Ijcp july 2017

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Volume 28, Number 2

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yy American Family Physician yy Cardiology yy Community Medicine yy Drugs yy Internal Medicine yy Neurology yy Obstetrics and Gynecology yy Oncology

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IJCP Group of Publications

Volume 28, Number 2, July 2017

Dr Sanjiv Chopra Group Consultant Editor Dr Deepak Chopra Chief Editorial Advisor

Dr KK Aggarwal Padma Shri Awardee Group Editor-in-Chief Dr Veena Aggarwal Group Executive Editor

IJCP Editorial Board Obstetrics and Gynaecology Dr Alka Kriplani, Dr Thankam Verma, Dr Kamala Selvaraj Cardiology Dr Praveen Chandra, Dr SK Parashar Paediatrics Dr Swati Y Bhave Diabetology Dr CR Anand Moses, Dr Sidhartha Das, Dr A Ramachandran, Dr Samith A Shetty, Dr Vijay Viswanathan, Dr V Mohan, Dr V Seshiah, Dr Vijayakumar ENT Dr Jasveer Singh, Dr Chanchal Pal Dentistry Dr KMK Masthan, Dr Rajesh Chandna Gastroenterology Dr Ajay Kumar, Dr Rajiv Khosla, Dr JS Rajkumar Dermatology Dr Hasmukh J Shroff, Dr Pasricha, Dr Koushik Lahiri, Dr Jayakar Thomas Nephrology Dr Georgi Abraham Neurology Dr V Nagarajan, Dr Vineet Suri, Dr AV Srinivasan Oncology Dr V Shanta Orthopedics Dr J Maheshwari

Anand Gopal Bhatnagar Editorial Anchor Advisory Bodies Heart Care Foundation of India Non-Resident Indians Chamber of Commerce & Industry World Fellowship of Religions

This journal is indexed in IndMED (http://indmed.nic.in) and full-text of articles are included in medIND databases (http://mednic.in) hosted by National Informatics Centre, New Delhi.

FROM THE DESK OF THE GROUP EDITOR-IN-CHIEF

105 Consent Revisited: Inability to Manage Complications Leads to Violence

KK Aggarwal

AMERICAN FAMILY PHYSICIAN

107 Hyperlipidemia: Drugs for Cardiovascular Risk Reduction in Adults

Allen R. Last, Jonathan D. Ference, Elizabeth Rollmann Menzel

118 Practice Guidelines 120 Photo Quiz CARDIOLOGY

125 Detection of Congenital Heart Disease by Fetal Echocardiography and Its Correlation with Karyotype

Dharmendra Jain, Saumya Singh, Madhu Jain, Anjali Rani, Ashish Verma, Shivi Jain

131 Cardiac Autonomic Dysfunction: A Systematic Review

Muhammad Uwais Ashraf, Asif Hasan, Mohd. Aslam, Juwairia Ashraf

COMMUNITY MEDICINE

138 Lead Toxicity Among Automobile Garage Workers in the Vicinity of Nalanda Medical College and Hospital, Patna and the Adjoining Areas of Patna, Bihar, India

MA Nasar, TF Subhani, RR Sinha

DRUGS

149 An Observational Study on the Efficacy, Safety and Tolerability of Rosuvastatin in Indian Patients with Dyslipidemia: The RID-3 Study

Nazir I Juvale, L Sreenivasa Murthy, Nitin S Gokhale, Manjula S, Krishna Kumar M

155 Pitavastatin, Its Antioxidant and Hypocholesterolemic Effect

Tarannum Fatima Subhani, MA Nasar, RR Sinha, I Bhattacharya

INTERNAL MEDICINE

164 A Case of Renal Osteodystrophy on a Background Disease of Polyostotic Fibrous Dysplasia

Kunal Parwani, Manish Mehta, Hemang Acharya, AC Tanna, Jemima Bhaskar

NEUROLOGY

167 Aqeductal Stenosis Presenting with Spastic Paraparesis and Recurrent Hydrocephalic Attacks

Amit Agrawal

169 Laryngeal Neurofibroma: An Unusual Manifestation of Neurofibromatosis Type 1

Banshi Lal Kumawat, Kaushik Rana, Tarachand Saini, Ankur Garg

OBSTETRICS AND GYNECOLOGY

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

172 Hemoperitoneum Complicating Acute Fatty Liver of Pregnancy

Shivang Sharma, MN Mehta, HK Acharya, AC Tanna, Jemima Bhaskar

ONCOLOGY

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

174 Fine Needle Aspiration Cytology of Rhabdomyosarcoma of Cheek: A Case Report

Copyright 2017 IJCP Publications Ltd. All rights reserved.

Rimjhim Shrimal, Annu Nanda, Sangeeta Lamba, Divya Sethi

PEDIATRICS

The copyright for all the editorial material contained in this journal, in the form of layout, content including images and design, is held by IJCP Publications Ltd. No part of this publication may be published in any form whatsoever without the prior written permission of the publisher.

177 Assessment of Knowledge Regarding Appropriate Imaging Modalities Amongst Pediatricians

Shital Bhattad, Suresh Bhattad, Anil Tapdiya

CONFERENCE PROCEEDINGS

Editorial Policies

179 7th World Congress of Diabetes (DiabetesIndia 2017)

The purpose of IJCP Academy of CME is to serve the medical profession and provide print continuing medical education as a part of their social commitment. The information and opinions presented in IJCP group publications reflect the views of the authors, not those of the journal, unless so stated. Advertising is accepted only if judged to be in harmony with the purpose of the journal; however, IJCP group reserves the right to reject any advertising at its sole discretion. Neither acceptance nor rejection constitutes an endorsement by IJCP group of a particular policy, product or procedure. We believe that readers need to be aware of any affiliation or financial relationship (employment, consultancies, stock ownership, honoraria, etc.) between an author and any organization or entity that has a direct financial interest in the subject matter or materials the author is writing about. We inform the reader of any pertinent relationships disclosed. A disclosure statement, where appropriate, is published at the end of the relevant article.

183 54th Annual Conference of Indian Academy of Pediatrics (PEDICON 2017) MEDILAW

187 Case of Limited Negligence on Part of the Doctor and Contributory Negligence by the Patient AROUND THE GLOBE

191 News and Views LIGHTER READING

196 Lighter Side of Medicine

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

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FROM THE DESK OF THE GROUP EDITOR-IN-CHIEF

Dr KK Aggarwal

Padma Shri Awardee Group Editor-in-Chief

Consent Revisited: Inability to Manage Complications Leads to Violence

C

onsent, as we know, is the authorization or grant of permission by the patient for treatment or any diagnostic, surgical or therapeutic procedure to be carried out by the doctor. A doctor has to take consent from the patient before proceeding with his treatment.

It is ethical and in today’s scenario, a legal requirement.

Any act done without permission is “battery” or physical assault and is liable for punishment.

A valid consent has three components: Disclosure, Capacity and Voluntariness i.e., provision of relevant information by the doctor, capacity of the patient to understand the information given and take a decision based on the adequate information without force or coercion. This is informed consent. Any permission given under any unfair or undue pressure makes the consent invalid.

The Hon’ble Supreme Court of India has defined “adequate information” in the landmark case of Samira Kohli vs. Dr Prabha Manchanda. This includes “(a) nature and procedure of the treatment and its purpose, benefits and effect; (b) alternatives if any available; (c) an outline of the substantial risks and (d) adverse consequences of refusing treatment.”

No doctor practices medicine without taking informed consent. Yet we read and hear of incidents of violence against doctors from all parts of the country. So, are we going wrong somewhere? Are we doing something wrong somewhere?

“Medicine is an art based on science”, said Dr William Osler. Complications, adverse events or untoward

incidents may occur at any time during the treatment.

What is important here, how competent, we are, as doctors or how competent is the hospital or the clinical establishment, in managing these complications or untoward incidents in a nonemergent situation.

Not being able to manage complications leads to violence.

The patient should be informed of every possible complication that may occur during this treatment, however rare they might be; even a complication rate as low as 0.1% might be 100% for that particular patient.

No surgery can be called as a ‘minor’ surgery.

Mistakes are made, but we believe that nothing will happen either to us or the patient. As I wrote few days back, it’s the case of "Kya pharak padta hai" to "bahut pharak padta hai". If nothing goes wrong, then "chalta hai". But, if something does go wrong or an unanticipated event occurs, then this becomes unacceptable “chalta nahi hai”.

The key word here is ‘anticipation’.

Anticipate what all can happen in the course of a treatment and be prepared to handle them or keep your patient informed. For example, you may need to shift the patient in an emergency to a higher care center and your establishment does not have an ambulance. Outsourcing an ambulance will delay patient transportation, and in an emergency situation, the longer the delay, more agitated are the patients or family members and may become violent.

Indian Journal of Clinical Practice, Vol. 28, No. 2, July 2017

105

FROM THE DESK OF THE GROUP EDITOR-IN-CHIEF Let’s take another example. You might need the services of a specialist, say a urologist, neurosurgeon or a nephrologist. If your hospital does not have these specialty doctors on its staff, then subsequent delays in procuring their services will increase risk of violence.

Should you have these services and other such facilities as standby? Yes, everything must be on standby. The standby fee is 25%, while presence fee is 100%.

This may increase the cost of treatment. The time has come when the patient must know that safety comes at a price in bigger hospitals.

Inform the patient and the family members beforehand, let the patient choose and accordingly the consent should be taken. Safety of the patient is very important and should be our primary objective.

A small set-up may not have all facilities as their bigger and better equipped counterparts. These smaller setups should keep the patient and/or family members informed about this lack of facilities and take consent.

Good communication can reduce the rapidly increasing problem of violent attacks on doctors and healthcare establishments.

“Adequate information” for consent should include not only the competency of the doctor to treat the case, but also include the competency of the doctor and/or the hospital to manage any emergencies or untoward incident in a nonemergent situation. Any breach in this duty is negligence.

This, I believe, is an area which we need to work on.

It is the inability to manage complications that leads to violence.

As doctors we SERVE our patients and the community and provide ÂÂ

Service which we have professionally trained for, which is

ÂÂ

Excellent i.e., anticipated

ÂÂ

Responsible, give our 100% to the patients and take responsibility

ÂÂ

Value - Group; each member of the group knows the duties of another, so no gap in service may result

ÂÂ

Enthusiasm: A positive happy atmosphere

This is how we can avoid incidents of assault and violent attacks on doctors from happening.

■■■■

106

Indian Journal of Clinical Practice, Vol. 28, No. 2, July 2017

AMERICAN FAMILY PHYSICIAN

Hyperlipidemia: Drugs for Cardiovascular Risk Reduction in Adults ALLEN R. LAST, JONATHAN D. FERENCE, ELIZABETH ROLLMANN MENZEL

ABSTRACT Guidelines from the American College of Cardiology/American Heart Association (ACC/AHA) and the U.K. National Institute for Health and Care Excellence (NICE) indicate that lipid-lowering drugs have benefit for primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD) events. The evidence is strongest for statins. ACC/AHA, NICE, and U.S. Preventive Services Task Force (USPSTF) guidelines recommend statin therapy based on patients’ risk of an ASCVD event, rather than treating to specific lipid levels. For patients with no previous ASCVD event, risk calculators should be used to determine the 10-year risk of ASCVD. The ACC/AHA guideline recommends starting moderate- to high-intensity statins if the risk is 7.5% or greater, whereas the NICE and USPSTF guidelines recommend statins if the risk is 10% or greater. Patients with known ASCVD should receive high-intensity statins unless they fall into special categories (e.g., older age) or do not tolerate high-intensity statins, in which case moderate-intensity statins are appropriate. Liver transaminase levels should be checked before starting statins; guidelines vary on if and when to recheck them in the absence of symptoms. Lipid levels should be rechecked one to three months after starting statins, although guidelines differ on subsequent checks. Other lipid-lowering drugs (e.g., bile acid sequestrants, ezetimibe) can be considered if patients do not tolerate statins. Niacin should not be used.

Some evidence supports adding ezetimibe to statin therapy in patients with acute coronary syndrome or chronic kidney disease.

The role of proprotein convertase subtilisin/kexin type 9 inhibitors is unclear, but initial studies suggest a decrease in the rate of acute ASCVD events in patients with hypercholesterolemia.

Keywords: Lipid-lowering drugs, atherosclerotic cardiovascular disease, statins, ezetimibe, hypercholesterolemia

T

he American College of Cardiology (ACC) and the American Heart Association (AHA) jointly issued a new guideline in 2013 on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults.1 This guideline presented significant changes to previous recommendations on the management of hyperlipidemia for primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD), which includes acute coronary syndrome, stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic

ALLEN R. LAST, MD, MPH, is an associate professor in the Department of Family and Community Medicine and program director of the Medical College of Wisconsin Fox Valley Family Medicine Residency Program, Appleton.

JONATHAN D. FERENCE, PharmD, is an associate professor, director of the Pharmcy Care Lab, and assistant dean of assessment and alumni affairs at the Wilkes University Nesbitt School of Pharmacy, Wilkes-Barre, Pa. At the time the article was submitted, Dr. Ference was a community preceptor for the Wright Center for Graduate Medical Education–Family Medicine Residency Program, Kingston, Pa. ELIZABETH ROLLMANN MENZEL, MD, is an assistant professor in the Department of Family and Community Medicine at the Medical College of Wisconsin Fox Valley Family Medicine Residency Program.

Source: Adapted from Am Fam Physician. 2017;95(2):78-87.

attack, and peripheral arterial disease presumed to be of atherosclerotic origin.

Recommendations and guidelines from the ACC/AHA, U.K. National Institute for Health and Care Excellence (NICE), and U.S. Preventive Services Task Force (USPSTF) have eliminated goals for low-density lipoprotein cholesterol (LDL-C) and non–high-density lipoprotein cholesterol levels because studies to date have focused on treatment intensity rather than cholesterol levels (Table 1).1-4 As a result of this shift, the ACC/AHA and NICE guidelines recommend a different intensity of statin therapy based on ASCVD risk (Table 2).1 The USPSTF recommends using low- to moderateintensity statins only in patients with a combination of at least one ASCVD risk factor and a 10-year ASCVD risk of at least 10%.3 The NICE guideline also uses a 10-year ASCVD risk of 10% or greater as the trigger for statin therapy, whereas the ACC/AHA guideline recommends a threshold of 7.5% or greater (Table 1).1-4 The ACC/AHA also recommends that patients with a 10-year risk between 5.0% and 7.5% be considered for statin therapy. Recommendations for statin initiation based on these guidelines are shown in Figure 1.1-3

Indian Journal of Clinical Practice, Vol. 28, No. 2, July 2017

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AMERICAN FAMILY PHYSICIAN Table 1. Key Recommendations for the Management of Lipid Levels and Cardiac Risk

Indicator Risk calculator Threshold for initiating statin therapy

ACC/AHA 2013 guideline1 NICE 2014 guideline2 Use Pooled Cohort Equations* Use QRISK2 because it includes (http://www.cvriskcalculator.com) kidney function as part of its calculation4 (http://www.qrisk.org) Initiate therapy if patient has 10- Initiate therapy if patient has 10-year ASCVD risk ≥ 10% year ASCVD risk ≥ 7.5%

Consider therapy if patient has 10-year ASCVD risk 5% to 7.5% Patients with clinical If 75 years or younger, use high- Atorvastatin, 80 mg ASCVD intensity statin

USPSTF 2016 recommendation3 Use Pooled Cohort Equations* Initiate therapy if one or more ASCVD risk factors† and 10-year ASCVD risk ≥ 10% Consider therapy if one or more ASCVD risk factors† and 10-year ASCVD risk < 10% No recommendation

If older than 75 years, use moderate-intensity statin Patients with If 40 to 75 years of age with Atorvastatin, 20 mg, in patients with: If 40 to 75 years of age with: diabetes mellitus diabetes and LDL-C of 70 to 189 Type 1 diabetes and age older No history of CVD, one or more ASCVD mg per dL (1.81 to 4.90 mmol than 40 years risk factors† (e.g., diabetes), and 10per L), use a moderate-intensity year ASCVD risk ≥ 10%, initiate low- to Type 1 diabetes for > 10 years statin (unless 10-year ASCVD moderate-intensity statin risk ≥ 7.5%, in which case use a Nephropathy or other ASCVD No history of CVD, one or more ASCVD risk risk factors high-intensity statin) factors,† and 10-year ASCVD risk < 10%, Type 2 diabetes and 10-year consider low- to moderate-intensity statin ASCVD risk ≥ 10% Patients with chronic No specific recommendation Atorvastatin, 20 mg No recommendation kidney disease stage 3b or worse Patients without Moderate-intensity statin if 40 to Atorvastatin, 20 mg, if 10-year If 40 to 75 years of age with: diabetes or chronic 75 years of age and LDL-C is 70 ASCVD risk ≥ 10% No history of CVD, one or more ASCVD risk kidney disease to 189 mg per dL and 10-year factors,† and 10-year ASCVD risk ≥ 10%, ASCVD risk ≥ 7.5% initiate low- to moderate-intensity statin

Patients with LDL-C High-intensity statin ≥ 190 mg per dL (4.92 mmol per L) Patients older than No specific recommendation 85 years Liver enzyme Measure at baseline; after that, testing with alanine measure only if clinically indicated† transaminase Follow-up lipid testing

Measure lipid panel at baseline, after four to 12 weeks to discuss adherence and lifestyle changes, and then at three- to 12-month intervals

No specific recommendation

No history of CVD, one or more ASCVD risk factors,† and 10-year ASCVD risk < 10%, consider low- to moderate-intensity statin No recommendation

Consider atorvastatin, 20 mg

Insufficient evidence for primary prevention recommendation in patients 76 years and older Measure at baseline, within three No recommendation months of starting statin, and at 12 months; after that, measure only if clinically indicated‡ Measure lipid panel at baseline and No recommendation non–HDL-C after three months; if < 40% decrease in non–HDL-C, consider titrating therapy; consider annual non–HDL-C testing

*The Pooled Cohort Equations risk calculator was developed using data from black and non-Hispanic white patients. The calculator may underestimate the risk for patients from certain racial or ethnic groups, including Native Americans, some Asian Americans (e.g., of south Asian descent), and some Hispanics (e.g., Puerto Ricans), and may overestimate risk for others, such as some Asian Americans (e.g., east Asian descent) and some Hispanics (e.g., Mexican Americans). In spite of these shortcomings, the ACC/AHA still recommends using the Pooled Cohort Equations for all patients regardless of ethnicity because it is more reliable than other risk calculators. †ASCVD

risk factors include dyslipidemia (LDL-C > 130 mg per dL [3.37 mmol per L] or HDL-C < 40 mg per dL [1.04 mmol per L]), diabetes, hypertension, or smoking. ‡Indications include unusual fatigue or weakness, loss of appetite, abdominal pain, dark colored urine, or yellowing of the skin or sclera.

Information from references 1 through 4.

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Indian Journal of Clinical Practice, Vol. 28, No. 2, July 2017

AMERICAN FAMILY PHYSICIAN Initiating Statin Therapy Recommend heart-healthy lifestyle to prevent ASCVD Clinical ASCVD? No

Yes

LDL-C ≥ 190 mg per dL (4.92 mmol per L)?

No

Yes High-intensity statin (moderate intensity if not a candidate for high intensity [e.g., age > 75 years, intolerance])

Diabetes mellitus?

No

Yes

Age 40 to 75 years and LDL-C 70 to 189 mg per dL (1.81 to 4.90 mmol per L)?

Age 40 to 75 years and LDL-C 70 to 189 mg per dL?

No

Yes Use Pooled Cohort Equations or QRISK2 to estimate 10-year ASCVD risk

No

Yes Primary prevention

Age < 40 years or > 75 years or LDL-C < 70 mg per dL

Estimate 10-year ASCVD risk with Pooled Cohort Equations or QRISK2

Age < 40 years or > 75 years and LDL-C < 190 mg per dL

Go to A

10-year ASCVD risk ≥ 10%?* Yes Recommend moderateor high-intensity statin† (moderate intensity if not a candidate for high intensity [e.g., age > 75 years, intolerance])

No Consider lower moderate-intensity statin†

< 5% 10-year ASCVD risk

A Consider additional factors (e.g., family history, LDL-C ≥ 160 mg per dL [4.14 mmol per L], high-sensitivity C-reactive protein ≥ 2 mg per L [19.05 nmol per L], coronary artery calcium score ≥ 300, ankle-brachial index < 0.9, or lifetime risk)

5% to < 10% 10-year ASCVD risk*

Consider low- or moderate-intensity statin†

≥ 10% 10-year ASCVD risk*

Recommend moderateor high-intensity statin†

Shared decision making (Figure 2) *ACC/AHA recommends initiating statin therapy for a 10-year risk ≥ 7.5%. NICE and USPSTF recommend a threshold of ≥ 10%. †USPSTF recommends low- or moderate-intensity statin only if one or more ASCVD risk factors and 10-year risk ≥ 10%.

Figure 1. Recommended approach to the initiation of statin therapy.

(ACC/AHA = American College of Cardiology/ American Heart Association; ASCVD = Atherosclerotic cardiovascular disease; LDL-C = Low-density lipoprotein cholesterol; NICE = National Institute of Health and Care Excellence; USPSTF = U.S. Preventive Services Task Force.

Information from references 1 through 3.

Although the ACC/AHA and NICE guidelines do not recommend treating to lipid goals, the ACC/AHA guideline recommends checking lipid levels four to 12 weeks after initiation of statins to determine a patient’s adherence and every three to 12 months thereafter as clinically indicated. The NICE guideline recommends checking lipid levels three months after starting statins, but not routinely after that. Liver transaminase levels should be checked before starting statins. However,

guidelines vary on if and when to recheck them in the absence of symptoms. Both guidelines emphasize that shared decision making is essential to any treatment plan (Figure 2).1,2,5 RISK CALCULATORS After reviewing validated risk-prediction tools, the ACC/AHA panel determined that none was sufficiently

Indian Journal of Clinical Practice, Vol. 28, No. 2, July 2017

109

AMERICAN FAMILY PHYSICIAN Monitoring Therapeutic Response and Adherence to Statin Therapy Shared decision making for statin therapy*

A Heart-healthy lifestyle Risk factor modification Monitor adherence to plan

Plan includes statin?

Yes

No

Fasting lipid levels 4 to 12 weeks after statin initiation show anticipated response†?

Yes

Return to A

QUESTIONS ABOUT THE GUIDELINE

No

Reinforce adherence Consider rechecking lipid levels in 3 to 12 months

Intolerance to recommended dosage?

Yes

No

Consider alternative statin or alternative dosing schedule, such as every other day or once-weekly dosing

Reinforce adherence

Consider nonstatin therapy (ezetimibe, bile acid sequestrant, proprotein convertase subtilisin/kexin type 9 inhibitors)

Consider increasing statin intensity

Exclude secondary causes

B Follow-up lipid levels in 4 to 12 weeks show anticipated response†?

No

Yes Reinforce adherence

Reinforce adherence

Consider rechecking lipid levels in 3 to 12 months

Consider increasing statin intensity or adding nonstatin therapy

Return to

B

*Shared decision making should include: benefits of ASCVD risk reduction (multiply 10-year ASCVD risk by anticipated risk reduction for recommended statin: 30% for moderate intensity, 45% for high intensity); risks of statins (e.g., diabetes mellitus: absolute risk = 0.39% [number needed to harm = 255] over 4 years; myopathy: approximately 0.5 excess cases per 1,000 over 5 years; rhabdomyolysis: approximately 0.1 excess cases per 1,000 over 5 years); medication interactions; patient preferences; and other risk factors (e.g., family history, LDL-C > 160 mg per dL [4.14 mmol per L], lifetime ASCVD risk, coronary artery calcium score, ankle-brachial index, high-sensitivity C-reactive protein). †Anticipated

response: high intensity: LDL-C reduction of at least 50% from baseline (untreated); moderate intensity: LDL-C reduction of 30% to 49% from baseline (untreated).

Figure 2. Approach to monitoring the therapeutic response and adherence to statins.

ASCVD = Atherosclerotic cardiovascular disease; LDL-C = Low-density lipoprotein cholesterol Information from references 1, 2, and 5.

110

accurate for calculating the 10-year risk of an ASCVD event and subsequently developed the new Pooled Cohort Equations risk calculator that is available at http://www.cvriskcalculator.com. Concerns have been raised that the new calculator may overestimate risk by as much as 75% to 150%,6 but it is nonetheless more accurate for determining risk than the previously recommended Framingham risk calculator.7,8 The NICE guideline, however, recommends using the QRISK2 calculator, which is available at http://www.qrisk.org/.4 Clinicians should use the Pooled Cohort Equations risk calculator, the QRISK2 calculator, or both to determine a patient’s risk.

Indian Journal of Clinical Practice, Vol. 28, No. 2, July 2017

Questions about the ACC/AHA guideline have focused on bias in the development. Nearly every panelist for the 2004 ACC/AHA guidelines, developed in collaboration with the National Heart, Lung, and Blood Institute,9 had industry ties. The ACC/AHA committee made efforts to exclude industry influence for the 2013 guideline, but seven of the 15 panelists still had ties to industry.10 Additionally, there is concern that current guidelines underestimate the risks associated with statins. Major risks from statin use include myopathy (incidence of 0.5 per 1,000 more than in the general population over five years) and rhabdomyolysis (incidence of 0.1 per 1,000 more than in the general population over five years).11 There is also a small increase in the risk of diabetes mellitus. Although the ACC/AHA guideline mentions a 0.1% risk of diabetes and some studies have found higher rates associated with statin use, a 2010 metaanalysis of 13 trials involving 91,140 patients found an overall absolute risk of diabetes of 0.39% (number needed to harm = 255) over four years.12 AAFP ENDORSEMENT The American Academy of Family Physicians (AAFP) endorses the ACC/AHA guideline with qualifications13: The Pooled Cohort Equations risk calculator has not been validated and may overestimate risk. Using a cutoff of 7.5% for the 10-year risk of an ASCVD event rather than 10% significantly increases the number of individuals taking statins. Many of the ACC/AHA recommendations were based on expert opinion, and several members on the guideline panel had conflicts of interest. The AAFP has not commented on the NICE or USPSTF guidelines.

AMERICAN FAMILY PHYSICIAN PRIMARY PREVENTION OF ASCVD The foundation of primary prevention of ASCVD is therapeutic lifestyle modifications, which were reviewed in a previous issue of American Family Physician.14 To augment the benefits of therapeutic lifestyle modification, medications developed for the treatment of lipid disorders are sometimes used for primary prevention. eTable A summarizes the contraindications, adverse effects, effectiveness, and administration considerations for these medications.

Statins Statins have been shown to reduce the risk of ASCVD events when used for primary prevention, regardless of baseline risk. However, the magnitude of benefit becomes greater as the baseline risk of cardiovascular disease increases. For example, the five-year numbers needed to treat (NNT) for the prevention of one ASCVD event are 160, 108, 80, 54, and 40 for baseline 10-year ASCVD risks of 5%, 7.5%, 10%, 15%, and 20%, respectively.15 Similarly, when used for primary prevention, statins reduce overall mortality rates in patients with a baseline ASCVD risk of 10% or greater (five-year NNT = 250 to 500), but may not benefit those at lower risk (i.e., less than 10%).

Individuals with diabetes are at an increased lifetime risk of ASCVD events, and a high level of evidence supports the use of statin therapy for the primary prevention of major ASCVD events in these patients 40 to 75 years of age.1 For individuals with diabetes who fall outside of this age range, statin therapy should be considered on an individual basis after considering risk reduction benefits, the potential for adverse effects and drug-drug interactions, and patient preferences.

A 2013 Cochrane review of 56,934 patients found that for every 1,000 persons treated with a statin for five years, 18 would avoid a major ASCVD event (i.e., myocardial infarction [MI], angina, or stroke; NNT = 56).11 Although the review focused on studies that included fewer than 10% of participants with known ASCVD, the inclusion of individuals with known cardiovascular disease may have overestimated the benefit of statins. A separate review indicated that statins are cost-effective for primary prevention.16 The Cholesterol Treatment Trialistsâ&#x20AC;&#x2122; Collaboration provided further evidence in support of statin use for primary prevention of ASCVD events. The metaanalyses of 27 studies (n = 174,149), using individual participant data from the majority of statin trials, demonstrated a reduction in major ASCVD events

(e.g., nonfatal MI, fatal coronary events, coronary revascularization, stroke) associated with statin use in low-risk individuals (five-year risk less than 10%).

The authors found that for each reduction of 39 mg per dL (1.01 mmol per L) in LDL-C, there were 11 fewer major vascular events per 1,000 persons treated for five years.17 However, statin therapy for primary prevention was not associated with reduced rates of vascular death in patients with a five-year risk less than 10%. A secondary analysis evaluating all-cause mortality did not find a benefit from statin therapy in low-risk groups (i.e., 10-year risk less than 10%).18 Another recent trial comparing moderate-intensity statin therapy with placebo in patients at an intermediate risk of cardiovascular disease (i.e., approximately 1% annual cardiovascular event risk) also demonstrated a reduction in MI (NNT = 250), stroke (NNT = 200), coronary heart disease (NNT = 200), and cardiovascularrelated hospitalization (NNT = 72) after a median of 5.6 years in patients receiving statins.19 Statin therapy was associated with an increased risk of cataract surgery (number needed to harm = 142) and muscle pain or weakness (number needed to harm = 91), and as with the Cholesterol Treatment Trialistsâ&#x20AC;&#x2122; Collaboration, there were no differences in cardiovascular or all-cause mortality.

Based on study findings, statin therapy may be recommended for primary prevention of cardiovascular events in patients with or without diabetes and a 10-year ASCVD risk of at least 7.5% according to the ACC/AHA guideline, or at least 10% according to the NICE and USPSTF guidelines (Figure 1).1-3

Nonstatins There is no convincing evidence that routine use of nonstatin lipid-lowering medications (i.e., ezetimibe, niacin, fibrates, and omega-3 fatty acids) are useful in the primary prevention of ASCVD.20 The addition of niacin demonstrated significant harm in a recent randomized controlled trial, and its use is no longer recommended.21 In early 2016, the U.S. Food and Drug Administration withdrew approvals for extendedrelease niacin and delayed-release fenofibric acid (fibrate) in combination with statins based on the lack of cardiovascular benefit reported in trials.22 In 2016, the ACC issued an Expert Consensus Decision Pathway (ECDP) on the role of nonstatin therapies in the management of ASCVD risk.5 The ECDP did not involve formal systematic reviews, grading of the evidence, or synthesis of the evidence. Rather, as expert opinion, its

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AMERICAN FAMILY PHYSICIAN goal was to provide practical advice for clinicians and patients in situations not covered by the 2013 ACC/AHA guideline until more evidence emerges. The consensus statement recommends that nonstatin therapy should be considered in at-risk individuals who do not achieve the expected statin response (e.g., 50% or greater LDL-C reduction with high-intensity statin therapy or 30% to 49% LDL-C reduction with moderate-intensity statin therapy) or who cannot tolerate the recommended statin dose. Nonstatin therapies should not, however, be considered as alternatives to evidence-based statin therapy unless intolerance has been systematically determined. A decision support tool to assist clinicians in this process is available at http://www.acc.org/ StatinIntoleranceApp. If nonstatins are used because of documented statin intolerance or a failure to achieve an expected response with statins, the ECDP recommends ezetimibe as firstline therapy or bile acid sequestrants as second-line therapy (e.g., if a patient cannot tolerate ezetimibe and the triglyceride level is less than 300 mg per dL [3.4 mmol per L]) for primary prevention in patients with or without diabetes, a 10-year ASCVD risk of 10% or greater, and a baseline LDL-C level of 70 to 189 mg per dL (1.81 to 4.90 mmol per L).5 These recommendations also apply to patients without ASCVD and a baseline LDL-C level of 190 mg per dL (4.92 mmol per L) or greater. However, in these patients, it is reasonable to consider a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor in combination with maximally tolerated statin therapy before a bile acid sequestrant because PCSK9 inhibitors are more effective at lowering LDL-C levels. The ECDP recommends that complex cases be referred to lipid subspecialists.

As a new class of medications, PCSK9 inhibitors are showing early promise for the prevention of ASCVD. PCSK9 is a natural protein that binds to and destroys LDL receptors in the liver, thereby preventing them from removing LDL-C from the circulation. The PCSK9 inhibitors block this protein, allowing the receptors to continue clearing LDL-C. A 2015 meta-analysis of 24 trials involving adults with hypercholesterolemia (individual trials consisted of mixed populations of primary and secondary prevention) found significant reductions in MI (NNT = 136 to 1,442) and all-cause mortality (NNT = 246 to 1,354) in patients who received PCSK9 inhibitors combined with maximally tolerated statin therapy compared with patients who received placebo or ezetimibe.23 The studies in the meta-analysis were limited by their short duration of follow-up (two months to

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two years),23 and the use of these medications is limited by high cost and the need for administration by injection.

Although promising, more data are needed on the long-term safety, effectiveness, and cost-effectiveness of PCSK9 inhibitors before they can be recommended for the primary prevention of ASCVD events in patients other than those with extreme LDL-C elevations (i.e., 190 mg per dL or greater).

SECONDARY PREVENTION OF ASCVD

Statins Statins are recommended for secondary prevention in almost all patients with established ASCVD.1,2 Statins benefit patients with established ASCVD independently of sex or baseline cholesterol levels.24,25 In adults with a history of ASCVD, statins decrease the five-year risk of death (NNT = 61), MI (NNT = 47), and stroke (NNT = 189).26-28 A 2015 meta-analysis of 27 secondary-prevention studies comparing statins (or more intensive statin therapy) with a control group (or less intensive statin therapy) demonstrated similar reductions in major vascular events in men (NNT = 91 for five years) and in women (NNT = 143 for five years) for each 39-mg-per-dL reduction in LDL-C levels.25 The effectiveness of statin therapy for reducing cardiovascular risk does not appear to differ among statins and should be considered a class effect.29 The comparative effectiveness likely relates more to the intensity of dosing than to the specific agent used.

If high-intensity statins are indicated (Table 11-4) but the patient cannot tolerate this level of statins, moderateintensity statin therapy is the preferred approach.

Similarly, moderate-intensity statins can be used in patients with established ASCVD who have a risk factor for statin-induced adverse effects, such as advanced age, frailty or small body frame, hypothyroidism, surgery (i.e., during the perioperative period), or alcohol abuse.30 In cases of true statin intolerance (i.e., intolerance to two or three statins with at least one at the lowest dose), nonstatin therapies may be considered.

Nonstatins To date, there are no convincing clinical data showing that niacin, fibrates, or omega-3 fatty acids, either as monotherapy or in addition to high-intensity statins, provide additional benefit for secondary prevention of ASCVD events with an acceptable margin of safety beyond that of high-intensity statins.1,31-40

AMERICAN FAMILY PHYSICIAN However, there is some initial evidence that ezetimibe may have a role in secondary prevention of ASCVD. The IMPROVE-IT trial randomized patients who experienced a recent acute coronary syndrome event to ezetimibe plus moderate-intensity simvastatin (40 mg daily) or to placebo plus simvastatin (40 mg daily).31 Combination therapy produced a 2% absolute risk reduction of the composite outcome (cardiovascular death, MI, or nonfatal stroke; 32.7% vs. 34.7%; NNT = 50 for six years). Most of the benefit came from a reduction in nonfatal MIs (NNT = 58 over six years). All-cause mortality, cardiovascular death, and discontinuation of medication because of adverse events did not differ between groups. It is important to note that the comparison group received less than the recommended dose of a statin (i.e., moderate-intensity rather than high-intensity). The most conservative conclusion that can be drawn from this trial is that a moderate-intensity statin plus ezetimibe may serve as an alternative in patients with acute coronary syndrome who do not tolerate high-intensity statin therapy.

The ACCâ&#x20AC;&#x2122;s ECDP acknowledges a gap in evidence from randomized controlled trials demonstrating benefit when adding nonstatins to statin therapy in patients with stable clinical ASCVD (i.e., an ASCVD event more than three months prior) who have not achieved an expected response to a statin. Ezetimibe (first line), a bile acid sequestrant (second line, if intolerant to ezetimibe and triglyceride level is less than 300 mg per dL), or a PCSK9 inhibitor (added to maximally tolerated statin and either ezetimibe or bile acid sequestrant) may be reasonable if patients and clinicians agree after engaging in shared decision making.5 The discussion should address the potential for further ASCVD risk reduction that can be expected from adding a nonstatin, the potential for adverse events or drug-drug interactions, and patient preferences. However, intensifying lifestyle modifications and addressing other major ASCVD risk factors should be considered before adding nonstatin therapy.

In patients with documented statin intolerance, the ECDP recommends referral to a lipid subspecialist.

Ezetimibe, a bile acid sequestrant, or both are recommended in these patients. A PCSK9 may be considered only if use of these medications does not produce a greater than 50% reduction in LDL-C levels.

STATINS FOR SPECIFIC VASCULAR CONDITIONS

Acute Coronary Syndrome High-intensity statin therapy is recommended for acute coronary syndrome. A systematic review of

three randomized trials comparing high-intensity vs. moderate-intensity statins in patients with acute coronary syndrome demonstrated reductions in all-cause mortality (NNT = 85; 95% confidence interval [CI], 55 to 236) and cardiovascular mortality (NNT = 109; 95% CI, 69 to 469) with high-intensity statin therapy.27

Cerebrovascular Disease Statin use lowers the risk of stroke, even in moderaterisk individuals (five-year ASCVD risk of 10% or less), with an NNT of 90 over five years, independent of age, sex, LDL-C levels, or previous diagnosis of vascular disease.17 There was concern that statins might increase the risk of hemorrhagic stroke and offset the benefits, but a meta-analysis of 31 trials did not demonstrate an association between statin use and hemorrhagic stroke risk.41

Peripheral Arterial Disease and Aortic Aneurysm A Cochrane review found that statin use among patients with peripheral arterial disease nearly doubled total walking distance, from an average of 175 to 327 m (574 to 1,073 ft); it also increased pain-free walking distances from 148 to 238 m (486 to 781 ft).42 A 2014 meta-analysis revealed that in patients with peripheral arterial disease, statin use reduced all-cause mortality (NNT = 12; 95% CI, 9 to 23).43 Similarly, statin use in patients with an abdominal aortic aneurysm repair lowers mortality rates (NNT = 12 for five years; 95% CI, 8 to 25).44 There is not, however, an effect on the rate of aneurysm expansion in patients who have not undergone repair.

STATIN THERAPY IN SPECIFIC POPULATIONS

Older Adults Few clinical trials have evaluated the use of statins in older patients. In a 2013 meta-analysis of eight trials that included patients with a mean age of 73.0 Âą 2.9 years who did not have clinical ASCVD, statin use was associated with a reduced risk of MI (NNT = 45 to 171) and stroke (NNT = 97 to 511).45 There was no difference, however, in all-cause mortality.

An earlier meta-analysis found that in patients 62 to 85 years of age with ASCVD, statin use reduced the risk of death (NNT = 28; 95% CI, 15 to 56), nonfatal MI (NNT = 38; 95% CI, 16 to 118), and stroke (NNT = 58; 95% CI, 27 to 177) over five years.46

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AMERICAN FAMILY PHYSICIAN Frail patients may be more likely to have adverse effects with statin therapy. Despite this, frail older adults still benefit; just one year of statin therapy has been demonstrated to lower mortality rates (adjusted hazard ratio = 0.67; 95% CI, 0.53 to 0.84) and slow physical functional decline.47 The NICE guideline recommends treating older patients up to 84 years of age the same as adults of any age, and that moderate-intensity statins should be considered for the prevention of nonfatal MI in patients older than 85 years.2 The USPSTF guideline concludes there is insufficient evidence to balance the risks and benefits of primary prevention with statins in persons 76 years and older.3 The ACC/AHA guideline does not have recommendations for patients older than 75 years unless they have clinical ASCVD, recommending moderate-intensity rather than highintensity statins in those patients.1 Shared decision making is especially important in frail older adults because the risk of adverse effects increases in this population while life expectancy is diminished, which may offset the potential benefits.

Chronic Kidney Disease In patients with chronic kidney disease who do not require dialysis, statin therapy reduces the risk of major cardiovascular events (NNT = 16 to 25), allcause mortality (NNT = 36 to 124), and cardiovascular mortality (NNT = 56 to 116).48 However, statin use may not reduce all-cause or cardiovascular mortality in patients on dialysis.49 For patients with chronic kidney disease, there is evidence to support the addition of ezetimibe to statin therapy. The SHARP trial found reductions in ischemic strokes (NNT = 112) and coronary revascularization (NNT = 84) with ezetimibe/simvastatin compared with placebo over five years in patients with chronic kidney disease.50 Moderate- to high-intensity statin therapy should be recommended for primary prevention in patients with stage 3b or more severe chronic kidney disease.

Pregnancy Because of the risks of fetal harm, women taking statins should be advised to discontinue treatment immediately if they become pregnant, and they should be counseled on intensive lifestyle modifications.5 Bile acid sequestrants may be appropriate in the interim.

Statin therapy may be resumed after completion of breastfeeding. Women who plan to become pregnant

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should discontinue statin use at least one to three months before attempting to conceive.

Note: For complete article visit: www.aafp.org/afp.

REFERENCES 1. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/ AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines [published corrections appear in J Am Coll Cardiol. 2015; 66(24):2812, and J Am Coll Cardiol. 2014;63(25 pt B):30243025]. J Am Coll Cardiol. 2014;63(25 pt B):2889-2934.

2. National Institute for Health and Care Excellence.

Cardiovascular disease: risk assessment and reduction, including lipid modification. NICE clinical guideline CG181. July 2014. http://www.nice.org.uk/guidance/ cg181. Accessed October 30, 2015.

3. Bibbins-Domingo K, Grossman DC, Curry SJ, et al. Statin use for the primary prevention of cardiovascular disease in adults: US Preventive Services Task Force recommendation statement. JAMA 2016;316(19):1997-2007.

4. Hippisley-Cox J, Coupland C, Vinogradova Y, et al.

Predicting cardiovascular risk in England and Wales: prospective derivation and validation of QRISK2. BMJ. 2008;336(7659):1475-1482.

5. Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 2016 ACC Expert Consensus Decision Pathyway on the role of non-statin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol. 2016;68(1):92-125.

6. Ridker PM, Cook NR. Statins: new American guidelines for prevention of cardiovascular disease. Lancet. 2013; 382(9907):1762-1765.

7. Pursnani A, Massaro JM, Dâ&#x20AC;&#x2122;Agostino RB Sr, Oâ&#x20AC;&#x2122;Donnell CJ, Hoffmann U. Guideline-based statin eligibility, coronary artery calcification, and cardiovascular events. JAMA. 2015;314(2):134-141.

8. Johnson KM, Dowe DA. Accuracy of statin assignment using the 2013 AHA/ACC Cholesterol Guideline versus the 2001 NCEP ATP III guideline: correlation with atherosclerotic plaque imaging. J Am Coll Cardiol. 2014; 64(9):910-919.

9. Grundy SM, Cleeman JI, Merz CN, et al.; National Heart, Lung, and Blood Institute; American College of Cardiology Foundation; American Heart Association.

Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines [published correction appears in Circulation.

2004;110(6):763]. Circulation. 2004;110(2):227-239.

10. Ioannidis JP. More than a billion people taking statins?

Potential implications of the new cardiovascular guidelines. JAMA. 2014;311(5):463-464.

AMERICAN FAMILY PHYSICIAN 11. Taylor F, Huffman MD, Macedo AF, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2013;(1):CD004816.

12. Sattar N, Preiss D, Murray HM, et al. Statins and the incident risk of diabetes: a collaborative meta-analyis of randomised statin trials. Lancet. 2010;375(9716):735-742.

13. American Academy of Family Physicians. Clinical practice guideline. Treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults.

June 2014. http://www.aafp.org/patient-care/clinicalrecommendations/all/cholesterol.html. Accessed March 3, 2016.

14. Kelly RB. Diet and exercise in the management of hyperlipidemia. Am Fam Physician. 2010;81(9):1097-1102.

15. DynaMed. Statins for primary and secondary prevention of cardiovascular disease. June 8, 2016. https://www. dynamed.com/topics/dmp~AN~T115052 [login required].

Accessed October 19, 2016.

16. Pandya A, Sy S, Cho S, Weinstein MC, Gaziano TA. Costeffectiveness of 10-year risk thresholds for initiation of statin therapy for primary prevention of cardiovascular disease [published correction appears in JAMA. 2015; 314(15):1647]. JAMA. 2015;314(2):142-150.

17. Mihaylova B, Emberson J, Blackwell L, et al.; Cholesterol Treatment Trialists’ (CTT) Collaborators. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012;380(9841): 581-590.

18. Abramson JD, Rosenberg HG, Jewell N, Wright JM. Should people at low risk of cardiovascular disease take a statin? [published correction appears in BMJ. 2014;348: g3329]. BMJ. 2013;347:f6123.

19. Yusuf S, Bosch J, Dagenais BG, et al.; HOPE-3 Investigators.

Cholesterol lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med. 2016;374(21): 2021-2031.

in adults with hypercholesterolemia: a systematic review and meta-analysis. Ann Intern Med. 2015;163(1):40-51.

24. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med. 1996;335(14):1001-1009.

25. Fulcher J, O’Connell R, Voysey M, et al.; Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials. Lancet. 2015;385(9976):1397-1405.

26. Gutierrez J, Ramirez G, Rundek T, Sacco RL. Statin therapy in the prevention of recurrent cardiovascular events: a sex-based meta-analysis. Arch Intern Med. 2012; 172(12):909-919.

27. Mills EJ, O’Regan C, Eyawo O, et al. Intensive statin therapy compared with moderate dosing for prevention of cardiovascular events: a meta-analysis of >40,000 patients. Eur Heart J. 2011;32(11):1409-1415.

28. Wilt TJ, Bloomfield HE, MacDonald R, et al. Effectiveness of statin therapy in adults with coronary heart disease.

Arch Intern Med. 2004;164(13):1427-1436.

29. Zhou Z, Rahme E, Pilote L. Are statins created equal?

Evidence from randomized trials of pravastatin, simvastatin, and atorvastatin for cardiovascular disease prevention. Am Heart J. 2006;151(2):273-281.

30. Pasternak RC, Smith SC Jr, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. Circulation.

2002;106(8):1024-1028.

31. Cannon CP, Blazing MA, Giugliano RP, et al.; IMPROVEIT Investigators. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25): 2387-2397.

20. Sando KR, Knight M. Nonstatin therapies for management of dyslipidemia: a review. Clin Ther. 2015;37(10): 2153-2179.

32. Sharma M, Ansari MT, Abou-Setta AM, et al. Systematic review: comparative effectiveness and harms of combination therapy and monotherapy for dyslipidemia.

Ann Intern Med. 2009;151(9):622-630.

21. Landray MJ, Haynes R, Hopewell JC, et al.; HPS2-THRIVE Collaborative Group. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014; 371(3):203-212.

33. Studer M, Briel M, Leimenstoll B, Glass TR, Bucher HC. Effect of different antilipidemic agents and diets on mortality: a systematic review. Arch Intern Med. 2005;165(7):725-730.

22. U.S. Food and Drug Administration. Withdrawal of approval of indications related to the coadministration with statins in applications for niacin extendedrelease tablets and fenofibric acid delayed-release capsules. Federal Register. April 18, 2016. https://www. federalregister. gov/articles/2016/04/18/2016-08887/ abbvie-inc-et-al-withdrawal-ofapproval-of-indicationsrelated-to-the-coadministration-with-statins.

Accessed October 17, 2016.

34. Jun M, Foote C, Lv J, et al. Effects of fibrates on cardiovascular outcomes: a systematic review and metaanalysis. Lancet. 2010;375(9729):1875-1884.

23. Navarese EP, Kołodziejczak M, Schulze V, et al. Effects of proprotein convertase subtilisin/kexin type 9 antibodies

35. Keene D, Price C, Shun-Shin MJ, Francis DP. Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomised controlled trials including 117,411 patients. BMJ. 2014;349:g4379.

36. Boden WE, Probstfield JL, Anderson T, et al.; AIM-HIGH Investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy [published

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AMERICAN FAMILY PHYSICIAN correction appears in N Engl J Med. 2012;367(2)189]. N Engl J Med. 2011;365(24):2255-2267.

37. Kwak SM, Myung SK, Lee YJ, Seo HG; Korean Metaanalysis Study Group. Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: a meta-analysis of randomized, double-blind, placebo-controlled trials. Arch Intern Med. 2012;172(9): 686-694.

38. Yokoyama M, Origasa H, Matsuzaki M, et al.; Japan EPA lipid intervention study (JELIS) Investigators. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis [published correction appears in Lancet. 2007; 370(9583): 220]. Lancet.

2007;369(9567):1090-1098.

39. Duggal JK, Singh M, Attri N, et al. Effect of niacin therapy on cardiovascular outcomes in patients with coronary artery disease. J Cardiovasc Pharmacol Ther. 2010;15(2): 158-166.

40. Marchioli R, Barzi F, Bomba E, et al. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)-Prevenzione. Circulation.

2002;105(16):1897-1903.

41. McKinney JS, Kostis WJ. Statin therapy and the risk of intracerebral hemorrhage: a meta-analysis of 31 randomized controlled trials. Stroke. 2012;43(8): 2149-2156.

42. Aung PP, Maxwell HG, Jepson RG, Price JF, Leng GC. Lipid-lowering for peripheral arterial disease of the lower limb. Cochrane Database Syst Rev. 2007;(4):CD000123.

44. Twine CP, Williams IM. Systematic review and metaanalysis of the effects of statin therapy on abdominal aortic aneurysms. Br J Surg. 2011;98(3):346-353.

45. Savarese G, Gotto AM Jr, Paolillo S, et al. Benefits of statins in elderly subjects without established cardiovascular disease: a meta-analysis [published correction appears in J Am Coll Cardiol. 2014;63(11):1122]. J Am Coll Cardiol.

2013;62(22):2090-2099.

46. Afilalo J, Duque G, Steele R, Jukema JW, de Craen AJ, Eisenberg MJ. Statins for secondary prevention in elderly patients: a hierarchical bayesian meta-analysis. J Am Coll Cardiol. 2008;51(1):37-45.

47. Galindo-Ocaña J, Bernabeu-Wittel M, Formiga F, et al.; PROFUND Project researchers. Effects of reninangiotensin blockers/inhibitors and statins on mortality and functional impairment in polypathological patients.

Eur J Intern Med. 2012;23(2):179-184.

48. Palmer SC, Navaneethan SD, Craig JC, et al. HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis. Cochrane Database Syst Rev. 2014;(5):CD007784.

49. Palmer SC, Navaneethan SD, Craig JC, et al. HMG CoA reductase inhibitors (statins) for dialysis patients.

Cochrane Database Syst Rev. 2013;(9):CD004289.

50. Baigent C, Landray MJ, Reith C, et al.; SHARP Investigators. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet.

2011;377(9784):2181-2192.

51. Last AR, Ference JD, Falleroni J. Pharmacologic treatment of hyperlipidemia [published correction appears in Am Fam Physician. 2012; 86(10):889]. Am Fam Physician.

2011;84(5):551-558.

43. Antoniou GA, Fisher RK, Georgiadis GS, Antoniou SA, Torella F. Statin therapy in lower limb peripheral arterial 52. Safeer RS, Lacivita CL. Choosing drug therapy for disease: systematic review and meta-analysis. Vascul patients with hyperlipidemia. Am Fam Physician. 2000; Pharmacol. 2014;63(2):79-87.

61(11):3371-3382.

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AMERICAN FAMILY PHYSICIAN

Practice Guidelines CDC UPDATES RECOMMENDATIONS FOR CONTRACEPTIVE USE Almost one-half of pregnancies are unintentional, with one-half of these in women not using a contraceptive method when conception occurred. Adolescents and young women, those who are racial or ethnic minorities, and those with lower levels of education and income are more likely to become pregnant unintentionally.

Guiding women and their partners in selecting an appropriate contraceptive method and ensuring its correct and consistent use can help with prevention.

The Centers for Disease Control and Prevention (CDC) first published the U.S. Selected Practice Recommendations for Contraceptive Use (U.S. SPR) in 2013 to provide direction for safe and effective use of contraceptive methods. These guidelines update the 2013 report.

Using the Guidelines The guidelines are arranged by contraceptive method and discussed in order from highest to lowest effectiveness. It should be noted that recommendations do not comment on every aspect of use, but instead provide the best evidence available for issues that commonly occur. In general, initiation, follow-up, and management of problems are discussed for each method, with the recommendations listed first, followed by comments and evidence summaries.

The U.S. Medical Eligibility Criteria for Contraceptive Use, which can be found at http://www.cdc.gov/ reproductivehealth/contraception/usmec.htm, contains recommendations for women who require additional contraceptive guidance for medical reasons. Charts and algorithms that summarize the recommendations can be found in the appendix of the original CDC guidelines.

The U.S. SPR website provides more helpful tools at http://www.cdc.gov/reproductivehealth/contraception/ usspr.htm.

ulipristal emergency contraceptive pills and added new recommendations regarding medications to help with inserting intrauterine devices (IUDs).

Physicians should counsel women to wait at least five days after taking ulipristal before starting or continuing their hormonal contraception. However, if using a method that is nonhormonal, it can be started or resumed immediately after taking ulipristal. If needed, a regular contraceptive method should be prescribed. If a woman opts for a method that would require an appointment with a physician (e.g., depot medroxyprogesterone, implants, IUDs), starting it at the same time as ulipristal is an option. Although this could make ulipristal less effective, it is a risk that should be balanced with the risk of not initiating regular contraception. Sexual intercourse should be avoided or barrier contraception used in the first week of starting or restarting regular contraception or until menses occurs. If there is no withdrawal bleeding in three weeks, a pregnancy test is recommended.

When performing IUD insertion, routine administration of misoprostol is not recommended, but its use may be beneficial in some women, including those in whom insertion has recently failed. To decrease pain associated with insertion, a paracervical block with lidocaine may be helpful.

Confirming a Woman is Not Pregnant

The 2016 guidelines updated recommendations about starting or resuming regular contraception after using

Most of the guidance indicates that a contraceptive method can be started anytime during a womanâ&#x20AC;&#x2122;s menstrual cycle, assuming she is not pregnant.

Physicians can be reasonably certain that a woman is not pregnant by using the following criteria, which have a high accuracy. If there are no signs or symptoms of pregnancy and at least one criterion is met, it can be assumed with reasonable certainty that the woman is not pregnant; however, a urine test can still be warranted based on the physicianâ&#x20AC;&#x2122;s clinical judgment.

If criteria are not met, then pregnancy cannot be ruled out with reasonable certainty. This is true even if there are negative results on a pregnancy test.

Source: Adapted from Am Fam Physician. 2017;95(2):125-126.

Criteria include that she has started her normal menses or had a spontaneous or induced abortion no more than seven days ago; has not participated in sexual intercourse since the start of her last normal menses; is

Updates

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AMERICAN FAMILY PHYSICIAN correctly and consistently using a reliable contraceptive method; is four weeks or less postpartum; or is fully or almost fully breastfeeding, has amenorrhea, and is less than six months postpartum.

against the benefits of making the contraceptive method available. Class C tests do not contribute considerably to safe and effective use.

Procedures

Before copper or levonorgestrel-releasing IUD insertion, bimanual examination and cervical inspection should be performed to determine uterine size and position, as well as to identify cervical or uterine abnormalities that could be a sign of infection or that could prevent IUD insertion. No examinations or tests are needed before using an implant, or initiating depot medroxyprogesterone or progestin-only pills. However, before starting combined hormonal contraceptives, blood pressure should be measured. Additionally, measuring baseline weight and body mass index could be useful to monitor women using all of these contraceptive methods.

Recommendations regarding the examinations and tests to perform before starting each contraceptive method in women presumed to be healthy are provided in the guidelines. The CDC has chosen to use a classification system created by the World Health Organization to determine their applicability. Class A indicates that the tests are essential and mandatory in all circumstances. Class B indicates that they contribute substantially to safe and effective contraceptive use, but their application can be considered within the public health context, service context, or both. Risks associated with not performing Class B tests should be weighed

Class A

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AMERICAN FAMILY PHYSICIAN

Photo Quiz NECK CREPITUS IN A RUNNER A 27-year-old man presented with constant right-sided neck, throat, and ear pain that began one day earlier after he completed an uneventful five-mile trail run.

There were no alleviating or exacerbating factors for the pain. He did not have trauma or injury to the area.

He reported a vague sensation of fluid moving around in his neck and a strange feeling in his throat with swallowing. He did not have dysphagia, odynophagia, fever, chills, or respiratory symptoms. He did not use drugs or alcohol.

On physical examination, he was well appearing with normal vital signs and normal oxygen saturation on room air. An ear examination was normal. The neck examination revealed minimally palpable crepitus at the right lateral aspect of the base of the neck. There was no skin warmth or erythema. Soft tissue neck radiography was performed (Figures 1 and 2).

Figure 1.

Question Based on the patientâ&#x20AC;&#x2122;s history, physical examination, and radiography findings, which one of the following is the most likely diagnosis?

A. Esophageal rupture.

B. Retropharyngeal abscess.

C. Spontaneous gas gangrene.

D. Spontaneous pneumomediastinum.

E. Spontaneous pneumothorax.

Figure 2.

SEE THE FOLLOWING PAGE FOR DISCUSSION.

Source: Adapted from Am Fam Physician. 2017;95(2):113-115.

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AMERICAN FAMILY PHYSICIAN

A

B

Figure 3. Free air or gas (arrows) in the deep tissue planes of the neck and upper thorax tracking superiorly from the mediastinal space. (A) Anteroposterior view. (B) Lateral view.

Discussion The answer is D: spontaneous pneumomediastinum.

Spontaneous pneumomediastinum is the sudden presence of free air or gas in the mediastinal space in a previously healthy patient. The deep tissue planes in the neck and upper thorax form a potential space for free air to track from the mediastinum to the cervical region (Figure 3), causing subcutaneous emphysema, as in this patient. Pneumomediastinum is rare and is often the result of thoracic trauma, surgical procedures, or pulmonary infections.1 Spontaneous pneumomediastinum is more common in children than adults. In adults, it predominantly occurs in healthy, thin young men. The underlying cause is alveolar rupture due to overdistention or increased alveolar pressure.2 There are case reports of spontaneous pneumomediastinum resulting from exertion in childbirth and during sports.3 Symptoms include the sudden onset of neck swelling, neck pain, odynophagia, chest pain, dyspnea, cough, and, less commonly, voice changes. On physical examination, subcutaneous crepitus in the neck may be noted. The diagnosis can usually be made with plain radiography of chest or neck soft tissue. Radiographs reveal subcutaneous emphysema or air in the tissue planes of the neck. Less commonly, axial computed tomography of the chest is needed to make the diagnosis. No treatment beyond rest and analgesics is recommended. Clinical findings typically resolve within seven days.

Esophageal rupture is a spontaneous tear of the esophageal wall due to increased pressure in the esophagus. Most cases are iatrogenic, usually from medical instrumentation such as endoscopy, but it can also occur with vomiting. Symptoms are severe retrosternal chest pain, dysphagia, and upper abdominal pain that is typically preceded by vomiting.

Esophageal rupture can cause mediastinitis and pneumomediastinum. Gas in the neck may be seen.

Diagnosis is made with a contrast esophagram or computed tomography.4 Retropharyngeal abscess is caused by a bacterial infection in the soft tissue posterior to the pharynx.

It is more common in children. Symptoms include dysphagia, odynophagia, drooling, decreased oral intake, neck swelling, refusal to move the neck, muffled â&#x20AC;&#x153;hot potatoâ&#x20AC;? voice, and fever. Typically, children with the condition are ill appearing. Radiography of the lateral neck may reveal widening of the prevertebral space, loss of cervical lordosis because of muscle spasm, a soft tissue mass in the posterior pharynx, or rarely, air fluid levels or gas in the prevertebral space only.5 Spontaneous gas gangrene, or clostridial myonecrosis, is a life-threatening muscle infection that develops after hematogenous seeding by Clostridium septicum from the gastrointestinal tract. It can occur anywhere in the skeletal muscles of the body. Symptoms include sudden onset of severe muscle pain and fever. Predisposing factors may include gastrointestinal lesions, such as

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AMERICAN FAMILY PHYSICIAN Summary Table Condition

Characteristics

Esophageal rupture

Severe retrosternal chest pain, dysphagia, and upper abdominal pain that is typically preceded by vomiting; gas in the neck may be seen if complicated by mediastinitis or pneumomediastinum

Retropharyngeal abscess

Dysphagia, odynophagia, drooling, decreased oral intake, neck swelling, refusal to move the neck, muffled “hot potato” voice, and fever; more common in children; radiography of the lateral neck may reveal widening of the prevertebral space, loss of cervical lordosis, a soft tissue mass in the posterior pharynx, or, rarely, air fluid levels or gas in the prevertebral space only

Spontaneous gas gangrene

Sudden onset of severe muscle pain and fever; tissue crepitus and tenderness, edema, bullae, and purple skin discoloration; often accompanied by systemic symptoms of sepsis; gas within the soft tissue on radiography or computed tomography

Spontaneous pneumomediastinum

Sudden onset of neck swelling, neck pain, odynophagia, chest pain, dyspnea, cough, and, less commonly, voice changes; subcutaneous crepitus in the neck may be noted; radiographs reveal subcutaneous emphysema and air in the tissue planes of the neck

Spontaneous pneumothorax

Sudden onset of chest pain and shortness of breath; hyperresonance and decreased breath sounds on the affected side; chest radiographs show displacement of the pleural line

carcinoma, and immunosuppression. Physical findings include tissue crepitus with tenderness, edema, bullae, and purple skin discoloration. Sepsis is common. Gas within the soft tissue on radiography or computed tomography is suggestive of gas gangrene and helps to differentiate it from other bacterial soft tissue infections.6 Spontaneous pneumothorax is the presence of gas or free air in the pleural space of the thoracic cavity.

Symptoms are sudden onset of chest pain and shortness of breath. Physical findings can be subtle and include hyperresonance and decreased breath sounds on the affected side. Chest radiographs (posteroanterior inspiratory and lateral films) may show displacement of the pleural line (the line between the lung and chest wall), but soft tissue radiographs are normal.7 REFERENCES 1. Huon LK, Chang YL, Wang PC, Chen PY. Head and neck manifestations of spontaneous pneumomediastinum.

Otolaryngol Head Neck Surg. 2012;146(1):53-57.

3. Murad AA. Spontaneous pneumomediastinum. BMJ Case Rep. 2011;2011.

4. Triadafilopoulos G. Boerhaave syndrome: effort rupture of the esophagus. UpToDate. http://www.uptodate. com/contents/boerhaave-syndrome-effort-ruptureof-the-esophagus?source=search_result&search=esop hageal+rupture&selectedTitle=1%7E24 (subscription required). Accessed February 15, 2015.

5. Wald ER. Retropharyngeal infections in children.

U p To D a t e . h t t p : / / w w w. u p t o d a t e . c o m / c o n t e n t s / retropharyngeal-infections-in-children?source=machineL earning& search=Retro pharyngeal+infections+in+children & selected Title=1%7E150&section Rank=1 & anchor= H12 #H1 (subscription required). Accessed February 15, 2015.

6. Stevens DL, Bryant A. Clostridial myonecrosis.

UpTo-Date. http://www.uptodate.com/contents/ clostridialmyonecrosis?source=machineLearning& search=gas+gangrene & selected Title=1%7E23 & section Rank=1&anchor=H2538563#H2538563(subscription required). Accessed February 15, 2015.

7. MacDuff A, Arnold A, Harvey J; BTS Pleural Disease Guideline Group. Management of spontaneous pneumothorax: British Thoracic Society Pleural Disease Guideline 2010. Thorax. 2010;65(suppl 2): ii18-ii31.

2. Maunder RJ, Pierson DJ, Hudson LD. Subcutaneous and mediastinal emphysema. Pathophysiology, diagnosis, and management. Arch Intern Med. 1984;144(7):1447-1453.

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CARDIOLOGY

Detection of Congenital Heart Disease by Fetal Echocardiography and Its Correlation with Karyotype DHARMENDRA JAIN*, SAUMYA SINGH†, MADHU JAIN‡, ANJALI RANI#, ASHISH VERMA¥, SHIVI JAIN$

ABSTRACT Background: Congenital heart diseases (CHDs) account for a third of all major congenital abnormalities in children; nearly 1,80,000 children are born with heart defect each year in India. Approximately, 10% of present infant mortality in India may be attributed to CHD alone. Such high mortality is due to laying less emphasis on its prenatal diagnosis by fetal echocardiography.

This study was done with objectives to find out the incidence of CHD in high risk cases and its correlation with karyotype and also evaluating the diagnostic accuracy of fetal echocardiography. Methods: Fetal echocardiography was performed in 142 high risk cases who attended antenatal clinic of Institute of Medical Sciences (IMS), Banaras Hindu University (BHU), Varanasi between July 2014 to June 2016 with maternal/fetal risk for CHD (maternal diabetes mellitus, collagen disorders, teratogen exposure, maternal TORCH infection, in vitro fertilization [IVF] conceived pregnancy, familial history of CHD, abnormal fourchamber view, monochorionic twins). Results: The incidence of major CHD was 28/1,000 live births and 56/1,000 live births for minor CHD in high risk group. Ventricular septal defect (16.6%) and hypoplastic left heart syndrome (16.6%) were the most common CHD detected. Family history of CHD increases the risk significantly. Fetal echocardiography was 75% (46.77-91.11, 95% confidence interval [CI]) sensitive and 94.5% (89.22-97.35, 95% CI) specific, with 92.91% (87.44-96.1, 95% CI) diagnostic accuracy. It was seen that 16.6% cases of CHD had aneuploidy detected on karyotyping (trisomy 21 and trisomy 18). Conclusion: Fetal echocardiography is highly sensitive and specific, when done by an experienced operator. Prenatal diagnosis of CHD and planned delivery in a cardiac facility had satisfactory immediate outcomes.

Keywords: Congenital heart disease, fetal echocardiography, karyotype, prenatal diagnosis

A

s a group, congenital heart disease (CHD) constitute a significant proportion (up to 25% in some studies) of congenital malformations that present in the neonatal period, and are a major cause of perinatal mortality and therefore significantly contribute to the economic burden on healthcare systems. They are frequently not detected by routine ultrasound screening examinations. Fetal echocardiography, being more sensitive and specific, is able to detect most of

*Assistant Professor Dept. of Cardiology †Resident ‡Professor #Associate Professor Dept. of Obstetrics and Gynecology ¥Associate Professor $Assistant Professor Dept. of Radiodiagnosis Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh Address for correspondence Dr Dharmendra Jain C-2, New Medical Enclave, Near Naria Gate, Banaras Hindu University Varanasi - 221 005, Uttar Pradesh E-mail:djaincard@gmail.com

the CHD cases. The main focus of this study was to find out the incidence of CHDs in high risk cases, the degree of risk associated with various individual risk factors, and the role of fetal echocardiography as a prenatal diagnostic tool. Newborns with structural anomalies were also investigated for any aneuploidy, to study the correlation.

METHODS The present study was a prospective observational study performed in high risk group (of fetal CHD) at the Dept. of Obstetrics and Gynecology, the Dept. of Radiodiagnosis & Imaging and Dept. of Cardiology, in the Institute of Medical Sciences (IMS), Banaras Hindu University (BHU), Varanasi, Uttar Pradesh.

All antenatal women attending the antenatal clinic at Dept. of Obstetrics and Gynecology, in Sir Sunderlal Hospital (SSH), BHU with any maternal indication (risk) of CHD (i.e., maternal metabolic disorder, collagen disorder, first trimester teratogen exposure, TORCH infection, in vitro fertilization [IVF] conceived pregnancy, bad obstetric history, maternal/fetal sibling with CHD) or fetal indication (i.e., abnormal level 2 scan,

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CARDIOLOGY monochorionic twins) were recruited for the study from July 2014 to June 2016. Written and informed consent was obtained from all the participants prior to their enrollment in the Dept. of Obstetrics and Gynecology.

Ultrasound fetal biometry, measurement of nuchal fold thickness, targeted imaging for fetal anomalies were performed on each antenatal women with the indication of CHD. Echocardiogram was performed by transabdominal route between 18-20 weeks of pregnancy.

RESULTS The data were collected from 142 high risk cases for fetal CHD. The analysis of the data collected have indicated that majority of high risk cases were between 25-29 years age group (45.1%) followed by 33.8% between 20-24 years age group. Maximum patients were multigravida (71.8%), among whom 31.3% had previous mid-trimester abortions and 11.7% had previous term intrauterine deaths (IUDs)/stillborns; 2.8% were monochorionic twin pregnancies. Indications of fetal echocardiography in study group are depicted in Table 1, which shows abnormal level 2 scan was the most common indication.

Abnormal Fetal Echocardiographic Findings and Postnatal Echocardiography Table 2 shows that among 142 high risk cases studied, fetal echocardiogram was abnormal in 10.5% (15/142) with 7.04% (10/142) confirmed postnatally. Ventricular septal defect (VSD; 16.6%) and hypoplastic left heart syndrome (HLHS; 16.6%) were the most common CHD detected. One tricuspid atresia (TA) and 1 pulmonary

stenosis (normal fetal echocardiography) were diagnosed in postnatal echocardiogram. The incidence of CHD was found to be 56/1,000 live birth for minor CHD and 28/1,000 for major cardiac defects.

Correlation of Individual Risk Factor with Cardiac and Extracardiac Anomaly Table 3 shows that among patients with metabolic disorder (i.e. diabetes mellitus) 6.7% neonates had cardiac anomaly and 20% had extracardiac structural anomaly.

It was observed that in pregnancies conceived through IVF, extracardiac structural anomaly was detected in 37.5% neonates, which is statistically significant (p > 0.05). Cardiac anomaly was detected in none. The analysis indicates that 10.5% newborns with maternal TORCH infection had cardiac anomaly, while 21% had other structural anomalies (p < 0.05).

It was found that if the previous issue of a patient had cardiac anomaly, there was a possibility that this cardiac anomaly could resurface in her next pregnancy. The data indicated that 23.1% cases had cardiac anomaly in present issue also (p < 0.05), while among those with previous issue with extracardiac anomaly, 10.5% had cardiac anomaly, in fetus (p > 0.05); 21.1% of newborns with maternal CHD had cardiac anomaly (p < 0.05).

Among maternal risk factors studied, familial history of congenital heart defect (maternal CHD)/sibling CHD had maximum association with CHD in newborn.

Maternal-Newborn Correlation of Cardiac Anomalies Recurrence of septal defect was seen in 14.2% (1/7 cases of atrioventricular septal defect in mother).

Table 1. Indications of Fetal Echocardiography in Study Group (n = 142) No. of patients

Percentage (%)

Metabolic disorder (diabetes mellitus)

15

10.6

Collagen disorder

1

0.7

Teratogen exposure

1

0.7

IVF conceived

8

5.6

TORCH infection

19

13.3

Previous issue with extracardiac anomaly

22

15.5

Previous issue with cardiac anomaly

18

12.7

Maternal congenital cardiac disease

20

14.1

Abnormal level 2 scan

62

43.7

Monochorionic twins

4

2.8

Maternal risk factors

Fetal risk factors

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CARDIOLOGY Table 2. Abnormal Fetal Echocardiographic Findings and Postnatal Echocardiography (n = 142) Fetal echocardiography

No. of patients (%)

Postnatally confirmed (%)

Cardiomegaly

5 (3.5)

40

Dextrocardia

1 (0.7)

100

Prominent PDA

1 (0.7)

100

VSD

2 (1.4)

100

ASD

1 (0.7)

100

1 (0.7)

0

1 (0.7)

0

Tetralogy of Fallot

1 (0.7)

100

Hypoplastic left heart syndrome

2 (1.4)

100

Left to right shunt

Rhythm abnormality Heart block/fetal arrhythmia Outflow tract abnormality Coarctation of aorta Cyanotic heart disease

Table 3. Correlation of Individual Risk Factor with Cardiac and Extracardiac Anomaly (n = 142) Maternal risk factor

Cardiac anomaly Not detected (%)

P value

Detected (%)

Extracardiac anomaly Not detected (%)

P value

Detected (%)

Metabolic disorder

14 (93.3)

1 (6.7)

0.649

12 (80)

3 (20)

0.089

Collagen disorder

1 (100)

0 (0.0)

0.999

1 (100)

0 (0.0)

0.999

Teratogen exposure

1 (100)

0 (0.0)

0.999

1 (100)

0 (0.0)

0.999

In vitro fertilization

8 (100)

0 (0.0)

0.968

5 (62.5)

3 (37.5)

0.002

TORCH infection

17 (89.5)

2 (10.5)

0.726

15 (78.9)

4 (21)

0.033

Previous issue with extracardiac congenital anomaly

17 (89.5)

2 (10.5)

0.726

22 (100)

0 (0.0)

0.242

Previous issue with congenital cardiac disorder

10 (76.9)

3 (23.1)

0.046

17 (94.4)

1 (5.6)

0.636

Maternal congenital cardiac disease

15 (78.9)

4 (21.1)

0.033

20 (100)

0 (0.0)

0.298

Monochorionic twin

4 (100)

0 (0.0)

0.984

3 (75)

1 (25)

0.227

One mother with ASD had tracheoesophageal fistula (TEF) in newborn, one mother with TEF had patent ductus arteriosus (PDA) in newborn, one mother with pulmonary stenosis had cardiomegaly in newborn.

Risk Estimation for Cardiac Anomaly The odds ratio (OR) and relative risk (RR) in a mother suffering with diabetes mellitus for having an issue with congenital cardiac malformation was 0.615 (0.075-5.068) and 1.560 (0.219-11.099), respectively, in maternal TORCH infection OR was 1.329 (0.268-6.594) and RR was 1.295 (0.307-5.46), in previous issue with

extracardiac structural anomaly OR was 1.329 (0.2686.594) and RR was 1.295 (0.307-5.46), in previous issue with cardiac anomaly OR was 4.0 (0.931-17.17) and RR was 3.308 (1.021-10.72), in cases with maternal congenital cardiac disease OR was 3.833 (1.029-14.28) and RR 3.237 (1.079-9.711).

Risk Estimation for Extracardiac Structural Anomaly The OR and RR in a mother with diabetes mellitus for having issue with any extracardiac structural anomaly was 3.278 (0.78-13.77) and 2.822 (0.856-9.295),

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CARDIOLOGY respectively, in IVF conceived pregnancies OR was 8.33 (1.71-40.58) and RR was 5.58 (1.86-16.68), in maternal TORCH infection OR was 3.83 (1.029-14.28) and RR was 3.237 (1.079-9.711), in previous issue with cardiac anomaly OR was 0.604 (0.073-4.982) and RR was 0.62 (0.085-4.565), in monochorionic twins OR was 3.848 (0.368-40.17) and RR was 3.136 (0.523-18.77).

Correlation of Cardiac Anomaly with Karyotyping Abnormality Out of 142 high risk cases studied, aneuploidy was detected in 7 (trisomy 21 [5], trisomy 18 [1], monosomy X [1]). Table 4 shows that among newborns with aneuploidy 28.6% had associated cardiac abnormality, but the association was not statistically significant.

Evaluation of Fetal Echocardiography in Study Group Fetal echocardiography was found to be 75% sensitive (95% CI: 46.77, 91.11) and 94.5% specific (95% CI: 89.22, 97.35) with diagnostic accuracy of 92.9% (95% CI: 87.44, 96.1) in detecting CHDs prenatally with positive predictive value of 56.25% (95% CI: 33.18, 76.9) and negative predictive value of 97.6% (95% CI: 93.18, 99.18).

Mode of Delivery and Pregnancy Outcome Mean gestational age at diagnosis of fetal cardiac anomaly and at their delivery was 27.5 weeks and 37.3 weeks, respectively. While 22.1% pregnancies in overall study group were delivered by lowersegment cesarean section (LSCS), the cesarean section rate was slightly higher (27.6%) in pregnancies with anomalous babies.

Approximately 46.8% newborns with structural anomalies were treated successfully with proper NICU care and early surgical intervention, 21.1% newborns died in neonatal period, 4.2% pregnancies with major anomalies were aborted and 6.3% resulted in stillborn.

Table 4. Correlation of Cardiac Anomaly with Karyotyping Abnormality Cardiac anomaly

Karyotype Normal

Abnormal

No.

%

No.

%

Not detected

125

92.6

5

71.4

Present

10

7.4

2

28.6

Ď&#x2021;2 = 3.8529; p = 0.0496.

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DISCUSSION In this study, major indication of fetal echocardiography was fetal abnormal level 2 scan (43.7%) followed by familial/sibling CHD (in 28.2% cases patients had previous issue with congenital structural anomaly, in 14.1% cases mother had congenital cardiac disease).

The incidences of CHD as seen in this study was 56/1,000 live births having minor CHD, 28/1,000 having major cardiac defects, which are higher if compared to the CHD prevalence in general population (6-8 per 1,000 pregnancies). The reason behind this difference could be due to undetected cases of CHDs in the general population, and present study being confined to high risk group at a tertiary center, with 43% already referred from periphery with abnormal anomaly scan.

VSD (16.6%) and HLHS (16.6%) were the most common CHD detected in our study.

In this study, correlation of pregestational diabetes with structural anomalies was statistically insignificant (p > 0.05). Balsells et al1 reported RR 2.66 (2.04-3.47) in cohort studies and OR 4.7 (3.01-6.95) in the single case-control study for major congenital heart defects in newborns of pregestational diabetic mothers. Present study indicates a lower risk as majority of cases had controlled diabetes (only 2/15 had glycosylated hemoglobin [HbA1c] >6) and due to presence of other confounding factors in nondiabetic mothers.

The correlation of IVF conceived pregnancy and maternal TORCH infection with cardiac anomaly was also found to be statistically insignificant. In IVF conceived pregnancy, cardiac anomaly was detected in none while RR/OR for extracardiac anomaly (1 Dandy-Walker syndrome, 1 renal dysplasia, 1 posterior urethral valve) were RR 5.58 (1.86-16.68)/OR 8.33 (1.7140.58). However, Davies et al2 conducted study on assisted conception in South Australia reported OR 1.26 (95% CI, 1.07-1.48) for any birth defect in IVF conceived pregnancies. Furthermore, in this study, 10.5% newborns with maternal TORCH infection had cardiac anomaly (2/19 cases - 1 dilated cardiomyopathy, 1 dextrocardia) and 21% had extracardiac anomaly (4/19 cases - meningomyelocele, cleft lip with cleft palate, hypoplastic kidney, club foot). The study also established that OR/RR for cardiac defect was OR 1.329 (0.268-6.594)/RR 1.295 (0.307-5.46), for extracardiac anomaly it was OR 3.83 (1.029-14.28)/RR 3.237 (1.0799.711). Padmavathy et al3 study done at Bangalore showed malformations in 25% newborns with TORCH IgM positive mother and in 3.5% newborns with TORCH IgG positivity.

CARDIOLOGY Significant association could be noticed between CHD in newborn and maternal CHD (4/19 cases) with OR 3.833 (1.029-14.28) and RR 3.237 (1.079-9.711). Also recurrence of septal defect was observed in 14.2% cases (1/7 cases). Oyen et al4 conducted study on 18,708 cases of CHD in Denmark reported overall RRÂ 8.38 (6.82-10.3) for same CHD in baby and 2.68 (95% CI 2.43-2.97) for dissimilar CHD. Most importantly, it was observed in the study that the patients with the previous childbirth with congenital cardiac defects also had significant association with CHD in newborn; 23.1% newborns with CHD in sibling had cardiac defect, OR 4.0 (0.93117.17), RR 3.308 (1.021-10.72). However, the recurrence risk of similar CHD in siblings could not be determined, as data regarding the exact type of lesion in siblings were not available. Further, Gill et al5 had observed that the incidences of CHD in pregnancies referred due to prevalence of sibling CHD to be 2.7%, and incidence of CHD for pregnancies referred due to maternal CHD was (2.9%). Such higher incidence in present study was due to presence of other confounding factors.

No cardiac defect was found in monochorionic twins and extracardiac congenital defects was identified in 25% cases (1/4 cases) with OR 3.848 (0.368-40.17) and RR 3.136 (0.523-18.77). Bahtiyar et al6 concluded that monochorionic/diamniotic twin gestations are at a higher risk for CHDs with RR, 9.18 (95% CI, 5.5115.29; p < 0.001) in presence of twin-twin transfusion syndrome (TTTS) and RR, 2.78 (95% CI, 1.03-7.52; p = 0.04) without TTTS. Fetal echocardiography is an essential tool in the evaluation of CHD and has dramatically improved the accuracy of diagnosis of CHD. The reported sensitivity of fetal echocardiography has ranged from 4% to 96% in various series depending upon the equipment, level of training, study design and examination technique.

It is highly sensitive and specific when done by an experienced operator. In present study, its sensitivity was found to be 75%, specificity 94.5% and diagnostic accuracy was 92.91% (87.44-96.1).

In this study, 16.6% cases of CHD had aneuploidy detected on karyotyping (2/12 cases). Trisomy 21 (in VSD) and trisomy 18 (in tricuspid atresia) were detected.

Trevisan et al7 reported the frequency of chromosomal abnormalities identified through karyotyping in cases of CHD to be 16.8%; Down syndrome being the most common (14.4%) followed by trisomy 18.

Intrapartum cesarean section was the mode of delivery in 22.1% patients while 77.9% patients delivered vaginally, in this study. Similarly, Walsh et al8 reported

LSCS is significantly higher in fetal CHD than nonanomalous controls (21% vs. 13.5%), predominantly related to cesarean section for nonreassuring fetal status. It was also identified that the rates of preterm delivery were higher in the cases of CHD. In this study, 46.8% newborns with structural anomalies were treated successfully with proper NICU care and early surgical intervention on the other hand 21.1% newborns died during the neonatal period. The mortality rate was higher in neonates having cardiac defects with associated extracardiac or chromosomal anomalies (40% and 50%, respectively), and also in cases with severe cardiac defects (HLHS, TA). Brown et al9 concluded that the setting in which neonatal CHD is first recognized (antenatal/postnatal) has an impact on preoperative condition, which in turn influences postoperative progress and survival after surgery.

Optimal screening procedures and access to specialist care will improve outcome for neonates undergoing cardiac surgery.

CONCLUSIONS It can be concluded that in the present study, the incidence of CHD was 56/1,000 live births for minor CHD, 28/1,000 for major cardiac defects. VSD (16.6%) and HLHS (16.6%) were the most common CHD detected.

Major indication for fetal echocardiography was abnormal level 2 scan (43.7%). Majority of patients were multigravida (71.8%) among whom 31.3% had previous mid-trimester abortions and 11.7% had previous term IUDs/stillborns, emphasizing significance of previous obstetric history. Among maternal risk factors studied, familial history of congenital heart defect (maternal CHD/sibling CHD) had maximum association with CHD in newborn; 16.6% cases of CHD had aneuploidy detected on karyotyping (trisomy 21 and trisomy 18).

Any fetal karyotyping abnormality is an indication for fetal echocardiography. Fetal echocardiography was found to be 75% sensitive and 94.5% specific with diagnostic accuracy of 92.9% in detecting CHDs prenatally. Increased intrapartum cesarean section rate was seen in pregnancies with anomalous babies, fetal distress being a major indication. Prenatal diagnosis of CHD and planned delivery in a cardiac facility had satisfactory immediate outcomes.

REFERENCES 1. Balsells M, GarcĂ­a-Patterson A, Gich I, Corcoy R. Major congenital malformations in women with gestational diabetes mellitus: a systematic review and meta-analysis.

Diabetes Metab Res Rev. 2012;28(3):252-7.

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CARDIOLOGY 2. Davies MJ, Moore VM, Willson KJ, Van Essen P, Priest K, Scott H, et al. Reproductive technologies and the risk of birth defects. N Engl J Med. 2012;366(19): 1803-13.

6. Bahtiyar MO, Dulay AT, Weeks BP, Friedman AH, Copel JA. Prevalence of congenital heart defects in monochorionic/diamniotic twin gestations: a systematic literature review. J Ultrasound Med. 2007;26(11):1491-8.

3. Padmavathy M, Mangala G, Malini J, Umapathy BL, Navaneeth BV, Bhatia M, et al. Seroprevalence of TORCH infections and adverse reproductive outcome in current pregnancy with bad obstetric history. J Clin Biomed Sci. 2013;3(2):14-23.

7. Trevisan P, Zen TD, Rosa RF, Silva JN, Koshiyama DB, Paskulin GA, et al. Chromosomal abnormalities in patients with congenital heart disease. Arq Bras Cardiol.

2013;101(6):495-501.

4. Øyen N, Poulsen G, Boyd HA, Wohlfahrt J, Jensen PK, Melbye M. Recurrence of congenital heart defects in families. Circulation. 2009;120(4):295-301.

8. Walsh CA, MacTiernan A, Farrell S, Mulcahy C, McMahon CJ, Franklin O, et al. Mode of delivery in pregnancies complicated by major fetal congenital heart disease: a retrospective cohort study. J Perinatol. 2014;34(12):901-5.

9.

5. Gill HK, Splitt M, Sharland GK, Simpson JM. Patterns of recurrence of congenital heart disease: an analysis of 6,640 consecutive pregnancies evaluated by detailed fetal echocardiography. J Am Coll Cardiol. 2003;42(5):923-9.

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Brown KL, Ridout DA, Hoskote A, Verhulst L, Ricci M, Bull C. Delayed diagnosis of congenital heart disease worsens preoperative condition and outcome of surgery in neonates. Heart. 2006;92(9):1298-302.

Routine CT Angiography to Detect Severe Coronary Artery Disease Prior to Transcatheter Aortic Valve Replacement A new retrospective study published in the Journal of Thrombosis and Thrombolysis was conducted on 50 patients undergoing both invasive coronary angiography (ICA) and routine pre-transcatheter aortic valve replacement (TAVR) computed tomography angiogram (CTA). Among the participants, approximately threefourth were ≥75 years old, of which 57% were females, half were diabetic and 45% had prior percutaneous coronary intervention (PCI). ICA results showed that 49% had significant coronary calcification. While a 39% incidence of severe proximal to mid vessel coronary artery disease by ICA was estimated. Additionally, onethird of the patients required PCI before TAVR. In addition, CTA could not exclude severe proximal to mid vessel CAD in 88% of patients. Nondiagnostic coronary CTA readings ranged between 25% and 72% according to segment analyzed, wherein only the left main segment had diagnostic quality CTA, in a majority of patients.

It was also noted that nondiagnostic coronary CTA readings were mainly due to the presence of calcification.

From the observations, it was inferred that routine chest CTA is an insufficient diagnostic tool to exclude severe CAD, primarily due to the presence of severe coronary calcification in TAVR patients.

A Multimodal Spatiotemporal Cardiac Motion Atlas from MR and Ultrasound Data A recent study published in the Medical Image Analysis proposed a framework to build a multimodal cardiac motion atlas from 3D magnetic resonance (MR) and 3D ultrasound (US) data. This study used multi-view algorithm to simultaneously reduce the dimensionality of both the MR and US derived motion data, in order to find a common space between both modalities to model their variability. Here, three different dimensionality reduction algorithms were investigated, which were principal component analysis, canonical correlation analysis, and partial least squares (PLS) regression on 50 volunteers. The results revealed that PLS gave out lowest errors, with a reconstruction error of <2.3 mm for MR-derived motion data, and <2.5 mm for US-derived motion data.

From the findings, the feasibility of using US data alone to analyze cardiac function based on a multimodal motion atlas was ascertained.

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CARDIOLOGY

Cardiac Autonomic Dysfunction: A Systematic Review MUHAMMAD UWAIS ASHRAF*, ASIF HASAN†, MOHD. ASLAM*, JUWAIRIA ASHRAF‡

ABSTRACT Autonomic dysfunction is directly associated with increased cardiovascular morbidity and mortality. It is often overlooked due to late clinical manifestations. A large number of clinical and noninvasive tests are now available to detect cardiac autonomic neuropathy (CAN) early. We present here a comprehensive review of testing for CAN as well as the methods to prevent and treat it.

Keywords: Autonomic dysfunction, cardiovascular morbidity, cardiac autonomic neuropathy, cardiac autonomic reflex tests

I

n a large number of previous studies, the relationship between autonomic nervous system (ANS) and cardiovascular morbidity has been underlined.

This relationship has more elaborately been studied in certain cardiac conditions like myocardial infarction (MI) and congestive heart failure (CHF). It has already been proven beyond doubt that dysregulation of ANS either in the form of increased sympathetic activity or reduced vagal tone may result in ventricular arrhythmias and even sudden cardiac death (SCD).

SCD is an increasingly dreaded condition proving nowadays to be the leading cause of cardiovascular mortality.1 The early signs of autonomic dysfunction are often missed, mainly because reliable clinical methods to ascertain and to monitor the ANS were still evolving until recently. There are many tools, at present, to evaluate the autonomic status of a patient and these include cardiovascular reflex tests, as well as biochemical and scintigraphic tests.

REFLEXES AND RECEPTORS IN CARDIAC AUTONOMIC FUNCTION Cardiac autonomic dysfunction in particular is a poorly understood disorder and even today there is

*Assistant Professor, Dept. of Medicine †Professor and Director, Centre of Cardiology JN Medical College, AMU, Aligarh, Uttar Pradesh ‡Ajmal Khan Tibbiya College, AMU, Aligarh, Uttar Pradesh Address for correspondence Dr Muhammad Uwais Ashraf Assistant Professor, Dept. of Medicine JN Medical College, AMU, Aligarh - 202 002, Uttar Pradesh E-mail: uwaisashraf@gmail.com

no standardized bedside test to quantitate cardiac autonomic neuropathy (CAN). The prevalence in the general population is also highly variable ranging from 1% to 90%.2 To maintain the cardiac autonomic functions, there exists an interplay between the arterial baroreceptors, 9th and 10th cranial nerves which carry the signals and the nucleus tractus solitarius (NTS) as well as the vasomotor center.

Low Pressure Cardiopulmonary Receptors of Heart These receptors respond to changes in blood volume and chemical stimuli. Thus, with a fall in volume, there occurs a reflex increase in heart rate. The vagal afferents reach the NTS, whereas the spinal sympathetic afferents carry inputs to the spinal cord. Thus, the cardiopulmonary receptors play an important role in modulating the heart rate.

Role of Chemoreceptors in Modulating the Cardiac Autonomic Functions The chemoreceptors which mediate the cardiac autonomic functions are located peripherally as well as centrally. The peripheral chemoreceptors are the carotid bodies which respond to hypoxemia, whereas the central chemoreceptors are situated in the brainstem and respond well to hypercapnia.

Indications of Autonomic Testing Following subsets of patients should undergo testing of autonomic functions: ÂÂ

All diabetic patients should ideally be screened for CAN as the incidence of CAN is increased in diabetes mellitus.

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All patients presenting with unexplained tachycardia should undergo autonomic testing for CAN.

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Patients presenting with features of chronotropic incompetence should undergo autonomic testing.

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Autonomic testing is essential in patients who present with a history of syncope.

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Patients with a family history of SCD should be screened for CAN.

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Patients of hypertrophic cardiomyopathy have an incidence of CAN and should be evaluated for the same.

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Certain systemic diseases warrant autonomic testing and these include chronic kidney disease, amyloidosis, etc.

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Autonomic dysfunction is a frequent accompaniment of certain neurological disorders like multi-system atrophy and Parkinson's disease.

DIAGNOSIS OF CARDIAC AUTONOMIC NEUROPATHY

Cardiac Autonomic Reflex Tests Following five tests have been described together as cardiac autonomic reflex tests (CARTs): ÂÂ

The response of heart rate to deep breathing: This maneuver assesses a beat-to-beat heart rate variation during paced deep breathing, that is, expiration to inspiration ratio (E:I).

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The response of heart rate to standing: This parameter is expressed as the ratio of the longest R-R interval (between the 20th and 40th beats) in response to change in posture from horizontal to vertical.

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The Valsalva maneuver: This evaluates the heart rate response checked during a provoked increase in intrathoracic and intra-abdominal pressures as well as after this maneuver. This is performed by asking the patient to exhale for 15 seconds against a fixed resistance.

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The blood pressure (BP) response to standing: This response is elicited as an assessment of BP variation via baroreflex after a change in position from recumbent to standing.

The response of BP to sustained handgrip: This maneuver is best explained as the increase in diastolic BP following sustained muscle contraction using a handgrip dynamometer.

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Heart Rate Variability The beat-to-beat variability in healthy persons is directly controlled by sympathetic and parasympathetic activity along with neurological factors like catecholamines and thyroid hormones. While assessing the heart rate variability (HRV), we generate the time and frequency domains from the R-R intervals recorded under paced breathing. The spectral analysis of the respiratory sinus arrhythmia can indicate where in the frequency domain the vagus is affecting the heart. These frequency domains are generated with the help of continuous wavelet transform method (Fourier transform) and is divided into three basic components: very low frequency, low frequency (LF) and high frequency (HF).

Baroreflex Sensitivity The physiology behind this test is that an increase in the BP causes a reflex increase in vagal tone and reduction in sympathetic activity, which causes reflex bradycardia and reduction in BP due to decrease in cardiac output as well as the peripheral vasodilatation.

The test for baroreflex sensitivity (BRs) can be performed by pharmacological methods as well as nonpharmacological techniques using intravenous epinephrine or physical maneuvers such as postural change.

Scintigraphy It is now possible to perform a quantitative scintigraphy evaluation of cardiac autonomic functions. This can be done with the help of single-photon emission computed tomography (SPECT), positron emission tomography (PET) and sympathetic neurotransmitter analogs for example I123-metaiodide-benylgnamide (I123-MIBG) SPECT, C11-metahydroxyephrine (C11-HED) PET and C11-ephrine.

Muscle Sympathetic Nerve Activity Muscle sympathetic nerve activity (MSNA) is a new technique which records the sympathetic nerve signals in the skeletal muscles either at rest or after physiological interventions with the use of microelectrodes into a fascicle or a distal sympathetic nerve of skin or muscle for example the peroneal nerve; this mechanism is known as microneurography.

Pulsatile Stress In a recent study, it was propounded that pulsatile stress, which is used to measure arterial stiffness, has a strong correlation with BRS and hence it can be used as a test for CAN. The arterial stiffness is expressed as carotid-femoral wave velocity.

CARDIOLOGY is the most overlooked form of neuropathy in type 2 diabetes and is a known risk factor for silent ischemia in patients with type 2 diabetes.

Microvascular Blood Flow It is known that CAN leads to vascular and neurological complications of lower limbs. Laser Doppler can be used to determine blood flow under basal conditions or after physical and pharmacological stimulation. Physical stimulation can be given by heating and pharmacological stimulation can be given by acetylcholine or sodium nitroprusside.

Intraepidermal Nerve Fiber Density Intraepidermal nerve fiber density (IENFD) is a highly sensitive as well as specific method to assess ANS especially to diagnose small fiber neuropathy. It has a sensitivity of 88-98% and specificity of 88.8-95%.3 The alterations in the innervations of the sweat glands can be assessed by IENFD, using Nuropad and Sudoscan.4

Conditions Related to CAN

Pathogenesis of CAN in type 2 diabetes mellitus: Hyperglycemia leads to oxidative stress due to mitochondrial production of free radicals. This leads to activation of poly (ADP-ribose) polymerase which acts in concert with other pathways (for example the hexosamine pathway, the polyol pathway) and with advanced glycosylation end-products and protein kinase C to give rise to glucose toxicity.9 Recently, there has been an emphasis on genetic predisposition to CAN in patients of type 2 diabetes mellitus. TCF7L2 gene has been found to be avidly related to CAN.10 Another study has documented that the T393C polymorphism of GNAS1 gene, which codes Gs-protein-X subunit is strongly associated with CAN.11 ÂÂ

Obstructive sleep apnea (OSA) and CAN: OSA is generally emerging as an important factor associated with CAN. It is a known fact that intermittent hypoxia, which occurs in OSA leads to oxidative stress and microvascular dysfunction giving rise to CAN.12 Not only is OSA a contributory factor of CAN, but CAN itself precipitates OSA in predisposed individuals, as CAN leads to changes in upper airway tone and changes in respiratory drive, which precipitate OSA.13

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Vitamin D and CAN: Many recent studies have shown that there is a strong association between vitamin D and its metabolites and the cardiac autonomic functions.14 Data is available to show that low 25-hydroxyvitamin D levels as well as low 1,25-dihydroxyvitamin D levels are associated with depressed cardiac autonomic functions.

Several animal studies in the past have shown that in vitamin D receptor knockout mice the cardiac myocytes have accelerated rates of contraction as compared to wild mice.

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CAN in fibromyalgia: Fibromyalgia is a chronic condition which is characterized by widespread pain over the body and over the past few years, the understanding of this condition regarding its pathophysiology has greatly advanced, and there is growing evidence that dysautonomia plays a pivotal role in the pathogenesis of fibromyalgia.15

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CAN in Brugada syndrome: It is now known that CAN exists in patients of Brugada syndrome, which is suggested by an increased incidence of ventricular tachyarrhythmias and sudden death in these patients. A recent study has underlined the role of presynaptic myocardial sympathetic dysfunction in Brugada syndrome.16

Primary Autonomic Failure ÂÂ

Pure autonomic failure (PAF): Over the years, it has become evident that in this condition, there is a state of generalized autonomic dysfunction which is manifested by orthostatic hypotension, syncope, disturbances of thermoregulation, bowel and bladder dysfunction and alterations in sudomotor and sexual functions.5

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Multiple system atrophy (MSA): Unlike PAF, this condition was more severe and it presents as orthostatic hypotension, progressive urinary and rectal incontinence, loss of sweating, atrophy of iris, impotence, tremors and rigidity.6 American Autonomic Society renamed the condition as MSA, and has further classified it into different subtypes: MSA-P, MSA-C and a mixed variant having features of both, i.e., parkinsonian, cerebellar or mixed types.

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Postural orthostatic tachycardia syndrome (POTS): It is a relatively milder form of chronic primary autonomic failure characterized by persistent tachycardia in upright position, which may escalate up to 160 bpm or more. These patients have a sudden increase in heart rate, which is >30 bpm within the first 5 minutes or may achieve a maximum heart rate of 120 bpm with mild reduction in BP.7

Secondary Autonomic Failure ÂÂ

Type 2 diabetes mellitus and CAN: It is already a known fact that peripheral neuropathy is one of the most common complications of diabetes mellitus.8 However, autonomic neuropathy, especially CAN

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CAN in Chaga’s disease: Previous studies have shown the presence of autonomic disturbances as demonstrated by echocardiography, ECG changes, Valsalva maneuver, etc. in Chaga’s disease.17 It has already been demonstrated that some myocardial lesions observed in Chaga’s disease were similar to those induced by catecholaminergic cardiotoxicity.

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CAN and obesity: In a recent study published in 2015, it was observed that CAN is present in a high proportion of obese patients.18 In this study, 428 obese patients were assessed by analyzing HRV during these standard tests viz. Valsalva, deep breathing and lying to standing.

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CAN in patients undergoing thoracic radiotherapy: It has already been noted that survivors of Hodgkin’s lymphoma who were treated by thoracic radiation therapy had increased exercise intolerance and cardiovascular mortality.

It was concluded from a recent study published in 2014, that incidence of CAN is increased in patients who have undergone thoracic radiotherapy.19

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CAN in systemic lupus erythematosus (SLE): CAN is a common manifestation of SLE. In a recent study, heart rate corrected interval (QTc) has been shown to be a predictor of CAN in systemic lupus. QTc has already been shown to be related to CAN in patients with type 2 diabetes mellitus and hence its utility as a tool for establishing CAN is established.20 CAN with left ventricular assist device (LVAD) implantation: In patients of CHF, it is known that CAN is profound and is related to the degree of left ventricular dysfunction as documented by reduced HRV in these patients. It was earlier thought that LVAD can improve HRV and improve cardiac output. However, in a recent study it was shown that in patients with LVAD, CAN is still evident.

In fact, it was found to be even more profound as compared to advanced CHF patients without LVAD.21 CAN in hemodialysis patients: Patients of end-stage renal disease (ESRD), who are on hemodialysis, have several independent risk factors, which can give rise to SCD. It has now been demonstrated that CAN is associated with higher risk of ventricular arrhythmias and SCD in this subset of patients. A systematic analysis of HRV in ESRD patients has suggested the presence of CAN in these patients, which can explain the high risk of SCD in these patients.22

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CAN in ischemic stroke: Many earlier studies have pointed towards the presence of CAN in ischemic stroke. A study published in 2007, has shown that CAN has an impact on functional outcome in patients of ischemic stroke.23

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CAN in leukemias: Recent studies have investigated the association of CAN in survivors of acute lymphoid leukemia (ALL) in childhood, through power spectral and time domain analysis of HRV. Analysis of PS/HRV (power spectral analysis of HRV) demonstrated that LF:HF area ratio was elevated in survivors of ALL compared to controls.24

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CAN in patients of Alzheimer’s disease (AD): Previous studies have documented the existence of CAN in patients of AD and it is opined to be due to the cholinergic deficit in the ANS. In fact, some of the autonomic disturbances can be ameliorated by treatment with an cholinesterase inhibitor.25

MANAGEMENT OF CAN There are two aspects for the treatment of CAN, one is aimed at symptomatic improvement and the other is aimed at slowing down the progression of CAN. However, effective modalities for the latter are limited.

In spite of that several potential treatment modalities have been evaluated. ÂÂ

Lifestyle modifications: Lifestyle changes have been shown to have a positive impact on CAN and are known to reduce the progression of CAN.10 This is especially true in patients of type 2 diabetes mellitus who develop CAN. In general, weight loss is known to show improvement on CAN indices.10 CAN has also been shown to get improved with aerobic exercises.

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Intensive glycemic control in diabetic patients: In diabetic patients, hyperglycemia is the most important pathogenic mechanism for CAN. Intensive control of blood glucose has proven to retard the progression of CAN.10 In the Diabetes Control and Complications Trial (DCCT), intensive blood glucose control reduced the incidence of CAN by 50% in type 1 diabetes mellitus patients over a 6.5 years follow-up.

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Experimental pharmacologic therapies: There is increasing evidence in the favor of specific pharmacotherapy targeting different pathogenic pathways. Glucagon-like peptide-1 (GLP-1) analogs and dipeptidyl peptidase IV (DPP-IV) inhibitors have shown cardioprotective and neuroprotective properties and hence are being shown as potential agents for treatment of CAN.26 It has also been

CARDIOLOGY shown that the use of vitamin E and C-peptide improves HRV indices.27 In a recent study, treatment with a combination of allopurinol, α-lipoic acid and nicotinamide has shown conflicting results with respect to slowing the progression of CAN.28 It has also been shown that the use of angiotensinconverting enzyme (ACE) inhibitors can improve the sympathetic/parasympathetic balance and can be beneficial in ameliorating CAN.29

Symptomatic Treatment Symptomatic treatment especially for orthostatic hypotension is also a part of the management of CAN. It includes dietary advices like taking smaller frequent meals, avoiding precipitating drugs for example diuretics, TCADs, α-blockers, etc. Certain physical counter-maneuvers may be advised for example by crossing, stooping and squatting. Patients should also be advised to increase fluid and salt intake. If these maneuvers fail, certain medications may be tried which include peripheral selective α-agonists like midodrine, synthetic mineralocorticoids like 9-α-fluorohydrocortisone, somatostatin and somatostatin analogs like octreotide. Some studies have also underlined the role of drugs like erythropoietin, desmopressin acetate, caffeine and acarbose in the management of CAN.28 CONCLUSION CAN is an important and emerging cause of cardiovascular morbidity and mortality. It is largely overlooked in clinical practice and hence diagnosed late when not much can be done. There are a large number of noninvasive methods to test for CAN and these can help detect this condition well in time. CAN is particularly essential to be diagnosed in diabetic individuals. Newer associations of CAN are being reported and special caution should be taken to subject these subset of patients to autonomic testing.

REFERENCES 1. Deo R, Albert CM. Epidemiology and genetics of sudden cardiac death. Circulation. 2012;125(4):620-37.

2. Basu AK, Bandyopadhyay R, Chakrabarti S, Paul R, Santra S. A study on the prevalence of cardiac autonomic neuropathy in type-2 diabetes in Eastern India. JIACM. 2010;11(3):190-4.

3. Holland NR, Stocks A, Hauer P, Cornblath DR, Griffin JW, McArthur JC. Intraepidermal nerve fiber density in patients with painful sensory neuropathy. Neurology.

1997;48(3):708-11.

4. Casellini CM, Parson HK, Richardson MS, Nevoret ML, Vinik AI. Sudoscan, a noninvasive tool for detecting diabetic small fiber neuropathy and autonomic dysfunction. Diabetes Technol Ther. 2013;15(11):948-53.

5. Mabuchi N, Hirayama M, Koike Y, Watanabe H, Ito H, Kobayashi R, et al. Progression and prognosis in pure autonomic failure (PAF): comparison with multiple system atrophy. J Neurol Neurosurg Psychiatry.

2005;76(7):947-52.

6. Stefanova N, Bücke P, Duerr S, Wenning GK. Multiple system atrophy: an update. Lancet Neurol.

2009;8(12):1172-8.

7. Agarwal AK, Garg R, Ritch A, Sarkar P. Postural orthostatic tachycardia syndrome. Postgrad Med J. 2007;83(981): 478-80.

8. Huang ES, Laiteerapong N, Liu JY, John PM, Moffet HH, Karter AJ. Rates of complications and mortality in older patients with diabetes mellitus: the diabetes and aging study. JAMA Intern Med. 2014;174(2):251-8.

9. Pop-Busui R. Cardiac autonomic neuropathy in diabetes: a clinical perspective. Diabetes Care. 2010;33(2):434-41.

10. Dimitropoulos G, Tahrani AA, Stevens MJ. Cardiac autonomic neuropathy in patients with diabetes mellitus.

World J Diabetes. 2014;5(1):17-39.

11. Yasuda K, Matsunaga T, Moritani T, Nishikino M, Gu N, Yoshinaga M, et al. T393C polymorphism of GNAS1 associated with the autonomic nervous system in young, healthy Japanese subjects. Clin Exp Pharmacol Physiol.

2004;31(9):597-601.

12. Ficker JH, Dertinger SH, Siegfried W, König HJ, Pentz M, Sailer D, et al. Obstructive sleep apnoea and diabetes mellitus: the role of cardiovascular autonomic neuropathy.

Eur Respir J. 1998;11(1):14-9.

13. Janovsky CC, Rolim LC, de Sá JR, Poyares D, Tufik S, Silva AB, et al. Cardiovascular autonomic neuropathy contributes to sleep apnea in young and lean type 1 diabetes mellitus patients. Front Endocrinol (Lausanne).

2014;5:119.

14. Jung CH, Jung SH, Kim KJ, Kim BY, Kim CH, Kang SK, et al.

The relationship between vitamin D status and cardiac autonomic neuropathy in patients with type 2 diabetes mellitus. Diab Vasc Dis Res. 2015;12(5):342-51.

15. Staud R. Autonomic dysfunction in fibromyalgia syndrome: postural orthostatic tachycardia. Curr Rheumatol Rep. 2008;10(6):463-6.

16. Tobaldini E, Brugada J, Benito B, Molina I, Montserrat J, Kara T, et al. Cardiac autonomic control in Brugada syndrome patients during sleep: the effects of sleep disordered breathing. Int J Cardiol. 2013;168(4):3267-72.

17. da Cunha AB. Chagas’ disease and the involvement of the autonomic nervous system. Rev Port Cardiol.

2003;22(6):813-24.

18. Laitinen T, Lindström J, Eriksson J, Ilanne-Parikka P, Aunola S, Keinänen-Kiukaanniemi S, et al. Cardiovascular

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CARDIOLOGY autonomic dysfunction is associated with central obesity in persons with impaired glucose tolerance. Diabet Med. 2011;28(6):699-704.

19. Jones LW, Eves ND, Haykowsky M, Joy AA, Douglas PS. Cardiorespiratory exercise testing in clinical oncology research: systematic review and practice recommendations. Lancet Oncol. 2008;9(8):757-65.

20. Alam MM, Das P, Ghosh P, Zaman MS, Boro M, Sadhu M, et al. Cardiovascular autonomic neuropathy in systemic lupus erythematosus. Indian J Physiol Pharmacol.

2015;59(2):155-61.

21. Compostella L, Russo N, Setzu T, Tursi V, Bottio T, Tarzia V, et al. Cardiac autonomic dysfunction in the early phase after left ventricular assist device implant: Implications for surgery and follow-up. Int J Artif Organs. 2013;36(6):410-8.

22. Thapa L, Karki P, Sharma SK, Bajaj BK. Cardiovascular autonomic neuropathy in chronic kidney diseases. JNMA J Nepal Med Assoc. 2010;49(178):121-8.

24. Nevruz O, Yokusoglu M, Uzun M, Demirkol S, Avcu F, Baysan O, et al. Cardiac autonomic functions are altered in patients with acute leukemia, assessed by heart rate variability. Tohoku J Exp Med. 2007;211(2):121-6.

25. Algotsson A, Viitanen M, Winblad B, Solders G. Autonomic dysfunction in Alzheimer’s disease. Acta Neurol Scand. 1995;91(1):14-8.

26. Salehi M, D’Alessio DA. New therapies for type 2 diabetes based on glucagon-like peptide 1. Cleve Clin J Med. 2006;73(4):382-9.

27. Manzella D, Barbieri M, Ragno E, Paolisso G. Chronic administration of pharmacologic doses of vitamin E improves the cardiac autonomic nervous system in patients with type 2 diabetes. Am J Clin Nutr. 2001;73(6):1052-7.

28. McCarty N, Silverman B. Cardiovascular autonomic neuropathy. Proc (Bayl Univ Med Cent). 2016;29(2): 157-9.

29. Malik RA, Williamson S, Abbott C, Carrington AL, Iqbal J, Schady W, et al. Effect of angiotensin-converting23. Xiong L, Leung HW, Chen XY, Leung WH, Soo OY, Wong enzyme (ACE) inhibitor trandolapril on human diabetic KS. Autonomic dysfunction in different subtypes of postneuropathy: randomised double-blind controlled trial. acute ischemic stroke. J Neurol Sci. 2014;337(1-2):141-6.

Lancet. 1998;352(9145):1978-81.

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Evaluating the Impact and Cost-effectiveness of Statin Use Guidelines for Primary Prevention of Coronary Heart Disease and Stroke Statins have shown efficacy in primary prevention of atherosclerotic cardiovascular disease. The 2013 American College of Cardiology-American Heart Association (ACC-AHA) guideline expands recommended statin use.

A new study published in the Circulation examined the cost-effectiveness of statin use. In this study, Cardiovascular Disease Policy Model was employed, to estimate the cost-effectiveness of the ACC-AHA, relative to its current use, Adult Treatment Panel III (ATP III) guidelines and universal statin use in all men between 45 and 74 years and women between 55 and 74 years, from 2016 to 2025.

The results revealed that either approach to the use of this drug produces substantial benefits and net cost savings, when compared to its current usage. In addition, a strict adherence to the ATP III guideline would result in 8.8 million more statin users, while ACC-AHA guideline would potentially result in up to 12.3 million more statin users than from ATP III guideline. Furthermore, it was estimated that moderate-intensity statin use in all men and women would result in 28.9 million more statin users than the ACC-AHA guideline. On the other hand, it was deduced that benefits would be greater in men than in women.

From the findings of this study, it was inferred that the ACC-AHA guideline for expanded statin use for primary prevention aims to treat more people, save more lives and cost less compared with ATP III, in both the genders.

Whereas individual benefits from long-term statin use for primary prevention depends more on the disutility associated with pill burden than their degree of cardiovascular risk.

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COMMUNITY MEDICINE

Lead Toxicity Among Automobile Garage Workers in the Vicinity of Nalanda Medical College and Hospital, Patna and the Adjoining Areas of Patna, Bihar, India MA NASAR*, TF SUBHANI†, RR SINHA*

ABSTRACT In India, particularly in state of Bihar, there are numerous small-scale and medium industries, which use lead-based raw materials that may pose health risks to workers. There are no workplace regulations for lead exposure. Moreover, there are no studies carried out on the blood lead levels (BLLs) of workers or on the contribution of common workplace practices to lead poisoning. A cross-sectional study on the BLLs of 45 automobile garage workers and 40 non-garage workers was carried out in the vicinity of Nalanda Medical College and Hospital, Patna, India. In addition to BLL analysis, data on some risk factors such as smoking, and chewing tobacco (gutka and pan parag) were gathered through structured questionnaires and interviews and data analysis was performed using SPSS (Version 16). The t-test was used to compare mean BLLs of study groups.

The analysis of variance (ANOVA), Kruskal-Wallis, Pearson chi-square and odds ratio tests were used to investigate the associations between specific job type, smoking and/or tobacco chewing, service years and occurrence of nonspecific symptoms with BLLs. The mean BLL of the automobile garage workers was found to be significantly greater than that of the controls.

The BLLs of all the lead-exposed individuals were found to be over 10 μg/dL, and 53% of them had BLLs ranging 12-20 μg/ dL, with the remaining 47% having over 20 μg/dL. The BLL of the workers increased with the duration of working in an automobile garage. Individuals involved in manual car painting comprise a larger percentage (58%) of those with the highest BLLs (≥20 μg/dL). Lead accumulation in individuals who chew tobacco in the work place was found to be faster than in those who are not used to chewing tobacco. The findings of the study have clearly demonstrated that the BLLs of automobile garage workers in Patna, Bihar are considerably high with a range of 11.73-36.52 μg/dL and the workers are in danger of impending lead toxicity. The BLLs of the workers are influenced by their occupational practices, chewing tobacco at the workplace, and the time spent working in an automobile garage.

Keywords: Lead, garage workers, blood lead level, tobacco, gutka

L

ead is one of the most widely distributed toxins in our environment. Although its toxic effects have been known for centuries, occupational exposure to lead that results in poisoning, be it moderately or clinically symptomatic, is still common in many countries of the world.1,2 Excessive occupational exposure over a brief period of time can cause a

syndrome of acute lead poisoning. Clinical findings in this syndrome include abdominal colic, constipation, fatigue and central nervous system dysfunction. With even greater doses, acute encephalopathy with coma and convulsions may occur, whereas in cases of milder exposures, headaches and personality changes may be the only signs of neurologic toxicity.3

*Dept. of Biochemistry Nalanda Medical College, Patna, Bihar †Dept. of Biochemistry NC Medical College, Panipat, Haryana Address for correspondence Dr MA Nasar Assistant Professor Dept. of Biochemistry Nalanda Medical College, Patna, Bihar

Children are particularly susceptible to lead intoxication that causes various neurological and behavioral problems, ranging from raised hearing threshold to reduction in intelligence quotient (IQ) at low blood lead concentrations. Although no threshold has been determined for the harmful effects of lead in children, a 1991 Centers for Disease Control and Prevention (CDC) Report of UK has put the blood lead level (BLL) of concern in children at 10 μg/dL. The level of concern

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COMMUNITY MEDICINE has changed over the past few decades, from 60 μg/dL (1960), to 30 μg/dL (1970), to 25 μg/dL (1985), to 10 μg/dL (1991).4 Occupational lead exposure in many developing countries is entirely unregulated, often with no monitoring of exposure.5 In India, although there are numerous small-scale and large industries which use lead-based raw materials that may pose health risks to workers, there are no workplace regulations for lead exposure and no data are available with the labor departments among the workers of small-scale lead-based units with regard to lead poisoning. Many people working for different manufacturing or service rendering organizations such as battery manufacturing workers, gas-station attendants, radiator repair workers, solderers of lead products and welders, are involved in jobs, which expose them to gradual health risks from exposure to lead without having any idea about the materials they are handling. Due to lack of awareness about their exposure, workers usually eat, smoke or drink while at work and such workplace practices may aggravate their exposure.6,7 In India and in some other developing countries, tobacco chewing at the workplace is a common practice.

The dried leaves of tobacco are chewed for their stimulating effects. After chewing the leaves, people may swallow the juice and throw away the residue or swallow whatever they chewed. In many work areas, the workers who chew tobacco (gutka) do so at the workplace. This is typically done by putting them into the mouth from time to time while performing duties.

Whatever the material that the workers are handling, they do not wash their hands each time they cut the packet and put them into their mouth. As a result, various toxic substances, including lead, that have stuck to the hands of these workers might easily get transferred onto the tobacco leaves surface and then ingested with the tobacco by the workers.

Relating the concentration of heavy metals, such as lead, in humans to an environmental and occupational level is crucial in order to determine areas of health risk. Most toxicology studies rely on BLL as the measure of exposure.8-10 Lead in shed deciduous teeth is sometimes quoted being regarded as a record of past lead exposure.11,12 Other materials that have been used to estimate the amount of lead in human beings include hair,13-15 urine and feces.16,17 Auto-garage workers in India are involved in car painting, soldering, welding and other repairing activities. The garage compounds in which the workers

carry out their daily activities are usually filled with fuel exhaust from automobiles entering or leaving the garage’s compounds. Moreover, workplace tobacco chewing is common practice for many auto-garage workers. Most of the workers have no idea about the toxic metals they might be exposed to; as a result, they pay little attention to protecting themselves from the possible inhalation or ingestion of such toxic substances, nor are they made aware of this or advised to take the necessary protective measures. Despite this fact, no study has been conducted to assess the BLLs of people working in auto-garages or of workers in other industries that are expected to pose health risks to workers. However, a single cross-sectional study on the occupational lead exposure of 51 workers in lead acid battery repair units of transport service enterprises at New Delhi, using δ-Aminolevulinic acid (δ-ALA) levels in the urine and serum as a biomarker, has been reported.18 According to data obtained, there are other smallscale industries involved in furniture production, food processing, metal and woodwork, bakery and pastry, flour-making and coffee processing. There are no large-scale industrial activities in the town, which are expected to expose workers to lead pollution. It could also be assumed in Patna that, despite the continued use of lead free petroleum, a situation where lead emissions from motor vehicles would constitute a serious risk to public health is not anticipated. Such a conclusion, however, would not be valid without evidence of completed work.

There are around more than 200 automobile garages in the city of Patna, each of which has an average of 15 workers. All of these garages offer multiple autorepair services in a single compound. Within this compound, all workers carry out their specific jobs near other colleagues engaged in other activities, moving around to share tools and help one another. Therefore, all the workers are exposed virtually to the same extent to the toxic substances resulting from all the services offered in the auto-garage. The problem of exposure may be further compounded with the chewing of tobacco (gutka) at the work place. Preliminary observations have revealed that the automobile garage workers who are used to chewing gutka, while at work are taking the gutka under poor hygienic conditions and they have no idea about the possible toxic substances they might ingest with the gutka or inhale from the surrounding air. As a result, they use no protective devices to minimize exposure.

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COMMUNITY MEDICINE Therefore, the BLLs of automotive garage workers around Patna might be higher than other people who are not occupationally exposed. On top of this, autogarage workers who are used to workplace gutka chewing and smoking might have higher BLLs than their colleagues who are not used to practicing these habits while at work. This study was therefore aimed at investigating the BLLs and associated health problems of automotive garage workers in Patna and relating the data to workplace practices of chewing gutka and smoking.

METHODS

Study Subjects and Study Design The study was a cross-sectional BLL survey that included blood lead sampling from 45 occupationally exposed garage workers (44 males, 1 female) and 40 controls (36 males, 4 females). The occupationally exposed group included individuals who were mainly involved in manual auto spray-painting or welding for a duration of around 5-15 years in the auto-garages, where excessive usage of petrol and petroleum by-products takes place with a daily exposure of 8-12 hours. The occupationally nonexposed group members were school and university students and teachers who had apparently no history of lead exposure, were non-smokers, nontobacco chewers and nonalcoholics.

Reagents and Laboratory Ware Analytical standard solutions of lead were prepared by serially diluting a 1,000 mg/L stock calibration standard solution (Spectro ECON). All chemicals and reagents used were of analytical grade purchased from Merck or Sigma Chemical Co.

Blood Sample Collection Venous blood samples (4 mL each) were collected from the 45 garage workers and, 40 apparently healthy nongarage workers using carefully labeled vacutainer tubes containing 7.2 mg K2EDTA by qualified medical laboratory professionals. All samples were then preserved at 4°C. Blood specimen collection was carried out using separate sterilized needles and gloves for each individual. All used needles and gloves were packed in appropriately labeled disposable bags and taken to the Nalanda Medical College and Hospital, Patna waste disposal unit.

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Sample Preparation The blood specimens were heated in a hot water bath at 37°C for 25 minutes and homogenized by shaking for 1 minute. Accurately measured 3 mL of each of the blood samples was transferred into a Pyrex test tube. A 3:1 mixture of trichloroacetic acid (TCA 5%) and perchloric acid solution (2 M) was added to each test tube and centrifuged for 25 minutes at 3,000 rpm.

The supernatant from each sample was decanted into a labeled sample bottle and the precipitate was further digested with 3.0 mL 2 M perchloric acid and centrifuged for 15 minutes. The supernatant from each centrifuged sample was decanted and mixed with its corresponding supernatant from the first digestion.

Finally, the digests were stored at 4°C until dispatched for analysis.

BLL Analysis The concentration of lead in the blood samples was determined by Flame Atomic Absorption Spectrometer (NovAA 300) at 283.3 nm after optimizing the various instrument parameters. Triplicate samples were analyzed in each determination and averages of triplicate measurements were taken for each sample.

Instrument drift was controlled by running standards after analyzing 10 samples. Quantification of lead in blood was carried out with the help of a standard lead solution.

Data Collection In addition to determining the concentration of lead in blood samples, data on some risk factors for lead poisoning such as: addiction to alcohol, smoking, tobacco chewing and eating and/or drinking habits at the workplace, were gathered through questionnaires and interviews. A standardized structured questionnaire, designed to yield information on associated risk factors with the observed BLL, was prepared in English and administered after obtaining consent from the participants of the study. Each item in the questionnaire was interpreted into the local language Hindi for those who did not understand English. In addition to the questionnaire, participants were interviewed privately on further points. The interviews included detailed demographic information, exposure history and the presence and nature of lead-related symptoms.

Statistical Analysis Statistical analyses of results were basically performed by using SPSS (Version 16). Comparison of mean BLLs of study groups was carried out using a t-test. One-way

COMMUNITY MEDICINE analysis of variance (ANOVA) was used to investigate the variation in BLL with the specific job types of the autogarage workers. The Pearson chi-square statistic and the odds ratio test were used to investigate the associations between BLL and service years, and BLL and occurrence of nonspecific symptoms, respectively.

The Kruskal-Wallis test was used to investigate the dependence of BLL on smoking and/or tobacco chewing habit in the workplace. All data were expressed as mean ± SD and the level of significance was determined at p < 0.05.

Ethical Consideration The study was conducted upon obtaining ethical clearance from the Institutional Ethics Committee of Nalanda Medical College and Hospital, Patna. The purpose of the study was clearly explained to the study participants following a pre-developed procedure and oral consent was obtained from each of the participating individuals and the auto-garage owners.

Blood specimen collection was carried out using a separate sterilized needle and glove for every individual. All used needles and gloves were packed in appropriately labeled disposable bags and taken to the Nalanda Medical College and Hospital waste disposal unit.

RESULTS

job categories 20.30 ± 4.52. The observed differences; however, were not statistically significant (p > 0.05). The BLLs of the garage workers were all >10 μg/dL, while 41% of the controls had BLLs lower than this value.

The remaining 59% of the controls had BLLs ranging 10-16 μg/dL. Among the garage workers, 53% had BLLs ranging from 12 to 20 μg/dL and the remaining 44% of them had 20 to 27 μg/dL. One person among the garage workers had a relatively higher BLL, 36.52 μg/dL and the person was identified to be an alcoholic, smoker, tobacco chewer and had served for 25 years in autogarages. The female garage worker who participated in the study had a BLL of 15.87 μg/dL. She had served for over 10 years, and did not chew tobacco, smoke or drink alcohol. The mean BLL of the 4 females among the controls was 10.13 μg/dL (95% CI: 9.36-10.90, median: 9.96 μg/dL; range: 9.38-11.22 μg/dL).

BLLs of Occupationally Exposed Group Relative to Service Years The proportion of individuals with BLLs <15, 15-20 or above 20 μg/dL among the garage workers with service years between 1-3, 3-6 and above 6 years are given in Figure 1. The figure clearly shows a steady increase in the proportion of individuals with higher BLLs with an increase in service years. The chi-square test has revealed that the dependence of BLL on service

BLLs of Occupationally Exposed and Nonexposed Groups

The BLLs of the auto-garage workers were found to vary with the specific job type they are involved in.

The mean BLL of the workers involved in manual auto-painting was 21.12 ± 5.59 μg/dL, that of welders 19.19 ± 4.08 μg/dL and that of workers involved in both

3-6 years

Above 6 years

60 No of individuals (%)

The mean lead concentrations of the garage workers and controls are given in Table 1. According to the t-test the difference between the mean BLL of the garage workers, 19.76 μg/dL (95% confidence interval [CI]: 18.45-21.06, median: 19.75 μg/dL; range: 11.7336.52 μg/dL), and that of the controls, 10.73 μg/dL (95% CI: 10.05-11.41, median: 10.40 μg/dL; range: 5.615.64 μg/dL) is significant (p < 0.05).

1-3 years 70

50 40 30 20 10 0 Below 15 µg/dL

15-20 µg/dL

Above 20 µg/dL

Blood lead level range

Figure 1. Proportion of the garage workers with BLLs <15 μg/dL, between 15-20 μg/dL and above 20 μg/dL in the 1-3, 3-6 and above 6 years of service categories.

Table 1. BLLs of the Garage Workers and Controls Category

Mean Pb conc (μg/dL ± SD)

95% CI (μg/dL)

Range (μg/dL)

% BLL ≥10 μg/dL

Garage workers

19.75 ± 4.46

18.45-21.06

11.73-36.52

100

Controls

10.73 ± 2.22

10.05-11.41

5.6-15.64

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COMMUNITY MEDICINE However, those who were nonsmokers but habituated to gutka chewing had a mean BLL of 20.19 ± 4.06 μg/dL (n = 7). Six of the seven gutka chewers had BLLs above 18 μg/dL and only one individual had a BLL of 13.89 μg/dL. The fact that both the gutka chewers and nonchewers are not smokers and that the BLLs of the nongutka chewers is significantly lower than that of the gutka chewers indicates that gutka chewing either accelerates lead accumulation or is an additional source of lead intake.

years is statistically significant (p < 0.05). Among the individuals in the 1-3 service years group, the relative number of individuals with BLLs of <15 μg/dL is greater than that of individuals with BLLs ranging from 15 to 20 μg/dL or above 20 μg/dL. Forty-six percent of the garage workers with service between 1-3 years and 14% of those with service between 3-6 years were found to have BLLs <15 μg/dL. Among the workers with more than 6 years of service, 68% had BLLs above 20 μg/ dL, 32% in the range from 15 to 20 μg/dL and none of them had <15 μg/dL. Individuals with more than 10 years of service comprise a larger percentage (88%) of those with BLLs above 20 μg/dL. This clearly shows the direct relationship between BLL and service years.

A similar difference between the two groups was not observed in the BLLs of the individuals with more than 3 years of service in the auto-garages. The impact of gutka chewing on lead accumulation steadily decreased with service years, and in individuals with more than 10 years of service its impact was not visible.

BLL and Smoking/Tobacco (Gutka) Chewing Habits The mean BLL of the total garage workers who were neither smokers nor tobacco chewers was 16.58 ± 3.5 μg/dL (n = 14) and that of the tobacco chewing nonsmokers was 20.17 ± 3.11 μg/dL (n = 25). According to the Kruskal-Wallis test, the observed BLL difference between the two groups is significant (p < 0.05). Table 2 illustrates the mean BLLs of the garage workers who were gutka chewers but not smokers and, non-gutka chewers and nonsmokers in the service year ranges of 1-3, 3-6 and above 6 years. As shown in this table, among the 11 individuals with service years ranging 1-3 years, the mean BLL of those who were habituated neither to gutka chewing nor to smoking had a mean BLL of 12.57 ± 0.88 μg/dL (n = 4).

Lead Toxicity Symptoms The odds ratio of the reported nonspecific symptoms in the garage workers in relation to the controls was calculated and the results obtained are shown in Table 3. The results clearly show that among the reported nonspecific symptoms, the occurrence of wrist drop, tingling and numbness in fingers and hands, nausea and decreased libido in the auto-garage workers are significantly greater than in the controls.

The proportion of individuals affected by the nonspecific symptoms among the individuals with BLLs: <16, 16-20 or above 20 μg/dL, was assessed and the results obtained are illustrated in Figure 2.

Table 2. Relationship of BLL with Smoking, Tobacco Chewing and/or Smoking Habit and Service Years Service years 1-3 years

3-6 years

Above 6 years

Tobacco (gutka) chewing

Smoking

n

Mean BLL (μg/dL)

Range (μg/dL)

Median (μg/dL)

CI (p = 0.05) (μg/dL)

×

×

4

12.57

11.73-13.8

12.37

11.69-13.45

√

√

-

-

-

-

√

×

7

20.19

13.89-27.1

19.91

×

√

-

-

-

-

×

×

2

18.51

16.51 & 20.51*

-

14.59-22.43

√

√

1

21.99

-

-

-

√

×

4

22.04

18.21-25.94

22

18.87-23.21

×

√

-

-

-

-

-

×

×

8

18.94

15.87-21.68

19.61

17.25-20.63

√

√

3

25.46

19.58-36.52

20.29

14.63-36.3

√

×

14

19.63

15.66-23.69

19.06

18.29-20.97

×

√

2

25.16

24.08 & 26.23*

-

23.06-27.26

n = Number of workers, × = Not smoking or tobacco chewing, √ = Smoking or tobacco chewing. *Where n = 2, both blood lead concentrations are given in place of the range.

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Indian Journal of Clinical Practice, Vol. 28, No. 2, July 2017

COMMUNITY MEDICINE Table 3. Reported Symptoms Among the Occupationally Exposed (n = 45) and the Controls (n = 40) and the Ratio of their Odds No of ‘Yes’ response for symptom Symptom

Cases

Controls

Odds ratio

P value

Depression

28

7

7.76*

0.00

Memory impairment

13

6

2.30

0.21

Sleep disturbance

23

9

3.60*

0.01

Concentration difficulty

9

11

0.66

0.32

Headaches

17

14

1.13

0.91

Wrist drop

25

1

48.75*

0.00

Tingling and numbness in fingers/hands

12

1

14.18*

0.01

Lack of appetite

12

5

2.55

0.18

Nausea

10

1

11.14*

0.02

Constipation

10

3

3.52

0.13

Abdominal discomfort

16

8

2.21

0.17

Decreased libido

21

3

10.79*

0.00

*Significant relative risk of occurrence in the auto-garage workers at p < 0.05.

<16 µg/dL

80

16-20 µg/dL

≥20 µg/dL

70

No of individuals (%)

60 50 40 30 20 10 0

Depression

Memory Imp.

Headache

Wrist drop

Ting. & numbness

Lack of appetite

Nausea

Decr. in libido

Type of nonspecific symptom

Figure 2. Nonspecific symptoms observed at different BLL.

The results clearly indicated an increase in the prevalence of all the symptoms with an increase in BLL. Among the symptoms assessed, depression, wrist drop and decreased libido were the most prevalent ones in the individuals with BLLs ≥20 μg/dL. About 80% of the garage workers in this BLL range reported having symptoms of depression, 75% for wrist drop and 58% for decreased libido.

Results of the odds ratio test for the relative occurrence of the nonspecific symptoms between the garage

workers with BLLs of <20 μg/dL (n = 25) and the controls (n = 40) are given in Table 4. The results clearly show that the occurrence of most of the symptoms in the garage workers is significantly greater than in the controls (p < 0.05). This could be a clear indication for the negative health impacts of BLLs as low as 10 μg/dL. During interviews, the garage workers reported some nonspecific symptoms, which were not included in the questionnaire. Among the workers, 15 (33.3%) reported having developed a feeling of metallic taste in their

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COMMUNITY MEDICINE Table 4. Reported Symptoms Among the Auto-Garage Workers with BLLs <20 μg/dL (n = 25) and the Controls (n = 40) and the Ratio of their Odds Yes responses for symptoms Symptoms

Cases

Controls

Odds ratio

P value

Depression

28

7

5.11*

0.02

Memory impairment

13

6

1.08

0.61

Sleep disturbance

23

9

3.18*

0.01

Concentration difficulty

9

11

0.50

0.55

Headaches

17

14

0.66

0.52

Wrist drop

25

1

26.00*

0.00

Tingling and numbness in fingers/hands

12

1

7.43*

0.04

Lack of appetite

12

5

2.20

0.06

Nausea

10

1

5.32*

0.04

Constipation

10

3

2.25

0.16

Abdominal discomfort

16

8

1.88

0.29

Decreased libido

21

3

8.22*

0.00

*Significant relative risk of occurrence in the auto-garage workers at p < 0.05.

mouth, 9 (20%) reported having blurred vision and 11 (24.4%) had dry white scars in one or two areas on their heads.

DISCUSSION Occupationally related BLL assessment has not previously been carried out in any part of Patna.

However, in a cross-sectional study carried out in New Delhi on lead exposure among storage battery repair workers by measuring urinary aminolevulinic acid levels, higher levels of urinary aminolevulinic acid were found in the storage battery repair workers and the possible parallel rise in BLLs of the workers was predicted. The results obtained in our study have shown that auto-garage workers have significantly greater BLL than the nongarage workers (p < 0.05).

This clearly indicates that auto-garage workers are more likely to be exposed to lead due to occupational incidences than the general population. Furthermore, the results obtained in our study are consistent with the results of other studies carried out on the determination of the BLLs of: Ninety-seven occupationally and nonoccupationally exposed individuals in Nigeria,19 workers involved in various types of jobs in the United Arab Emirates,20 31 male nonsmoking industrial workers in Iran21 and apprentices working in leadrelated industries in Turkey.6 Among the lead-exposed garage workers, the mean BLL of individuals who were mainly involved in manual auto-painting (21.12 ± 5.59 μg/dL) was slightly higher than that of the mechanics

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(19.19 ± 4.08 μg/dL). Comparison of the mean values by using a t-test has shown that the observed difference was not; however, statistically significant. A study done in Bangkok on 52 mechanics, 27 dye sprayer and 20 controls, reported mean BLLs of 8.7 μg/dL, 12.02 μg/dL and 6.63 μg/dL, respectively.22 The mean BLLs obtained by these researchers for all the three groups were much lower than those obtained in our study. The relative difference between the BLLs of the mechanics and the auto-painters in their study (27.6%); however, is greater than that of the difference obtained in our study (9.1%). The observed higher BLL in the painters than in the mechanics might indicate a greater exposure of the dye sprayers relative to the mechanics.

The painters, in addition to the oral exposure routes, are more likely exposed to inhalation of lead fumes found in the dyes than those workers engaged in other autorepairing activities. This could be a possible reason for the observed BLL difference between the two groups.

The garage workers were found to exhibit significantly higher levels of the nonspecific symptoms, which included: Depression, sleep disturbance, wrist drop, tingling and numbness in fingers and hands, nausea and decrease in libido relative to the controls. Moreover, the prevalence of these symptoms was higher in the workers with higher service years than in those with lower service years. Comparison of the prevalence of the nonspecific symptoms between the occupationally exposed individuals with BLLs <20 μg/dL (n = 25) with that of the controls (n = 40) has also revealed that

COMMUNITY MEDICINE there is a significantly greater prevalence of most of the symptoms in the garage workers. The Association of Occupational and Environmental Clinics (AOEC) has revealed the health effects of various BLLs on lead-exposed adults, and according to this document, the nonspecific symptoms such as: Headache, sleep disturbance, fatigue and decreased libido are shown to occur in the BLL range between 20 and 39 μg/dL. However, the findings of our study suggest that these symptoms are exhibited by lead-exposed individuals at lower BLLs (10-20 μg/dL) than indicated in the AOEC document. Our report on the variations of the nonspecific symptoms between the two groups is entirely from what the two groups revealed in the questionnaires and interviews. Although this may be suggestive of the adverse effects of lead (Pb) on the exposed individuals relative to the nonexposed, a close medical investigation is required to affirm that the epidemiologic variations between the two groups are exclusively results of the difference in the BLLs of the groups.

The BLLs of the workers are influenced by their occupational practices and roughly paralleled with the duration of occupational lead exposure. Workplace gutka chewing and lack of awareness about the ill health effects of lead and the routes through which it enters the human body contributes to the easy entry of lead into the body of the workers and the resulting elevated BLL. Further large-scale screening and regular monitoring of automobile-garage workers is urgently needed to reduce long-term adverse effects of lead exposure.

Tobacco chewing has been found to enhance lead accumulation in the first 1-3 years of service in the occupationally exposed individuals. The mean BLL of the gutka chewers in the 1-3 service year range was 61% higher than the mean BLL of the nonchewers in the same service year range. The observed elevated level of lead in the gutka chewers could most likely be due to oral ingestion. The garage workers are chewing gutka at the workplace. Moreover, they chew the gutka while carrying out their work and do not wash their hands each time they cut the packets and put them in their mouth. This makes lead entry into the digestive system easier, thereby increasing BLL.

3. Landrigan PJ. In: Rosenstock L, Cullen MR (Eds.).

Textbook of Clinical Occupational and Environmental Medicine. Saunders: Philadelphia; 1994. pp. 745-54.

Several potential limitations of our study may have affected the analysis. The records of environmental Pb exposure in the proximity of the auto-garages were not available because monitoring of Pb in air was not enforced. Any observed difference in response to occupational and environmental Pb exposure may, therefore, be attributed to a degree of exposure to Pb. The participants in the control group were selected from university students and teachers. As a result, absence of some epidemiological symptoms in this group might not be exclusively attributed to lower BLL relative to the automotive-garage workers.

REFERENCES 1. Vaglenov A, Creus A, Laltchev S, Petkova V, Pavlova S, Marcos R. Occupational exposure to lead and induction of genetic damage. Environ Health Perspect. 2001;109(3): 295-8.

2. Bhagwat VR, Patil AJ, Patil JA, Sontakke AV. Occupational lead exposure and liver functions in battery manufacture workers around Kolhapur (Maharashtra). Al Ameen J Med Sci. 2008;1(1):2-9.

4. Centers for Disease Control and Prevention. Preventing Lead Poisoning in Young Children: A Statement by the Centers for Disease Control. US Department of Health and Human Services, Public Health Service, Atlanta; 1991.

5. Lovei M. Eliminating a silent threat: World Bank support for the global phase-out of lead from gasoline. In: George AM (Eds.). Proceedings of the International Conference on Lead Poisoning Prevention and Treatment. Bangalore, India: The George Foundation; 1999. pp. 169-80.

6. Pala K, Turkkan A, Gucer S, Osman E, Aytekin H. Occupational lead exposure: blood lead levels of apprentices in Bursa, Turkey. Ind Health. 2009;47(1):97-102.

7. Grandjean P, Hollnagel H, Olsen NB. Occupationally related lead exposure in the general population.

A population study of 40-year-old men. Scand J Work Environ Health. 1981;7(4):298-301.

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CONCLUSION

10. Ratcliffe JM. Developmental and behavioural functions in young children with elevated blood lead levels. Br J Prev Soc Med. 1977;31(4):258-64.

The BLLs of automotive-garage workers in Patna are noticeably high with a range of 11.73-36.52 μg/dL and the workers are in danger of impending lead toxicity.

11. Needleman HL, Gunnoe C, Leviton A, Reed R, Peresie H, Maher C, et al. Deficits in psychologic and classroom performance of children with elevated dentine lead levels.

N Engl J Med. 1979;300(13):689-95.

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1983;286(6376):1458-9.

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14. Phil RO, Drake H, Vrana F. Hair analysis in learning and behaviour problems. In: Brown AC, Crounse RG (Eds.). Hair, Trace Elements and Human Illness. Praeger Publications; 1980. pp. 128-43.

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19. Fatoki OS, Ayoade D. Lead assay in blood of occupationally and non-occupationally exposed donors. Int J Environ Health Res. 1996;6(3):195-200.

15. Thatcher RW, Lester ML, McAlaster R, Horst R. Effects of low levels of cadmium and lead on cognitive functioning in children. Arch Environ Health. 1982;37(3):159-66.

20. Bener A, Almehdi AM, Alwash R, Al-Neamy FR. A pilot survey of blood lead levels in various types of workers in the United Arab Emirates. Environ Int. 2001;27(4):311-4.

16. Chisolm JJ. Current status of lead exposure and poisoning in children. South Med J. 1976;69(5):529-31.

21. Aliasgharpour M, Hagani H. Impact of occupational lead exposure on industrial workers health condition in Tehran-Iran. Eastern J Med. 2005;10:20-3.

17. Hammond PB, Clark CS, Gartside PS, Berger O, Walker A, 22. Suwansaksri J, Teerasart N, Wiwanitkit V, Chaiyaset T. Michael LW. Fecal lead excretion in young children as High blood lead level among garage workers in Bangkok, related to sources of lead in their environments. Int Arch public concern is necessary. Biometals. 2002;15(4):367-70.

Occup Environ Health. 1980;46(3):191-202.

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Patient Position has no Impact on Disability Outcomes in Acute Stroke According to the results of the HeadPoST study, disability outcomes after acute stroke did not differ significantly between patients assigned to a lying-flat position for the first 24 hours and those in a sitting-up position with the head elevated to at least 30° for 24 hours. These findings were published June 22, 2017 in the New England Journal of Medicine.

Testing for Zika Virus in Placental Tissue can Confirm Diagnosis According to a study published online June 23, 2017 in the Morbidity and Mortality Weekly Report, placental testing provided a confirmed diagnosis of recent maternal Zika virus infection for 10% of live births with possible maternal exposure to Zika virus that lacked definitive evidence of a maternal or congenital Zika virus infection.

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An Observational Study on the Efficacy, Safety and Tolerability of Rosuvastatin in Indian Patients with Dyslipidemia: The RID-3 Study NAZIR I JUVALE*, L SREENIVASA MURTHY†, NITIN S GOKHALE‡, MANJULA S#, KRISHNA KUMAR M$

ABSTRACT Background: Dyslipidemia is a major modifiable risk factor for cardiovascular disease (CVD) and is closely associated with its pathophysiology. An observational study was conducted to evaluate the lipid-lowering efficacy and safety of Rosuvastatin in Indian subjects with dyslipidemia by measuring the change in low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and total cholesterol (TC), over a period of 3 months. Methodology: This was a multicentric, open-labeled, nonrandomized, observational study to assess the lipid-lowering efficacy and safety of Rosuvastatin in Indian subjects with Dyslipidemia (RID) for 12 weeks. The signed informed consent was obtained from all the subjects who participated in the study. Rosuvastatin was given at a dose of 10/20 mg o.d. for 3 months. Physical and systemic examination data and lipid profile of each recruited patient were documented before initiating therapy (baseline) and at the end of 3 months (posttreatment). Results: A total of 6,278 subjects completed the study. In our study, total of 88.1% subjects (N = 5,531) had a pre-treatment TC value of >200 mg/dL. Post-treatment with Rosuvastatin, this number reduced to 38.30% (N = 2,404). There was a significant reduction in LDL-C levels with 97.2% of the subjects having decreased LDL-C levels post-treatment with Rosuvastatin. After 12 weeks of treatment with Rosuvastatin, 59.9% of the subjects had HDL-C levels of >40 mg/dL and 56.7% of the study subjects achieved triglycerides (TG) target levels of <150 mg/dL. There were no significant drug-related adverse or serious events reported with Rosuvastatin in this study reiterating safety of Rosuvastatin. Conclusion: In our study, Rosuvastatin significantly decreased the TC, LDL-C, TG and increased the HDL-C levels, thereby, indicating a significant change in the levels of all the lipid parameters with good tolerability.

Keywords: Dyslipidemia, risk factor, cardiovascular disease, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, total cholesterol, Rosuvastatin, triglycerides

C

ardiovascular disease (CVD) is a leading cause of death worldwide, and mortality due to CVD is higher in low- and middle-income countries.1 In India, there has been an alarming increase in the prevalence of CVD over the past two decades so much so that it accounts for 24% of all deaths among adults aged 25-69 years. Indians have been found to develop CVD at a younger age than other populations.2 The likely causes for the increase in the CVD rates include lifestyle changes associated with urbanization and the epidemiologic and nutritional transitions that

*Hon. Professor of Medicine, Grant Medical College, Mumbai, Maharashtra Consultant Interventional Cardiologist, Saifee Hospital, Mumbai, Maharashtra †Professor of Medicine, Dr BR Ambedkar Medical College, Bangalore, Karnataka ‡Consultant Cardiologist, Lilavati Hospital, Mumbai, Maharashtra #Vice President $Senior Manager Dept. of Medical Services, Micro Labs Ltd, Bangalore, Karnataka

accompany economic development. Dyslipidemia has been closely linked to the pathophysiology of CVD and is a key independent modifiable risk factor for CVD.3 The Third National Health and Nutrition Examination Survey (NHANES III) has shown that 64% of subjects with hypertension also have dyslipidemia and conversely, approximately 47% of subjects with dyslipidemia have hypertension. Dyslipidemia is a major modifiable risk factor for CVD and is closely associated with the pathophysiology of CVD.4 Asians, particularly Indians, have a unique pattern of dyslipidemia; with lower high-density lipoprotein cholesterol (HDL-C), increased triglyceride (TG) levels and higher proportion of small dense low-density lipoprotein cholesterol (LDL-C), with characteristic centripetal obesity.5 Dyslipidemia is an abnormal amount of lipids (HDL-C, LDL-C, TG and total cholesterol [TC]) in blood. Most of dyslipidemias are hyperlipidemias, an elevation of lipids in the blood. Prevention, detection,

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AIM OF THE STUDY Rosuvastatin in Indian subjects with Dyslipidemia (RID)-3 study was aimed to evaluate the lipid-lowering efficacy and safety of Rosuvastatin in Indian subjects with dyslipidemia by measuring the change in LDL-C, HDL-C and TC, over a period of 3 months.

METHODOLOGY This was a multicentric, open-labeled, nonrandomized, observational study to assess the lipid-lowering efficacy and safety of Rosuvastatin in Indian dyslipidemic subjects for 12 weeks. The inclusion criteria were all male and nonpregnant female dyslipidemic subjects; age range between 18-80 years. The subjects with following criteria were excluded: Pregnant or lactating female subjects; TG >500 mg/dL and creatinine >20 mg/dL known hypersensitivity to Rosuvastatin; subjects who were suffering from hepatic or kidney dysfunction; subjects with hypothyroidism; history of drug or alcohol abuse and refusal to sign informed consent forms. Safety of Rosuvastatin in subjects with dyslipidemia was assessed by monitoring the frequency and type of adverse events (AEs) occurring in subjects.

Investigators were selected in this study from urban and suburban centers by convenience sampling. Seven hundred fifty centers were included in this study.

Informed consent was taken from all participating subjects. Physical and systemic examination data and lipid profile of each recruited subject was done before initiating therapy (baseline) and at the end of 3 months (post-treatment). Rosuvastatin was given at a dose of 10/20 mg o.d. for 3 months.

Statistics Demographic characteristics and results of lipid profile tests are summarized with descriptive statistics, including mean and standard deviation (SD) for continuous variables, and frequency and percentages for categorical variables. t-test is used and p ≤ 0.05 is considered to be significant.

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RESULTS A total of 7,500 subjects were recruited in the study; 6,278 subjects completed the 12-week study.

Among them, 4,384 (69.83%) were men and 1,898 (30.17%) women. Mean age of the subjects during the recruitment was 54.28 ± 7.8 years. Mean weight was 73.1 ± 9.08 kg and mean body mass index (BMI) was 28.34 ± 4.28 kg/m2 (Table 1). The participant patient age group distribution is represented in detail in Figure 1.

Of the included population, 29.76% were smokers, whereas 21.07% were chronic alcoholics.

Mean Change in LDL-C Levels After Treatment for 12 Weeks There was a significant reduction in the number of subjects who had high levels of LDL-C. Prior to Rosuvastatin treatment, 85.9% of subjects had >130 mg/dL of LDL-C. After 12 weeks of treatment with Rosuvastatin, 51% of the study subjects achieved <130 mg/dL of LDL-C. The mean change in LDL-C levels of <100 mg/dL category was -41.94 ± 36.73 mg/dL; 33.4% were in the ‘near optimal range’ of 100-129 mg/dL of LDL-C and mean change was -52.82 ± 47.16 mg/dL. There was a significant reduction of LDL-C levels in Table 1. Demographic Characteristics of Study Subjects Mean age (years)

54.28 ± 7.8

Gender (M/F) %

69.83/30.17

Mean body weight (kg)

73.1 ± 9.08

Mean BMI

(kg/m2)

28.34 ± 4.28

Systolic blood pressure/Diastolic blood pressure (mmHg)

40

152.33 ±16.39/ 94.06 ± 8.74

35.27

35 30 Percentage (%)

treatment and control of dyslipidemia should be of high priority in controlling of CVD.5 Rosuvastatin is a new generation hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, which exhibits some unique pharmacologic and pharmacokinetic properties. It has low extrahepatic tissue penetration, low potential for CYP3A4 interactions and substantial LDL-C lowering capacity and therefore has distinct advantages.5,6

27.9

25 18.66

20 15

10.37

10 5 0

6.32 1.48 <30

31-40

41-50

51-60

Age group

Figure 1. Recruited patient age group.

61-70

>70

DRUGS 97.2% of the subjects post-treatment with Rosuvastatin (Table 2 and Fig. 2).

Baseline

Post-treatment

40 Percentage of study subjects in corresponding LDL-C categories

Mean Change in HDL-C Levels After 12 Weeks Pre-treatment with Rosuvastatin, two-third of the subjects (66%) had suboptimal HDL-C (<40 mg/dL).

After 12 weeks of treatment with Rosuvastatin, 3,567 subjects achieved HDL-C levels in the range of 40-60 mg/dL. The mean increase in HDL-C levels was 7.82 ± 6.13 mg/dL. Furthermore, 193 subjects had HDL-C levels >60 mg/dL at the end of study. Following treatment with Rosuvastatin at the end of 12 weeks, 60% of the study subjects had >40 mg/dL of HDL-C levels (Fig. 3 and Table 3).

37.8 33.4

35

35.9 31.6

30 25 20

18.2 14

15 10 5

12.2

11.2

2.9

2.8

0 100-129 mg/dL

<100 mg/dL

130-159 mg/dL

160-189 mg/dL

>190 mg/dL

Figure 2. LDL-C level changes in Rosuvastatin-treated dyslipidemic subjects.

Mean Change in TC Levels After Treatment for 12 Weeks

Percentage of study subjects in corresponding HDL-C categories

In our study, total of 88.1% subjects (N = 5,531) had a pre-treatment TC value of >200 mg/dL. Posttreatment with Rosuvastatin, this number reduced to 38.30%. The changes in TC levels are represented in Table 4 and Figure 4. In <200 mg/dL category, 3,874 (61.7%) of subjects had achieved the target and the mean change of TC in the study subjects was -54.43 ± 46.73 mg/dL. The percentage of subjects in the borderline high category of 200-239 mg/dL, decreased to 24.3% after 12 weeks from 35.25% before treatment. In subjects >240 mg/dL category, there was a significant decrease from 52.85% pre-treatment to 14% post-treatment (Fig. 4 and Table 4).

Baseline

70

Post-treatment

66

60

56.8

50

40.1

40

31.9

30 20 10

2.1

0 <40 mg/dL

40-60 mg/dL

3.1

>60 mg/dL

Figure 3. HDL-C level changes in Rosuvastatin-treated dyslipidemic subjects.

Table 2. Study Inference on LDL-C Parameter at Baseline and End of Study (3 Months) LDL-C (mg/dL)

Baseline (N)

Baseline (%)

Post-treatment (N)

Post-treatment (%)

Change in LDL-C levels (mg/dL)

<100 Optimal

187

2.9

1,141

18.2

∆ 41.94 ± 36.73

100-129 (Near optimal/ above optimal)

698

11.2

2,097

33.4

∆ 52.82 ± 47.16

130-159 Borderline high

2,376

37.8

1,985

31.6

∆ 39.37 ± 25.38

160-189 High

2,251

35.9

881

14

∆ 38.12 ± 27.59

766

12.2

174

2.8

∆ 43.12 ± 39.22

>190 Very high

Table 3. HDL-C Levels Before and After Treatment with Rosuvastatin in the RID-3 Study HDL-C (mg/dL)

Baseline (N)

Baseline (%)

Post-treatment (N)

Post-treatment (%)

Change in HDL-C levels (mg/dL)

<40

4,145

66

2,518

40.1

∆ 5.24 ± 4.21

40-60

2,006

31.9

3,567

56.8

∆ 7.82 ± 6.13

127

2.1

193

3.1

∆ 13.17 ± 9.71

>60

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DRUGS Table 4. Changes in TC Before and After Treatment with Rosuvastatin TC (mg/dL)

Baseline (N)

Baseline (%)

Post-treatment (N)

Post-treatment (%)

Change in TC levels (mg/dL)

747

11.9

3,874

61.7

∆ 54.43 ± 46.73

200-239 Borderline high

2,213

35.25

1,523

24.3

∆ 39.18 ± 37.88

>240 High

3,318

52.85

881

14

∆ 42.48 ± 39.02

<200 Desirable

Table 5. Changes in TG Level Before and After Treatment with Rosuvastatin TG (mg/dL)

Baseline (N)

Baseline (%)

Post-treatment (N)

Post-treatment (%)

Change in TG levels (mg/dL)

<150 Normal

1,217

19.4

3,559

56.7

∆ 51.13 ± 49.88

150-199 Borderline high

3,743

59.6

2,138

34

∆ 49.18 ± 41.88

200-499 High

1,318

21

581

9.3

∆ 42.48 ± 39.02

Table 6. Mean Change in Lipid Levels (mg/dL) After 12 Weeks of Treatment with Rosuvastatin Compared to Baseline Baseline

After 12 weeks

Difference

P value

LDL-C (mg/dL)

165.08 ± 57.87

121.2 ± 48.68

-43.88

0.001**

HDL-C (mg/dL)

41.5 ± 8.68

50.21 ± 16.14

+8.71

0.001**

TG (mg/dL)

245.46 ± 51.36

197.51 ± 73.21

-47.95

0.01*

TC (mg/dL)

281.23 ± 89.72

194.11 ± 76.82

-87.12

0.001**

**Highly significant; *Moderately significant.

50 35.25

30

10

24.3 14

11.9

281.23

350

52.85

40

After 12 weeks

400

61.7

60

20

Baseline

Post-treatment

Lipid levels (mg/dL)

Percentage of study subjects in corresponding TC level categories

Baseline 70

245.46

300 250 200 150

197.51

165.08

194.11

121.2 41.5 50.21

100 50 0

0 <200 mg/dL

200-239 mg/dL

>240 mg/dL

LDL-C

HDL-C

TG

TC

Figure 4. TC level changes in Rosuvastatin-treated dyslipidemic subjects.

Figure 5. Mean change in lipid levels (mg/dL) after 12 weeks of treatment with Rosuvastatin compared to baseline.

Mean Change in TG Levels After Treatment for 12 Weeks

21% of the subjects had high TG levels at the start of the study and only 9.3% had high TG levels after 12 weeks of treatment with Rosuvastatin (Table 5).

The RID-3 study results showed that in <150 mg/dL category, 3,559 (56.7%) subjects had achieved target. The mean change was -51.13 ± 49.88 mg/dL. At the baseline, 59.6% of study subjects were in the borderline high (150-199 mg/dL) category and at 12 weeks, this number reduced to 34%. In the subjects with high cholesterol category (200-499 mg/dL),

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In our RID-3 study, overall changes in lipid levels were clinically and statistically significant. The LDL-C levels reduced from 165.08 ± 57.87 mg/dL to 121.2 ± 48.68 mg/dL. There was a mean increase in HDL-C levels by 8.71 mg/dL. The reduction in TGs and TC was also significant (Table 6 and Fig. 5).

DRUGS

10 9

Percentage (%)

8 7 6 5

4.39

4

3.5

3 2

1.08

1.05

Hypersensitivity

Pedal edema

1 0

1.7

1.57

Weight gain

Muscular pain

Abdominal pain

1.06

Diarrhea

1.97

Vomiting

Nausea

Figure 6. Adverse events reported during Rosuvastatin treatment.

In our study, overall the AEs reported were generally mild. These included nausea, vomiting, abdominal pain, muscular pain, weight gain and few others.

Around 16.32% of the subjects in the study population experienced AEs (Fig. 6).

DISCUSSION In our study, lipid parameters like LDL-C, TC, HDL-C significant changes from the baseline were seen posttreatment with Rosuvastatin. These study results were consistent with the published studies.

The LDL-C reduction is important to achieve the treatment goals suggested by Adult Treatment Panel III guidelines.5 In our RID-3 study, 51% of the study subjects achieved <130 mg/dL of LDL-C in 12 weeks of treatment with Rosuvastatin. There was a significant reduction in LDL-C levels with 97.2% of the subjects having lower LDL-C levels with Rosuvastatin treatment.

In our study, total of 88.1% subjects (N = 5,531) had a pretreatment TC value of >200 mg/dL. Post-treatment with Rosuvastatin, this number reduced to less than 40%.

Our results showed even better results than the LUNAR study (Comparison of lipid-modifying efficacy of Rosuvastatin in subjects with acute coronary syndrome).7 Nearly 60% of the subjects with suboptimal HDL-C levels showed positive improvement with Rosuvastatin treatment.

In Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin [STELLAR] study, HDL-C increased by 8-11% and TG reductions was about 22% with Rosuvastatin treatment.8 In the present study, HDL-C increased by 20.98% in the study subjects. The TG reduction in our study subjects was 20%.

Several clinical trials have unequivocally established the efficacy of statins in reducing the risk of CVD due to its antidyslipidemic effects.9 In a study by Shah et al, Rosuvastatin was significantly effective at reducing LDL-C and achieving LDL-C goals.10 Our study results demonstrate that Rosuvastatin is effective in altering the lipid profile in Indian subjects with dyslipidemia.

Rosuvastatin was demonstrated to be the most costeffective statin.10,11 The Use of Rosuvastatin versus Atorvastatin iN type 2 diabetes mellitUS (URANUS) study compared Rosuvastatin with Atorvastatin for the reduction of LDL-C. At the starting dose and following dose titration, Rosuvastatin was significantly more effective than atorvastatin at reducing LDL-C and achieving European LDL-C goals in subjects with type 2 diabetes mellitus.12 In the present study, overall, Rosuvastatin was welltolerated. The percentages of subjects who reported AEs during randomized treatment were similar to the previous trials.13 In studies conducted by Trivedi et al and Park et al, AEs were reported by 18-24% of the total participating subjects.2,4 In our study, AEs were reported in less than 16.32% of the total study population (Fig. 6).

There were no deaths or serious AEs reported during the treatment with Rosuvastatin. In RID-3 study, AEs reported by subjects included nausea, vomiting, abdominal pain, muscular pain, weight gain, which were mostly transient and mild. All the subjects who had reported the AEs recovered completely without any medications being given and none of them had any sequelae, which establishes the safety of Rosuvastatin.

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DRUGS measuring effects of rosuvastatin using intravascular ultrasound in Japanese subjects (COSMOS). Cardiovasc Ther. 2013;31(6):335-43.

CONCLUSION The RID-3 study highlights the efficacy, safety and tolerability of Rosuvastatin therapy in patients with dyslipidemia. In our study, Rosuvastatin significantly lowered LDL-C, TC, TG levels and improved the HDL-C levels. There were no significant drug-related adverse or serious events reported with Rosuvastatin.

The RID-3 study findings establish that Rosuvastatin as a valuable choice for the first-line treatment to achieve lipid goals in the management of dyslipidemia in Indian patients and also to prevent the clinical sequelae of atherosclerotic CVD. REFERENCES 1. Joshi SR, Anjana RM, Deepa M, Pradeepa R, Bhansali A, Dhandania VK, et al; ICMR-INDIAB Collaborative Study Group. Prevalence of dyslipidemia in urban and rural India: the ICMR-INDIAB study. PLoS One. 2014;9(5):e96808.

2. Trivedi H, Mehta HS, Parmar M, Gupta Y, Sheth J, Kalidoss K, et al. An open label, prospective, multi-center, observational study to evaluate the lipid-lowering efficacy and safety of Rosuvastatin in Indian dyslipidemics in routine clinical practice. Indian Med Gazette.

2014;3:313-20.

3. Aggarwal RK, Showkathali R. Rosuvastatin calcium in acute coronary syndromes. Expert Opin Pharmacother.

2013;14(9):1215-27.

4. Park JS, Shin JH, Hong TJ, Seo HS, Shim WJ, Baek SH, et al. Efficacy and safety of fixed-dose combination therapy with olmesartan medoxomil and rosuvastatin in Korean patients with mild to moderate hypertension and dyslipidemia: an 8-week, multicenter, randomized, double-blind, factorial-design study (OLSTA-D RCT: OLmesartan rosuvaSTAtin from Daewoong). Drug Des Devel Ther. 2016;10:2599-609.

6. Lee CW, Kang SJ, Ahn JM, Song HG, Lee JY, Kim WJ, et al. Comparison of effects of atorvastatin (20 mg) versus rosuvastatin (10 mg) therapy on mild coronary atherosclerotic plaques (from the ARTMAP trial). Am J Cardiol. 2012;109(12):1700-4.

7. Pitt B, Loscalzo J, Monyak J, Miller E, Raichlen J. Comparison of lipid-modifying efficacy of rosuvastatin versus atorvastatin in patients with acute coronary syndrome (from the LUNAR study). Am J Cardiol.

2012;109(9):1239-46.

8. Deedwania PC, Hunninghake DB, Bays HE, Jones PH, Cain VA, Blasetto JW; STELLAR Study Group. Effects of rosuvastatin, atorvastatin, simvastatin, and pravastatin on atherogenic dyslipidemia in patients with characteristics of the metabolic syndrome. Am J Cardiol. 2005;95(3): 360-6.

9. Qian C, Wei B, Ding J, Wu H, Cai X, Li B, et al. Metaanalysis comparing the effects of rosuvastatin versus atorvastatin on regression of coronary atherosclerotic plaques. Am J Cardiol. 2015;116(10):1521-6.

10. Shah SN, Arneja J. Efficacy of rosuvastatin in achieving target HDL, LDL, triglycerides and total cholesterol levels in type 2 diabetes mellitus (T2DM) with newly diagnosed dyslipidaemia: an open label, nonrandomised, noninterventional and observational study in India. J Assoc Physicians India. 2013;61(10):721-6, 732.

11. Miller PS, Smith DG, Jones P. Cost effectiveness of rosuvastatin in treating patients to low-density lipoprotein cholesterol goals compared with atorvastatin, pravastatin, and simvastatin (a US Analysis of the STELLAR Trial).

Am J Cardiol. 2005;95(11):1314-9.

12. Berne C, Siewert-Delle A; URANUS Study Investigators.

Comparison of rosuvastatin and atorvastatin for lipid lowering in patients with type 2 diabetes mellitus: results from the URANUS study. Cardiovasc Diabetol. 2005;4:7.

5. Kawashiri MA, Yamagishi M, Sakamoto T, Takayama T, 13.

Hiro T, Daida H, et al; COSMOS Investigators. Impact of intensive lipid lowering on lipid profiles over time and tolerability in stable coronary artery disease: insights from a subanalysis of the coronary atherosclerosis study ■■■■

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Jones PH, Davidson MH, Stein EA, Bays HE, McKenney JM, Miller E, et al; STELLAR Study Group. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial). Am J Cardiol. 2003;92(2):152-60.

DRUGS

Pitavastatin, Its Antioxidant and Hypocholesterolemic Effect TARANNUM FATIMA SUBHANI*, MA NASAR†, RR SINHA†, I BHATTACHARYA*

ABSTRACT This study was an attempt to establish the extent of increased oxidative stress in hypercholesterolemic patients and to evaluate the effect of pitavastatin on the oxidative stress and antioxidant status. The blood samples of 15 subjects (age- and sex-matched) each from Group I (healthy subjects), Group II (hypercholesterolemic patients with pitavastatin treatment) and Group III (hypercholesterolemic patients without any hypolipidemic drug) were taken and centrifuged for separation of plasma. Plasma was used for the estimation of vitamin E. The separated cells were washed thrice with 0.9% w/v cold normal saline and used for the assay of percentage hemolysis of RBCs, malondialdehyde, superoxide dismutase and hemoglobin. Levels of oxidative stress were higher in hypercholesterolemic in comparison to control and pitavastatin group. Levels of antioxidants were higher in pitavastatin group than hypercholesterolemic but were lower than controls. From these findings, it was concluded that there is an increase in oxidative stress in hypercholesterolemia but it decreased significantly after 2 months of pitavastatin therapy and antioxidant status also improves in patients taking pitavastatin.

Keywords: Oxidative stress, antioxidant effects, pitavastatin, hypercholesterolemic patients

T

he statins like pitavastatin significantly reduce cholesterol synthesis through inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) reductase and are widely prescribed for hyperlipidemia to reduce the risk of atherosclerotic complications.1 Their efficacy in reducing cardiovascular morbidity and mortality has been demonstrated in large intervention trials.1 However, debate continues as to whether the beneficial effects of statins can be ascribed purely to their ability to reduce cholesterol or whether additional actions, independent of cholesterollowering, play a significant role.1-3 Studies have shown that oxidized low-density lipoprotein (LDL) is a major correlate of oxidative stress in hypercholesterolemic patients and statins may reduce oxidative stress by reducing enhanced plasma levels of LDL, which are

*Associate Professor Dept. of Biochemistry Rama Medical College Hospital and Research Centre, Hapur, Ghaziabad, Uttar Pradesh †Dept. of Biochemistry, Nalanda Medical College, Patna, Bihar Address for correspondence Dr Tarannum Fatima Subhani Associate Professor Dept. of Biochemistry Rama Medical College Hospital and Research Centre, Hapur, Ghaziabad, Uttar Pradesh E-mail: drtarannum_fatima@rediffmail.com

more susceptible to peroxidation in hypercholesterolemia and change the LDL structure, making them more resistant to peroxidation.1,4,5 Some studies have further shown that statins may also inhibit NAD(P)H oxidase, thus decreasing the generation of reactive oxygen species (ROS), thereby adding or synergizing biological effects of antioxidants.4,6 Some studies have also shown that statins or their metabolites may act as antioxidants, directly or indirectly by removing “aged LDL”, which is more prone to oxidation from the circulation.7 On the basis of these findings, it is evident that among their properties statins also possess antioxidant activities.8,9 Therefore, the aim of the present investigation was to evaluate the scientific evidence of pitavastatin for such an effect and its possible clinical relevance. The antioxidant effects of statins contribute to inhibition of atherogenesis, stabilization of atherosclerotic plaque, inhibition of myocardial hypertrophy and remodeling and modulation of vascular tone.6 Based on these arguments, which formed the backbone of this study, an attempt was made to find out if there really was an increased oxidative stress in hypercholesterolemics and was it relatively decreased following pitavastatin therapy when compared to normal individuals.

In this study, the levels of malondialdehyde (MDA), percentage hemolysis and superoxide dismutase (SOD) in red blood cells (RBCs) and vitamin E in plasma were

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DRUGS measured. RBCs were chosen as they are well-known to be prone to increased hazards of free radical damage.

Moreover, these cells have a finite life span in circulation and their sequestration and disposal by macrophages may be related to the extent of peroxidative damage caused to their membrane lipids, cytoskeletal proteins and enzymes.

EXPERIMENTAL

Study Population This study was conducted on 3 groups of 15 subjects each in the age group of 40-70 years. Both male and female subjects were taken in all groups. ÂÂ

ÂÂ

ÂÂ

Group I: Consisted of 15 healthy subjects (8 males and 7 females) between the age group 40-70 years having normal lipid profile (Control group).

Group II: Consisted of 15 patients (8 males and 7 females) who were already diagnosed as hypercholesterolemic and who were given treatment with HMG-CoA reductase inhibitor, pitavastatin for minimum of 2 months with a minimum dosage of 2 mg/day of pitavastatin.

Treatment with pitavastatin was given only in this group in order to compare the results with control and hypercholesterolemic group without any hypolipidemic drug.

Group III: Consisted of 15 hypercholesterolemic patients (8 males and 7 females) diagnosed recently but were not taking any of the lipid-lowering agents (Hypercholesterolemic group).

Selection of Cases The test Group II and III for this study consisting of 15 individuals in each group were taken from outdoor of Medicine of Rama Medical College Hospital and Research Centre, Hapur, Ghaziabad, Uttar Pradesh, India.

While choosing the subjects for the test and control groups, care was taken to eliminate those with habits like smoking, tobacco chewing, alcohol consumption and also those with history of chronic inflammatory diseases like tuberculosis, rheumatoid arthritis, diabetes mellitus and malignancy all of which play a vital role in contributing to oxidative stress injury. Approval to carry out these studies on human subjects was obtained from Institutional Clinical Ethics Committee of Rama Medical College Hospital and Research Centre, Hapur, Ghaziabad, Uttar Pradesh, India and their guidelines were followed for the studies.

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Sample Collection Five milliliters of venous blood was collected in ethylenediaminetetraacetic acid (EDTA) containers from the median cubital vein or basilic vein of the each study subjects under strict aseptic conditions.

The blood samples were centrifuged at 3000 rpm for 10 minutes within 3-hour of collection. Plasma was separated and used for the estimation of vitamin E. The separated cells were washed thrice with 0.9% w/v cold normal saline, after which they were suspended in an equal volume of the same saline solution. This was then stored as 50% cell suspension at refrigerator (4-50C) and was used for the assay of: ÂÂ

Percentage hemolysis of RBCs at 0 and 2-hour (which represented before and after incubation with hydrogen peroxide (H2O2), respectively)

ÂÂ

Malondialdehyde (MDA)

ÂÂ

Superoxide dismutase (SOD)

ÂÂ

Hemoglobin (Hb).

Lipid Peroxidation (MDA) Red cell lipid peroxidation was studied as thiobarbituric acid (TBA) reaction products. The method of Stocks and Dormandy was followed with certain modifications.10 The sample under test was heated with TBA at low pH and a pink chromogen, allegedly a (TBA)2 - MDA adduct was measured spectrophotometrically at wavelength of 535 nm.11 One milliliter of erythrocyte suspension was added to 8.5 mL of 0.9% w/v of normal saline and mixed well. Then 0.5 mL of 0.44 M H2O2 was added. From this mixture, 2.5 mL of aliquot was immediately taken, to which 1 mL of 28% trichloroacetic acid (TCA) in 0.1 M sodium meta-arsenite was added. This was mixed well and allowed to stand for 10 minutes, after which it was centrifuged. Three milliliter of the supernatant was then taken, to which 1 mL of 1% TBA in 50 mM NaOH was added. This was then kept in a boiling water bath for 15 minutes and later immediately cooled under tap water. The pink chromogen was determined spectrophotometrically at the wavelength of 535 nm.

Values were expressed as nanomoles of MDA formed per dL of RBC, taking the molar extinction co-efficient as 1.56 × 105.10 MDA (nanomoles/100 mL of RBC) was determined using the equation: AT × 109 × 100 × DF × V ε Where AT is the absorbance of test sample, DF is dilution factor, V is volume RBC suspension and є is the extension coefficient.

MDA =

DRUGS Oxidative Hemolysis of RBCs or Percentage Hemolysis of RBCs Oxidative hemolysis of erythrocytes was measured at 0 and 2 hours, which indicated before and after 2 hours incubation with H2O2, respectively by the method of Kartha and Krishnamurthy.12 Principle of this method is based on the fact that an accelerated form of nonenzymatic breakdown can be induced in red cells on exposure to H2O2.10 One milliliter of RBC suspension was added to 8.5 mL of 0.9% w/v of normal saline and mixed well. Then 0.5 mL of 0.44 M H2O2 was added and incubated at 37°C. Immediately, aliquots of 0.5 mL each were withdrawn and put into two different centrifuge tubes labeled as ‘saline’ and ‘water’, respectively.

To the centrifuge tube labeled ‘saline’, 4.5 mL of 0.9% w/v of normal saline was added and centrifuged. The supernatant was then separated and its absorbance (optical density) was determined at 520 nm in a colorimeter. This represented nonhemolyzed RBCs (NH) at 0 hour or before incubation with H2O2.

One milliliter of plasma was thoroughly mixed with 1 mL of redistilled 95% ethanol in a 15 mL stoppered tube. Three milliliter of petroleum ether was then added and the tube was shaken vigorously for 3 minutes.

This was then centrifuged and 2 mL of clear supernatant was transferred to a clear dry cuvette. The optical density was measured at 450 nm in a colorimeter for carotenes, taking petroleum ether as blank.

Petroleum ether was then evaporated off at room temperature and the residue was dissolved in 1 mL chloroform. One milliliter of 95% ethanol was then added followed by 1 mL of 0.2% a,a’-dipyridyl and 0.1 mL of 0.1% FeCl3. Exactly after 1.5 minutes, absorbance was measured at 520 nm in a colorimeter.

Concentration of vitamin E (mg/L) of plasma was determined using the equation: C=

AT − AC AS

Where AT, AC and AS are absorbance of test, carotene and standard sample, respectively.

Superoxide Dismutase

To the centrifuge tube labeled ‘water’, 4.5 mL of distilled H2O was added and centrifuged. The supernatant was then separated and its optical density was determined at 520 nm in a colorimeter. This represented complete hemolysis of RBCs (CH) at 0 hour or before incubation with H2O2.

The method of Beauchamp and Fridovich was followed for measurement of SOD.

The above procedure was again repeated after 2 hours incubation with H2O2 at 370C. The centrifuge tubes labeled ‘saline’ and ‘water’ now represented nonhemolyzed (NH) and completely hemolyzed (CH) RBCs at 2 hours or after incubation with H2O2.

Inhibition of the reduction of nitroblue tetrazolium (NBT) by superoxide radicals, generated by the illumination of riboflavin in the presence of oxygen.

An electron donor, methionine, was used for the assay of SOD.15

Percentage hemolysis of RBCs at 0 and 2 hours was determined using the equation: Hemolysis (%) =

O.D of NH (saline) × 100 O.D of CH (water)

Vitamin E (a-tocopherol) Plasma vitamin E was measured using the Emmorie Engel reaction. Emmorie Engel reaction is based on the reduction of ferric to ferrous ions by tocopherols, which then forms a red complex with a,a’-dipyridyl.

Tocopherol and carotenes were extracted into petroleum ether and the extinction at 450 nm was measured.

A correction was made for carotenoids after adding FeCl3. Reading was taken at 520 nm, exactly after 90 seconds.13,14

The enzyme SOD catalyses the reaction: [SOD] O2− + O2− + 2H+

2H2O2

Preparation of Hemolysate This was done by the method of McCord and Fridovich.16 To 1 mL of erythrocytes (washed with 0.9% w/v of normal saline), 1 mL of deionized water was added to lyse the cells. To this, 0.5 mL of distilled ethanol followed by 0.3 mL of chloroform was added, mixed well and allowed to stand for 15 minutes. Now added 0.2 mL of H2O and centrifuged at 4°C. The supernatant contains SOD activity and was used for the assay of SOD after dilution with potassium phosphate (K-PO4-) buffer (PH 7.8, 0.05 M). 0.1 mL of hemolysate was diluted with 1.9 mL of K-PO4- buffer.

This was the final diluted hemolysate that was used in the procedure given below.

Indian Journal of Clinical Practice, Vol. 28, No. 2, July 2017

157

DRUGS Four test tubes were taken and labeled as ‘Test’, ‘Control’, ‘Test blank’ and ‘Control blank’, respectively.

To the ‘Test’ 2.9 mL of reaction mixture with NBT containing 149 mg of methionine, 4.93 mL of NBT (1 mg/mL), 0.63 mL of riboflavin (1 mg/mL) and made up to 100 mL with K-PO4- buffer (PH 7.8/0.05 M) and 0.1 mL of diluted hemolysate was added.

To the ‘Test blank’ 2.9 mL of same reaction mixture without NBT and 0.1 mL of diluted hemolysate was added.

To the ‘Control’ 2.9 mL of same reaction mixture with NBT and 0.1 mL of K-PO4- buffer (PH 7.8/0.05 M) was added. To the ‘Control blank’ 2.9 mL of the same reaction mixture without NBT and 0.1 mL of K-PO4buffer (PH 7.8/0.05 M) was added.

Each of the above parameters was now taken in a 10 mL beaker. The beakers were kept in an aluminum foil lined box fitted with a 15 W fluorescent lamp for 10 minutes.

The absorbance was measured at wavelength of 560 nm in a spectrophotometer for all the four beakers.

One unit of SOD activity was taken as that producing 50% inhibition of NBT reduction. The values were expressed as units/g Hb. It was calculated using the equation: Unit/dL SOD (x) =

3 2 100 C−T × × × 0.5 0.1 0.1 ½C

SOD activity (units/g) Hb =

x [Units/g Hb of SOD] Hb

Where x is units/dL SOD, C and T are absorbance of control and test, respectively.

Estimation of Hemoglobin The Hb content of erythrocytes was determined by the cyanmethemoglobin method.17 Hb was treated with a reagent containing potassium ferricyanide, potassium cyanide and potassium dihydrogen phosphate (Drabkin’s reagent). The ferricyanide oxidizes Hb to methemoglobin, which is converted to cyanmethemoglobin by the cyanide. Absorbance was measured at 540 nm in a colorimeter.

Twenty microliter of RBC suspension was added to 4 mL of ferricyanide reagent and allowed to stand for 4 minutes. The absorbance was measured at 540 nm against a reagent blank in a colorimeter. The absorbance of the standard solution was measured by directly taking 4 mL of the standard cyanmethemoglobin solution

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(60 mg/dL).18 Hemoglobin (g/dL) was determined using the equation: AT × dilution factor × AS conc. of std. (mg/dL) 1000

Hemoglobin (g/dL) =

Where AT and AS are absorbance of test and standard, respectively.

Statistical Analysis All the biochemical parameters were compared using Fishers ‘F’ test for analysis of variance (ANOVA) except hemolysis. Students paired t-test was used for hemolysis (0 hour and 2 hours). The statistical software “SPSS Version 11” (Statistical Package for Social Sciences) was used for this purpose.

RESULTS AND DISCUSSION In this study, the products of lipid peroxidation, hemolysis of RBCs and antioxidant levels were compared between those having high cholesterol level, those who were on treatment with pitavastatin for a minimum of 2 months (minimum dosage of 2 mg/day) and those who were normal individuals taken as controls having normal lipid profile and of the same age group.

Free oxygen radicals and insufficient antioxidant enzymes have been implicated in the pathogenesis Statins have of hypercholesterolemia.2,4,19,20 been used effectively for the treatment of hypercholesterolemia.2,20,21 These facts formed the basis of this study i.e., to investigate the antioxidant system and oxidative stress in hypercholesterolemic patients as well as in patients who were treated with pitavastatin for a minimum of 2 months.

The mean total cholesterol levels of the 3 groups are given in Table 1. In patients taking pitavastatin, the mean total cholesterol reduced after 2 months of treatment (246.66 ± 8.54 mg/dL) as compared to hypercholesterolemic patients (325.33 ± 11.23 mg/dL).

Table 1. Mean Total Cholesterol Levels of the 3 Groups (Control, Pitavastatin and Hypercholesterolemic) Group

N

Mean total cholesterol level (mg/dL)*

Control

15

161.25 ± 5.43

After minimum 2 months of pitavastatin therapy

15

246.66 ± 8.54

Hypercholesterolemic

15

325.33 ± 11.23

N = No. of subjects,

*mean

± SD, N = 15, SD = Standard deviation.

DRUGS hypercholesterolemic group (4.52 ± 1.06%) as compared to pitavastatin (2.48 ± 0.67%) and control groups (1.69 ± 1.04%), but in pitavastatin group it was more than control but less than hypercholesterolemic group, both before (2.48 ± 0.67%) and after incubation (3.52 ± 0.81%) with hydrogen peroxide (Table 3). The values were statistically highly significant both before and after incubation with hydrogen peroxide (p < 0.05). This could be explained on the basis of increased oxidative stress in hypercholesterolemia and effect of pitavastatin in reducing oxidative stress in hypercholesterolemic patients after 2 months of treatment. Mean vitamin E levels were lower in pitavastatin group (7.74 ± 1.05 mg/dL) and lowest in hypercholesterolemic group (6.28 ± 0.68 mg/dL) as compared to control group (9.31 ± 1.36 mg/dL) as shown in Table 4. The values were statistically highly significant (p < 0.05). These studies have shown that vitamin E plays a critical role in protecting polyunsaturated fatty acids of cell membranes against lipid peroxidation through its freeradical quenching activity at an early stage of freeradical attack, thus suppressing hemolysis.22 This has made it one of the important factors determining the susceptibility of red cells to auto-oxidation hemolysis.22 Vitamin E appeared to be highly efficient as an antioxidant and is accepted as a first-line of defense against lipid peroxidation.22-25

RBC Malondialdehyde As a measure of oxidative stress, MDA the endproduct of lipid peroxidation was estimated by the TBA method. RBC MDA levels were highest in hypercholesterolemic group (742.67 ± 74.10 μmol/L) and lowest in control group (545.63 ± 48.03 μmol/L).

The values were statistically highly significant (p = 0.001) when compared hypercholesterolemic group with control group and statistically significant (p = 0.034) when compared control group with pitavastatin group as indicated in Table 2.

High level of MDA in hypercholesterolemic group suggested increase oxidative stress in patients of hypercholesterolemia. Its relatively lower level in pitavastatin group suggested decreased oxidative stress.

These findings further favor antioxidant properties of statins like pitavastatin.2

Percentage Hemolysis of RBCs and Vitamin E Percentage hemolysis of RBCs was measured as an indicator of damage to RBC membrane as a result of oxidative stress. Amongst the antioxidants, vitamin E was chosen because, despite its low molar concentration in membranes, it effectively serves as the major lipid-soluble, chain-breaking antioxidant.22 This study has shown increased hemolysis of RBCs in the

Table 2. Mean RBC MDA Levels of the 3 Groups (Control, Pitavastatin and Hypercholesterolemic) Group

N

Mean (μmol/L)

SD

Control

15

545.63

48.03

P

Remarks

Pitavastatin

15

590.23

39.63

0.034

S

Hypercholesterolemic

15

742.67

74.10

0.001

HS

Name of the test used - Fishers ‘F’ test - for analysis of variance (ANOVA), N = No. of subjects, SD = Standard deviation, p value = Probability, HS = Highly significant, S = Significant.

Table 3. Percentage Hemolysis of RBCs Before and After Incubation of the 3 Groups (Control, Pitavastatin Hypercholesterolemic) Group

N

Mean (%)

SD

P

Remarks

Control

15

1.69

1.04

Pitavastatin

15

2.48

0.67

0.001

HS

Hypercholesterolemic

15

4.52

1.06

0.001

HS

Control

15

2.78

0.88

Pitavastatin

15

3.52

0.81

0.001

HS

Hypercholesterolemic

15

6.01

1.12

0.001

HS

Hemolysis before incubation

Hemolysis after incubation

Name of the test used - Fishers ‘F’ test.

Indian Journal of Clinical Practice, Vol. 28, No. 2, July 2017

159

DRUGS Table 4. Plasma Vitamin E Levels of the 3 Groups (Control, Pitavastatin and Hypercholesterolemic) Group

N

Mean (mg/dL)

SD

P

Remarks

Control

15

9.31

1.36

Pitavastatin

15

7.74

1.05

0.001

HS

Hypercholesterolemic

15

6.28

0.68

0.001

HS

Name of the test used - Fishers ‘F’ test.

Table 5. RBC Superoxide Dismutase Levels of the 3 Groups (Control, Pitavastatin and Hypercholesterolemic) Group

N

Mean (units/mg)

SD

Control

15

8078.63

762.50

P

Remarks

Pitavastatin

15

7432.69

657.92

0.001

HS

Hypercholesterolemic

15

5281.79

525.19

0.001

HS

Name of the test used - Fishers ‘F’ test.

The popular finding that vitamin E is inversely related to the respective tissue MDA level fits here as MDA in this study was found to be highest in hypercholesterolemic group (742.67 ± 74.10 μmol/L) and lowest in control group (545.63 ± 48.03 μmol/L). The increased hemolysis of RBCs in hypercholesterolemic group could be further documented by the decreased levels of vitamin E, which is a first-line of defense against membrane damaging lipid peroxidation.22-25 In pitavastatin group, the level of vitamin E was more than hypercholesterolemic group but less than control group (Table 4). The results of percentage hemolysis of RBCs were in the same order; it was least in control, more than control in pitavastatin group and highest in hypercholesterolemic group. The controls had highest level of vitamin E as they are considered to be the group with least oxidative stress due to normal lipid profile of their blood. It may be hypothesized that due to increased oxidative stress in hypercholesterolemic group, utilization of vitamin E, which is an antioxidant, might have increased. This agreed with the work of Moriel et al.19

Superoxide Dismutase Superoxide dismutase was chosen in this study as it plays an important role in the removal of superoxide radicals (O2-) formed in red cells and because Hb and SOD have been shown to be in close association with red cells. In addition to this, some studies have also been suggested that SOD is one of the most important enzymes in the front line of defense against oxidative stress and is more effective in protecting the RBCs against damage by exogenous O2-, especially at higher concentrations.26-28 This study showed

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Indian Journal of Clinical Practice, Vol. 28, No. 2, July 2017

low levels of SOD in hypercholesterolemic group (6.28 ± 0.69 units/mg) as shown in Table 5. In pitavastatin group (7.74 ± 1.05 units/mg), SOD level was more than hypercholesterolemic but less than controls. The values were statistically highly significant (p < 0.05).

The low levels of SOD in the cellular and extracellular fluids reduce their oxygen derived free radical (ODFR) scavenging capacity making the tissues more vulnerable to ODFR damage.28 The low level of SOD in hypercholesterolemic patients is indicative of increased oxidative stress in patients of hypercholesterolemia (Table 5).

Studies have shown that in hypercholesterolemia, there was reduced activity of SOD which improved after 2 months of treatment with pitavastatin, further strengthens the idea of increased oxidative stress in hypercholesterolemics and reduction of oxidative stress after the use of pitavastatin which inhibits superoxide anion production, preserves intracellular SOD and prevents the ROS permeation into lipoproteins.2,26,27 Thus, we can conclude that the trends seen in this study definitely suggest that there is an increased oxidative stress occurring as a result of hypercholesterolemia and after the use of pitavastatin, oxidative stress decreases for which there may be two reasons. First, due to decreased cholesterol levels and secondly due to antioxidant effect of pitavastatin as shown by many studies.

CONCLUSION This study was an attempt to establish the extent of increased oxidative stress in hypercholesterolemic patients and to evaluate the effect of pitavastatin on the oxidative stress and antioxidant status after 2 months of treatment.

DRUGS Levels of oxidative stress were higher in hypercholesterolemic in comparison to control and pitavastatin group. Levels of oxidative stress in pitavastatin group were lower than hypercholesterolemic but were higher than control group. Levels of antioxidants were higher in pitavastatin group than hypercholesterolemic but were lower than controls.

From these findings, we can conclude that there is an increase in oxidative stress in hypercholesterolemia but it decreases significantly after 2 months of pitavastatin therapy and antioxidant status also improves in patients taking pitavastatin.

Acknowledgment The authors are very much thankful to the Medicine Department, paramedics and the entire management of Rama Medical College Hospital and Research Centre, Hapur, Ghaziabad, Uttar Pradesh for their cooperation and help.

REFERENCES 1. Mason JC. Statins and their role in vascular protection.

Clin Sci (Lond). 2003;105(3):251-66.

2. Yilmaz MI, Baykal Y, Kilic M, Sonmez A, Bulucu F, Aydin A, et al. Effects of statins on oxidative stress. Biol Trace Elem Res. 2004;98(2):119-27.

3. Rosenson RS. Non-lipid-lowering effects of statins on atherosclerosis. Curr Cardiol Rep. 1999;1(3):225-32.

4. De Caterina R, Cipollone F, Filardo FP, Zimarino M, Bernini W, Lazzerini G, et al. Low-density lipoprotein level reduction by the 3-hydroxy-3-methylglutaryl coenzyme-A inhibitor simvastatin is accompanied by a related reduction of F2-isoprostane formation in hypercholesterolemic subjects: no further effect of vitamin E. Circulation. 2002;106(20):2543-9.

5. Shovman O, Levy Y, Gilburd B, Shoenfeld Y. Antiinflammatory and immunomodulatory properties of statins. Immunol Res. 2002;25(3):271-85.

6. Beltowski J. Statins and modulation of oxidative stress.

Toxicol Mech Methods. 2005;15(2):61-92.

7. Rosenblat M, Hayek T, Hussein K, Michael A. Atorvastatin therapy increases monocyte/macrophage paraoxonase 2 expression and reduces oxidative stress in hyprecholesterolemic patients. Lett Drug Des Disc.

2004;1(3):269-74.

8. Norata GD, Pirillo A, Catapano AL. Circulation.

2004;109:3164.

9. Ky B, Burke A, Tsimikas S, Wolfe ML, Tadesse MG, Szapary PO, et al. The influence of pravastatin and atorvastatin on markers of oxidative stress in hypercholesterolemic humans. J Am Coll Cardiol. 2008;51(17):1653-62.

10. Stocks J, Dormandy TL. The autoxidation of human red cell lipids induced by hydrogen peroxide. Br J Haematol.

1971;20(1):95-111.

11. Halliwell B, Chirico S. Lipid peroxidation: its mechanism, measurement, and significance. Am J Clin Nutr. 1993;57(5 Suppl):715S-724S; discussion 724S-725S. 12. Kartha VN, Krishnamurthy S. Effect of hypervitaminosis A on hemolysis and lipid peroxidation in the rat. J Lipid Res. 1978;19(3):332-4.

13. Bieri JG, Teets L, Belavady B, Andrews EL. Serum vitamin E levels in a normal adult population in the Washington, D.C., area. Proc Soc Exp Biol Med. 1964;117:131-3.

14. Teitz NW. Textbook of Clinical Chemistry. 1986. pp.

1285-8.

15. Fridovich I. Superoxide dismutases. Annu Rev Biochem.

1975;44:147-59.

16. McCord JM, Fridovich I. Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein).

J Biol Chem. 1969;244(22):6049-55.

17. Drabkin DL, Austin JH. J Biol Chem. 1932;98:719.

18. van Assendelft OW, Zijlstra WG, van Kampen EJ, Holtz AH. Stability of haemiglobincyanide reference solutions. Clin Chim Acta. 1966;13(4):521-4.

19. Moriel P, Plavnik FL, Zanella MT, Bertolami MC, Abdalla DS. Lipid peroxidation and antioxidants in hyperlipidemia and hypertension. Biol Res. 2000;33(2):105-12.

20. Ng DS. The role of statins in oxidative stress and cardiovascular disease. Curr Drug Targets Cardiovasc Haematol Disord. 2005;5(2):165-75.

21. DavĂŹ G, Romano M, Mezzetti A, Procopio A, Iacobelli S, Antidormi T, et al. Increased levels of soluble P-selectin in hypercholesterolemic patients.

Circulation.

1998;97(10):953-7.

22. Packer L. Protective role of vitamin E in biological systems.

Am J Clin Nutr. 1991;53(4 Suppl):1050S-1055S. 23. Argani H, Ghorbani A, Rashtchizade N, Rahbaninobar M. Effect of Lovastatin on lipid peroxidation and total antioxidant concentrations in hemodialysis patients.

Lipids Health Dis. 2004;3:6.

24. Garibaldi S, Fabbi P, Bertero G, Altieri P, Nasti S, Manca V. Markers of oxidative stress evaluated in patients with ischemic heart disease at the time of their first clinical manifestation. Ital Heart J. 2002;3:49S-51S. 25. Simon E, Paul JL, Soni T, Simon A, Moatti N. Plasma and erythrocyte vitamin E content in asymptomatic hypercholesterolemic subjects. Clin Chem. 1997;43(2): 285-9.

26. Oski FA. Vitamin E - a radical defense. N Engl J Med. 1980;303(8):454-5.

27. Klatt P, Lamas S. Regulation of protein function by S-glutathiolation in response to oxidative and nitrosative stress. Eur J Biochem. 2000;267(16):4928-44.

28. Gupta VK, Mallika V, Gupta Y, Srivastava DK. Oxygen derived free radicals in clinical context. Ind J Clin Biochem. 1992;7:3-10.

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Every citizen of India should have the right to accessible, affordable, quality and safe heart care irrespective of his/her economical background

Sameer Malik Heart Care Foundation Fund An Initiative of Heart Care Foundation of India

E-219, Greater Kailash, Part I, New Delhi - 110048 E-mail: heartcarefoundationfund@gmail.com Helpline Number: +91 - 9958771177

“No one should die of heart disease just because he/she cannot afford it” About Sameer Malik Heart Care Foundation Fund

Who is Eligible?

“Sameer Malik Heart Care Foundation Fund” it is an initiative of the Heart Care Foundation of India created with an objective to cater to the heart care needs of people.

Objectives Assist heart patients belonging to economically weaker sections of the society in getting affordable and quality treatment.

Raise awareness about the fundamental right of individuals to medical treatment irrespective of their religion or economical background.

Sensitize the central and state government about the need for a National Cardiovascular Disease Control Program.

Encourage and involve key stakeholders such as other NGOs, private institutions and individual to help reduce the number of deaths due to heart disease in the country.

To promote heart care research in India.

All heart patients who need pacemakers, valve replacement, bypass surgery, surgery for congenital heart diseases, etc. are eligible to apply for assistance from the Fund. The Application form can be downloaded from the website of the Fund. http://heartcarefoundationfund.heartcarefoundation. org and submitted in the HCFI Fund office.

Important Notes The patient must be a citizen of India with valid Voter ID Card/ Aadhaar Card/Driving License.

The patient must be needy and underprivileged, to be assessed

by Fund Committee.

The HCFI Fund reserves the right to accept/reject any application for financial assistance without assigning any reasons thereof.

The review of applications may take 4-6 weeks.

All applications are judged on merit by a Medical Advisory Board who meet every Tuesday and decide on the acceptance/rejection of applications.

The HCFI Fund is not responsible for failure of treatment/death of patient during or after the treatment has been rendered to the patient at designated hospitals.

To promote and train hands-only CPR.

Activities of the Fund Financial Assistance

The HCFI Fund reserves the right to advise/direct the beneficiary to the designated hospital for the treatment.

Financial assistance is given to eligible non emergent heart patients.

Apart from its own resources, the fund raises money through donations, aid from individuals, organizations, professional bodies, associations and other philanthropic organizations, etc.

The financial assistance granted will be given directly to the treating hospital/medical center.

After the sanction of grant, the fund members facilitate the patient in getting his/her heart intervention done at state of art heart hospitals in Delhi NCR like Medanta – The Medicity, National Heart Institute, All India Institute of Medical Sciences (AIIMS), RML Hospital, GB Pant Hospital, Jaipur Golden Hospital, etc. The money is transferred directly to the concerned hospital where surgery is to be done.

Drug Subsidy

The HCFI Fund has the right to print/publish/webcast/web post details of the patient including photos, and other details. (Under taking needs to be given to the HCFI Fund to publish the medical details so that more people can be benefitted).

The HCFI Fund does not provide assistance for any emergent heart interventions.

Check List of Documents to be Submitted with Application Form Passport size photo of the patient and the family A copy of medical records Identity proof with proof of residence Income proof (preferably given by SDM)

The HCFI Fund has tied up with Helpline Pharmacy in Delhi to facilitate

BPL Card (If Card holder)

patients with medicines at highly discounted rates (up to 50%) post surgery.

Details of financial assistance taken/applied from other sources (Prime Minister’s Relief Fund, National Illness Assistance Fund Ministry of Health Govt of India, Rotary Relief Fund, Delhi Arogya Kosh, Delhi Arogya Nidhi), etc., if anyone.

The HCFI Fund has also tied up for providing up to 50% discount on imaging (CT, MR, CT angiography, etc.)

Free Diagnostic Facility

Free Education and Employment Facility

The Fund has installed the latest State-of-the-Art 3 D Color Doppler EPIQ 7C Philips at E – 219, Greater Kailash, Part 1, New Delhi.

HCFI has tied up with a leading educational institution and an export house in Delhi NCR to adopt and to provide free education and employment opportunities to needy heart patients post surgery. Girls and women will be preferred.

This machine is used to screen children and adult patients for any heart disease.

Laboratory Subsidy HCFI has also tied up with leading laboratories in Delhi to give up to 50% discounts on all pathological lab tests.

About Heart Care Foundation of India

Help Us to Save Lives The Foundation seeks support, donations and contributions from individuals, organizations and establishments both private and governmental in its endeavor to reduce the number of deaths due to heart disease in the country. All donations made towards the Heart Care Foundation Fund are exempted from tax under Section 80 G of the IT Act (1961) within India. The Fund is also eligible for overseas donations under FCRA Registration (Reg. No 231650979). The objectives and activities of the trust are charitable within the meaning of 2 (15) of the IT Act 1961.

Heart Care Foundation of India was founded in 1986 as a National Charitable Trust with the basic objective of creating awareness about all aspects of health for people from all walks of life incorporating all pathies using low-cost infotainment modules under one roof.

HCFI is the only NGO in the country on whose community-based health awareness events, the Government of India has released two commemorative national stamps (Rs 1 in 1991 on Run For The Heart and Rs 6.50 in 1993 on Heart Care Festival- First Perfect Health Mela). In February 2012, Government of Rajasthan also released one Cancellation stamp for organizing the first mega health camp at Ajmer.

Objectives Preventive Health Care Education Perfect Health Mela Providing Financial Support for Heart Care Interventions Reversal of Sudden Cardiac Death Through CPR-10 Training Workshops Research in Heart Care

Donate Now...

Heart Care Foundation Blood Donation Camps The Heart Care Foundation organizes regular blood donation camps. The blood collected is used for patients undergoing heart surgeries in various institutions across Delhi.

Committee Members

Chief Patron

President

Raghu Kataria

Dr KK Aggarwal

Entrepreneur

Padma Shri, Dr BC Roy National & DST National Science Communication Awardee

Governing Council Members Sumi Malik Vivek Kumar Karna Chopra Dr Veena Aggarwal Veena Jaju Naina Aggarwal Nilesh Aggarwal H M Bangur

Advisors Mukul Rohtagi Ashok Chakradhar

Executive Council Members Deep Malik Geeta Anand Dr Uday Kakroo Harish Malik Aarti Upadhyay Raj Kumar Daga Shalin Kataria Anisha Kataria Vishnu Sureka

This Fund is dedicated to the memory of Sameer Malik who was an unfortunate victim of sudden cardiac death at a young age.

Rishab Soni

HCFI has associated with Shree Cement Ltd. for newspaper and outdoor publicity campaign HCFI also provides Free ambulance services for adopted heart patients HCFI has also tied up with Manav Ashray to provide free/highly subsidized accommodation to heart patients & their families visiting Delhi for treatment.

http://heartcarefoundationfund.heartcarefoundation.org

INTERNAL MEDICINE

A Case of Renal Osteodystrophy on a Background Disease of Polyostotic Fibrous Dysplasia KUNAL PARWANI*, MANISH MEHTA†, HEMANG ACHARYA‡, AC TANNA#, JEMIMA BHASKAR¥

ABSTRACT Polyostotic fibrous dysplasia of bone is a rare disorder. It caused multiple bone deformities of skull and face in this patient.

In addition, since the patient was suffering from chronic kidney disease which causes secondary hyperparathyroidism, he had additional features of renal osteodystrophy also.

Keywords: Cortical expansion of bone, facial asymmetry, secondary hyperparathyroidism, McCune-Albright syndrome, renal osteodystrophy

T

his patient is being treated for chronic kidney disease (CKD) by maintenance hemodialysis.

Incidentally, his abnormal facial asymmetrical appearance and microstomia due to expansion of frontal bones, maxilla and mandible caused us to investigate further and diagnose polyostotic fibrous dysplasia of bone.

CASE REPORT Mr R, a 24-year-old patient is a known case of CKD undergoing maintenance hemodialysis in GG Hospital, Jamnagar, Gujarat twice weekly. Unlike any other CKD case, patient has bony changes and atypical bony abnormalities in his skull.

These bony abnormalities include: ÂÂ

Leonine facies (Fig. 1)

ÂÂ

Asymmetry of maxilla

ÂÂ

Hypertrophy of mandible

ÂÂ

Hypertrophy of hard palate Figure 1. Leonine facies.

*2nd Year Resident †Professor and Head ‡Professor #Assistant Professor ¥Senior Resident Dept. of Medicine Shri MP Shah Govt. Medical College, Jamnagar, Gujarat Address for correspondence Dr Jemima Bhaskar No. 404, Kings Palace Mehulnagar, Opp. BSNL Telephone Exchange, Jamnagar, Gujarat E-mail: jemimabhaskar@yahoo.com

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ÂÂ

Microstomia

ÂÂ

Abnormal dentation (Fig. 2).

On evaluating further patient also has: ÂÂ

Genu varus

ÂÂ

Abnormal gait

ÂÂ

Short stature.

INTERNAL MEDICINE

Figure 3. NECT skull and face.

Figure 2. Abnormal dentation.

There is no pigmentation over any part of body, nor any visual or auditory abnormalities. No abnormality was detected on CVS or RS examination.

Lab investigations revealed following results: TC 6,900/mm3, hemoglobin (Hb) - 10.3 g/dL, platelet count 1,43,000/mm3, serum creatinine - 7.9 mg/dL, serum urea - 112 mg//dL, RBS - 110 mg/dL, serum sodium 139 mmol/L (normal range 136-145 mmol/L), serum potassium - 3.7 mmol/L (normal range 3.5-5.4 mmol/L), serum calcium - 9.3 mg/dL (normal range 9-11 mg/dL), serum phosphate - 1.5 mg/dL (normal range 2.34.7 mg/dL), serum parathyroid hormone - 205.6 pg/mL (normal range 15-68.3 pg/mL), Hb- electrophoresis normal, hepatitis B surface antigen (HbsAg) nonreactive and hepatitis C virus - positive.

NECT skull and face (Fig. 3): Cortical expansion with poor differentiation of corticomedullary junction was noted in skull, visible facial bones and spine.

Multiple tiny lytic lesions with ground glass opacities were noted involving visible facial bones and spine.

Nasal cavity, orbital cavity, atlas, axis, pterygoids, nasal septum were normal.

Figure 4. NECT pelvis with both hips.

NECT pelvis with both hips (Fig. 4): Diffuse bone sclerosis predominantly involving end plates of visible lumbar vertebra.

Diffuse bone sclerosis with resorption involving bilateral iliac wings.

Cortical expansion with poor differentiation of corticomedullary junction and changes of bone resorption diffusely involving bilateral femoral head, neck and pelvic bones.

Multiple lytic lesions with ground glass opacities noted in diaphysis of visible proximal part of femur.

Extensive soft tissue and vascular calcification.

DISCUSSION Fibrous dysplasia of bone is a rare condition. There is fibrous tissue replacement of the skeleton. It may be: 1) monostotic or 2) polyostotic. Thirdly, the polyostotic form may be associated with cafĂŠau-lait spots with abnormal function of endocrine

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INTERNAL MEDICINE organs causing thyrotoxicosis, Cushing’s syndrome, acromegaly, hyperparathyroidism, hyperprolactinemia and precocious puberty known as McCune-Albright syndrome.

neck (bilateral) and pelvic bones also have ground glass opacities. He also has ground glass opacities involving diaphysis of proximal femur and facial bones and poor differentiation of corticomedullary junction.

The monostotic form is most common and is diagnosed between 20 to 30 years. The polyostotic form begins in childhood and may progress with age. It is a benign tumor that has been likened to a localized developmental arrest.

The patient also has CKD. He is on maintenance hemodialysis twice weekly. His parathyroid hormone levels are raised due to secondary hyperparathyroidism of CKD. The radiological pictures showed features of secondary hyperparathyroidism due to renal osteodystrophy such as extensive soft tissue and vascular calcification, diffuse bone sclerosis with some areas of resorption of iliac wings and lumbar vertebra and multiple tiny lytic lesions of facial bones and spine.

In polyostotic fibrous dysplasia, which accounts for 27% of all cases, the lesions are radiolucent areas with cortical expansion, which most commonly involve the maxilla and other craniofacial bones and diaphysis of the proximal femur and tibia. The cortex is thin and bulged outward by the underlying fibrous tissue. The epiphyses are not involved and the extensive fibrous replacement of the diaphysis extends only up to the epiphyseal growth plates. The affected bone is irregular and long bones become bent. Pathologic fractures occur but displacement is prevented by the fibrous tissue. A characteristic hyperostosis develops at the base of the skull and may obliterate the sinuses and encroach on the foramina due to periosteal new bone formation with periosteal elevation. There may be asymmetry of head and face.

Radiographic findings: There is a characteristic dense hyperostotic formation, which enlarges the base of skull and creates a leonine facies. In long bones, the fibrous dysplastic lesions are well-defined radiolucent areas with thinned out cortices and ground glass appearance. If extensive cartilage is formed, there is “cloud of smoke” effect.

Morphology: The lesional tissue is tan white and gritty and is composed of curvilinear trabeculae that mimic Chinese letters.

Usually calcium, phosphorus, parathyroid hormone, 1,25-dihydroxyvitamin D levels are normal. Patients with extensive polyostotic lesions may have hyperphosphatemia and hypophosphaturia.

This patient has cortical expansion of frontal bones causing frontal bossing, of the maxilla causing asymmetry of the cheeks and downward projection of the palate into the mouth cavity, of the mandible causing upward projection of the floor of the mouth resulting in gross microstomia. The femoral head and

The three major components of bone disease in renal osteodystrophy are osteomalacia, osteosclerosis due to secondary hyperparathyroidism and soft tissue calcification. He had all these features in addition to the changes of polyostotic fibrous dysplasia, namely cortical expansion of bone and diffuse ground glass appearance.

CONCLUSION The combination of renal osteodystrophy and polyostotic fibrous dysplasia is a very rare entity, hence the presentation.

Acknowledgment In grateful acknowledgment to Dr Bhuvana MD, Professor of Radiology, ESI Medical College, Chennai, for her erudite diagnosis of the CT scans.

SUGGESTED READING 1. Harrison’s Principle of Internal Medicine. Vol 2, 18th Edition, 2012.

2. Robbins and Cotran’s Pathologic Basis of Disease.

8th Edition, 2010 3. Richard Cruess, William Rennie. Adult Orthopaedics.

Vol 1, 1st Edition, 1984.

4. Samuel Turek. Orthopaedics Principles and their Application. Vol 1, 4th Edition, 1984.

5. Belhoucha B, Abelatif H, Nouri H, Rochdi Y, Amine B, Aderdour L, et al.

Simultaneous maxillary and mandibular brown tumors as the first presentation of secondary hyperparathyroidism. Am J Med Case Rep. 2014;2(11):240-2.

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NEUROLOGY

Aqeductal Stenosis Presenting with Spastic Paraparesis and Recurrent Hydrocephalic Attacks AMIT AGRAWAL

ABSTRACT Patient with late-onset aqueductal stenosis apart from the long-standing features of raised intracranial features can also present with gait disturbances and motor weakness. Recognition of this entity is important as treatment of hydrocephalus will result in improvement in weakness and gait as seen in present case.

Keywords: Aqueduct stenosis, hydrocephalus, gait disorder, spastic gait

C

ongenital aqueductal stenosis (CAS) is the most common cause of aqueductal narrowing.

Despite its congenital origin, the alteration of cerebrospinal fluid (CSF) dynamics can remain compensated and undiagnosed for several years, and symptoms related to hydrocephalus due to CAS may not occur until adult life.1 CAS can be a cause of hydrocephalus in 10% of adult patients, causing massive enlargement of the lateral and third ventricles, and clinical presentation may be acute or chronic.2-4 We present a case of adult-onset idiopathic aqueductal stenosis presented with features of raised intracranial pressure which were ignored in the past and gradual weakness of both lower limbs, now developed rapid deterioration that recovered after ventriculoperitoneal shunt.

CASE REPORT An 18 years right-handed gentleman presented with history of headache off and on 12-year duration, slow but progressive weakness and stiffness of both lower limb of similar duration. Now since 1 month he noticed rapid deterioration in power in lower limbs and also

Professor of Neurosurgery Dept. of Neurosurgery MM Institute of Medical Sciences and Research, Mullana, Ambala, Haryana Address for correspondence Dr Amit Agrawal Professor of Neurosurgery MM Institute of Medical Sciences and Research Maharishi Markandeshwar University, Mullana, Ambala - 133 203, Haryana E-mail: dramitagrawal@gmail.com, dramit_in@yahoo.com

noticed weakness in the right hand with difficulty in doing day-to-day activities. He also had history of loss of consciousness off and on with tonic posturing without any jerky movements and diagnosed to have seizures and was on regular treatment without benefit.

He was also diagnosed to have Hansenâ&#x20AC;&#x2122;s disease for 2 years and was on regular treatment. His general and systemic examination was unremarkable. Higher mental functions were normal. Cranial nerves were normal except bilateral papilledema. Motor examination revealed increased tone in both lower limbs and exaggerated deep tendon reflexes in all four limbs with bilateral ankle clonus. Power was 4/5 in both lower limbs and had weakness of grip of right hand. Sensory examination was normal. Planters were bilateral extensor. Gait was spastic. Computed tomography (CT) scan showed massive dilatation of lateral and third ventricles and small size fourth ventricle suggestive of block at aqueductal level (Fig. 1). Patient underwent right ventriculoperitoneal shunt and following surgery

Figure 1. MRI scan head showing massive dilatation of lateral and third ventricle.

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NEUROLOGY he improved, his spasticity was reduced and his motor power was improved to grade 5/5.

DISCUSSION Late-onset idiopathic aqueductal stenosis (IAS) may become manifest clinically either by headaches or by hydrocephalic symptoms such as gait disturbance, urinary urge, visual disturbance, papilledema, dementia and cognitive impairment.2,5,6 Episodes of hydrocephalic attack (loss of consciousness and decerebrate posture without tonic-clonic movements) can be confused with seizures as in present case.

However, one should be careful as both conditions may co-exist.2 Gait disturbances as the presenting feature in late-onset idiopathic aqueductal stenosis are rare but well-recognized entity.7-10 Patients presenting with spastic gait and weakness of the legs is extremely unusual and sometimes can be confused with cervical spinal cord as the site of the responsible lesions.7 Hydrocephalus as the cause of spastic gait can only be sorted out after appropriate investigations (i.e., CT scan or magnetic resonance imaging [MRI]).7 The underlying pathomechanisms of gait disturbances may include mechanical distension of fibers of the corticospinal tract and of dopaminergic pathways but also disturbed supraspinal control mechanisms of gait secondary to compromised autoregulation and blood flow in the periventricular and deep white matter.10-12 This assumption would also explain the reversibility of spasticity and gait disturbances after third ventriculostomy and shunting.10 Recognition of this entity is important, in particular with regard to the observation that CSF diversion either by third ventriculostomy or by shunting may result in pronounced amelioration or resolution of gait disturbances.5,10 Endoscopic third ventriculostomy, re-establishing a physiological route of CSF dynamics, has become the treatment of choice for aqueductal stenosis in most neurosurgical centers. Endoscopic third ventriculostomy has fewer complications and revisions are rare, but some patients need shunt surgery to improve despite a patent ventriculostomy.2 Shunt surgery is associated with high complication rates and many patients need revisions, but the effectiveness is high.2 In our set up

with limited resources, ventriculoperitoneal shunt was performed to divert the CSF with relief of symptoms of raised intracranial pressure and improvement in gait and motor power.

REFERENCES 1. Villani R, Tomei G, Gaini SM, Grimoldi N, Spagnoli D, Bello L. Long-term outcome in aqueductal stenosis.

Childs Nerv Syst. 1995;11(3):180-5.

2. Tisell M, Tullberg M, Hellström P, Blomsterwall E, Wikkelsø C. Neurological symptoms and signs in adult aqueductal stenosis. Acta Neurol Scand. 2003;107(5): 311-7.

3. Chahlavi A, El-Babaa SK, Luciano MG. Adult-onset hydrocephalus. Neurosurg Clin N Am. 2001;12(4): 753-60, ix.

4. Lee JK, Kim JH, Kim JS, Kim TS, Jung S, Kim SH, et al.

Secondary amenorrhea caused by hydrocephalus due to aqueductal stenosis: report of two cases. J Korean Med Sci. 2001;16(4):532-6.

5. Fukuhara T, Luciano MG. Clinical features of lateonset idiopathic aqueductal stenosis. Surg Neurol.

2001;55(3):132-6; discussion 136-7.

6. Caporal R, Segrestaa JM, Dorf G. Endocrine expressions of hydrocephalus. A case of primary amenorrhoea revealing a stenosis of the foramen of Magendie. Acta Endocrinol (Copenh). 1983;102(2):161-6.

7. Watson CP. Spastic gait and acquired aqueductal stenosis in an adult. Arch Neurol. 1980;37(2):116.

8. Zeidler M, Dorman PJ, Ferguson IT, Bateman DE. Parkinsonism associated with obstructive hydrocephalus due to idiopathic aqueductal stenosis. J Neurol Neurosurg Psychiatry. 1998;64(5):657-9.

9. Curran T, Lang AE. Parkinsonian syndromes associated with hydrocephalus: case reports, a review of the literature, and pathophysiological hypotheses. Mov Disord. 1994;9(5):508-20.

10. Leheta O, Boschert J, Krauss JK, Whittle IR. Festination as the leading symptom of late onset idiopathic aqueductal stenosis. J Neurol Neurosurg Psychiatry. 2002;73(5): 599-600.

11. Krauss JK, Faist M, Schubert M, Borremans JJ, Lücking CH, Berger W. Evaluation of gait in normal pressure hydrocephalus before and after shunting. Adv Neurol.

2001;87:301-10.

12. Petzinger G, Perez E, Fahn S. Motor features of normal pressure hydrocephalus. Mov Disord. 1994;9:126.

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NEUROLOGY

Laryngeal Neurofibroma: An Unusual Manifestation of Neurofibromatosis Type 1 BANSHI LAL KUMAWAT*, KAUSHIK RANA†, TARACHAND SAINI†, ANKUR GARG†

ABSTRACT Neurofibromas are benign nerve sheath tumors which arise from the Schwann cells of the nerve sheath. Neurofibroma may occur anywhere in the body including head and neck, lips, palate, tonsil, tongue, posterior pharyngeal area. Larynx is a very unusual site for neurofibroma. Very few cases are described in the literature. Herein, we report a case of laryngeal neurofibroma involving aryepiglottic fold and false vocal cord. Treatment options include surgical resection of tumor.

Keywords: Laryngeal neurofibroma, Schwann cells, surgical resection

L

aryngeal neurofibromas are exceedingly rare tumors. They can occur either sporadic or as a part of neurofibromatosis type 1 or type 2 (NF-1 and NF-2) but are more commonly associated with NF-1. NF-1 also called von Recklinghausen’s disease, is an autosomal dominant disorder and diagnostic criteria are defined as presentation with 2 or more of the following: Six or more café-au-lait spot: (1.5 cm or larger in postpubertal and 0.5 cm or larger in prepubertal individuals), two or more neurofibromas of any type or 1 or more plexiform neurofibroma, axillary or inguinal freckling, optic glioma, two or more iris lisch nodules, a characteristic bony lesion (dysplasia of the sphenoid bone, dysplasia or thinning of long cortex of long bones), first-degree relative with NF-1.

Laryngeal neurofibromas affect larynx in descending order as arytenoids, aryepiglottic fold, false vocal cord followed by ventricle of larynx and usually present with symptoms like hoarseness of voice, dyspnea and dysphagia.

of voice and difficulty in swallowing especially for solid food for last 10 months. Patient also had 3 months history of low back pain, slowly progressive weakness of both lower limbs and urinary hesitancy.

On examination, multiple neurofibromas were present over back, upper limb and sternum (Fig. 1). Peripheral nerves were not thickened. All cranial nerves were normal except hoarseness of voice. On motor system examination spasticity was present in all four limbs and power was 4/5 on the Medical Research Council (MRC) grade in both lower limbs and upper limbs. Reflexes were brisk in four limbs with extensor plantar response bilaterally. On examination of family members, his two younger brothers also had multiple neurofibromas but were not having other complaints.

On laryngoscopic examination, a smooth lobulated mass was seen in left supraglottic region involving aryepiglottic folds and extending to false cord (Fig. 2B).

CASE REPORT A 48-year-old male presented with complaints of insidious onset, gradually progressive hoarseness

*Senior Professor †Senior Resident Dept. of Neurology SMS Medical College, Jaipur, Rajasthan Address for correspondence Dr Tarachand Saini E-379, Bank Colony, Murlipura Scheme, Jaipur, Rajasthan E-mail: drtcsaini20@gmail.com

Figure 1. Multiple neurofibromas over back and large neurofibroma over right forearm, right arm and sternum.

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NEUROLOGY

Figure 2. A: MRI spine T2W sagittal image showing extramedullary intradural mass (neurofibroma) compressing the cord at D3 vertebral level and at cervicomedullary junction.

B: Smooth lobulated mass is seen in left supraglottic region involving aryepiglottic folds and extending to false vocal cord.

There was no ulceration and signs of inflammation.

Magnetic resonance imaging (MRI) spine showed extramedullary intradural mass (neurofibroma) compressing the cord at D3 and cervicomedullary junction (Fig. 2A). MRI brain was normal. Patient was advised surgical excision of tumor but he refused for surgery.

DISCUSSION Laryngeal neurofibromas are nonencapsulated, rounded, white masses present along the course of involved nerves and nerve fibers usually traverse the mass.1 Laryngeal neurofibroma are more common in female than male.2 Young population affected more with age ranged from 2 to 60 years in reported cases.3,4 In our case, laryngeal neurofibroma arise as a lobulated mass from left aryepiglottic fold with

extension to false vocal cord that is a common site for laryngeal neurofibroma as reported by Pearlmen et al.5 Common symptoms of endolaryngeal neurofibroma are hoarseness of voice, dyspnea and dysphagia that were present in our case. Supance et al6 reported that laryngeal neurofibroma are more frequently present as a solitary lesion than combined occurrence with NF-1, while our case was associated with NF-1 as he had multiple neurofibromas over whole body and positive family history. As tumor is benign in nature, total excision is adequate. Large tumors can be excised through external approaches, like laryngofissure, lateral pharyngotomy, lateral thyrotomy whereas small tumors are excised endoscopically. Neurofibroma associated with von Recklinghausen’s disease have 4.6-16% chance of sarcomatous changes.

REFERENCES 1. Figi FA, Stark DB. Neurofibroma of the larynx; presentation of five cases. Laryngoscope. 1953;63(7):652-9.

2. Chen YW, Fang TJ, Li HY. A solitary laryngeal neurofibroma in a pediatric patient. Chang Gung Med J. 2004;27(12):930-3.

3. Stanley RJ, Scheithauer BW, Weiland LH, Neel HB 3rd. Neural and neuroendocrine tumors of the larynx.

Ann Otol Rhinol Laryngol. 1987;96(6):630-8.

4. Gstöttner M, Galvan O, Gschwendtner A, Neher A. Solitary subglottic neurofibroma: a report of an unusual manifestation. Eur Arch Otorhinolaryngol.

2005;262(9):705-7.

5. Pearlman SJ, Friedman EA, Appel M. Neurofibroma of the larynx. Arch Otolaryngol. 1950;52(1):8-14.

6. Supance JS, Quenelle DJ, Crissman J. Endolaryngeal neurofibromas. Otolaryngol Head Neck Surg (1979).

1980;88(1):74-8.

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Sleep Problems may be Early Sign of Alzheimer’s Poor sleep may be a sign that people who are otherwise healthy may be more at risk of developing Alzheimer’s disease later in life than people who do not have sleep problems, according to a study published in the July 5, 2017, online issue of Neurology. Subjects who reported worse sleep quality, more sleep problems and daytime sleepiness had more biological markers for Alzheimer’s disease in their spinal fluid than those who did not report sleep problems.

Zolpidem may Also Benefit Noninsomnia Neurologic Disorders In a systematic review of 67 studies on neurologic disorders, zolpidem tartrate was also found to benefit patients with noninsomnia neurologic disorders, including patients with movement disorders such as Parkinson's disease or dystonia and those in a vegetative state.

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OBSTETRICS AND GYNECOLOGY

Hemoperitoneum Complicating Acute Fatty Liver of Pregnancy SHIVANG SHARMA*, MN MEHTA†, HK ACHARYA‡, AC TANNA#, JEMIMA BHASKAR¥

ABSTRACT Acute fatty liver of pregnancy (AFLP) is a rare complication of full-term pregnancy and presents with jaundice and hepatic encephalopathy in the third trimester. Maternal and fetal mortality is increased and diagnosis should not be confused with HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome, disseminated intravascular coagulation (DIC) and fulminant viral hepatitis occurring in pregnancy as those conditions are usually self-limiting, whereas AFLP should be treated with utmost caution and care.

Keywords: Acute fatty liver, jaundice, encephalopathy, ascites, DIC, HELLP syndrome

J

aundice during pregnancy can be as simple as viral hepatitis or as serious as acute fatty liver of pregnancy (AFLP), which presents as acute liver cell failure and severe jaundice and is usually associated with pregnancy-induced hypertension (PIH), acute kidney injury and disseminated intravascular coagulation (DIC). This patient had all these associated problems but eventually fully recovered.

hepatic encephalopathy with DIC and ascites. When the ascites was aspirated it was found to be hemorrhagic.

CASE REPORT

Serum glutamic-pyruvic transaminase (SGPT) = 98 | 69 | 43 | 33 units/L

A 28-year-old female was admitted with twin pregnancy around 36 weeks of gestation with PIH. She gave a history of lower-segment cesarean section (LSCS) 9 years earlier. Clinically, there was PIH, nausea, jaundice and altered coagulation profile with low platelet and raised prothrombin time (PT) and evidence of DIC.

Investigations: (Initial sample and repeat samples) Serum bilirubin 8.6 | 7.3 | 2.4 | 1.4 mg/dL Prothrombin time (PT) = >60 sec | 16.2 sec Activated partial thromboplastin time (APTT) = >60 sec | 38.5 sec

Viral markers = A | B | C | E negative Hemoglobin - 5.6 | 9.5 | 11.1 g/dL D-dimer - positive WBC - 21,700 | 15,600 | 10,000 | 6800/mm3 Platelets - 65,000 | 1,10,000 | 1,50,000/mL

She was taken up for emergency cesarean section and was given whole blood and fresh-frozen plasma. On 2nd post-op day, she developed renal failure and later

Blood urea - 62 | 38 mg/dL

*2nd Year Resident †Professor and Head ‡Professor #Assistant Professor ¥Senior Resident Dept. of Medicine Shri MP Shah Govt. Medical College, Jamnagar, Gujarat Address for correspondence Dr Jemima Bhaskar No. 404, Kings Palace, Mehulnagar, Opp. BSNL Telephone Exchange, Jamnagar, Gujarat E-mail: jemimabhaskar@yahoo.com

DISCUSSION

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Serum creatinine - 3.0 | 1.8 | 0.7 mg/dL USG abdomen = Liver size normal with coarse echoes with septate ascites. No evidence of subcapsular hematoma.

Jaundice in pregnancy has three different pregnancies: It may be peculiar to the pregnant state, it may be unrelated to pregnant state or it may be when pregnancy is superimposed on chronic liver disease (Table 1).

Acute fatty liver of pregnancy (AFLP) presents with a spectrum ranging from modest hepatic dysfunction

OBSTETRICS AND GYNECOLOGY Table 1. Jaundice in Pregnancy Jaundice peculiar to the pregnant state

Jaundice unrelated to pregnant state Jaundice when pregnancy is superimposed on chronic liver disease

yy Intrahepatic cholestasis (obstetric hepatosis may be recurrent yy Severe pre-eclampsia, eclampsia, HELLP syndrome yy Acute fatty liver (acute yellow atrophy of the liver) yy Severe hyperemesis gravidarum yy Endotoxic shock -DIC

yy Chronic hepatitis yy Viral hepatitis:virus A-E, G yy Cirrhosis, tumors yy Gallstone - obstructive jaundice yy Drug-induced - isoniazid, phenothiazines yy Hemolytic jaundice - mismatched blood transfusion, malaria, Clostridium welchii infection, etc.

to hepatic failure, coma and death. It affects about 1 in 13,000 deliveries. Affected women present usually in third trimester, symptoms include bleeding due to altered coagulation factors, vomiting, jaundice and coma. In about 30% of cases, the presenting symptoms may be those of coexistent pre-eclampsia. It is more common in twin pregnancy.

serum bilirubin was very high and she was bleeding into peritoneum as PT was very high and prognosis was very guarded, she finally rallied around after 1 month of treatment, came out of encephalopathy. PT got corrected, DIC and renal failure become normal.

Ascites is very rare in acute liver cell failure and hemoperitoneum is even more rare in AFLP.

The liver cells contain diffuse microvesicular fat droplets with widespread hepatic and metabolic, disturbances involving mitochondria and ribosomes. Ascites is found in 50% of patients. Severe bleeding is frequent and DIC is found in 10% of cases. Leukocytosis is usual with neutrophilia and thrombocytopenia, raised PT, APTT and raised ammonia. There is raised serum bilirubin and liver enzymes. Ultrasound of liver shows increased echoes in 50% of cases.

The usual cause of hemoperitoneum is rupture of subcapsular hematoma of liver. This patient did not have a subcapsular hematoma of liver as confirmed by USG abdomen. She also had severe hypoprothrombinemia, which usually presents as upper gastrointestinal bleeding but she presented as hemoperitoneum.

AFLP is a catastrophic illness of third trimester with maternal and fetal mortality of 80-90%. Death due to DIC, hepatorenal failure, hepatic encephalopathy and gastrointestinal hemorrhage is common. AFLP is often confused with HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome. In HELLP syndrome, there is no evidence of DIC, deep jaundice or hepatic encephalopathy. It is a self-limiting disease and should not be confused with AFLP. Our patient came in third trimester of twin pregnancy around 36 weeks. She had associated evidence of PIH and was taken up for cesarean section. She also had nausea, jaundice, ascites, DIC, renal failure, hepatic encephalopathy and hemoperitoneum. Although her

CONCLUSION This case is being presented for its rarity and full recovery of the patient although she had a very rare complication of hemorrhagic ascites, which is usually unheard of as a complication of AFLP. SUGGESTED READING 1. Manual of Practical Problems in Obstetrics - Donald School. 1st Edition, 2012. pp. 188-9.

2. Disease of the Liver and Biliary System – Sheila Sherlock.

9th Edition, 1993. pp. 452-5.

3. Obstetrics-Normal and Problem Pregnancies. 3rd Edition, 1996 p. 1119.

4. Pathologic Basis of Disease – Robbins and Contran. 3rd Edition, 2010.

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ONCOLOGY

Fine Needle Aspiration Cytology of Rhabdomyosarcoma of Cheek: A Case Report RIMJHIM SHRIMAL*, ANNU NANDA†, SANGEETA LAMBA‡, DIVYA SETHI#

ABSTRACT Rhabdomyosarcoma is an aggressive malignant neoplasm of skeletal muscle origin, mostly occurring in children, with most cases in head and neck region, other common sites being the genitourinary tract, the retroperitoneum and to a lesser extent, the extremities. Here, we report a case of an oral rhabdomyosarcoma in an 11-year-old girl and describe the clinical, cytological, histopathological and immunohistochemical findings.

Keywords: Rhabdomyosarcoma, fine needle aspiration cytology, cheek

R

habdomyosarcoma (RMS) is a malignant soft tissue neoplasm of skeletal muscle origin, which was first described by Weber in 1854. It accounts for 6% of all malignancies in children under 15 years of age.1 It occurs most commonly in the head and neck region, the genitourinary tract, the retroperitoneum and to a lesser extent, the extremities.2 In the head and neck region, the most commonly affected sites are the orbit, the paranasal sinuses, soft tissues of the cheek and neck.3 Oral RMS is a rare neoplasm accounting for only 0.04% of all head and neck malignancies.4 In the oral cavity, the most common sites are tongue, palate and buccal mucosa.

examined intraorally, a 2 × 2 cm firm mass was full with smooth surface involving the left buccal mucosa.

Fine needle aspiration (FNA) was performed using 22 gauge needle. Slides were prepared and stained with Giemsa stain. FNA smears revealed a high-degree of cellularity displaying clusters of large tumor cells having round to oval hyperchromatic nuclei, showing nuclear overlapping and prominent nucleoli at places (Fig. 2). Stripped nuclei were common. Binucleate and multinucleate cells were seen. A few mitotic figures and occasional bizarre forms were also noted. A diagnosis

CASE REPORT An 11-year-old girl presented with the complaint of a painful swelling in her mouth of 3-month duration.

There was no history of trauma or any systemic disease. On examination, there was facial asymmetry and a diffuse swelling 4 × 4 cm, which was tender on palpation, was full on left cheek (Fig. 1). When

*Senior Resident Dept. of Pathology, ESI Hospital, Rohini, Delhi †Professor and Head ESI Hospital and Dental College, Rohini, Delhi ‡Senior Specialist #Specialist Dept. of Pathology, ESI Hospital, Rohini, Delhi Address for correspondence Dr Divya Sethi C-5/20, Sector-11, Rohini, Delhi - 110 085 E-mail: dr.divyasethi@gmail.com

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Figure 1. Clinical photograph showing large (4 × 4 cm) swelling left cheek causing facial asymmetry.

ONCOLOGY of poorly differentiated malignant tumor was made and urgent biopsy with immunohistochemistry (IHC) was advised.

An incisional biopsy was done and sent for histopathology. Microsections predominantly showed clusters of small round cells with round or oval hyperchromatic nuclei and eosinophilic cytoplasm separated by fibrovascular septa and scattered rhabdomyoblasts having eccentric vesicular nuclei and abundant densely eosinophilic cytoplasm (Fig. 3).

Figure 2. FNA smears revealing clusters and singly scattered large tumor cells with round to oval hyperchromatic nuclei and nuclear overlapping with prominent nucleoli at places (Giemsa; 100X).

A

B

C

D

Figure 3. A - Small round cells and scattered rhabdomyoblasts having eccentric vesicular nuclei and abundant densely eosinophilic cytoplasm. Arrow points the mitotic figure (H&E; 400X); B - Tumor cells show cytoplasmic positivity for muscle specific actin (100X); C - Tumor cells show cytoplasmic positivity for Desmin (400X); D - Tumor cells show nuclear positivity for Myogenin 1 (400X).

Moderate anisocytosis and mitotic figures were noted.

A diagnosis of small round cell tumor/RMS was made and IHC was performed for further typing. The tumor cells were strongly positive for muscle specific actin, desmin and myogenin 1. On the basis of above findings, a diagnosis of oral embryonal RMS was made.

DISCUSSION Rhabdomyosarcoma (RMS) is the third most common extracranial malignant tumor in children after neuroblastoma and Wilmâ&#x20AC;&#x2122;s tumor. The incidence of RMS is highest in children aged 1-4 years, lower in children aged 10-14 years and lowest in children aged 15-19 years.5 The patient in present case was 11 years old falling into intermediate risk group. About 35% of all RMS occur in the head and neck regions, with the orbit being the most frequent site. Males are affected more commonly than females by oral RMS with most common site being the tongue, followed by soft palate, hard palate and buccal mucosa.6 The index case was an 11-year-old girl showing involvement of buccal mucosa.

Clinical features may vary from a small cutaneous nodule on the face to an extensive fast growing facial swelling, which may be associated with pain, trismus, paresthesia, facial palsy and nasal discharge.1 The patient in present case presented with a rapidly growing tender mass causing facial asymmetry and mouth opening was partially restricted.

FNA is usually one of the initial investigations in such cases, but it is rarely possible to make a definite diagnosis of RMS on the basis of cytology alone. The differentials being other small round cell tumors including Ewingâ&#x20AC;&#x2122;s sarcoma, neuroblastoma, malignant lymphoma and poorly differentiated carcinoma.

Therefore, it is essential to perform histopathology and IHC for the definite diagnosis.

A careful histopathological examination is essential to differentiate this tumor from other small round cell tumors. In this case, there was marked pleomorphism which differentiated it from Ewingâ&#x20AC;&#x2122;s sarcoma which shows loosely cohesive clusters of small uniform round cells with round nuclei and lack nucleoli. In neuroblastoma, small clusters of cells are usually separated by a pale blue to light purple fibrillar matrix.7 No rosettes or delicate fibrillary background stroma that represents the neuropil in neuroblastoma were seen. Pleomorphism of tumor cells and lack of lymphoglandular bodies separated the tumor from lymphomas.

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ONCOLOGY RMS histologically has been divided into four broad subtypes: botryoid spindle cell RMS, alveolar RMS, embryonal RMS and undifferentiated RMS.8 The most common type of head and neck RMS are of embryonal type.

The use of IHC for desmin, myogenin and MyoD1 confirms skeletal muscle differentiation and is mainly beneficial for the diagnosis of RMS.9 The MyoD family include four proteins Myogenin, MyoD1, Myf-5 and MRF-4. Antibodies to Myogenin and MyoD1 have high sensitivity and specificity for skeletal muscle differentiation.

They are positive in about 90% of the RMS and the diagnosis of RMS is established only if at least one of these proteins is positive.9 Myogenin was strongly positive in the present case, confirming the diagnosis of RMS.

REFERENCES 1. Chigurupati R, Alfatooni A, Myall RW, Hawkins D, Oda D. Orofacial rhabdomyosarcoma in neonates and young children: a review of literature and management of four cases. Oral Oncol. 2002;38(5):508-15.

2. Duraes GV, Jham BC, Mesquita ATM, dos Santos CRR, Miranda JL. Oral embryonal rhabdomyosarcoma in a child: a case report with immunohistochemical analysis.

Oral Oncol Extra. 2006;42(3):105-8.

3. Al-Khateeb T, Bataineh AB. Rhabdomyosarcoma of the oral and maxillofacial region in Jordanians: a retrospective analysis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2002;93(5):580-5.

4. Chi AC, Barnes JD, Budnick S, Agresta SV, Neville B. Rhabdomyosarcoma of the maxillary gingiva.

J Periodontol. 2007;78(9):1839-45.

5. Gordón-Núñez MA, Piva MR, Dos Anjos ED, Freitas RA. Orofacial rhabdomyosarcoma: report of a case and review of the literature. Med Oral Patol Oral Cir Bucal. 2008;13(12):E765-9.

6. Hicks J, Flaitz C. Rhabdomyosarcoma of the head and neck in children. Oral Oncol. 2002;38(5):450-9.

CONCLUSION In conclusion, although rare, the possibility of an oral RMS should be kept in mind while dealing with intraoral lesions especially in children. Children who present with facial swelling and pain in the outpatient need to be investigated appropriately.

FNAC is a simple, accurate and safe modality, which can provide tremendous information in such a setting. It is an excellent diagnostic tool and can help the clinician to choose subsequent investigations judiciously.

7. Akhtar M, Iqbal MA, Mourad W, Ali MA. Fine-needle aspiration biopsy diagnosis of small round cell tumors of childhood: a comprehensive approach. Diagn Cytopathol.

1999;21(2):81-91.

8. Miloglu O, Altas SS, Buyukkurt MC, Erdemci B, Altun O. Rhabdomyosarcoma of the oral cavity: a case report. Eur J Dent. 2011;5(3):340-3.

9. Andrade CR, Takahama Junior A, Nishimoto IN, Kowalski LP, Lopes MA. Rhabdomyosarcoma of the head and neck: a clinicopathological and immunohistochemical analysis of 29 cases. Braz Dent J. 2010;21(1):68-73.

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Radioembolization Improves QOL in Locally Advanced Liver Cancer According to findings of the phase 3 SARAH trial presented June 29, 2017 at the 19th World Congress on Gastrointestinal Cancer (WCGC) in Barcelona, Spain, treating locally advanced hepatocellular carcinoma (HCC) with radioembolization with yttrium-90 resin microspheres results in better tumor responses and quality-of-life (QOL) compared to sorafenib the current standard of care.

Cancer and Heart Patients in GMCH to Get Medicines at 50-70% Discount Cancer patients and heart patients at the Government Medical College and Hospital (GMCH), Nagpur can now get medicines at 50-70% lesser cost following a government scheme called Amrit (affordable medicine and reliable implants for treatment) being implemented in GMCH by the Central Government. Besides medicines, implants like stents, valves etc., will also be available at concessional rates at a special store that would become functional by July end or August beginning at the Super Speciality Hospital (SSH) attached to GMCH.

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PEDIATRICS

Assessment of Knowledge Regarding Appropriate Imaging Modalities Amongst Pediatricians SHITAL BHATTAD*, SURESH BHATTAD†, ANIL TAPDIYA‡

ABSTRACT Background and objectives: Medical imaging is crucially important for diagnosing many pediatric diseases. But most of the imaging studies are inappropriate and unnecessary. Role of pediatricians is important in prescribing an appropriate diagnosing tool. We hereby present a study assessing knowledge of pediatricians regarding prescribing appropriate imaging modalities.

Material and methods: We studied 78 pediatricians’ views with the help of a preformed questionnaire regarding imaging modalities. Results: Fifty-four out of 78 pediatricians were unaware when to advise neuroimaging in a child with headache, as low as reasonably achievable (ALARA) principle was known only to 3 pediatricians, 19 pediatricians did not know that in head injury we prefer CT scan. Knowledge regarding diethylene-triamine pentaacetic acid (DTPA) scan, micturating cystourethrogram (MCU) and the National Institute for Health and Care Excellence (NICE) guidelines, which are used for diagnostic evaluation of urinary tract infections (UTI) in children, was very poor. Conclusion: We conclude that knowledge about prescribing specific imaging modalities in children is poor amongst pediatricians.

Keywords: Medical imaging, pediatricians, appropriate diagnosing tool, knowledge

M

edical imaging has a remarkable role in the practice of clinical medicine.1,2 Evidence indicates that between 10% and 20% of medical imaging studies are unnecessary or inappropriate.1 There are two important and internationally accepted precepts in diagnostic imaging - justification and optimization.3 The latter means keeping the dose of ionizing radiation ‘as low as reasonably achievable’ (the ALARA principle), while still enabling diagnosticquality imaging. This is the responsibility of imaging technologists and radiologists.4 Justification is the decision as to whether the potential benefits of diagnostic imaging outweigh the inherent risks (i.e., is it appropriate?) and justification is the responsibility of the clinician. And for pediatricians, knowledge of

*Assistant Professor Government Medical College, Latur, Maharashtra †Professor MIMSR Medical College, Latur, Maharashtra ‡Junior Resident Government Medical College, Latur, Maharashtra Address for correspondence Dr Shital Bhattad Assistant Professor Government Medical College, Latur, Maharashtra E-mail: shitalbhattadgondhali@gmail.com

appropriate imaging is of much significance, since it is seen that many of us don’t know when to advise magnetic resonance imaging (MRI) or when to advise computed tomography (CT). Many times we do imaging unnecessarily. So, the aim of the study was to assess knowledge regarding imaging modalities in pediatricians.

AIM Assessment of knowledge regarding appropriate prescription of imaging modalities in pediatricians.

MATERIAL AND METHODS Study design: Questionnaire based observational study.

We studied 78 pediatricians’ views with the help of a preformed questionnaire regarding imaging modalities.

Validated questionnaire was prepared. We collected the data which were analyzed on excel sheet.

RESULTS Our results were surprising… we found that knowledge regarding prescribing appropriate imaging was very poor amongst pediatricians. Views of a total number of 78 pediatricians were recorded. Mean experience of practicing was 11 years. Still many of them were unaware of when to advise which imaging

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PEDIATRICS Table 1. Knowledge Regarding Advising Radiologic Diagnostic Evaluation Amongst Pediatrician Question Number given correct answer Percentage (%) Indication for neuroimaging in a child with headache 24 30.76 Knowledge about advising specific bone X-ray for age assessment 53 67.94 CT or MRI for a patient with truncal ataxia?

57 73.07 Why would you prefer CT/MRI in above case?

28 35.89 What is ALARA principle?

3 3.84 What are NICE guidelines?

10 12.82 For transverse myelitis or ADEM which imaging investigation?

52 66.66 What is MCU? 24 30.76 DTPA assesses what? structure/function 20 25.64 Head injury what you will advise CT or MRI 59 75.64

modality. Fifty-four pediatricians were unaware when to advise neuroimaging in a child with headache.

ALARA principle was known only to 3 pediatricians, 19 pediatricians still not know that in head injury we prefer CT scan. Knowledge regarding diethylenetriamine pentaacetic acid (DTPA) scan, micturating cystourethrogram (MCU) and the National Institute for Health and Care Excellence (NICE) guidelines, which are used for diagnostic evaluation of urinary tract infections (UTI) in children, was very poor (Table 1).5

provided that these included white matter lesions.9 MRI is far more sensitive than CT and demonstrates lesions characteristic of demyelination.

DISCUSSION

1. Chorney ET, Lewis PJ. Integrating a radiology curriculum into clinical clerkships using case oriented radiology education. J Am Coll Radiol. 2011;8(1):58-64, 64.e1-4.

Fifty-four pediatricians were unaware when to advise neuroimaging in a child with headache. Guidelines for neuroimaging in children with headache are given in 20th edition of Nelson Textbook of Pediatrics.6 As regards the second question from our questionnaire, 25 pediatricians were not having knowledge about which X-ray to be prescribed at that particular age for estimating bone age. For the third and fourth questions, majority were not aware why we prefer MRI over CT for truncal ataxia. MRI promises to be an effective, noninvasive means of visualizing intracranial pathology. It is especially useful for the evaluation of posterior fossa and cervical spinal cord disease of childhood; CT evaluation is frequently suboptimal in this region.7 For question number 6, NICE guidelines are to be used for diagnostic evaluation of UTI in children. These guidelines help us in recommending imaging schedule for children with UTI.5 Many of them had lack of knowledge regarding MCU and DTPA scan, which is used to assess renal function.8 For diagnosing acute disseminated encephalomyelitis (ADEM), recently they have included MRI findings along with clinical symptoms. The occurrence in a previously healthy child of acute symptoms associating the following at onset: more than one neurological deficit (‘polysymptomatic’ onset); change in mental state and any combination of alterations seen on MRI,

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CONCLUSION The results of the study led to the conclusion that knowledge regarding prescribing appropriate imaging modalities is very poor amongst pediatricians.

REFERENCES

2. Islami Parkoohi P, Jalli R, Danaei M, Khajavian S,Askarian M. Medical students’ knowledge of indications for imaging modalities and cost analysis of incorrect requests, Shiraz, Iran 2011-2012. Iran J Med Sci. 2014;39(3):293-7.

3. Remedios D, Drinkwater K, Warwick R; Clinical Radiology Audit Committee (CRAC), The Royal College of Radiologists, London. National audit of appropriate imaging. Clin Radiol. 2014;69(10):1039-44.

4. Mendelson RM, Montgomery BD. Towards appropriate imaging: Tips for practice. Aust Fam Physician.

2016;45(6):391-5.

5. Baumer JH, Jones RW. Urinary tract infection in children, National Institute for Health and Clinical Excellence. Arch Dis Child Educ Pract Ed. 2007;92(6):189-92.

6. Kliegman, Robert, Richard E Behrman, Waldo E Nelson. Nelson Textbook of Pediatrics. 20th Edition.

7. Packer RJ, Zimmerman RA, Bilanuik LT, Leurssen TG, Sutton LN, Bruce DA, et al. Magnetic resonance imaging of lesions of the posterior fossa and upper cervical cord in childhood. Pediatrics. 1985;76(1):84-90.

8. Song C, Bang JK, Park HK, Ahn H. Factors influencing renal function reduction after partial nephrectomy. J Urol.

2009;181(1):48-53; discussion 53-4.

9. Young NP, Weinshenker BG, Lucchinetti CF. Acute disseminated encephalomyelitis: current understanding and controversies. Semin Neurol. 2008;28(1):84-94.

CONFERENCE PROCEEDINGS

7th World Congress of Diabetes (DiabetesIndia 2017) GLP-1 receptor agonist activities and glucagon receptor antagonist activities.

THE INDIAN PHENOTYPE - BREAKING THE NEXUS WITH SGLT2 INHIBITORS Dr SR Aravind, Bengaluru ÂÂ

In India, approximately 66.9% patients fail to maintain HbA1c goal.

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The so-called Indian phenotype refers to certain unique clinical and biochemical abnormalities in Indians which include increased insulin resistance, greater abdominal adiposity, i.e., higher waist circumference despite lower body mass index (BMI), lower adiponectin and higher high sensitive C-reactive protein levels.

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Indians require comprehensive antidiabetic management with a team-based approach to deal with individual aspects of care.

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SGLT2 inhibitors have 5 key benefits in type 2 diabetes patients: Fast action; glucose-lowering; weight loss and BP reduction; flexibility; possible CV, renal and other pleiotropic benefits.

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SGLT2 inhibitors inhibit glucose reabsorption in the renal proximal tubule; even patients with refractory type 2 diabetes are likely to respond.

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Pancreatic transplantation can successfully restore normoglycemia and have positive impact on diabetes complications; requires immunosuppressive therapy; utilization is limited by organ availability.

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Islet transplantation - Successful in short-term in select centers; does not provide durable control of glycemia; remains an experimental procedure.

DIABETES MANAGEMENT IN INTENSIVE CARE Dr Vijay Panikar, Mumbai ÂÂ

Etiologies of in-patient hyperglycemia - Previously diagnosed diabetes; previously undiagnosed diabetes and stress hyperglycemia.

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A1c for diagnosis of diabetes in the hospital - A1c >6.5%.

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Focus of novel drug development - Insulin receptor signaling.

Glycemic target in ICU - 140-180 mg/dL; non-ICU target: FPG - 80-120 mg/dL, pre-meal BG - <140 mg/dL, post-meal BG - <180 mg/dL.

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Efficacy, safety and cost with outcome data should be the primary determinant in any antidiabetic prescription.

For majority of critically ill patients in ICU, insulin infusion should be used to control hyperglycemia.

BG >180 mg/dL should trigger insulin initiation.

ÂÂ

Starting an insulin infusion: Give a priming bolus of regular insulin 0.1 U/kg body weight, if BG >300 mg/dL; infusion initiation (U/hr): initial rate of infusion = current BG/100.

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Hypoglycemia protocol - BG ≤70: Suspend insulin, give 25% dextrose (100-BG) × 0.8

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Adjusting the insulin infusion rate: ↑ BG from prior CBG: ↑ infusion dose; BG ↓ <30 mg% from prior CBG: ↑ infusion dose; BG ↓ >30 mg% from prior BG: Same infusion dose till BG <180.

NOVEL THERAPIES IN DIABETES Dr Shashank Joshi, Mumbai ÂÂ

ÂÂ

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Each drug has issues, but insulin, metformin and sulfonylureas (SUs) have been around for >50 years.

Metformin and SUs are the cheapest antidiabetic drugs.

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When to use a new drug - When it is clearly safer than old drug; when it produces an effect that is clearly better; when it is substantially less costly.

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SGLT2 inhibitors are here to stay.

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New options in sensitizers - PPAR-γ agonists; B3AR agonists; GSK-3 inhibitors; PTP-1B inhibitors, RXR agonists.

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PTP-1B is a new target for the treatment of obesity and associated comorbidities.

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Dual-acting peptide for diabetes (DAPD) is a GLP-1/glucagon hybrid peptide that exhibits both

INCREASED SUSCEPTIBILITY OF INDIANS TO DIABETES Dr CS Yajnik, Pune ÂÂ

Indians get diabetes at a younger age and lower BMI compared to Europeans. This could be due to genetic differences, but there is little proof of this.

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CONFERENCE PROCEEDINGS ÂÂ

For the last 150 years, Indians have gained little height which is probably due to famines and poor diet.

ÂÂ

India is the world’s capital for both low birth weight babies and diabetes. Poor growth in the mother’s womb contributes to higher susceptibility of Indians to diabetes (Barker’s theory).

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Indians are short and thin but more adipose compared to Europeans.

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These body characteristics develop in the womb.

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Indians have weaker pancreas and too much body fat, a combination which brings on diabetes.

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Thus, history and biology combine to increase the risk of diabetes.

injuries to healthcare professionals administering the insulin.

GASTROPARESIS IN DIABETES - MORE THAN AN AUTONOMIC NEUROPATHY Dr Ashish S Dengra, Jabalpur ÂÂ

One of most distressing component of diabetic autonomic neuropathy (DAN) is diabetic gastroparesis (DGP), which is usually neglected.

ÂÂ

DGP is usually associated with retinopathy, neuropathy and nephropathy as well as poor glycemic control.

ÂÂ

Gastroparesis should be suspected in individuals with erratic glucose control. Upper GI symptoms should lead to consideration of all possible causes, including autonomic dysfunction.

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Major clinical features of this disorder are early satiety, anorexia, nausea, vomiting, epigastric discomfort and bloating. Episodes of nausea or vomiting may last days to months.

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Even with mild symptoms, gastroparesis interferes with nutrient delivery to the small bowel and therefore disrupts the relationship between glucose absorption and exogenous insulin administration.

This can result in wide swings of glucose levels and unexpected episodes of postprandial hypoglycemia and apparent “brittle diabetes.”

Therefore, gastroparesis should be suspected in patients with erratic glucose control.

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The finding of retained food in the stomach after an 8- to 12-hour fast in the absence of obstruction is diagnostic of gastroparesis.

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Gastric emptying of a solid meal by scintigraphy is considered the gold standard for diagnosis.

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For patients with DGP, the goal of management is to maintain adequate glucose control, control upper GI symptoms, ensure adequate hydration and nutrition, improve gastric emptying and prevent complications.

EXERCISE AND DIABETES: EVIDENCE? Dr JK Mokta, Shimla Exercise improves fitness and reduces fat. It improves CV function and CHD risk profile. It increases selfconfidence. It improves glucose control. It improves insulin sensitivity. It reduces diabetes risk by 60%.

FORUM FOR INJECTION TECHNIQUE AND THERAPY EXPERT RECOMMENDATIONS INDIA - NEW RECOMMENDATIONS 2017 Dr Sanjay Kalra, Karnal ÂÂ

The shortest needle: The shortest needles (4 mm pen and 6 mm syringe needles) are safe, effective and less painful. These should be the first-line choice for all patients. The 4 mm pen needle is considered the safest for adults and children regardless of age, gender, ethnicity or BMI. Patients reported it to be less painful.

ÂÂ

Detect and avoid injection into areas of lipodystrophy: 31% of patients experienced lipohypertrophy (lipo). Patients with lipo had higher HbA1c, daily insulin use, rates of unexplained hypoglycemia and glycemic variability.

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Rotation of injection sites can be correctly performed by: Spacing injections within a site approximately 1 fingerbreadth apart, using a single injection site no more frequently than every 4 weeks.

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180

Single-use: Patients should be made aware of the association between needle re-use and lipo, and between re-use and injection pain or bleeding. Pen and syringe needles should only be used once.

They are no longer sterile after use. Re-use of needles increases the risk of accidental needle-stick

Indian Journal of Clinical Practice, Vol. 28, No. 2, July 2017

TRANSLATING CVOT INTO CLINICAL PRACTICE Dr JC Mohan, New Delhi ÂÂ

DM and CV events prevention - there are potential benefits of optimal glycemic control.

ÂÂ

SGLT2 inhibitors are promising agents.

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SGLT2 inhibitors and CV outcome trials (EMPAREG, DECLARE TIMI 58, CANVAS)- reduction in sympathetic tone, anti-aldosterone effect, reduced MV oxygen demand.

CONFERENCE PROCEEDINGS ÂÂ

SGLT2 inhibition brings about multidimensional changes.

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In established CVD + Diabetes, to gliflozinise or not is no longer a question.

HYPOGLYCEMIA: THE BARRIER FOR TIGHT GLYCEMIC CONTROL

ÂÂ

The mean HbA1c decreased from 7.96% to 7.03% by the end of 15 days. The GV curves helped in recognizing and treating masked or asymptomatic hypoglycemic events. It also graphically shows intervals of optimal and suboptimal glycemia.

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AGP study in the patient provides the doctor with an opportunity to have a complete glycemic picture of the patient.

ÂÂ

It offers a reliable, predictive, standardized visualization of the glucose data.

ÂÂ

Researchers were able to not only reduce GV but were also able to improve the quality-oflife of patients by reducing the frequency of hypoglycemia.

Dr NK Soni, Ghaziabad ÂÂ

Hypoglycemia includes all episodes of an abnormally low plasma glucose that expose the individual to harm - PG <70 mg/dL (3.9 mmol/L).

ÂÂ

Hypoglycemia occurs in both T1DM and patients with T2DM.

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Hypoglycemia can occur at any level of glycemia, but the risk increases with more intensive therapy.

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It is a major limiting factor for intensive DM control.

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Beware of nocturnal, unawareness forms.

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Treat and try to prevent recurrence.

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Educate yourself, your patients and their families.

exercise-induced

and

USE OF AMBULATORY GLUCOSE PROFILE FOR IMPROVING MONITORING AND MANAGEMENT OF T2DM Dr Manish Agrawal, Ahmedabad ÂÂ

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SMBG forms an integral part of diabetes care and management. A good metabolic control can be achieved by a combination of regular blood glucose monitoring, good patient education and appropriate treatment.

The ambulatory glucose profile (AGP) device consists of a small, round sensor - around the size of a 10 rupee coin that has to be applied on the back of the arm; it measures the interstitial blood glucose every minute with the help of a small filament that is inserted subcutaneously.

A study was done to show GV in apparently wellcontrolled type 2 diabetic patients and consequent decrease in GV with appropriate dietary and medical management.

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In all, 108 patients with type 2 diabetes with an HbA1c level of 7.5-8.5% were selected for the study.

An AGP sensor was applied to the patients. Out of the 108 subjects, 106 completed the study.

ÂÂ

There were no adverse device effects. Ninety-eight patients had therapy changes while the rest had diet and lifestyle modifications.

MANAGEMENT OF DIABETES IN PATIENTS WITH CVD Dr Anil Kumar Virmani, Jamshedpur ÂÂ

Therapy today has affected a tipping point at the crosss-roads of T2DM and CVD # Paradigmshift → differentiation by CV effects with regard to the hierarchy of antihyperglycemic drugs.

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Multiple risk factor intervention → control of HT/ dyslipidemia and aspirin for secondary prevention.

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Goals of treatment and drugs need to be individualized.

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Lifestyle modification with smoking cessation is must in all.

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Metformin remains the optimal drug for monotherapy → low cost, proven safety record, weight reduction or neutrality and possible benefits on CV outcomes have secured its place as the favored initial drug choice.

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It’s time to resurrect pioglitazone → judicious selection of patients and pharmacovigilance.

STANDARDS OF CARE IN TYPE 1 DIABETES Prof Sudip Chatterjee, Kolkata Type 1 diabetes is increasing in India and worldwide.

Lack of teamwork makes management of the disease extremely time consuming for the physician. All physicians must know that the disease is sometimes lethal. Dietary restrictions are a low priority nowadays.

Psychological factors are of utmost importance and must be addressed. The standard of care is that patients should maintain HbA1c of 7.5%, though this is not always possible. Diabetes care in the school has to be adapted to Indian conditions.

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CONFERENCE PROCEEDINGS dosage of such vaccines may vary in diabetes patients with chronic kidney disease.

ROLE OF VOGLIBOSE IN MANAGEMENT OF GLYCEMIC VARIABILITY Dr Sudhirr Bhandarri, Jaipur ÂÂ

Glycemic variability (GV) refers to swings in blood glucose levels that occur at the same time on different days. GV may lead to micro- as well as macrovascular complications. Target HbA1c levels can be reached by lifestyle modification together with combination drug therapy targeting both fasting and postprandial hyperglycemia.

ÂÂ

An increase in PPG has a greater prognostic significance in terms of GV. Not only HBA1c, but PPG also needs to be controlled.

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Insulin, DPP-4 inhibitors, GLP-1 analogs are commonly recommended to control GV.

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Association of GV and the presence and severity of coronary artery disease (CAD) in patients with type 2 diabetes is well-established. AGIs are unique drugs which control PPG by their effect on intestinal lumen rather than effect on blood.

Voglibose is a very commonly used AGI in India which has shown to control GV and reduce PPG excursions in T2DM patients.

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Voglibose treatment decreases intrinsic insulin secretion, probably via the delay in intestinal absorption of carbohydrates. Voglibose inhibits overwork of the pancreatic beta cells. Hence, it is considered to be a beneficial drug in the treatment of NIDDM patients. It is effective in lowering the daily glycemic excursions in T2DM patients.

VACCINATION IN DIABETES

SILENT ISCHEMIA IN DIABETES - HOW FAR TO INVESTIGATE? Dr Jamal Ahmad, Aligarh Silent myocardial ischemia: is common especially in the diabetic population; is a marker of significant CAD; is associated with an adverse prognosis; is diagnosed by a positive eTT, myocardial perfusion scan or stress echo.

High-risk markers in diabetes are abnormal resting ECG; peripheral vascular disease; erectile dysfunction and cardiac autonomic neuropathy. Intensive risk factor modification is required.

GLUCOSE-LOWERING STRATEGIES AND CV OUTCOMES Dr SK Sharma, Jaipur ÂÂ

Every 1% increase in HbA1c is associated with 25% increase in CVD mortality.

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Metformin - reduces insulin resistance in liver and skeletal muscle; decreases total cholesterol, apo(B), LDL-C and TG; increases HDL-C; is also associated with weight loss.

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Among T2DM patients with documented CAD, metformin appears to be associated with lower mortality and CV risk than secretagogues. Beneficial effects of metformin in heart failure patients have been demonstrated.

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SUs stimulate insulin release from pancreatic beta cells, increase insulin sensitivity. Therapy with basal insulin glargine for >6 years had a neutral effect on CV outcomes.

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DPP-4 inhibitors reduced atherosclerotic lesions in animal models; in humans vildagliptin has been associated with decrease in intima media thickness, a surrogate marker for early atherosclerosis.

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Vildagliptin reduces postprandial lipemia. SGLT2 inhibitors have shown promising results in terms of CV safety.

Dr OP Sharma, New Delhi Long-standing type 2 diabetes has issues of immunity.

Patients suffering from diabetes continue to get repeated infections. These infections are both bacterial and viral. There are vaccines which give passive immunity against certain infections. The use of such vaccines in patients with diabetes has a role in the prevention of such infections. Some of them are given once in life time while others have to be repeated. The

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CONFERENCE PROCEEDINGS

54th Annual Conference of Indian Academy of Pediatrics (PEDICON 2017) to be looked into, as it signifies undertaking this intervention when not medically warranted.

IMPACTS OF RISING RATES OF CESAREAN SECTION & OFFERING POTENTIAL SOLUTIONS Dr Ajay Gambhir, New Delhi ÂÂ

Provision of Emergency Obstetric Care (EmOC) to all women with complications during pregnancy, childbirth and the postpartum period is essential to reduce maternal and perinatal mortality and maternal and neonatal morbidity.

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Cesarean section or C-section is an important tool in the EmOC arsenal.

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Since 1985, the ideal rate for C-sections has been considered to be 10-15%; since then C-section have become increasingly common in both developing and developed countries.

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Three decades later, in the face of rising rates of C-section and by the directions of the international community, including governments and clinicians to re-visit these rates, the WHO came up with a statement in 2015: “At a population level, C- section rates higher than 10% are not associated with reductions in maternal and newborn mortality rates.”

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Guidelines from a handbook of WHO released in 2009 meant for assessing access to and use of EmOC in different populations revealed, (C-section as a proportion of all births) as one of the critical indicators for monitoring EmOC services availability and use.

Lower limit for this indicator has been set as

5% keeping in mind the rate of life-threatening obstetric complication occurrence where a C-section may prove to be a life-saving intervention. A C-section rate <5% indicates lack of availability, access and/or use of CEmOC services.

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In the face of this confusion about the desired rates, the WHO 2015 comes up with another important statement: “Every effort should be made to provide caesarean sections to woman in need, rather than striving to achieve a particular rate.”

C-section rates: Where does the World stand? ÂÂ

Brazil tops the charts on this dubious indicator with a C-section rate as high as 56%. Developed countries like the USA, Switzerland, Germany and even some South Asian countries like Thailand and Sri Lanka have about a third of their deliveries taking place through the cesarean route.

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As expected, C-section rate is low in Sub-Saharan African countries, as they are known to have poor EmOC services, a major factor for the high MMR in these countries.

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The C-section rate of South East Asian countries averages 10%, while the African countries show the least rates, at an average of 4%.

C-section rates: Where does India stand? ÂÂ

India lacks comprehensive data on C-section.

Available data is primary survey data or data from the HMIS. The latter provides relatively robust data on the situation in the public health facilities, but not so for the deliveries and C-sections being done at the private sector facilities.

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NFHS-4 data for 17 States and UTs represents that C-section rate is significantly higher in the Southern states vs Northern States. Telangana has the dubious distinction of having the highest rate of 58%, while the lowest CSR of 6.2% has been reported in Bihar.

APPROACH TO JAUNDICE IN INFANCY

C-section rate in and around 10% of all births

Prof Anupam Sibal, New Delhi

is ‘reasonable’ that balances adequacy of EmOC services for those in need, while also ensuring that this intervention is not abused.

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Conjugated hyperbilirubinemia at any age in an infant is pathological.

Upper limit has been set as 15% and considered

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Any newborn with jaundice and dark yellow urine staining the diaper ± pale stools should be strongly suspected to have cholestasis.

as threshold that must not be crossed. In practical terms, this means that C-section rate >15% needs

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CONFERENCE PROCEEDINGS ÂÂ

Biliary atresia, infection and metabolic disorders are the most important causes of jaundice in infancy.

ÂÂ

Metabolic disorders recognized.

being

and Encouragement. With 1 in 5 people in India being adolescents, there is a need to ensure that the foundations laid during adolescence are strong enough as they are the future of the country.

ÂÂ

Infective and metabolic causes should be ruled out in sick infants with uncorrected coagulopathy.

What takes place during the adolescent period affects health during the adult years and even influences the well-being of the next generation.

ÂÂ

GGT should always be a part of LFTs.

ÂÂ

Liver biopsy provides a definitive diagnosis in majority of cases.

ÂÂ

Early diagnosis and referral is the key for good prognosis, especially for biliary atresia.

ÂÂ

Nutritional support and vitamin/mineral supplementation is recommended in all babies.

ÂÂ

Liver transplantation is definite therapy for babies with liver failure. Liver transplantation is now wellestablished in India with success rates comparable to the best centers in the West. The first successful liver transplantation was performed in India in Apollo, Delhi in 1998.

are

increasingly

Pediatricians play an important role as trusted advisors to parents, and can be key drivers of change in the society. I am sure that the ‘Adolescent Ambassadors’ program will catalyze the collective strength of pediatricians as key influencers to effect an impactful change in the health and well-being of adolescents as a significant segment of our society.

INVASIVE TO NONINVASIVE VENTILATION IN NEONATES Dr Anup Thakur, New Delhi ÂÂ

In preterm infants with RDS, CPAP is associated with reduced mortality and reduced respiratory failure. So, CPAP should be used in preterm infants with RDS.

ÂÂ

CPAP should be used early in course of RDS to reduce need for mechanical ventilation.

ÂÂ

Using CPAP immediately after birth with subsequent selective surfactant administration may be considered as an alternative to routine intubation with prophylactic or early surfactant administration in preterm infants.

ÂÂ

If it is likely that respiratory support with a ventilator will be needed, early administration of surfactant followed by rapid extubation is preferable to prolonged ventilation.

ÂÂ

Preterm infants after extubation should be preferably managed on CPAP to reduce reintubation and mechanical ventilation.

ÂÂ

Short bi-nasal prongs are more effective than a single nasal or nasopharyngeal prong.

PEDIATRICIANS AS ADOLESCENT AMBASSADORS Dr Pramod Jog, Pune (President, IAP 2016) The 10 teen parenting essentials that the ACE (Adolescent Care Endeavor) 10/10 program recommends are: 1. Ensure regular sound sleep of 8 hours every night.

2. Encourage eating balanced food and wholesome breakfast (This would include inculcating the habit of drinking at least 6-8 glasses of water/day, consumption of plenty of vegetables, salads and fruits and discouraging foods high in sugar, fat and salt).

3. Ensure 60 minutes of daily physical activities.

4. Ensure annual health check up to monitor growth and development and psychological assessment.

5. Vaccinate boys and girls with Tdap vaccine and girls (10-12 years) with HPV vaccine.

6. Monitor school performance and studies.

7. Ensure communication and use teachable moments.

8. Monitor digital media usage every day and teach healthy use of media.

9. Know and stay connected with the friends of the adolescent.

10. Be observant of change in the behavior/mood.

Healthy parenting is the PULSE of adolescent care, which demands Parents’ Unconditioned Love, Support

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INFECTION MIMICS Dr Tanu Singhal, Mumbai ÂÂ

For most clinical syndromes including fever, infections are the commonest cause.

ÂÂ

In a small proportion of patients, noninfectious causes are however responsible. These include autoimmune disorders, malignancy, drugs, inborn errors of metabolism and miscellaneous conditions.

CONFERENCE PROCEEDINGS ÂÂ

Common infection mimics are systemic-onset JRA, Kawasaki disease, drug fever, hemophagocytic syndrome, leukemia and lymphoma.

ÂÂ

The presentation is like infection and laboratory parameters also mimic infection (leukocytosis, raised ESR, thrombocytosis, raised CRP, etc.).

ÂÂ

Suspect a noninfectious cause, if the patient does not respond to carefully chosen first-line antibiotics.

ÂÂ

The diagnosis of infection should be reconsidered and investigations reviewed rather than jumping to second level antibiotics.

ÂÂ

The diagnosis evolves over time.

obstetricians and emphasis on documentation are the highlights, which should be practiced by all. ÂÂ

Electronic cardiac monitor is preferable for HR assessment in those who require PPV, but may not be practicable in smaller hospitals. Acquiring a pulse oximeter is an alternate device, which can assess SpO2 as well as HR.

ÂÂ

CPAP as an alternative for routine intubation and surfactant administration in preterms less than 32 weeks gestation is feasible in referral hospitals.

A T-piece resuscitator for CPAP is worth an investment.

ÂÂ

Caregivers should allow parents to participate in decision making whether resuscitation is the best interest - birth between 22 and 24 weeks of gestation and some serious congenital and chromosomal anomalies.

ÂÂ

Ethics and ethical care at the end of life should be implemented in all levels of newborn care.

NEONATAL AND PEDIATRIC NUTRITION Dr Pankaj Garg, New Delhi ÂÂ

Breastfeeding is best for optimal physical and mental growth of babies. Delayed cord clamping at birth has been rated as the most cost-effective strategy to improve iron status of children.

Vitamin D 400 IU/day should be given to all newborns, except newborns <1,800 g where dose should be 800-1,000 IU/day.

CASE PRESENTATION ON VENTILATION

ÂÂ

Brain growth is almost complete in first 2 years of life and iodine, iron and DHA sufficiency is very important for optimal brain growth.

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Noninvasive ventilation including CPAP, BiPAP and high-flow nasal cannula is a well-tolerated alternative to invasive ventilation in the PICU.

ÂÂ

Most childhood malnutrition starts at the time of complementary feeding.

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Iron and zinc deficiency are the most important micronutrient deficiencies in early life nutrition.

Stunting defined as Z score of >-2 SD is the most important factor for mortality and morbidity in pediatric population.

NIV should only be tried, where facilities are equipped to handle endotracheal intubation at any given point of time.

ÂÂ

Decision to place a patient on positive pressure mechanical ventilation remains essentially clinical.

ÂÂ

Know your ventilator; the choice of ventilator and mode depends on the comfort of the operator.

ÂÂ

Individualize application of PEEP.

ÂÂ

Dr Rachna Sharma, New Delhi

ÂÂ

Infants and children require at least 6 g of iodine fortified salt at current levels of fortification.

ÂÂ

VLBW infants should be started on iron at 4-6 weeks of life compared to full-term babies where iron is started at 6 months of life.

ÂÂ

Proven role of prone positioning in case of refractory hypoxemia.

ÂÂ

Weaning - No tailor made formula; patient decides.

Preterm babies weighing <1,800 g should be given human milk fortifier along with breast milk for optimal bone growth, better weight gain and head circumference gain.

ÂÂ

Child can be weaned to NIV.

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Dr Chandrika Rao, Bengaluru ÂÂ

Evaluate every child for nonaccidental trauma.

ÂÂ

Dr PP Maiya, Dr SM Nimbalkar, Dr Vineet Saxena, Dr Rhishikesh Thakur, Dr Somashekar; Bengaluru

Historical indicators and physical exam findings are suggestive of violence.

ÂÂ

Increased emphasis on Team spirit is very relevant and can easily be practiced. Talking to parents and

Do not usually present with complaints of abuse or violence.

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Evaluate risk factors and Red Flags.

NEW NRP GUIDELINES, FEASIBILITY AND IMPLEMENTATION IN INDIAN SCENARIO

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PREVENTION OF VIOLENCE IN CHILDREN

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CONFERENCE PROCEEDINGS ÂÂ

If you find a concerning injury: Screen for occult injury.

ÂÂ

Screen for medical conditions.

ÂÂ

Report.

HIGH RISK ADOLESCENT BEHAVIOR AND ROLE OF MEDIA Dr Suchit Tamboli, Ahmednagar, Maharashtra ÂÂ

Media has a very powerful influence on adolescent behavior. Media history taking should be part of OPD practice.

ÂÂ

The leading causes of youth morbidity and mortality today are the outcomes of high risk behaviors that have been linked with media exposure.

ÂÂ

Parental and community engagement is essential to guide adolescents. Selection of media, under what condition/s and content of media affects the behavior.

ÂÂ

I: Immunization (measles vaccine and rotavirus vaccine)

Channelling creative energy into positive mass media content could well help to reduce the high risk behavior rates among adolescents.

ÂÂ

A: Antibiotics and adjuncts (remember they are low down in the list, limited indications)

Behavioral problems can be reduced if media is used as third parent instead of servant.

ÂÂ

Monitoring mobile and computer use and setting clear limits helps.

ÂÂ

It is important to keep an eye on the child’s online activity. Internet addiction and cyber stalking should be identified early.

ÂÂ

Incorporating media education since 3 years is very essential.

ZODIAC OF DIARRHEA MANAGEMENT Dr Pramod Jog, Pune (President, IAP 2016) Diarrhea remains as one of the leading causes of under-5 child mortality in India. ZODIAC is an acronym, which I am presenting to simplify the management of diarrhea.

Z: Zinc (gives Z security to the gut) O: ORS D: Diet (and continuation of breastfeeding)

C: Cleanliness (personal and public) and common sense ANTIFUNGAL PROPHYLAXIS IN NICU: IS IT WORTH IT? Dr Rohit Arora, Gurgaon ÂÂ

Fungal sepsis is an important cause of morbidity and mortality in NICUs.

ÂÂ

In NICUs with high rates of invasive candidiasis, fluconazole prophylaxis may be considered in neonates with birth weights <1,000 g (A-I).

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LATEST GUIDELINES FOR TUBERCULOSIS Dr Prof Rajeshwar Dayal, Agra ÂÂ

Every effort should be made to demonstrate the presence of Mycobacterium tuberculosis.

Antifungal drug resistance, drug-related toxicity and neurodevelopmental outcomes should be observed (A-III).

ÂÂ

CBNAAT (GeneXpert) has emerged as a valuable diagnostic tool and is the preferred initial investigation of choice.

A risk-based approach rather than Blanket prophylaxis is probably a better choice for NICU units with low rates of fungal sepsis.

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All TB patients should be tested for HIV.

ÂÂ

Clinical judgment is supreme.

ÂÂ

Daily treatment regimen is now recommended.

Ensure drug compliance.

ÂÂ

Contact screening and prophylaxis is essential.

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Meticulous and sympathetic management of MDRTB is vital.

Nonpharmacological measures have been shown to be effective in prevention of fungal infection.

More studies are needed to determine long-term impact of fluconazole on the developing neonate.

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MEDILAW

Case of Limited Negligence on Part of the Doctor and Contributory Negligence by the Patient The State Commission has erred in holding the respondent guilty of only limited medical negligence and on the other hand holding the appellant guilty of “contributory negligence” by not following the advice of respondent.

Although I had not written down in the prescription, it was made clear verbally to the appellant that the eye drops were to be used three times a day for a limited period of 2 weeks and its overuse was harmful.

We uphold the order of the State Commission that the respondent is guilty only of “limited medical negligence” by not giving a written prescription and instead verbally advising the appellant. The appellant is guilty of “contributory negligence” by not visiting the respondent for follow-up visits as advised on more than one occasion and instead consulting one doctor after another and also continuing Mitomycine-C for long period on his own volition.

Proceed

Lesson: The order dated 31.08.2006 in Complaint Case No. C-21/95 of the State Consumer Disputes Redressal Commission Delhi stated “̋By not prescribing in writing in the prescription that medicine Mitomycine-C should be used, at first instance, only for 2 weeks, OP has committed an offence of limited medical negligence as complainant also cannot be excused for contributory negligence by not approaching the treating doctor after few days and hopping from one doctor to another and continued using the medicine for long resulting in dry-eye syndrome causing loss of vision in the eye.”

eye would become normal. However, during the course of using this medicine, appellant’s eye further deteriorated and became very dry and there was loss of vision in that eye. Appellant complained about this to the respondent, who changed the medicine, which only further aggravated the condition.

COURSE OF EVENTS ÂÂ

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June 1993: Following a minor complaint of a cosmetic nature in his left eye, the appellant consulted respondent, who is an eye surgeon, in his clinic in Daryaganj, who after examining him informed that he was suffering from an innocuous growth known as pterygium and since there was likelihood that the growth may increase, excision was advised through a minor surgery, which would ensure that the appellant’s eye would become normal within 5 days.

Appellant, therefore, agreed to undergo this surgery.

October 1993: The respondent conducted the surgery on the appellant at his clinic and the appellant was thereafter prescribed medicines for both local application, which included Mitomycine-C, as also oral medication. However, soon after, the appellant’s left eye became red and there was acute pain and irritation, which persisted, and therefore he consulted the respondent, who assured him that if he continues to regularly use Mitomycine-C, his

ÂÂ

The appellant consulted another ophthalmologist Dr G, who informed him that his left eye had become very dry due to wrong prescription of Mitomycine-C and he was advised to consult Dr P at Hospital A, New Delhi.

ÂÂ

Dr P confirmed that the eye had got damaged due to prolonged use of Mitomycine-C.

ÂÂ

The appellant thereafter went to hospital B where this diagnosis was confirmed by a cornea specialist, Dr A. He was advised to stop using all the medicines, including Mitomycine-C.

ÂÂ

Being aggrieved because of the medical negligence and deficiency in service on the part of respondent, because of which the appellant’s eye became dry,

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MEDILAW he issued a legal notice to respondent to pay him ` 10 lakhs as compensation but received no response. ÂÂ

Appellant, therefore, approached the State Commission with a complaint of medical negligence and deficiency in service against respondent and requested that he be directed to pay ` 10 lakhs as damages and compensation since there was total loss of vision in appellant’s left eye, which had adversely affected both his professional and personal life, as also any other relief as deemed appropriate.

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Respondent on being served filed a written rejoinder denying the above allegations, which he termed as false, frivolous and vexatious. It was contended that appellant approached him with a condition known as pterygium, which is a growth of extra skin and if it reached the pupil area of the eye, it could permanently hamper the appellant’s vision. Surgery was, therefore, necessary, which was satisfactorily conducted. The appellant thereafter advised both oral medication as also medicine through local application.

ÂÂ

After a week, when the healing of the appellant’s eye was completed, respondent advised the respondent to use Mitomycine-C for 2 weeks since this was necessary to prevent recurrence of pterygium. This medicine, which comes in the form of injection, was converted into eye drops for use three times a day and appellant was verbally told that over use of this medicine for more than 2 weeks is harmful.

ÂÂ

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Unfortunately, the appellant did not heed this advice and instead of coming back for a further check up appears to have continued using Mitomycine-C and taking treatment from various other doctors as per his own whim and fancy.

It was only on 03.03.1994 i.e., after over 4 months that appellant visited the respondent and told him that he was still continuing the use of Mitomycine-C. Respondent immediately asked him to discontinue the same and to come back after 15 days.

ÂÂ

The appellant again did not heed this advice and consulted the respondent after 3 months i.e., on 22.06.1994 when he was prescribed natural tear drops and lacrilube ointment.

ÂÂ

A perusal of these facts clearly indicate that it was the appellant who was responsible for the damage caused to his left eye by prolonged use

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of Mitomycine-C on his own volition and against medical advice given by respondent. There was, therefore, no deficiency in service or medical negligence of respondent. ÂÂ

The State Commission after hearing the parties and on the basis of evidence produced before it held the respondent guilty of “limited negligence” by not advising the appellant in writing to use Mitomycine-C only for a particular limited period.

The relevant part of the order of State Commission reads as follows:

“By not prescribing in writing in the prescription that medicine Mitomycine-C should be used, at first instance, only for 2 weeks to OP has committed an offence of limited medical negligence as complainant also cannot be excused for contributory negligence by not approaching the treating doctor after few days and hopping from one doctor to another and continued using the medicine for long resulting in dryeye syndrome causing loss of vision in the eye. OP is guilty of this limited medical negligence amounting to deficiency in service due to which the complainant has lost his vision of one eye though he can also be not absolved from contributory negligence which is a mitigating circumstance for awarding compensation.”

The State Commission, therefore, held that a lump-sum compensation of ` 50,000/- to the appellant would meet the ends of justice. ÂÂ

Being aggrieved by the lesser compensation, the present first appeal has been filed before National Consumer Disputes Redressal Commission (NCDRC).

ALLEGATION OF THE APPELLANT ÂÂ

Learned counsel for the appellant contended that the State Commission erred in holding the respondent guilty of only limited medical negligence and on the other hand holding the appellant guilty of “contributory negligence” by not following the advice of respondent.

ÂÂ

Following the surgery, the appellant did visit the respondent doctor for further check-up prior to 03.03.1994. According to appellant, respondent had prescribed him Mitomycine-C on 18.10.1993 and the prescription did not indicate either the duration for taking the medicine or its possible harmful side effects.

ÂÂ

The appellant was also not advised when he should come back for a follow-up check. Further, when the appellant visited the respondent on 03.03.1994 with a serious complaint regarding his operated eye,

MEDILAW respondent again sought to hide the correct facts by recording that the condition of appellant’s eye as also the vision was normal. ÂÂ

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Since the appellant had already started losing his eyesight and he was having acute pain in his eye, he was constrained to approach other doctors, who advised the appellant to immediately stop the use of Mitomycine-C. It was these doctors who informed him that the problem in his left eye had occurred due to over use of Mitomycine-C, which should not have been used for more than 2 weeks.

Counsel for the appellant further stated that the conduct of the respondent was suspect before the State Commission as is evident from the fact that he did not produce the necessary documents on the ground that these had been destroyed in a fire.

Because of the medical negligence and callousness on the part of respondent, appellant lost the vision in his left eye causing him a great deal of mental agony and adversely affecting his work as a senior clerk in the Supreme Court of India.

visited the respondent, who immediately directed him to discontinue the use of this medicine. ÂÂ

Learned counsel for respondent pointed out that a senior ophthalmologist of Hospital A, Dr M, has confirmed to him in writing that appellant had consulted him and also informed him that he was continuing to use Mitomycine “on his own”.

ÂÂ

Appellant continued to disregard medical advice of Respondent even after 03.03.1994 by not coming for follow-up visits, which he was advised to do by respondent, who had prescribed him some other medicines and wanted to assess their effect.

ÂÂ

From the above facts, it is clear that appellant, who was not an illiterate person and who had been clearly orally advised to use Mitomycine-C eye drops only for a limited duration by respondent, failed to follow this advice and continued to use the medicine on his own, for which respondent cannot be held responsible, particularly since appellant did not even come for the follow-up visit after 2 weeks. There was no medical negligence or deficiency in service on the part of respondent, who had prescribed the right medicine and given correct advice regarding its limited period of use.

The present first appeal, therefore, having no merit deserves to be dismissed.

REJOINDER OF THE RESPONDENT ÂÂ

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Learned counsel for respondent denied the above allegations and stated that it is not factually correct that respondent had prescribed Mitomycine-C to the appellant on 18.10.1993 i.e., immediately following the surgery. In fact, he was prescribed other medicines and ointments after the surgery and it was only after a week when the eye had healed that Mitomycine-C was prescribed to the appellant.

It is a proven fact in ophthalmology medical literature that Mitomycine-C is successful in checking the recurrence of pterygium, which has a very high incidence of recurrence and is routinely prescribed for limited periods following such surgeries. It was under these circumstances that respondent rightly prescribed this medicine to the appellant. Although not written down in the prescription, it was made clear verbally to the appellant that the eye drops were to be used three times a day for a limited period of 2 weeks and its over use was harmful.

This is further confirmed by the fact that respondent converted only one vial of Mitomycine-C injection into eye drops, which would have lasted at the most for a little over 2 weeks. From this fact alone, it is clear that the Appellant had been procuring this medicine and getting it converted into eye drops from some other doctor(s) and in this way using it for several weeks i.e., till 03.03.1994 when he next

OBSERVATIONS OF NCDRC ÂÂ

The appellant visited the respondent’s clinic with a complaint in his left eye and was detected with pterygium, for which a minor surgery was conducted is not in dispute.

ÂÂ

It is also a fact that appellant was prescribed Mitomycine-C by respondent, which is a drug of choice, to ensure that pterygium does not recur since it has a high degree of recurrence.

ÂÂ

While it is a fact (as also observed by the State Commission) that no directions were given by respondent in writing to appellant regarding the duration for which the drug should be used or any written precaution against its prolonged use, we find force in the contention of respondent that since he had converted only one vial of Mitomycine injection into eye drops, this itself indicates that the intention was clearly for its limited use for about 2 weeks and not for several months.

ÂÂ

When specifically asked by us, learned counsel for the appellant also fairly conceded that respondent had converted only one vial of Mitomycine injection into eye drops, thus confirming the respondent’s clear intention regarding its use for a limited period. It is, thus, apparent that appellant

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MEDILAW had been using this medicine for several weeks by getting the Mitomycine injection converted into eye drops through some other source and not by the respondent, for which respondent cannot be held responsible. ÂÂ

It was under these circumstances that the State Commission had held the respondent guilty of only “limited medical negligence” for not having put down in writing the dosage and duration of the medicine in the prescription slip.

ORDER OF THE NCDRC We agree with this finding. We further agree that the appellant is guilty of “contributory negligence” by not visiting the respondent for follow-up visits as advised on more than one occasion and instead consulting one

doctor after another and also continuing Mitomycine-C for long period on his own volition, which resulted in the dry eye syndrome and consequent loss of vision in the left eye. To sum up, we uphold the order of the State Commission that respondent is guilty only of “limited medical negligence” by not giving a written prescription and instead verbally advising the appellant, for which a compensation of ` 50,000/- is reasonable and we, therefore, confirm the same. The present first appeal is dismissed. Respondent is directed to pay a sum of ` 50,000/- to the appellant within 6 weeks, failing which it will carry interest @ 6% per annum for the period of default. No costs.

REFERENCE 1. Case no. 692 of 2006, NCDRC; Order date 16.01.2013.

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AROUND THE GLOBE

News and Views Mild-to-moderate OSA Increases Risk of Hypertension According to a study presented at the 2017 SLEEP meeting in Boston, jointly sponsored by the American Academy of Sleep Medicine and the Sleep Research Society, young adults in their 20s with mild obstructive sleep apnea (OSA) were at a 90% increased risk for developing hypertension during 10 years of follow-up.

While, those in their 30s, mild OAS was associated with an 80% increase in risk of hypertension.

Antibiotic-associated Adverse Events are Common, Says Study Findings of yet another study underscore the importance of judicious prescribing of antibiotics.

A study reported online June 12, 2017 in JAMA Internal Medicine examined the medical records of 1,488 adult hospitalized patients for 30 days after starting antibiotics found that 20% of patients experienced at least 1 antibiotic-associated adverse drug events (ADEs). The most common ADEs were gastrointestinal, renal and hematologic abnormalities.

HIV-positive Status Increases Risk of Cervical HPV Infection to Precancerous Lesions According to a study reported in Cancer Epidemiology, Biomarkers and Prevention, online June 1, women with human immunodeficiency virus (HIV) infection had a 2.5 times higher rate of progression from human papillomavirus (HPV) to high-grade squamous intraepithelial lesions (HSIL) than women who were HIV-negative women. HPV-16/18 infection and CD4+ count <200/mm3 were the unfavorable factors in HIVpositive women.

Scientists Discover Rare Genetic Susceptibility to Common Cold Researchers at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH) have identified a rare genetic mutation that results in a markedly increased susceptibility to infection by human rhinoviruses, the main causes of the common cold, according to the Global Burden of Disease Study. The patient was found to have a mutation in the IFIH1 gene leading to formation of dysfunctional MDA5 proteins in respiratory tract cells.

This case report has been published online June 12, 2017 in the Journal of Experimental Medicine.

Long-term Metformin Treatment Reduces Risk of Heart Disease in Adults with Type 1 Diabetes According to results of international REMOVAL trial, metformin may be an effective long-term strategy worthy of adding to an individual’s diabetes care plan in order to reduce the risk of heart disease in adults with type 1 diabetes. These findings were presented June 11, 2017 at the American Diabetes Association’s 77th Scientific Sessions in San Diego.

Extracorporeal Leukocytapheresis is Effective for Inducing Clinical Remission in Ulcerative Colitis A multicenter, retrospective, observational study evaluating the clinical outcomes and risk factors for relapse of ulcerative colitis at 1 year after extracorporeal leukocytapheresis (LCAP) found most patients achieved clinical remission within 1 year and remained relapsefree following LCAP. A higher Lichtiger clinical activity index (CAI) and leukocyte count post-LCAP were risk factors for relapse.

Bhutan and Maldives Eliminate Measles Bhutan and Maldives have eliminated measles, a highly infectious disease that is a major childhood killer globally. The two countries have become the first in World Health Organization (WHO) South-East Asia Region to be verified for having interrupted endemic measles virus transmission, ahead of the 2020 Regional target. “Bhutan and Maldives have demonstrated how a highly contagious virus like measles can be eliminated.

WHO commends them for this momentous public health achievement. While endemic measles virus transmission has been interrupted, both Bhutan and Maldives continue to be at risk of measles virus importation. Hence, both countries must continue efforts against measles and rubella and protect high-risk populations to effectively deal with any importations,” said Dr Poonam Khetrapal Singh, Regional Director of WHO South-East Asia announcing the findings and conclusions of the WHO South-East Asia Regional Verification Commission for Measles Elimination and Rubella control…

(SEARO-WHO, June 13, 2017).

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AROUND THE GLOBE Both Oral and Injectable Insulin Provide Comparable Glycemic Control in Type 2 Diabetes A long-acting, oral insulin tablet once-daily has been found to safely improve glycemic control at 8 weeks as effectively as the common, injected insulin glargine U100 once-daily in people with type 2 diabetes, according to a study presented June 13, 2017 at the American Diabetes Association’s 77th Scientific Sessions in San Diego.

Raised Brain Amyloid Linked to Risk of Future Cognitive Decline Data from the Alzheimer’s Disease Neuroimaging (ADNI) Study reported June 13, 2017 in the Journal of the American Medical Association in a group of a cognitively normal cohort followed up for a median of 3.1 years show that elevated baseline brain amyloid, compared with normal brain amyloid level, was associated with higher risk of cognitive decline.

Bright-light Treatment an Effective Adjunct for Fibromyalgia Therapy, Says Study Results of a pilot study presented June 5, 2017 at SLEEP 2017, the 31st Annual Meeting of the Associated Professional Sleep Societies in Boston suggest that morning bright-light treatment may be an effective adjunctive treatment for fibromyalgia as it was found to significantly improve function and pain sensitivity compared to evening light treatment.

Avoid Systematic Lymphadenectomy in Clinically Negative Lymph Nodes in Advanced Ovarian Cancer The Lymphadenectomy In Ovarian Neoplasms (LION) study has concluded that in patients with advanced ovarian cancer with both intra-abdominal complete resection and clinically negative lymph nodes, systematic pelvic and para-aortic lymphadenectomy neither improve overall nor progression-free survival. The study presented June 3, 2017 at the recently concluded American Society of Clinical Oncology (ASCO) 2017 Annual Meeting in Chicago suggests avoid systematic lymphadenectomy to reduce postoperative morbidity and mortality.

FAST Not to be Used Routinely in Hemodynamically Stable Children with Blunt Torso Trauma According to a study of more than 900 hemodynamically stable children with blunt torso trauma published June 13, 2017 in JAMA, randomization to either Focused Assessment with Sonography in Trauma (FAST) or standard trauma examination did not result in significant improvement in the rate of abdominal computed

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tomographic scans, time in the ER, hospital charges, or missed intra-abdominal injuries. FAST uses ultrasound to look for internal bleeding.

Naldemedine Effective in Opioid-induced Constipation in Patients with Chronic Noncancer Pain According to results from the COMPOSE-1 and COMPOSE-2 trials reported online May 30, 2017 in The Lancet Gastroenterology and Hepatology, naldemedine was effective in relieving opioid-induced constipation in patients with chronic noncancer pain. Naldemedine is a once-daily, oral, peripherally acting mu-opioid receptor antagonist.

Health Ministry Launches Intensified Diarrhea Control Fortnight The Ministry of Health and Family Welfare has launched the Intensified Diarrhea Control Fortnight (IDCF) in order to intensify efforts to reduce child deaths due to diarrhea. The Ministry has made it a national priority to bring health outcomes among children to a level equitable with the rest of the world. Through this initiative, the Ministry will mobilize health personnel, State Governments and other stakeholders to prioritize investment in control of diarrhea, one of the most common childhood illnesses.

It aims to create mass awareness about the most effective and low-cost diarrhoea treatment—a combination of oral rehydration salt (ORS) solution and zinc tablets.

During the fortnight, intensified community awareness campaigns on hygiene and promotion of ORS and zinc therapy will be conducted at state, district and village levels. Nearly 12 crore under 5-children will be covered during the program across the country…

(Press Information Bureau, Ministry of Health and Family Welfare, 14th June, 2017)

Prices of Many Essential Drugs to Rise up to 2.29% Post-GST New Delhi, June 13 (PTI) Prices of majority of essential drugs will increase by up to 2.29% when the Goods and Services Tax (GST) regime kicks in from next month.

The government has fixed GST rate of 12% on most of the essential drugs as against the current tax incidence of around 9%. However, some select medicines such as insulin will see a reduction in prices with the government revising GST rate downwards to 5% from 12% proposed earlier. The National List of Essential Medicines includes the likes of Heparin, Warfarin, Diltiazem, Diazepam, Ibuprofen, Propranolol and Imatinib.

AROUND THE GLOBE Drug price regulator National Pharmaceutical Pricing Authority (NPPA) has already notified that the revised ceiling prices of scheduled drugs, where excise duty is levied on MRP, will be calculated by applying a factor of 0.95905 to the existing ceiling price. This will be exclusive of applicable GST rates. On the other hand, those scheduled formulations which are exempted from excise duty, their existing notified ceiling price would also be the new ceiling price, exclusive of GST rates, NPPA added.

balance and gait testing in these patients undergoing taxane chemotherapy observed decreased balance after the first chemotherapy cycle, which progressed with cumulative exposure. Patients also demonstrated slower walking speeds as they progressed through treatment.

These observations were published in the July 2017 issue of the journal Breast Cancer Research and Treatment.

In the case of nonscheduled formulations, NPPA has said that companies would have no option but to absorb the net increase if prices go up beyond the permissible limit of 10% of MRP due to increase in tax incidence on the GST implementation. “I am confident that GST implementation will be by and large smooth and will not cause any major disruption in the availability of drugs in the country,” NPPA Chairman, Bhupendra Singh told PTI. In case of those medicines such as insulin, on which the GST rate has been revised downward to 5% from 12% proposed earlier, companies will be required to reduce the maximum retail price. NPPA said in case of savings due to lower rate of tax, the benefit may be passed on to the consumers as per the antiprofiteering clause in the GST rules... (PTI, 13th June)

Results of a prospective population-based cohort study in patients aged 75 years or older with a first transient ischemic attack, ischemic stroke or myocardial infarction treated with mainly aspirin-based antiplatelet drugs for secondary prevention suggest that a protonpump inhibitor (PPI) should be coprescribed in these patients to protect against disabling or fatal upper gastrointestinal (GI) bleeding. The study was published online in The Lancet on June 13, 2017.

SGLT2 Inhibitors Associated with Reduced CVD in Type 2 Diabetes Patients Data from the CVD-REAL study presented June 13, 2017 at the American Diabetes Association’s 77th Scientific Sessions in San Diego show that use of sodium-glucose transporter-2 inhibitors (SGLT2i) in patients with type 2 diabetes is associated with lower mortality rates and hospitalization rates for heart failure, both with or without existing cardiovascular disease (CVD) and regardless of the specific SGLT2i used.

Telemedicine as Effective as In-person Visit for Headache, Suggests Study According to a study published in the June 14, 2017, online issue of Neurology, for people with nonacute headaches or headaches that came on gradually, telemedicine i.e., consulting the neurologist by video for treatment may be as effective as an in-person traditional office consultation.

Chemotherapy-induced Peripheral Neurotoxicity Increases Risk of Falls in Breast Cancer Patients Chemotherapy-induced peripheral neurotoxicity (CIPN) affects balance and gait in breast cancer patients. A study evaluating patient-reported outcomes concurrently with

Coprescribe PPI to Protect Against GI Bleed in Older Patients on Aspirin

Adrenalectomy Effective for Young Female Patients with Unilateral Primary Aldosteronism Adrenalectomy can be effective treatment for unilateral primary aldosteronism, particularly in younger and female patients, suggests the Primary Aldosteronism Surgical Outcome (PASO) study reported online May 30, 2017 in The Lancet Diabetes and Endocrinology.

Fewer antihypertensive medications and absence of left ventricular hypertrophy were other factors independently associated with complete clinical success.

Researchers recommend evaluation of outcomes in the first 3 months post-surgery, again at 6-12 months and then annually.

Pruritus is an Important Symptom in Patients with Psoriasis Pooled analysis from randomized trials examining systemic therapies as treatment for adults with moderate-to-severe plaque psoriasis or atopic dermatitis show that moderate-to-severe plaque psoriasis can be as itchy as atopic dermatitis. The systematic review and meta-analysis is published in the June 2017 issue of the Journal of the American Academy of Dermatology.

AHA Presidential Advisory on Dietary Fats and Cardiovascular Disease The American Heart Association (AHA) has published a presidential advisory on dietary fats and cardiovascular disease (CVD) published June 15, 2017 in the journal Circulation. The advisory reviews and discusses the scientific evidence, including the most recent studies,

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193

AROUND THE GLOBE on the effects of dietary saturated fat intake and its replacement by other types of fats and carbohydrates on CVD. The AHA continues to recommend replacing saturated fats with poly- and monounsaturated vegetable oil to help prevent heart disease. The advisory reports that ÂÂ

Trials that lowered intake of saturated fat and replaced it with polyunsaturated vegetable oil reduced CVD by about 30%; similar to statins.

ÂÂ

Trials showed that lower intake of saturated fat coupled with higher intake of poly- and monounsaturated fat is associated with lower rates of CVD.

ÂÂ

Coconut oil, which is predominantly saturated fat and widely touted as healthy, raised LDL cholesterol the same way as other saturated fats found in butter, beef fat and palm oil.

ÂÂ

Replacement of saturated fat with mostly refined carbohydrate and sugars is not associated with lower rates of CVD. (AHA News Release, June 17, 2017)

Serial Neuroimaging should be Done for Early Diagnosis of Zika Virus Infection During Pregnancy A case series of pregnancies affected by Zika virus infection reported online June 6, 2017 in the journal Obstetrics & Gynecology show that the median time between Zika virus symptom onset and microcephaly (head circumference less than 3 standard deviations below the mean) was 18 weeks (range 15-24 weeks). The earliest diagnosis was at 24 weeks of gestation. These findings highlight the need for serial and detailed head and brain neuroimaging for early diagnosis.

One in Five Children in Rich Countries Lives in Poverty: UNICEF One in five children in high-income countries lives in relative income poverty, and an average of one in eight faces food insecurity, according to a new report released by the United Nations Children’s Fund (UNICEF). The latest ‘Report Card’ issued by the UNICEF Innocenti Research Centre underscores that rich nations also face challenges meeting global commitments to children.

“Report Card 14 is a wake-up-call that even in highincome countries progress does not benefit all children,” said Sarah Cook, Director of UNICEF Innocenti.

Building the Future: Children and the Sustainable Development Goals in Rich Countries is the first report to assess the status of children in 41 high-income

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countries in relation to the Sustainable Development Goals (SDGs) identified as most important for child wellbeing. It ranks countries based on their performance and details the challenges and opportunities that advanced economies face in achieving global commitments to children… (UN, June 15, 2017)

Once-daily Insulin may be an Effective Alternative to Basal-bolus Insulin Regimen in Diabetes Findings from the Insulin Degludec/Liraglutide vs.

Basal-Bolus Therapy in Patients with Type 2 Diabetes: DUAL VII trial presented June 10, 2017 at the American Diabetes Association (ADA) 2017 Scientific Sessions in San Diego show that in patients with A1c >7% on metformin and insulin glargine U100 (IGlar), once-daily IDegLira vs. basal-bolus insulin (once-daily glargine + three or more injections of short-acting insulin aspart) resulted in similar A1c reductions, lower insulin dose, weight loss and lower risk of hypoglycemic episodes.

Use of Sign Language After Cochlear Implant may Slow Verbal Development A study in the July 2017 issue of the journal Pediatrics found that following cochlear implants, over 70% of children without sign language exposure achieved spoken language similar to their age-mates with normal hearing, compared to only 39% of those exposed to sign for three or more years. Children whose families used spoken language exclusively also had better speech recognition skills and more intelligible speech after three years of implant use.

Screen Adolescents with Treatment-resistant Depression for Sleep-disordered Breathing A study presented June 6, 2017 at SLEEP 2017: 31st Annual Meeting of the Associated Professional Sleep Societies in Boston has demonstrated an association between sleep disordered breathing and persistent depressive symptoms and poor response to standard pharmacologic treatments in adolescents.

Amphotericin Superior to Itraconazole for Treatment of Talaromycosis in HIV-infected Adults Intravenous amphotericin B (0.7-1.0 mg/kg/day) was superior to itraconazole capsules (600 mg/day × 3 days, followed by 400 mg/day × 11 days) as initial treatment for talaromycosis in HIV-infected adults with respect to mortality, clinical response, and fungicidal activity at 6 months, says a study reported June 15, 2017 in the New England Journal of Medicine. Talaromyces marneffei infection is a major cause of systemic mycosis in HIVinfected persons.

Ind e ISS xed N 0 with 971 -08 IndME 76 D

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Asian Journal of Clinical Cardiology

In This Issue

Asian Journal of Diabetology

—

Emerging role of Cardiac MRI in Ischemic and Non-ischemic Cardiomyopathy

—

Acute Renal Failure and Silent Myocardial Infarction Following Multiple Honey Bee Stings

—

Superficial Brachial Artery: Its Embryological and Clinical Significance

—

Glucose Tolerance in Nondiabetic Patients after First Attack of Acute Myocardial Infarction and its Outcome

—

A Case of Left Atrial Myxoma Presenting as Severe Pulmonary Hypertension

—

Double-Chambered Right Ventricle with Transient 2:1 Atrioventricular Block: A Rare Presentation

—

Cornary Artery Air Embolism

Volume 17, Number 5

more...

January-March 2015

Volume 1, Number 1

Asian Journal of Obs & Gynae Practice Asian Journal of Paediatric Practice

Volume 18, Number 3

Dr Swati Y Bhave

Dr KK Aggarwal

Editor

Group Editor-in-Chief

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LIGHTER READING

HUMOR

Lighter Side of Medicine OLD AGE SECRET Grandpa was celebrating his 100th birthday and everybody complimented him on how athletic and well-preserved he appeared.

“Gentlemen, I will tell you the secret of my success,” he cackled. “I have been in the open air day after day for some 75 years now.”

The celebrants were impressed and asked how he managed to keep up his rigorous fitness regime.

“Well, you see my wife and I were married 75 years ago. On our wedding night, we made a solemn pledge. Whenever we had a fight, the one who was proved wrong would go outside and take a walk.”

WELL LET’S JUST WAIT AND SEE WHAT DEVELOPS A man came running in the office and yelled, “Doctor, doctor! My son just swallowed a roll of film!” The doctor calmly replied, “Well let’s just wait and see what develops.”

YOU SHOULD WRITE MORE LEGIBLY As an English professor, my father would often write little notes on student essays. Often he worked late, and as the hours passed, his handwriting deteriorated.

One day a student came to him after class with an essay that had been returned. “Mr McDonald,” he said, “I can’t make out this comment you wrote on my paper.” My father took the paper and, after studying it, sheepishly replied, “It says that you should write more legibly.”

to ask what’s wrong. Maynard replies, “What’s wrong? Well, you’d be screaming too if you didn’t have a driver!”

WONDERFUL CONFESSION BY A GIRL IN CHURCH AND AMAZING REPLY SHE GOT. She: I am in love with a boy who is far away from me.

I’m in India and he lives in UK. We met on marriage website.

Became friends on FaceBook.

Had long chats on WhatsApp. Proposed each other on Skype.

And now 2 months of relationship through Viber.

I need your blessings and good wish, Oh God. Guy besides her said: Now get married on Twitter.

Have fun on Tango.

Buy your kids from eBay. Send them through Gmail.

And if you are fed up with your husband or kids then, unko OLX pe bech de…

Dr. Good and Dr. Bad SITUATION: A type 1 diabetic female of 17 years of age was reported to have low satisfaction with life and self-esteem.

THESE THINGS ARE COMMON IN ADOLESCENTS NOW A DAYS

THIS INDICATES HIGH DIABETES DISTRESS

There’s a double decker bus driving down the street full of passengers. On the lower level of the bus, everyone’s having a good time, talking, laughing and singing along to the music playing.

On the upper part of the bus, Maynard is in a panic. He’s screaming, terrified and holding onto others as the bus moves along the street. Finally, someone gets up and walks to the top of the bus

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Indian Journal of Clinical Practice, Vol. 28, No. 2, July 2017

© IJCP Academy

DOUBLE DECKER BUS

LESSON:

According to a recent study, an association has been established between diabetes distress, higher HbA1C values and poorer psychological health factors. This can be dealt with by using a brief diabetes distress questionnaire which may, in turn, help in identifying the need for additional screening, education and treatment for overall health and well-being.

Diabetes Educ. 2016 Dec 7. pii: 0145721716680888.

Information for Authors Manuscripts should be prepared in accordance with the ‘Uniform requirements for manuscripts submitted to biomedical journals’ compiled by the International Committee of Medical Journal Editors (Ann. Intern. Med. 1992;96: 766-767).

Indian Journal of Clinical Practice strongly disapproves of the submission of the same articles simultaneously to different journals for consideration as well as duplicate publication and will decline to accept fresh manuscripts submitted by authors who have done so.

The boxed checklist will help authors in preparing their manuscript according to our requirements. Improperly prepared manuscripts may be returned to the author without review. The checklist should accompany each manuscript.

Authors may provide on the checklist, the names and addresses of experts from Asia and from other parts of the World who, in the authors’ opinion, are best qualified to review the paper.

Covering letter –

– –

The covering letter should explain if there is any deviation from the standard IMRAD format (Introduction, Methods, Results and Discussion) and should outline the importance of the paper.

Principal/Senior author must sign the covering letter indicating full responsibility for the paper submitted, preferably with signatures of all the authors.

Articles must be accompanied by a declaration by all authors stating that the article has not been published in any other Journal/Book. Authors should mentioned complete designation and departments, etc. on the manuscript.

Manuscript – Three complete sets of the manuscript should be submitted and preferably with a CD; typed double spaced throughout (including references, tables and legends to figures).

–

The manuscript should be arranged as follow: Covering letter, Checklist, Title page, Abstract, Keywords (for indexing, if required), Introduction, Methods, Results, Discussion, References, Tables, Legends to Figures and Figures.

–

All pages should be numbered consecutively beginning with the title page.

Note: Please keep a copy of your manuscript as we are not responsible for its loss in the mail. Manuscripts will not be returned to authors.

Title page Should contain the title, short title, names of all the authors (without degrees or diplomas), names and full location of the departments and institutions where the work was performed,

name of the corresponding authors, acknowledgment of financial support and abbreviations used.

– The title should be of no more than 80 characters and should represent the major theme of the manuscript.

A subtitle can be added if necessary.

– A short title of not more than 50 characters (including inter-word spaces) for use as a running head should be included.

– The name, telephone and fax numbers, e-mail and postal addresses of the author to whom communications are to be sent should be typed in the lower right corner of the title page.

– A list of abbreviations used in the paper should be included. In general, the use of abbreviations is discouraged unless they are essential for improving the readability of the text.

Summary – The summary of not more than 200 words. It must convey the essential features of the paper.

– It should not contain abbreviations, footnotes or references.

Introduction – The introduction should state why the study was carried out and what were its specific aims/objectives.

Methods – These should be described in sufficient detail to permit evaluation and duplication of the work by others.

– Ethical guidelines followed by the investigations should be described.

Statistics The following information should be given: – The statistical universe i.e., the population from which the sample for the study is selected.

– Method of selecting the sample (cases, subjects, etc. from the statistical universe).

– Method of allocating the subjects into different groups.

– Statistical methods used for presentation and analysis of data i.e., in terms of mean and standard deviation values or percentages and statistical tests such as Student’s ‘t’ test, Chi-square test and analysis of variance or non-parametric tests and multivariate techniques.

–

Confidence intervals for the measurements should be provided wherever appropriate.

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

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Discussion –

This should consist of a review of the literature and relate the major findings of the article to other publications on the subject. The particular relevance of the results to healthcare in India should be stressed, e.g., practicality and cost.

References These should conform to the Vancouver style. References should be numbered in the order in which they appear in the texts and these numbers should be inserted above the lines on each occasion the author is cited (Sinha12 confirmed other reports13,14...). References cited only in tables or in legends to figures should be numbered in the text of the particular table or illustration. Include among the references papers accepted but not yet published; designate the journal and add ‘in press’ (in parentheses). Information from manuscripts submitted but not yet accepted should be cited in the text as ‘unpublished observations’ (in parentheses).

At the end of the article the full list of references should include the names of all authors if there are fewer than seven or if there are more, the first six followed by et al., the full title of the journal article or book chapters; the title of journals abbreviated according to the style of the Index Medicus and the first and final page numbers of the article or chapter. The authors should check that the references are accurate. If they are not this may result in the rejection of an otherwise adequate contribution.

Examples of common forms of references are: Articles Paintal AS. Impulses in vagal afferent fibres from specific pulmonary deflation receptors. The response of those receptors to phenylguanide, potato S-hydroxytryptamine and their role in respiratory and cardiovascular reflexes.

Q. J. Expt. Physiol. 1955;40:89-111.

Figures – Two complete sets of glossy prints of high quality should be submitted. The labelling must be clear and neat.

– All photomicrographs should indicate the magnification of the print.

– Special features should be indicated by arrows or letters which contrast with the background.

– The back of each illustration should bear the first author’s last name, figure number and an arrow indicating the top. This should be written lightly in pencil only. Please do not use a hard pencil, ball point or felt pen.

– Color illustrations will be accepted if they make a contribution to the understanding of the article.

–

Do not use clips/staples on photographs and artwork.

–

Illustrations must be drawn neatly by an artist and photographs must be sent on glossy paper. No captions should be written directly on the photographs or illustration. Legends to all photographs and illustrations should be typed on a separate sheet of paper. All illustrations and figures must be referred to in the text and abbreviated as “Fig.”.

Please complete the following checklist and attach to the manuscript: 1. Classification (e.g. original article, review, selected summary, etc.)_______________________________ 2. Total number of pages ________________________ 3. Number of tables ____________________________ 4. Number of figures ___________________________

Books

5. Special requests _____________________________

Stansfield AG. Lymph Node Biopsy Interpretation Churchill Livingstone, New York 1985.

6. Suggestions for reviewers (name and postal address)

Articles in Books

2.____________ 2.________________

Strong MS. Recurrent respiratory papillomatosis. In: Scott Brown’s Otolaryngology. Paediatric Otolaryngology Evans JNG (Ed.), Butterworths, London 1987;6:466-470.

3.____________ 3.________________

4.____________ 4.________________

Tables –

These should be typed double spaced on separate sheets with the table number (in Roman Arabic numerals) and title above the table and explanatory notes below the table.

Legends – These should be typed double spaces on a separate sheet and figure numbers (in Arabic numerals) corresponding with the order in which the figures are presented in the text.

–

198

The legend must include enough information to permit interpretation of the figure without reference to the text.

Indian Journal of Clinical Practice, Vol. 28, No. 2, July 2017

Indian 1.____________Foreign 1.________________

7. All authors’ signatures________________________ 8.

Corresponding author’s name, current postal and e-mail address and telephone and fax numbers __________________________________________

Online Submission Also e-Issue @ www.ijcpgroup.com For Editorial Correspondence

Dr KK Aggarwal

Group Editor-in-Chief Indian Journal of Clinical Practice E-219, Greater Kailash Part-1 New Delhi - 110 048. Tel: 40587513 E-mail: editorial@ijcp.com Website: www.ijcpgroup.com

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