. (2013), “Reduction in Carotid Intima-media Thickness After Pancreatic Islet Transplantation in Patients with Type 1 Diabetes”, Diabetes Care, Vol. 36(2), pp. 450–6.

19. Thompson, D.M., Meloche, M. and Ao, Z. et al. (2011), “Reduced Progression of Diabetic Microvascular Complications with Islet Cell Transplantation”, Transplantation, Vol. 91(3), pp. 373–8.

20. Gruessner, R.W. and Gruessner, A.C. (2013), “The Current State of Pancreas Transplantation”, Nat. Rev. Endocrinol., Vol. 9(9), pp. 555–62.

21. Gerber, P.A., Pavlicek, V. and Demartines, N. et al. (2008), “Simultaneous Islet-kidney vs. Pancreas-kidney Transplantation in Type 1 Diabetes Mellitus”, Diabetologia, Vol. 51(1), pp. 110–9.

22. Vincenti, F., Mendez, R. and Pescovitz, M. et al. (2007), “A Phase I/II Randomized Multicenter Trial of Efalizumab, A Humanized Anti-CD11a, Anti-LFA-1 in Renal Transplantation”, Am. J. Transplant, Vol. 7(7), pp. 1770–7.

23. Posselt, A.M., Bellin, M.D. and Tavakol, M. et al. (2010), “Islet Transplantation in Type 1 Diabetics using an Immunosuppressive Protocol Based on the Anti-LFA-1 Antibody Efalizumab”, Am. J. Transplant, Vol. 10(8), pp. 1870–80.

24. Scharp, D.W. and Marchetti, P. (2014), “Encapsulated Islets for Diabetes Therapy: History, Current Progress and Critical Issues Requiring Solution”, Adv. Drug Deliv. Rev., Vol. 67–68, pp. 35–73.

25. O’Sullivan, E.S., Vegas, A. and Anderson, D.G. et al. (2011), “Islets Transplanted in Immunoisolation Devices: A Review of the Progress and the Challenges that Remain”, Endocr Rev., Vol. 32(6), pp. 827–44.

26. Ekser, B., Ezzelarab, M. and Hara, H. et al. (2012), “Clinical Xenotransplantation: The Next Medical Revolution?”, Lancet, Vol. 379(9816), pp. 672–83.

27. Pagliuca, F.W., Millman, J.R. and Gurtler, M. et al. (2014), “Generation of Functional Human Pancreatic Beta Cells in Vitro”, Cell, Vol. 159(2), pp. 428–39.

28. Rezania, A., Bruin, J.E. and Arora, P. et al. (2014), “Reversal of Diabetes with Insulin-producing Cells Derived in Vitro from Human Pluripotent Stem Cells”, Nat. Biotechnol., Vol. 32(11), pp. 1121–33.



IntroductionPosterior Reversible Encephalopathy Syndrome (PRES)

is a clinico-radiological disorder characterised by the sudden onset of neurological symptoms associated with potentially reversible lesions affecting posterior cerebral white matter of brain. The differential diagnosis is broad due to the heterogeneity of symptoms which include seizure, headache, visual disturbance and altered mental status. Diagnosis is made using computerised tomography (CT) or, most commonly, magnetic resonance imaging (MRI), the latter using diffusion weighted imaging (DWI). Prompt recognition of this entity is extremely important, if the treatment is delayed, there is a risk of permanent brain injury.The name of this condition has undergone a change since the fi rst description of 15 cases in 1996 by Hinchey et al., who coined the term ‘Reversible Poste rior Leukoencephalopathy Syndrome’. The present term ‘PRES’ has been coined to refl ect its association with elevated blood pressure[1].The term reversible posterior leukoencephalopathy could

be a misnomer as the condition may not always reversible and is not necessarily restricted to the posterior regions of the brain and can also affect both white and grey matter.

Table 1: Causes of Posterior Leukoencephalopathy

Common Uncommon1. Hypertensive encephalopathy2. Toxaemia of pregnancy3. Renal impairment with

hypertension• Renal failure• Haemolytic-uraemic

syndrome• Acute glomerulonephritis

4. Infection, sepsis, shock• Immunosuppressive and

cytotoxic drugs• Cyclosporin A• Interferon-alpha• Cisplatin• Tacrolimus• Cytarabine• Intravenous

immunoglobulins• Erythropoietin• Gemcitabine• Tiazofurin• Kinase inhibitor

1. Collagen vascular disorders• Systemic lupus

erythematosus• Systemic sclerosis• Wegener’s• Polyarteritis nodosa• Antiphospholipid

syndrome2. Thrombotic-thrombocytopenic

purpura3. Acquired immunodefi ciency

syndrome4. Acute intermittent porphyria5. Following organ

transplantation6. Following repeated blood

transfusion

The epidemiology of PRES is largely unknown due to the paucity of large pro spective series. The syndrome has been described both in pediatrics and adult age group and the median age at presentation is approximately 40 years based on existing registry data. Females appear to be affected more than males. The onset of disease is

1MD (Medicine), DM (Nephrology) AIIMS, New Delhi,Senior Consultant Nephrologist, Head, Deptt. of Nephrology, Jaswant Rai Speciality Hospital, Meerut (U.P.)2FRCP (Glasgow), FRCP (Ireland), FACP (Philadelphia),FAAN (USA), DM (Neurology), MD (Medicine), MBBS, Senior Consultant Neurologist, Director and Head, Deptt. of Neurosciences, Jaswant Rai Speciality Hospital, Meerut (U.P.)E-mail: [email protected], [email protected]/[email protected]

ABSTRACT

Among the myriad of diseases that can cause acute reversible neurological dysfunctions, the Posterior Reversible Encephalopathy Syndrome (PRES) with its diverse etiology and varied presentation needs attention. At risk population includes those with chronic hypertension, eclempsia, autoimmune disease, chronic kidney disease and drug induced especially anti-cancer and immunosuppressant drugs. Once thought of its relation only to existing hypertension, its always reversibility and affection only to posterior cerebral cortex, the term PRES is now a misnomer as this is not always reversible and is not necessarily restricted to posterior region of brain with advancement in radiological diagnostic techniques, the kidney diseases as risk factor for PRES is getting more and more popularity in a good subset of patients. However a prompt diagnosis and rapid correction of underline cause makes it reversible both clinically and radiologically.

Keywords: PRES, Hypertension, Seizure, Posterior Regions, Reversibility

Posterior Reversible Encephalopathy Syndrome (PRES): From a Nephrologist Eye

Dr. Prashant Bendre1 and Dr. (Prof.) Bhupendra Chaudhary2

Review Article



usually acute or sub-acute and subsequent course is of rapid progression for few next days. Clinical features usually disappear after appropriate treatment is started, and the majority of the patients recover completely.[2]

There are a variety of medical conditions associated with PRES namely hypertension, renal disease, dialysis dependency, malignancy, and transplantation. PRES has been observed in the context of many multi-system diseases that are commonly associated with kidney disease such as pre eclampsia, vasculitis and systemic lupus erythematosus. It has also been reported in infection, sepsis and shock. (Table 1)Despite these consistent associations with kidney disease risk factors, the literature regarding occurrence of PRES in individuals with established kidney disease is relatively sparse.

Cli nical PresentationPRES is a rapidly evolving condition and is clinically characterised by headache, altered alertness and behavior ranging from drowsiness to stupor, seizures, vomiting, altered mental status including confusion and diminished speech, abnormalities of vision and occasionally focal neurological signs. The onset is usually subacute but may begin abruptly by a seizure. Seizures are common at the onset and are usually initial manifestations of the disease but can also develop later. Seizures may begin focally but usually become generalized. Multiple seizures are more common than single events. Status epileptics may develop. Lethargy and somnolence are often the fi rst signs noted. Temporary restlessness and agitation may alternate with lethargy. Stupor and frank coma may develop, but usually patients remain responsive to stimuli. Memory and the ability to concentrate are impaired, although severe amnesia is unusual.Abnormalities of vision are nearly always observed and are the most characteristic clinical manifestation of this syndrome. Patients often report blurred vision or visual hallucination, hemianopia, visual neglect, and frank cortical blindness may occur. Some cortically blind patients also have denial of blindness (Anton’s syndrome). Fundus examination along with pupillary responses are often normal. The tendon refl exes are often brisk, and some patients have weakness and incoordination of the limbs and gait ataxia.

Pathophysiology of PRESBefore exploring the pathogenesis of PRES, let us fi rst understand some concepts of cerebral blood fl ow. Auto-regulation refers to the ability of an organ to alter its vascular resistance and maintain normal blood fl ow despite changes in arterial pressure. This is particularly important in the brain, an organ that receives approximately 15% of cardiac output. Cerebral blood fl ow must be maintained constant despite fl uctuations in systemic arterial pressure. In the setting of low blood

pressure cerebral arterioles will dilate to increase fl ow to the capillaries. In contrast, high blood pressure will result in arteriolar vasoconstriction to limit fl ow downstream. Such is the sophistication of this system, the human brain can maintain normal perfusion within a range of mean arterial pressure between approximately 60 and 140 mm Hg.[3]

Beyond these thresholds of autoregulation brain injury will occur due to hypoperfusion or hyperperfusion, respectively. The hallmark of PRES is vasogenic edema. The advent of DWI has facilitated the differentiation of vasogenic edema from cytotoxic edema, the latter an irreversible phenomenon due to tissue infarction. Controversy exists, however, as to the pathogenesis of vasogenic edema in PRES and the role of hypertension. Two theories, recently reviewed by Bartynski, have been suggested.In the most popular [Vasogenic] theory, severe systemic hypertension overwhelms the auto-regulatory capacity of the cerebral vasculature (principally arterioles) leading to hyper-perfusion, arteriolar dilatation, injury to the capillary bed and vasogenic edema. Sympathetic stimulation can raise the upper threshold of auto-regulation; therefore, the predilection of PRES for the posterior brain, where there is a relative lack of sympathetic innervation, adds weight to this hypothesis. Although logical, there are a number of problems with this theory. First, blood pressure is not always elevated in PRES, and this is particularly true in cases associated with immunosuppression and organ transplantation. In addition, the degree of vasogenic edema does not always correlate with the severity of hypertension.The second [Cytotoxic] theory states that the principal problem is cerebral vasoconstriction that causes downstream hypo-perfusion, ischaemia and vasogenic edema due to capillary leak. This is seen in many cases in which the blood pressure is either normal or minimally elevated in many cases of PRES, and this suggests that Hypertension cannot be the sole cause of injury in all cases. PRES is often seen in autoimmune diseases, organ transplantation and pre-eclampsia, where systemic processes operate rather than hypertension.[4]

These pathophysiological mechanisms in these conditions include autoimmunity and endothelial cell activation and/or injury. Endothelial cell dysfunction can lead to altered vascular tone, vasospasm hypoperfusion and ischaemia. Vascular endothelial growth factor (VEGF) is produced by the cerebral vessels in response to hypoxia and this increases their permeability, thereby resulting in edema. This injury encountered in PRES, is usually located in the watershed areas of the brain (esp. in the posterior cerebral areas), which are most susceptible to hypo perfusion.Both these theories are not mutually exclusive and may play roles together in many patients.



Heterogeneity of PRESOriginally PRES was defi ned as a posterior phenomenon, but almost all areas of the brain can be affected. The classical pattern of vasogenic edema in the parietal or occipital region is still seen in a majority of cases. Frontal lobe involvement, however, has been reported to be as high as 68%. In the Berlin PRES study, involvement of frontal and temporal lobes occurred in one half of cases. Lesions involving the infra-tentorial region, particularly the cerebellum, were encountered in more than half of cases.In large case series intracranial haemorrhage has been encountered in 15 to 32% of cases. In a study of haemorrhagic PRES, seizure and confusion were the most common presenting features; however, hypertension was surprisingly not a signifi cant factor in the development of haemorrhage.The Berlin PRES study demonstrated that, of those who had repeat imaging performed, 43% had incomplete resolution of edema on repeat MRI. A sig nifi cant factor associated with incomplete resolution was higher MAP at presentation. The presence of haemorrhage also shows a worse outcome.

PRES in Chronic Kidney DiseaseRenal dysfunction also appears to predispose the brain to posterior leukoencephalopathy, because of associated hypertension, chronic uraemia or fl uid overload. Human recombinant erythropoietin is used to treat chronic anaemia in patients with end-stage renal failure. Erythropoietin aggravates hypertension which can lead to hypertensive encephalopathy.

PRES in End Stage Renal Diseases (ESRD)Because of the consistent association of severe hypertension, autoimmunity, and organ transplantation with PRES it is expected to have a close association of renal disease namely ESRD with PRESS .However a literature search does not point to the frequency of PRES in CKD. In a larger published series of PRES, kidney disease does not feature prominently except in solid organ transplantation. PRES has been observed in a number of individuals receiving peritoneal dialysis. Most of these cases had signifi cant hypertension at presentation and responded to BP control with or without ultrafi ltration.In some patients the onset of PRES was within weeks of commencing haemodialysis. This suggests a vulnerability period during which time patients were becoming accustomed to fl uctuations in MAP by alterations to their ‘dry weight.’ A key learning point from these cases is the need for meticulous extracellular fl uid volume and blood pressure control at the time of commencement of dialysis. Anuric patients in particular need very close monitoring and avoidance of long inter-dialytic gaps. In

a recent review of three cases of PRES in haemodialysis patients, severe hypertension was the key clinical fi nding and responded well to strict volume control without the need for anti-hypertensive agents. Two of these patients developed PRES within three months of starting haemodialysis.Clinically silent white matter lesions are common in individuals with kidney disease and probably refl ect associated vascular disease. In an interesting study of patients undergoing their fi rst haemodialysis, MR brain imaging was performed within 30 minutes before and after the dialysis treatment. Baseline imaging demonstrated a diffuse increase in apparent diffusion coeffi cient (ADC) in ESRD patients compared to controls indicative of interstitial edema. In the post-dialysis images, the ADC further increased particularly in the frontal lobes, suggestive of worsening interstitial edema. None of the patients who underwent haemodialysis experienced signifi cant neurological symptoms. Brain imaging abnormalities without accompanying symptoms after dialysis has been reported elsewhere. It is likely, therefore, that dialysis patients do experience neurological sequelae of their treatment, but only a proportion comes to clinical attention.

PRES in Post-TransplantationThe incidence of PRES post-transplantation varies depending on the type of organ transplanted. A retrospective single-centre study of 4222 solid organ transplants showed an overall incidence of PRES of 0.49%.[5]

In both kidney transplant and liver transplants, PRES was diagnosed at the time of co-existent infection or organ rejection. In the context of a complex transplant recipient with infection and/or rejection, it is diffi cult to attribute a single aetiology to the development of PRES.

Typi cal Neuroimaging FeaturesNeuroimaging of PRES is typically associated with high signal intensity on T2 weighted images predominantly in the posterior regions of cerebral hemispheres, which is caused by subcortical white matter vasogenic edema. The most common affected areas are occipital lobes and posterior parietal lobes. The imaging abnormalities are often symmetrical, however asymmetrical involvement is not usual. MRI abnormalities of PRES are more better demonstrated on fl uid-attenuated inversion recovery imaging (FLAIR), with nulling of the ventricular and subarachnoid CSF signal, the parenchymatous oedematous lesions esp. those in cortex are much better demonstrated on FLAIR images than on conventional T2 weighted images.[6-7] Supplemental diffusion-weighted imaging (DWI) and apparent diffusion coeffi cient (ADC) map images are helpful in distinguishing vasogenic edema, the predominant abnormality in PRES, from



cytotoxic edema, which can also occur and may represent foci of irreversible ischemia as in case of “Top of Basilar Syndrome” which produces bilateral occipital lobe infarctions. Because vasogenic rather than cytotoxic edema is the principal basis for the lesions, regions demonstrating high signal intensity on T2-weighted images correspond to slightly increased or isointense signal intensity on diffusion-weighted images[8]. In ADC mapping, the hyperintense lesions on T2-weighted images correlate with increased ADC values (appear brighter). Most PRES lesions do not enhance on T1-weighted images. Contrast enhancement in the areas of T2 signal abnormality occurs in a few patients and may represent a dynamic fea ture related to the timing of imaging after the onset of symptoms and severity of lesions. Gadolinium enhancement in areas of T2 abnormality is inconsistent and typically not a striking fi nding.

Hypodense lesions of PRES are well visualised even with CT scan. An outstanding feature of PRES syndrome is reversibility of the imagine abnormalities. Complete reversibility is generally regarded as a defi ning feature of PRES. Resolution of PRES neuroimaging abnormalities probably occurs in the range of several days to weeks but if appropriate management is delayed, there is a great risk of permanent neurological damage because of ensuing cerebral infarction or hemorrhages.

Atypical Neuroimaging FeaturesAlthough classic neuroimaging features of PRES with involvement of the posterior head regions are easily recognized, features that may generally be regarded as atypical are often present in patients, such as signifi cant anterior involvement, cortical lesions, recurrent PRES episodes, foci of permanent injury, hemorrhage into lesions, and unilaterality. High signal intensity on T2-weighted image lesions can occur in regions other than the parieto-occipital areas, frequently involving the frontal lobes, basal ganglia, thalami, or brainstem. The

PRES lesions typically do not exclude the anterior head re-gions. Frontal lobe involvement is a common feature seen in most of these patients. Similarly, PRES lesions do not have to be restricted to the white matter. Although white matter is predominantly involved, gray matter lesions, anterior lesions, and isolated brainstem involvement are becoming increasingly appreciated.[9-10]

TreatmentThe posterior leukoencephalopathy syndrome needs to recognised promptly, as it is reversible and readily treated by controlling blood pressure, discontinuing the offending immunosuppressive agent or decreasing the dose and treatment of underlying sepsis. Delay in initiating the appropriate treatment may result in permanent damage to the brain. This highlights the need for meticulous extracellular fl uid volume control during this potentially vulnerable period. In patients with solid organ transplantation where cyclosporine or tacralimus are thought to be the culprit, stopping these drugs acutely may lead to acute organ rejection and death. So close consultation with the transplant physician is important. Patients experiencing seizures become seizure free after resolution of imaging abnormalities and do not require long term anti-epileptic drug treatment.

ConclusionPRES is an uncommon diagnosis among patients with renal diaeases. However, the varied clinical presentation and the increasing recognition of heterogeneous imaging fi ndings make it diffi cult to be accurate about its true incidence. The reversibility of PRES is not always present, hypertension is a signifi cant driver of brain injury, often in the setting of recent commencement of haemodialysis.Thus, knowledge of posterior reversible ephalopathy syndrome is of great signifi cance in day to day clinical practice. The cause of this syndrome is multifactorial. The mechanism of the syndrome is, probably, a brain-capillary leak syndrome related to hypertension, fl uid retention, and possibly the cytotoxic effects on the vascular endothelium. Clinicians must be aware of this common clinico-radiological syndrome, as its recognition obviates unnecessary diagnostic procedures. Moreover, early treatment of this syndrome may prevent permanent neurological damage.

References1. Hinchey, J., Chaves, C., Appignani, B., Breen, L., Pao,

L. and Wang, A. et al. (1996), “A Reversible Posterior Leukoencephalopathy Syndrome”, N. Engl. J. Med., Vol. 334, pp. 494–500.

2. Schwartz, R.B. (1996), “A Reversible Posterior/Leukoencephalopathy Syndrome”, N. Engl. J. Med., Vol. 334, p. 1743.

Fig. 1 Fig. 2

MRI (Flair Image) Showing Posterior Reversible Encephalopathy Syndrome (PRES). Arrows in Fig. 1, Points to Bilateral Parietal Lobe Hyper-Intensity that is Characteristic of Vasogenic Edema in the Posterior Reversible Encephalopathy Syndrome, Seen in Women with End Stage Renal Disease



3. Ay, H., Buonanno, F.S., Schaefer, P.W., Le, D.A., Wang, B. and Gonzalez, R.G. et al. (1998), “Posterior Leukoencephalopathy without Severe Hypertension; Utility of Diffusion Weighted MRI”, Neurology, Vol. 51, pp. 1369–76.

4. Dinsdale, H. (1983), “Hypertensive Encephalopathy”, Neurol Clin., Vol. 1, pp. 3–15.

5. Lanzino, G., Cloft, H., Hemstreet, M.K., West, K., Alston, S. and Ishitani, M. (1997), “Reversible Posterior Leukoencephalopathy Following Organ Transplantation, Description of Two Cases”, Clin Neurol Neurosurg, Vol. 99, pp. 222–26.

6. Garg, R.K. (2001), “Posterior Leukoencephalopathy Syndrome”, Postgrad Med. J., Vol. 77, pp. 24–8.

7. Antunes, N.L., Small, T.N., George, D., Boulad, F., Lis, E. (1999), “Posterior Leukoencephalopathy Syndrome may not be Reversible”, Pediatr Neurol., Vol. 20, pp. 241–3.

8. Taylor, M.B., Jackson, A. and Weller, J.M. (2000), “Dynamic Susceptibility Contrast Enhanced MRI in Reversible Posterior Leukoencephalopathy Syndrome Associated with Haemolytic-uraemic Syndrome”, Br. J. Radiol., Vol. 73, pp, 438–42.

9. Pavlakis, S.G., Frank, Y., Kalina, P., Chandra, M. and Lu, D. (1997), “Occipital-parietal Encephalopathy: A New Name for an Old Syndrome”, Pediatr Neurol., Vol. 16, pp. 145–8.

10. Yamamoto, T. (1999), “Reversible Posterior Leukoencephalopathy, Is it Reversible and thus Benign?”, Intern Med., Vol. 38, pp. 4–5.



Introduction

Lyme disease is multisystem illness caused by a tick borne spirochete. The disease is not contagious

between humans and is spread via an Ixodes genus deer tick bite(1,2,3) Typical symptoms include fever, headache, fatigue, and a characteristic skin rash called ery-thema migrans (EM). If left un-treated, infec-tion can spread to joints, the heart, and the nervous sys-tem. Unilateral or bilateral fa-cial palsy may occur in upto 11% of the pa-tients. Lyme disease is diagnosed based on symptoms, physical fi ndings (e.g., rash), and the possibility of expo-sure to infected ticks. Laboratory testing is helpful if used

correctly and performed with validated methods. Most cases of Lyme disease can be treated successfully with a few weeks of antibiotics.

Case ReportA 23 year old male presented to our hospital with history of mild grade fever, right side facial palsy and non pruritic non vesicular rashes and altered sensorium since one day. During the previous two weeks he had been complaining of weakness and headache. The laboratory examination demonstrated a white cell count of 11.700 with 56% neutrophils, 40% lymphocytes and 3% monocytes, hemoglobin 14.9g/dL and Platelet count of 20,000/mm3. Lumbar puncture revealed a white blood cell count of <5, protein 41mg% and sugar 63.5%. Gram stain and culture of cerebrospinal fl uid (CSF) were negative after 72 hours. CSF viral markers were negative. Serum Lyme Immunoglobin M was positive at 1.6 (positive at >1.1).He was diagnosed with disseminated lymes disease with facial plasy. He was started on iv cefuroxime (500 mg) twice a day for 5 days followed by 250 mg orally twice a day for the next 10 days. Considering the severity of the disease (patient being in altered sensorium), oral doxycycline was also added to the therapeutic regime. Symptoms resolved completely within two weeks of initiating antibiotic therapy.

DiscussionLyme disease (LD), caused by the spirochete bacteria of the genus Borrelia. LD occurs in stages, with different clinical manifestations that refl ect the immune response to B. burgdorferi. The hallmark of a stage I, early localized infection, is characterized by EM accompanied by systemic viral-like symptoms, including fever, malaise,

1Professor, Department of Internal Medicine, King George Medical University, Lucknow2,3Senior Resident, Department of Internal Medicine, King George Medical University, Lucknow4Associate Professor, Department of Internal Medicine, King George Medical University, Lucknow

ABSTRACT

Facial nerve palsy can result from a variety of etiologies. The paralysis of the facial nerve disturbs motor function to the muscles of facial expression and results in a fl accid appearance of the face (unilateral or bilateral). A unique cause of facial palsy is lymes disease, a multisystemic illness caused by a tick-borne spirochete. This case report details the clinical course, clinical features, and outcome of a 23 year old male presenting with acute onset facial palsy associated with Lymes disease. Positive Lyme disease spirochete titers are helpful in the diagnosis. Antibiotics should be given to patients with facial palsy in order to treat any other concurrent manifestations of the illness and to prevent subsequent complications. The physician should consider this etiology in all otherwise idiopathic facial paralyses. A review of the literature and the implications of facial nerve palsy are discussed below.

Keywords: Bell’s Palsy,Facial Nerve Palsy, Lyme Disease, Erythema Marginatum

Acute Onset Facial Nerve Palsy Associated with Lyme Disease

Arvind Kumar Mishra1, Shubham Agarwal2, Rohit Anand3, and K.K. Gupta4

Case Report



headache, and joint pain. Stage II, early disseminated infection, develops within 1–9 months following an untreated infection, and is due to hematogenous spread of bacteria to sites distant from the original EM lesion. Early disseminated infection affects the skin, heart, and the nervous system. Fifty percent of patients develop multiple EM lesions that are typically small and can occur anywhere on the body. Cardiac involvement is seen in 0.3%–4% of cases, and is usually characterized by varying degrees of transient atrioventricular block. Less than 10% of untreated patients develop cranial nerve palsy or lymphocytic meningitis. Cranial nerve VII is often affected, resulting in unilateral or bilateral facial palsy(4,5). A study by Cook et al. suggests that Lyme disease may account for up to 50% of all facial nerve paralysis in children, thus making it the single most common cause. (1) Meningitis is associated with episodic headache and mild neck stiffness. Spinal fl uid examination may reveal lymphocytic pleocytosis and elevated levels of protein and B. burgdorferi-specifi c antibody.Stage III, late LD, occurs months to years after the original tick exposure, and includes neurologic manifestations that may progress to encephalopathy, peripheral neuropathy, encephalomyelitis, and arthritic symptoms.The diagnosis of early LD can be made on the clinical presentation of the classical EM and on a history of known tick bite or probable exposure, considering that serologic testing is too insensitive in the early acute phase of LD. Supporting serologic evidence is necessary to secure the diagnosis for disseminated stages. The laboratory diagnosis of LD is rarely based on the microscopic visualization of the Borrelias pirochete in clinical setting.Early LD and EM are treated with antibiotics on an outpatient basis. Doxycycline (100 mg twice daily by mouth), amoxicillin (500 mg twice a day by mouth), or cefuroxime (250 mg twice a day by mouth) for 10–14 days are equally effi cacious(6,7,8). In cases of Facial Nerve Paralysis, the antibiotic course is extended for 21 to 28 days. Steroids are usually not recommended.(9) Doxycycline is often the drug of choice, because it is also considered the treatment for the Gram-negative bacterium Anaplasmaphagocytophilum, a potential tick-borne coinfection.Coinfections can include Anaplasmaphagocytophilum, which causes human granulocytic anaplasmosis, and babesiosis.(10) The risk for coinfections is increased, due to the ixodid tick being a vector for all three. Symptoms of a babesiosis infection include fatigue, malaise, weakness, fever (.38°C), myalgia, arthralgia, and anorexia. Severe babesiosis infections may progress

to acute respiratory distress syndrome, disseminated intravascular coagulation, congestive heart failure, renal failure, myocardial infarction, splenic infarcts or splenic rupture, and death. However, in our case the patient in consideration was clinically excluded for co-infection with Anaplasmaphagocytophilum.

ConclusionLyme disease is not regularly seen in visiting patients. One has to consider this disease in a patient presenting with fever, rash, facial palsy and altered sensorium as observed in our case. Diagnosis was confi rmed by Lyme immunoglobin M. Patient was treated adequately to get back to normal in two weeks. High degree of suspicion is required to clinically diagnose the likelihood of lyme disease.

References1. Cook, S., Macartney, K. and Rose, C. et al. (1997), “Lyme

Disease and Seventh Nerve Paralysis in Children”, Amer J. Otolaryngology, Vol. 18(5), Vol. 320–323.

2. Belani, K. and Regelmann, W. (1989), “Lyme Disease in Children”, Rheum DisClin North Am., Vol. 15, pp. 679–690.

3. Christen, H.J., Bartlau, N. and Hanefeld, F. et al. (1992), “Peripheral Facial Palsy in Childhood–Lyme Boreliosis to be Suspected Unless Proven Otherwise”, Acta Paediatr Scand., Vol. 79, pp. 1219–1224.

4. Clark, J.R., Carlson, R.D., Sasaki, C.T., Pachies, A.R. and Steere, A.C. (1985), “Facial Paralysis in Lyme Disease”, Laryngoscope, Vol. 95, pp. 1341–5.

5. Shapiro, E.D. and Gerber, M.A. (1997), “Lyme Disease and Facial Nerve Palsy”, Arch PediatrAdolesc Med., Vol. 151, pp. 1183–4.

6. Bakken, J.S. and Dumler, J.S. (2000), “Human Granulocytic Ehrlichiosis”, Clin Infect Dis., Vol. 31, pp. 554–60.

7. Dumler, J.S. and Walker, D.H. (2001), “Tick-borne Ehrlichioses: More of them, Higher Incidences, and Greater Clinical Diversity”, Lancet Infect Dis., Vol. 1, pp. 21–8.

8. Bakken, J.S. and Dumler, J.S. (2002), “Ehrlichia and Anaplasma Species”, In: Yu, V., Weber, R., Raoult, D., eds. Antimicrobial Therapy and Vaccine, 2nd ed. New York: Apple Trees Productions, pp. 875–82.

9. Shapiro, E. (2000), “Lyme Disease”, In: Behrman, et al., eds. Nelson Textbook of Pediatrics, 16th ed. Philadelphia, Pa: WB Saunders Co; pp. 910–914.

10. Martínez-Balzano, C., Hess, M., Malhotra, A. and Lenox, R. (2012), “Severe Babesiosis and Borrelia Burgdorferico-infection”, QJM., Epub June 7, 2012.



1FRCP (Glasgow), FRCP (Ireland), FACP (Philadelphia), FAAN (USA), DM (Neurology), MD (Medicine), MBBS, SENIOR Consultant Neurologist,Director and Head, Deptt. of Neurosciences,Jaswant Rai Speciality Hospital, Meerut (U.P.)E-mail: [email protected]/[email protected]

Stethoscope: An Unmatched Bicentenary JourneyDr. (Prof.) Bhupendra Chaudhary

Medical History

Invented in France in 1816 by French Physician R.T.H. Laennec at the Necker-Enfants Malades Hospital in Paris,

the unmatched golden tool of medical fraternity “The Stethoscope” has just completed its bicentenary journey.Laennec invented the stethoscope because he was uncomfortable placing his ear on women’s chests to hear heart sounds. He observed that a rolled notebook, placed between the patient’s chest and his ear, could amplify heart sounds without requiring physical contact. Laennec’s device was consisted of a wooden tube and was monoaural but was very much similar to the common ear trumpet, a historical form of hearing aid; indeed, his invention was almost indistinguishable in structure and function from the trumpet, which was commonly called a “microphone”. Laennec called his device the “stethoscope” (stetho- + -scope, “chest scope”), and he called its use “mediate auscultation”, because it was auscultation with a tool intermediate between the patient’s body and the physician’s ear.[1-2]

R.T.H. Laénnec

A succession of different designs followed his, including, eventually, a “binaural” type with two earpieces. In the early 1850s, there was a rush of designs for a new Stethoscope that used both the ears. This new “binaural” (‘bi-aural’) instrument was felt to be the future of auscultation. Actually, the idea for a Binaural Stethoscope was fi rst introduced in 1829.

An Irish Physician Arthur Leared presented a model of a “double” Stethoscope (Binaural) made of gutta-percha at the Great Exhibition in London in 1851. The fi rst commercially marketed model was that of Nathan Marsh of Cincinnati in 1851. His model was made of Indian rubber and contained the fi rst recorded diaphragm chest piece. However, it proved bulky and cumbersome and quickly faded. The diaphragm would not re-surface for 50 years.In 1852, Dr. George Philip Cammann of New York produced the fi rst recognized usable Binaural Stethoscope. Cammann did not claim to have the original idea for a Binaural Stethoscope. He claimed only to have designed a practical instrument that uses both ears and could be used in clinical practice which has become the standard ever since. The manufacturer of the original instrument, George Tiemann, named the Stethoscope Cammann’s Stethoscope.

Laénnec with his Monaural Wooden Tube Stethoscope

Early stethoscope of Laénnec(Science Museum, London)

Stethoscopes of Laénnec

Binaural Stethoscope



In 1940, Rappaport and Sprague designed a new stethoscope, which became the standard by which other stethoscopes are measured, consisting of two sides, one of which is used for the respiratory system (the diaphragm), the other for the cardiovascular system (the bell). The bell transmits low frequency sounds while the diaphragm transmits higher frequency sounds. The Rappaport-Sprague model stethoscope was heavy and short (18–24 in (46–61 cm)) with an antiquated appearance recognizable by their two large independent latex rubber tubes connecting an exposed-leaf-spring-joined-pair of opposing “f”-shaped chrome-plated brass binaural ear tubes with a dual-head chest piece.Several other minor refi nements were made to stethoscopes, until in the early 1960s David Littmann, a Harvard Medical School professor, created a new stethoscope that was lighter than previous models and had improved acoustics (3M-Littmann).[3]

In 1999, Richard Deslauriers patented the fi rst external noise reducing stethoscope, the DRG Puretone. It featured two parallel lumens containing two steel coils which dissipated infi ltrating noise as inaudible heat energy.

In 2015, Dr. Tarek Loubani announced an open-source 3D-printed stethoscope based on the 1960s-era Littmann Cardiology 3 stethoscope, which is out of patent. The 3D-printed equivalent is nearly an order of magnitude more affordable than the aforementioned non-3D-printed stethoscope and is intended to make the medical device more accessible to obtain, particularly in developing countries.[4]

References1. Laennec, R.T.H., Forbes, John and Sir, A. (1835), Treatise

on the Diseases of the Chest and on Mediate Auscultation, New York: Samuel Wood & Sons; Philadelphia : Desilver Thomas & Co.

2. Laennec’s New System of Diagnosis, The Quarterly Journal of Foreign Medicine and Surgery and of the Science Connected with Them, Vol. 2, pp, 51–68, 1820.

3. History of Littmann Stethoscope at a Glance. 3M.com Retreived 2010-01-25.

4. Ananthi, S. (2006), A Text-Book of Medical Instruments, pp. 290–296, New Age International, ISBN 8122415725.



Renal Papillary Necrosis (RPN) is an Ischemic Necrobiosis of the Papilla in the Medulla of the Kidney

The etiology of renal papillary necrosis includes diabetes, analgesic abuse or overuse, sickle cell disease,

pyelonephritis, renal vein thrombosis, tuberculosis, and obstructive uropathy. RPN may be asymptomatic but

when present, symptoms include fever and chills, fl ank and or abdominal pain haematuria and acute ureteral obstruction from sloughed papillae. Ultrasound shows fi lling defects in the pelvi calyceal system or ureter, necrosis of papillae in the cavities in medullary region.

In the presence of papillary sloughing, CT may depict hydronephrosis and fi lling defects in the renal pelvis or ureter, which also may contain calcifi cations.

Knowledge Forum

References1. Kim, S.H. (2003), “Renal Papillary Necrosis”, In: Kim, S.H.,

ed. Radiology Illustrated: Uroradiology, Philadelphia, Pa: Saunders, pp. 273–310.

2. Friedrich, N. (1877), “Ueber Necrose Der Nierenpapillen Bei Hydronephrose”, Arch Pathol Anat, Vol. 69, pp. 308–312.

3. Saifuddin, A. and Bark, M. (1991), “Case Report: Computed Tomography Demonstration of Renal Papillary Necrosis”, Clin Radiol, Vol. 44(4), pp. 275–276.

4. Edmondson, H.A., Reynolds, T.B. and Jacobson, H.G. (1966), “Renal Papillary Necrosis with Special Reference to Chronic Alcoholism: A Report of 20 Cases”, Arch Intern Med., Vol. 118(3), pp. 255–264.

5. Lindvall, N. (1960), “Renal Papillary Necrosis: A Roentgenographic Study of 155 Cases”, Acta Radiol, Vol. 192.



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Father’s Name ______________________________________________________________Gender M FQualifi cation : _____________________________________________________________________________________________( Mention the discipline in which postgraduate qualifi cation obtained)Institution/University : _____________________________________________________________________________________Year of Obtaining fi rst postgraduate qualifi cation : _____________________________________________________________API Member (Yes / No), If yes Membership No. _______________________________________________________________Mailing Address : __________________________________________________________________________________________ __________________________________________________________________________________________________________Contact No. : __________________________E – mail: ____________________________________________________________Permanent Address : _________________________________________________________________________________________________________________________________________________________________________________________________Applied for: (Please appropriate after reading the conditions overleaf)Life Member(LM) Associate Member(AM) Provisional Associate Member (PAM) (For PG Students)To the best of our knowledge and belief, the above particulars are correct and we consider him/her a fi t and proper person to be admitted as a member of the association._______________________ ___________________________Signature of Proposer Signature of Seconder

Name ________________________________ Name________________________________________API Membership No.___________________ API Membership No. __________________________UP API Membership No. _______________ UP API Membership No._______________________

Life membership Subscription (Inclusive of Admission Fee) Rs. 4000/- ( Rupees Four thousand only) is herewith enclosed vide Bank Draft No. __________________ Dated ____________ in Favour of “API-U.P. CHAPTER” Payable at Lucknow.

Subject to approval of the Governing Body in a Special Meeting, I agree to become a member and if admitted, to abide by the Rules and Regulations of the Association._______________________Signature of Candidate....................................................................................................................................................................................................................

For Offi ce UseAdmitted / Not Admitted Vide Governing Body Meeting Dated : ________________ held at __________________Payment received Rs. ____________________ Vide Bank Draft No. ________________ dated ___________________drawn on ___________________________________Bank.Membership No.: L/AM/PAM _______________



Documents to be Enclosed:

• Photocopy of registration with UP Medical Council of India or the Central Medical Council of India.• Photocopy of the postgraduate qualifi cation.

There are Two Categories of Membership:1. Life Member: Any person who is a member of Central body of Association of Physicians of India and is residing in Uttar Pradesh of India is eligible to become life member of U.P. Chapter. Central API membership is permissible to those who hold a postgraduate degree M.D. or D.M. or its equivalent in Internal Medicine from any institution or University recognised by the Medical Council of India or approved by the Governing body of the Association of Physicians of India provided he/she is not engaged in general or dispensing practice. Internal Medicine includes specialities such as Cardiology, Gastroenterology, Diabetology, Nephrology, Neurology, Clinical Hematology, Chest, Immunology, Rheumatology, Medical Oncology, Psychiatry, Pediatric Medicine, Dermatology, Radiation Medicine, Ultrasonography and others approved by Governing Body.

2. Associate Life Member: There are three categories of Associate Life Member:I. Those who are eligible to become Ordinary or Life member of Central body of API but have not become so far.II. Any person holding a postgraduate degree or diploma recognized by Medical Council of India in any branch of

Medical Science but is not eligible to become life member is eligible to become Associate Life Member.III. Provisional Associate Member: A Postgraduate student in Medicine may be enrolled as “Provisional Associate

Member” on payment of full membership fees of the chapter. Such Membership will ordinarily last for fi ve years unless the member informs about completion of postgraduate courses. In such cases he/she will be considered for Life Member/ Associate Life Members as per fulfi llment of the requirement.

Note:• Associate Life Member shall not have right to vote, propose, second or contest any position of the governing body. They shall also

not be entitled for participation, except when stated otherwise, in any “Award Session” or for recommendation for any distinction conferred by the U.P. Chapter.

• Photocopy of this form can also be used.



For Office use only

R/No.

Photograph

Date

Membership No. API Membership Application Form

To, The General Secretary The Association of Physicians of India-Noida Chapter–– T-21, Sector-11, Noida-201301 Tel : 0120-2538432-9810210479 We hereby propose the admission

Name (Surname)

First Name

Middle Name

L E

T T

E R

S )

Qualifications :

(Mention the branch of Medicine in which Postgraduate qualification is obtained) University : Year of obtaining first Postgraduate qualification :

Address

(B L

O C

K

Tel. (Office) :

Email :

as a LIFE (Please appropriate)

:

City District

State PIN

Tel. (Resi.) : Fax :

Mobile :

LIFE ASSOCIATE member of the Association POST GRADUATE MEMBERSHIP

MEMBERSHIP FEES : Life Member / Life Associate Member : ` 5000 plus admission fees Details of payment : In favour of “Association of Physicians of India-Noida Chapter” (Cheque* / DD / Cash • For Life / Associate Members: I hereby direct The Association of Physicians of India to transfer ` 5000

• I hereby state that the above information given is true and correct. Note for proposer / seconder : To the best of our knowledge and belief the above particulars are correct, and we consider him/her a fit proper person to be admitted as a member of the Association. Subject to the approval of the Governing Body in an ordinary or a special meeting, I agree to become a member and if admitted, to abide by the Rules and Regulations of the Association.

Signature of Candidate Note by Secretary

Xerox copies of registration with Medical Council and Postgraduation Certificate by a recognised university should accompany the application form For PG letter from head of the institution should accompany the application form with clear dates of joining the department and MBBS certificate (Xerox copies)

N.B. Kindly read carefully the rules and regulations printed overleaf before filling this form.



“Declare the past, diagnose the present, foretell the future”

Hippocrates

“As to diseases, make a habit of two things—to help, or at

least, to do no harm”

Hippocrates

MEDICAL QUOTATIONS

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Thanks & Regards

Editor-in-Chief UP JIMI Dr. S. ChakravortyMob: 9810210479

E-mail: [email protected]

Contact Person

API GOVERNING BODY

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