22 Miscellaneous

SECTION 22

Beyond Medicine

216.

NETAJI ORATION Physician: The Healer and the Professional Satish V Khadilkar

1001

217.

Medical Practices on Cross Roads DN Upasani

1005

218.

Personalized Medicine: Making Effective Therapy Safe for Every Individual Ramchandra D Lele

1007

219.

Doctor-Patient Relationship Ambika Prasad Mohanty

1011

220.

Democratizing Knowledge to Improve Care for the Underserved: Project ECHO Sanjeev Arora, Kumud Rai, Sunil Anand

1014

221.

ADVANCE to ADVANCE on: The First Evidence of Legacy Effect in the Management of Hypertensive Diabetic Patients Sanjay Kalra

1017

222.

Laughter is the Best Medicine Anil Chaturvedi

1019

223.

Medicine is a Serious Business?

Arulrhaj, Aarathy Kannan, Ajinkya Borhade, Sachin Babhalsure

1021

224.

Saga of Man, Microbiome and P4 Bedside Medicine Prakash Pispati

1024

225.

Nuclear Medicine as a Problem Solver in Diagnosis and Therapy Vikram R Lele

1027

226.

Does Modern Medicine Increase Life-expectancy: Quest for the Moon Rabbit?

Sundeep Mishra

1032

227.

The Heart and Lung cannot Live without Each Other Bhavin Jankharia

1041

228.

New Approach to Management of Erectile Dysfunction in 2017 Deepak K Jumani

1043

229.

Chronic Fatigue Syndrome Jalees Fatma

1051

230.

Reducing Breast Cancer: Risks and Options Karthik Ghosh, Amit K Ghosh

1054

231.

A Rational Approach to Cancer Pain Management PN Jain

1058

232.

Smartphone Applications in Clinical Medicine Shriram V Kulkarni, Sagar Sinha, Adhar Kulkarni, Chitra S Kulkarni, Vivek Redkar, Swaraj S Devlalkar, Sayali S Devlalkar, Aditya S Kulkarni, Arun Kurhe, Om Kulkarni

1061

233.

Air Ambulance Services Transport of Critically Sick Patients Munish Prabhakar, Geeta Kampani, Ashok Chandna

1064

234.

Recent Management of Lymphoedema SB Gogia

1067

235.

Sahaja Yoga for Management of Stress & Life Style Diseases Sandeep Rai, Madhur Rai, Yashoda Kattimani, Vishesh Agarwal

1069

236.

Important Drug Interactions Every Physician Must Know Sumeet Singla, AK Agarwal, RK Singal

1072

237.

Knowledge Management: Bringing About A New Era in Medicine Aditya Ghosh, Amit K Ghosh

1082

238.

Prognostication – A Lost Skill in Medicine M Raveendran

1090

239.

Assessment of Uncounsious Patient Saurabh Jain

1094

240.

Salt Sensitivity in Hypertension Shashank R Joshi

1098

241.

The ICMR INDIAB Study – A Compendium of Type 2 Diabetes in India: Lessons Learnt for the Nation Viswanathan Mohan, Ranjit Mohan Anjana, Rajendra Pradeepa, Ranjit Unnikrishnan, Tanvir Kaur, Ashok Kumar Das 1104

C H A P T E R

216

NETAJI ORATION

Physician: The Healer and the Professional Satish V Khadilkar

“Healing is the mandate of medicine; professionalism is how it is organised” Sylvia Cruess

INTRODUCTION

We physicians live in difficult times today, when the general outlook of the Indian Society has changed perceptibly over the previous decade or two. From a position of being the respected pillars of the society, our fraternity is being looked upon with suspicion, alleged with commercialism and insensitivity.1 The rapidity and extent of this change is remarkable and therefore it is important to understand the reasons and try to change the perceptions.

Physicians have two roles to play, that of the healer and the professional. A glance at the history tells us that since eternity, the human race has had healers. They have existed in all civilizations and populations playing their part in the art of healing, which was largely abstract and unmeasurable. In India and china, healers also combined the use of plants and other available natural substances to reduce symptoms and thus had another dimension to the process of healing. However, this knowledge was handed down from one generation to the other and was not based on rigorous testing. In the nineteenth century, ‘science of medicine’ began to grow in mediaeval Europe and England. As the science grew, it made itself purchasable and the industrial revolution which happened simultaneously provided money to buy the science. Thus came into existence the profession of medicine. Till this time, the tenets of medicine were more implicit than explicit but the growth of organised medicine and entry of the corporate sector converted it into a profession like any other. With this development, the autonomy of the medical practitioner reduced and so did the respect.2 Moreover, the explosion of knowledge in medicine meant that students and the practitioners had to spend most of their time coping up with the influx of information and the art of healing took a back seat.

This article will evaluate the basis the ongoing issues encountered by the medical professionals and the society and put in perspective the current role of physician; the healer and the professional.

BEGINNINGS

Most medical aspirants getting admissions to government and municipal institutions have to apply themselves

seriously, undergo very rigorous training and take extremely competitive examinations in order to secure marks necessary to be admitted to good medical colleges.

At that stage, they are very young and completely focussed on examinations. They become, by force of circumstances, accomplished “MCQ solvers”. We thus select intelligent young individuals who have acquired the knack of solving MCQs; but is this ideal intake material for medicine?

Working in the Grant Medical Collage and Sir J J group of Hospitals, I have been in contact with medical student for a number of years and wonder whether this selection method has a bias; and such intake is rather less suitable for the institution of medicine which requires individuals to understand human suffering and act with empathy.

Moreover, most of these young individuals do not know what medicine stands for and why are they in medicine.

A while ago, I undertook a questionnaire based survey to study their reasons for choosing medicine as a career and the answers were ‘my parents wanted me to be a doctor’ ‘every one said that there should be a doctor in the family’ ‘all my friends took biology’ and the likes. Very few of them seem to have entered the field because they wanted to help others. As you can see, this selection bias results in early frustration and lifelong difficulties.

TRAINING

Conventional medical training at the undergraduate level focusses on acquiring and memorizing a large volume of knowledge ‘better than others in the class’ because post-graduation will only be awarded to the person who has larger fund of knowledge and can reproduce it in examinations. The current training programs do not encourage free thinking, but thrust unmanageable loads of information and invite a competition, who remembers best! Due to ever increasing fund of medical knowledge and the need to secure marks, candidates can not pay adequate attention to acquiring skills of interacting with and understanding their patients; instead preferring to visit libraries and mugging up answers from guides. The competitive motto of the current times is well exemplified by this snippet “two medical students are in a jungle and see a tiger. As one gets ready to run, the second asks him, do you really think we will outrun the tiger? He repliesno. I have to only out run you!”

Post graduate training is no different. Analytically minded individuals with some knowledge under their belts set out to seek scientific pleasures out of the illnesses of their

BEYOND MEDICINE

1002 patients. I have often seen medical students gathered

around a patient having the most rare syndrome, the like of which they may never see again, discussing the phenomena zealously, but completely ignoring the common ‘garden variety’ diseases like tuberculosis and leprosy, because these are looked upon as ‘not enough for their intellect’. The ‘bright’ student who diagnoses a rare condition earns respect from his peers. The current system promotes the ‘young Einstein’ in them but is medicine about the quest for the rare? Is medicine about one-upmanship? When and how does one get them to understand that their job is to treat the common diseases well, and then if a rare condition comes by, use all the guile to catch it as well.

The same illness plagues young lecturers and tutors, who are trying to prove to their eager audience that they know a lot and not truly caring about imparting patient care aspects on the receptive psyche of young students.

I have been teaching the MD medicine batches for over two decades and have for myself experienced the slow evolutionary transition in me; from a young neurologist vomiting out all my acquired syndromic knowledge, to gradually understanding the need for imparting values as well. Simple things like thanking the patient for coming along for the benefit of the students, inquiring whether he or she has had lunch, came to me sluggishly. Finally, I started to appreciate the process wherein students not only understood the subject but felt the desire to help the suffering patients. As I reflect, the time taken for this transition was unduly long and no one told me what to teach when I started. Medical teachers need to be taught to include and promote the ‘healer qualities’ in their teachings as much as the scientific details.

ROLE MODELS AND APPRENTICESHIP

Early years are most impressionable and if one is lucky to see and work with some of the iconic ‘role model physicians’ he inadvertently imbibes the qualities of such a teacher. These do not restrict to the abilities of making a diagnosis, but more importantly impart understanding and executing good bedside manners, respect basic human dignity and tackling difficult ground realities.

In this respect, spending a year or two with a renowned clinician was time well spent, a luxury neither affordable nor available today, due the length of medical courses and the scarcity of role models. Modern students are lucky to have Dr. Google, the knowledge provider, but they still need to follow renowned ‘human’ [humane] teachers to learn the art of healing.

MEDICAL PRACTICE

So friends, a young post graduate armed with competitive success, deriving pleasure in the scientific aspects of the illness, gets exposed to the real medical world, which today is governed by the corporate czars. He finds himself following their diktats, which are driven with different aims, and soon turns into a mechanistic part of the wheel of the great new system of medicine, his autonomy and identity endangered. As we live in a time of instant success, he is tempted to bend his ways to seek rapid

rewards and social positions, as he sees these as fruition of his toils.

As years roll by and personal and social gains accumulate, he begins to comprehend that the ‘science’ which he spent years to learn, is quite imperfect and hence results unpredictable. He goes through phases like ‘if I do not know, somebody will know’ to ‘nobody seems to know’ and at this rather late stage, realises that this incomplete science has to be utilized to reduce the suffering of his patients and then starts to appreciate his role as a healer, using kind words and soothing approach, keeping patient before himself.

As you will see from the above, in this journey of the current medical personnel, keeping the suffering patients foremost has indeed become the last frontier, being acquired much late in the struggle for existence. This exactly is what is not appreciated by the society as they observe us today.

WHAT DO OUR PATIENTS AND THE SOCIETY WANT?

Our patients want us to be available, affordable, amicable and knowledgeable, in that order! Look at how different the society’s expectations are from the individual’s personal objectives. While the doctor wants to achieve name, peer recognition, social position, a good life etc, society is looking for somebody who is kind, forgiving and understanding. As society sees it, the real requirement of the job is to understand fellow human beings and be able to address to their worries, concerns, doubts and emotions; to be their friend, philosopher and guide. In short, they appreciate the healer in us, but in the modern times the healer is expected to be professional.3 Society wants us to be human, to understand them, provide caring and compassionate treatment, their secrets guarded and their dignity preserved4. This is completely understandable because the very nature of our job requires patients to tell us about personal matters and to submit to invasive procedures and the information arising from them4. In the modern times, society also wants us to be well informed, competent, transparent and accountable. With the years we spend in acquiring knowledge, the later parts of the expectation are usually well met but it is the role of the healer, which is neither taught nor discussed5.

Once we realise this, it is easy to find corrective steps.

Medical graduates, from very early times, need to put their perspectives and ambitions right. It should be realised early on that they are in this field to help and alleviate suffering and those are the main goals towards which they need to work; all the scientific knowledge that they acquire only forms the tool towards achieving this goal. As has been said “Don’t climb a mountain with an intention that the world should see you; climb the mountain with the intention to see the world.” Similarly, one wades through medicine to treat patients well and see their smiles; and name, fame, funds and peer recognition will come along with it. These are by-products of practicing good medicine, not its primary aim.

Working of the human body is very complex and the

HOW TO EXECUTE THE DUAL ROLES OF THE HEALER AND THE PROFESSIONAL?

In these times of unprecedented change, questioning society, falling status of medicine, the future will depend upon the fraternity’s ability to be healers as well as professionals. To perform both roles simultaneously, physician has to nurture attributes which are necessary for exceling in both aspects. These are outlined in the diagram below.

HEALER Compassion Empathy Insight

ATTRIBUTES OF PHYSICIAN

PROFESSIONAL Team Work Self Regula�on Responsibility to Society

patient will develop confidence in him or her. Pony tails, 1003 tattoos, slippers and jeans prevailing amongst young doctors in the wards is one such observation, detrimental to performing the role of dependable healer. On the right are the special attributes of the professional, which are also not included in training and need to be learnt as one comes in to the world of medicine. These will get increasingly important as the present era of reducing individual autonomy in medicine requires coordination amongst medical professionals.

Survey of literature1,7,8 gives interesting insights into professionalism in medicine. Early literature is supportive of professionalism but has recognised tensions between larger goal of medicine and self-interest. Sixties and seventies have been very critical and have largely documented failures of medicine and even questioned its relevance to the society. Writings from the eighties onwards have reflected on the new reality, that is, the dominance of the state and corporate sector and decreasing influence of medicine men in the total organization9.

Literature at this time also has begun re-emphasising the societies’ need for ‘the healer’. The social scientists have returned to faith in the value of professions as a remedy, particularly for medicine. The current needs of the society are of a healer working as a professional. The need is for using knowledge to heal or cure, guarantee competence, to be able to work in partnership with patients, being accountable and demonstrating morality and virtue at all times10.

WHAT DO DOCTORS EXPECT FROM THE SOCIETY?

Medicine men expect respect, autonomy and a functioning Openness system of medicine which does not put undue demands Pa�ent dignity and on its doctors. In India, organised medicine exists in bits autonomy Competence and pieces and as a result puts inordinate demands on its Presence Commitment doctors. To achieve what we expect from the society, we Confiden�ality have to wake up to ‘one voice of medicine’. In our country, Integrety and we have not yet been very proactive towards this and honesty therefore our group is not well heard. Medicine men have Morality and to get together, appeal to the society and make our needs ethics felt. We must also look for partners who could be patients, advocacy groups, health managers, corporate sectors and media in an effort to rebuild the image of the professional Ofthethe properties see incolumn, the overlap column, Of properties that youthat see inyou the overlap competence is the only one that healer. We must convince the society of the advantages of is the courses. only one that iscurricula reallyand taught in theprepare is reallycompetence taught in the medical Our books, examinations the medical courses. Our books, curricula and examinations having us, the ‘professional healers’ around.

graduates in the knowledge aspect of the science. The column to the left and most of the theit graduates thebutknowledge aspect of the overlap prepare reflects what takes to be a in healer is not taught and practised in the The training modern time calls for us to fulfil the role of the healer science. to the left and ofmost of thein overlap programs.

WorkingThe withcolumn the less privileged sections the society the government andprofessionalism. We must address the principle with municipal colleges, young do be not a seehealer the need to is learn of communication, to of loss of trust which are, perception of decreased reflects what it doctors takes to but notskills taught and causes dignity of the patients and to be Working compassionate.

Moreover, are no respect practised basic humanin the training programs. with the lesstherealtruism, failure to self-regulate and most importantly, text books incorporated in curricula address to these have to be imbibed from privileged sections of which the society inthese, the so government and lack of a single voice representing medicine. At the present master clinicians and colleges, you have toyoung be luckydoctors today to be lastneed point in the left municipal dowith notone! seeThe the time there is a need for all us healers to understand column,to thelearn ‘presence’ is very relevant.

Unless the doctor has this presence, is suitably attired skills of communication, to respect basic human professionalism, and to sustain the professional model and carries himself well, it is unlikely that the patient will develop confidence in him or her. dignity of the patients and to be compassionate. Moreover, with integrity, self-regulation and accountability.

Pony tails, tattoos, slippers and jeans prevailing amongst young doctors in the wards is one there are no text books incorporated in curricula which such observation, detrimental to performing the role of dependable healer. On the right are address to these, so these have to be imbibed from master THE MOST IMPORTANT PART TO NURTURE IN THIS MODEL the special attributes of the professional, which are also not included in training and need to clinicians and you have to be lucky today to be with one! IS ITSasSOUL –THE HEALER be learnt as one comes in to the world of medicine. These will get increasingly important Theeralast point in the left column, the ‘presence’ is very amongst the present of reducing individual autonomy in medicine requires coordination REFERENCES relevant.

Unless the doctor has this presence, is suitably medical professionals.

1. Landon BE, Reschovsky J, Blumenthal D. Changes in career

attired and carries himself well, it is unlikely that the

Survey of literature1,7,8 gives interesting insights into professionalism in medicine.

Early literature is supportive of professionalism but has recognised tensions between larger goal of medicine and self-interest. Sixties and seventies have been very critical and have

CHAPTER 216

cycle of life and death cannot be presently altered. What remains in our hands as physicians is to try to improve the quality of life. In this respect, if patients were to write books, they will consist of very few lines indeed! Our ministrations and therapies lead to many a change in test results and restorations of processes, which do not necessarily change the perspectives and limitations for the patients. This realisation leads us to the understanding of what William Osler has said ‘Cure sometimes, treat often, comfort always’. For thousands of years, we have been healers and we shall always remain healers. Modern times have lead to a large evidence base, plethora of tests and methods have been added to our armamentarium, but quite clearly we shall remain healers in time to come, we need to teach our young how to do it professionally6.

6.

Cruess RL, Cruess SR. Teaching medicine as a profession in the service of healing. Acad Med 1997; 72:941-952.

American

7.

Mechanic D. Changing medical organization and the erosion of trust. Milbank Q 1996; 74:171-189.

3.

Sullivan W. Work and Integrity: The Crisis And Promise of Professionalism in North America. New York: Harper Collins; 1995.

8.

Schlesinger M. A loss of faith: the sources of reduced political legitimacy for the American medical profession. Milbank Q 2002; 80:185-235.

4.

Cruess SR, Cruess RL. Professionalism: a contract between medicine and society. CMAJ 2000; 162:668-669.

9.

Bloche MG. Clinical loyalties and the social purposes of medicine. JAMA 1999; 281:268-274.

5.

Barondess JA. Medicine and professionalism. Arch Intern Med 2003; 163:145-149.

10. Emanuel EJ, Emanuel LL. What is accountability in health care? Ann Intern Med 1996; 124:229-239.

satisfaction among primary care and specialist physicians, 1977-2001. JAMA 2003; 289:442-449.

1004

BEYOND MEDICINE

2. Starr P. The Social Transformation Medicine. New York: Basic Books; 1984.

of

C H A P T E R

217

Medical Practices on Cross Roads DN Upasani

Gone are the days when doctor was considered as an incarnation of GOD or at least next to God. The ancient system of practice of medicine in India was responsible for the above public opinion. Vaidyaraj used to practice this profession without any remuneration from the patient, but the whole society used to look after the needs (which were, no doubt, very meager) of the family of Vaidyaraj.

Doctor was a respected person in the society.

patients about the doctors, the hospitals and medical profession at large. Patients started looking to medical profession with suspicion with reciprocation by the doctors about the patients. Doctors and hospitals were dragged to the consumer forums, civil courts and even to criminal courts for negligence, deficient service or culpable homicide not amounting to murder. Doctors are manhandled, clinics ransacked and hospitals set on fire.

Gradually the system went into oblivion and the doctor was required to look after the needs of his family himself.

Hence, there was a need to earn money and hence collection of Tee.s from patients. There was, however, neither a fear in the mind of a patient of negligence on the part of the doctor, nor the doctor could dream of ‘treating’ the patient for unnecessary or imaginary illnesses and to charge the patient for the same.

For a straight forward, honest doctor, it is a very gloomy situation. Few doctors on their own and few hospitals for achieving their business goals may be doing unethical activities and dragging even honest doctors in their net by offering incentives (cuts and commissions). However, large part of the medical profession even today is unhappy about such practices. There is no need to feel depressed or worried. Right thinking persons in the society and judiciary are still supporting the medical profession.

With the evolution of the ‘Civilization’, the status of a person started getting evaluated on the basis of his bank balance, than on the qualities in him. Commercialization started setting in, even in the medical profession. Society started changing their perception of the doctor from a ‘healer’ to ‘service provider’, just like a carpenter, mason or plumber; ‘you pay him money and he is bound to give you service to your satisfaction and commensurate with the amount paid.

Consumer Protection Act, 1986 was enacted to curb the unethical practices of other service providers but soon it was made applicable to the medical profession also. Examining the patient on the strength of various investigations rather than the clinical examination became the norm of the medical practice, and one who fails to fall in line with it started getting questioned for not doing so not only by the patients but also the courts.

The entry of corporate houses in the business of medicine worsened the situation. Rather than the doctors running the hospitals, CEOs and MBAs started running the medical profession and the focus was changed from giving efficient treatment to the patient to profit making.

The hospitals changed to 5 star hotels concept. More and more costly gadgets were installed to attract the patients.

To make good the expenditure on purchase, running and maintenance of these gadgets, the concept of their ‘optimal’ utilization was set in and hence targets were given to doctors for their utilization.

It increased the cost of medical treatment many folds and was the beginning of ordering unnecessary investigations and procedures. This increased the unhappiness of the

Landmark Supreme Court judgement by the bench headed

by Chief Justice of India Mr. Lahoti in Jacob Mathew v/s State of Punjab has clearly stated that a patient with advanced cancer is likely to die in spite of due care and all such cases cannot be cases of negligence. Justice Katzu and Justice R.M. Lodha of The Supreme Court in a case Dr. Martin D’souza v/s Mohammed Ishfaq have upheld the decision of the doctor of using a particular antibiotic (though it has severe side effects) in a specific condition of the patient.

The Supreme Court in the Jacob Mathew case has categorically stated that police and court should not entertain a private complaint and arrest a doctor unless a credible opinion from an independent specialist is taken and a prima facie case established. Bolam Rule is an established principle in medical practice. Justice McNair in Bolam c/s Friern Hospital states that doctor needs to exercise ordinary skill of an ordinary, average competent man; a special skill is not expected to be exercised.

The doctors and hospitals suffer because of lots of things like the following - right from admission, the hospital staff behaves rudely, no one helps the patient, doctor does not have time to listen to patients’ complaints, doctor is many a times busy on his mobile, when patient is talking to him, doctor does not talk to relatives, never answers their queries, asks them to keep away, doctor examines the patient in most cursory manner, even there is no examination at all (investigations are enough for the doctor to know the patient and his illness), there is no attempt to explain to the patient and his relatives

1006 about the plan of treatment, doctor avoids telling the true

BEYOND MEDICINE

condition of the patients’ illness and gives false hopes of full recovery. In case of sad outcome, the doctor has no courtesy to share the grief. In such situations, how can we expect the patients/ relatives to be good, kind, respectful to us?

There is indeed no need to fear about. If you are good, competent, compassionate and an upright doctor, the patient and his whole family respects you. The family, even today, has faith in the doctor, but they are now more observant, smart, inquisitive and well informed because of internet. They, therefore, want to know as to what is happening. Therefore, Be good by heart Be a knowledgeable, competent doctor Show empathy to the patients Listen to the patients and relatives with interest Take the patient and family into confidence

Explain your plan of treatment, plus/minus points in treatment Make them party to the decision making process Take informed consent Be true in giving hopes and assurance Discuss the improvements and deteriorations in patients’ health from time to time If required, share their grief; in short develop interpersonal relationship Keep records of the treatment given, advises given, permissions sought I am sure that if you act with these things at the back of your mind, you will always be respected and will never suffer any medico legal problems.

Wishing you a happy medical career!

C H A P T E R

218

Personalized Medicine: Making Effective Therapy Safe for Every Individual

INTRODUCTION

The Institute of Medicine (IOM) USA, in a 1999 report “to Err is human” estimated that about 100000 deaths occurred annually in USA alone due to adverse effects of therapy. In 2006 the IOM estimated that medication errors harm 1.5 million people, costing the nation at least $3.5 billion annually. IOM recommended that by 2010 all prescriptions should be written electronically, with builtin warnings about drug – drug interactions and side effects. Alas, this has not happened yet.

It is a sobering thought for all doctors that about 10-20 percent of Hospitalized patients and 2-5% of out patients develop adverse effects of medications. A small group of frequently administered drugs account for the majority of adverse reactions. Most adverse drug reactions occur soon after administration. Many effects are seen after a month or more e.g. INAH hepatitis; many effects occur after several months e.g. chloroquine. Some adverse effects take years (mutagenesis, teratogenesis). Some effects are seen in the next generation (e.g. thalidomide in pregnant women, slibesterol given to mothers causes vaginal tumors in off springs).

During the first trimester of pregnancy, when organogenesis is taking place, the risk of drug induced effects is the greatest, but exposure any time during pregnancy may delay or distort normal fetal development.

Advanced age lowers kidney glomerular filtration, reducing drug clearance from the same dose. Hepatic and renal disease alter drug pharmacokinetics. Inherited enzyme defects like G6 PD deficiency can cause drug complications.

UNIQUENESS OF EACH INDIVIDUAL

Ayurveda (science of life) embodies experiential wisdom of over 5000 years. Charak Samhita States: “Every individual is different from another and hence should be considered as a different entity. As many variations are there in the universe, all are seen in human beings” Personalized medicine has been a distinct feature of Ayurveda, Unani and homeopathic practice of medicine.

R.D. Lele2 observes that safety record of homeopathy is 100%.

The greatest impact of the Human Genome project (2000 AD) on clinical medicine is the appreciation of the extra ordinary molecular and biochemical individuality of each person. Gene polymorphism occurs in 1 in 1000 DNA base pairs in the human genome. This is reflected in the diversity of the gene products – structural proteins,

Ramchandra D Lele

channel proteins, transporters enzymes and binding proteins, receptors and post receptor signaling cascades.

Polymorphism can occur not only in the protein coding sequence but also in the upstream promoter sequence.

Such polymorphism influences the activities of several enzyme mediated processes. The most common gene polymorphism is the single nucleotide polymorphism (SNP). Of the 3 million SNPs in the entire human genome only 60000 are in the exons or coding regions of DNA (CSNPs) which help in the hunt for genes of clinical interest. There are on an average 4-8 SNPS in every gene either in the exons or in the nearby exon intron boundaries in the upstream regulatory regions.

Genes of interest can be pin pointed using SNPs. At the molecular level mutations in gone, leading to alteration in gene products or altered regulation of gene expression provide an understanding of disease. New techniques such as complementary DNA micro assay (CDNA) are now available which will facilitate analyses of individual variations in the whole genome and the expression profile of all genes in all types of cells and tissues.

Table 1 summarizes recent advances in this field.

DRUG – DRUG INTERACTIONS

As important as predicting the efficacy of a drug is predicating and thus preventing adverse drug reactions.

In general practice and in hospitalized patients several drugs (4-8) may be taken concurrently. Hence it is essential to understand the basic mechanism of drug – drug interactions.

1.

Pharmacological incompatibility e.g. Penicillin + gentamicin / heparin / phenytoin neutralization.

2.

Pharmacokinetics: Antacids absorption of antibiotics.

3.

Metabolism: Enzyme induction. Enzyme inhibition: isoniazid enhances hypoglycemic effects of antidiabetic drugs.

interfere

with

Pharmacogenetics defines DNA sequence variations in genes encoding transporters receptors, drug metabolizing enzymes such as CYP2C19 etc. Tamilian populations in India have poor or intermediate metabolism compared to Caucasian populations.

Concept of chirality: A pair of molecules which are mirror images of each other are called enantiomers. S-amlodipine, S-pantoprazole, S-atenolol, S-metoprolol at half doses are as effective as the racemic mixtures. S-Thalidomide is teratogen while R thalidomide is sedative.

BEYOND MEDICINE

1008 Table 2 given examples of genetic determinates of

responses to drugs. Pharmacogenomics now provides an opportunity to analyze the drug metabolizing enzymes (super family of cytochrome P450 CYP 1 CYP2 and CYP 3). Determination of an individual patient’s genotype will be particularly important in use of antipsychotic drugs.

For example, the drug remoxipride has to occupy 70-85% of dopamine D2 receptors in the brain to be effective. To achieve this end, point some patients need only 50mg / day while others may need 1 g / day. Use of radiolabel receptor ligand and external detector probe can enable determination of optimal dose by receptor occupancy.

Similarly, to block 80% of platelets some patients need as little as 30 mg aspirin per day while at the other end some patients may need 1 gm/day. Hence for those in the first category the standard 300 mg dose is toxic while for the second category the dose is only a placebo” Illustrative examples: Role of genotyping in optimizing warfarin dosage in prosthetic valve replacement – genetic variations of CYP 2Cq and VKORC1; dose determination by pharmacogenetic algorithm.

Clopidogrel dosage determined by CYP2C192 and iT744C of P2Y12.

NEW TOOLS FOR SNP ANALYSIS AND EDITING

Affymetrix, based in Santa Clara California USA, founded

by Dr. Stephen Fodor in 1992 developed methods for fabricating DNA micro arrays called “Gene chip”. In 1994 an HIV genotype Gene chip was introduced. Affymetrix Gene chip arrays assist in quick scanning for particular genes in a biological sample with oligonucleotide microarrays. A single chip can be used to analyze 20,000 SNPs to probe 6817 genes in one assay. Chips can be used only once.

Affymetrix uses photolithography to manufacture its quartz gene chips. Various inexpensive plastic based technologies are being produced at lower prices than Affymetrix quartz chips.

In January 2014 USA FDA cleared a first of its kind whole genome post-natal blind test – Cytoscan Dx Assay to diagnose genetic causes of development delay, intellectual disability, congenital abnormalities or dysmorphic features in children who have some sort of intellectual disability.

The current cost of Affymetrix chip is US$ 3000. The challenge is to make the chip affordable to the Indian population as early as possible. Drug companies have an enlightened self-interest in making this happen. This will save them billions of dollars paid by them in compensation for drug induced damage.

The future of health case lies in preventative genetic testing.

Genome PatriJM, MapmygenomeJM Indian Genomics company founded in Hyderabad has developed in 2013, simple saliva based test which gives genetic predisposition for many chronic and life threatening diseases, genetic traits that influence medical outcomes, response to drugs, drug sensitivity and drug dosage, carrier status, diet and

fitness well-being and life style improvement. The cost is Rs. 25000.

Baby Map DNA test Covers 171 developmental, genetic and metabolic disorders after drawing a simple drop of blood 24-28 hours after birth. The cost is Rs. 25000. A genetic counselor is available to discuss the results.

While 99.9% of the genome is the same in all humans, the 0.1% that varies from person to person is the key to all the diversity among humans.

Map My Genome provides personalized health solutions and actionable steps for individuals towards a healthier life, preventive health care. The aim is to touch 100 million lives and save a million lives by 2013”.

Genome patri decodes DNA and predicts genetic risk for more than 100 diseases, traits inherited conditions, carrier status and drug responses, predictive assessment of cardiovascular, neurological and oncological conditions, women’s wellness and reproductive health.

In the recent Rio Olympics India got only one silver and one bronze medal. SMART. SPORT assesses individual genetic predisposition to either sprint / power muscle exercises.

CVD SNP 55K Bead chips and illumine Micro assay system PLINK software and Kyoto encyclopedia of Gene and Genomics software. Illumina’s veracode golden Gate Genotyping Assay of entire genome in 3 days for $100.

The challenge is to make this technology available and affordable to every individual Indian.

In future editing our genes will be possible with a low cost very precise gene editing technique CRISPR (Clustered regularly interspersed, short palindrome repeats). Prashant Mala, born in Rajasthan and educated at IIT-B, Johns Hopkins and Harvard explains the intricate working of CRISPR. “Ability to target a new genomic site simply requires one to alter the sequences of the guide RNA. It is a very easy to use and cost effective. A DNA strand is slit open; target portion sniffed off by CRISPR – prefab desired portion is inserted and DNA joined up again. This can be used for removing disease – causing genes and inserting genes with desirable characteristics.

As an illustrative example Steven Johnson Syndrome, a fatal reaction to drug abacavir is due to a mutation in HLA B5701.Identification of this gene and elimination of this gene is now possible. A well-known physician of Kolkata was sued by his own student for the death of his wife due to Steven Johnson Syndrome caused by medication (and granted compensation amounting to Rs. 9 crores).

CPIC: CLINICAL PHARMACOGENETICS IMPLEMENTATION CONSORTIUM

Patients suffer because doctors fail to warn them about side effects of drugs.

C M Gulhati, editor MIMS has been championing the cause of safe drugs for decades. Pregnant women and children below 12 are particularly vulnerable.

Table 1: Recent Advances Genomics: Study of gene sequences 3.5 billion DNA base pairs in exons (Coding regions) and introns has pairs (non coding regions) Structural genomics: Precise 3 dimensional structure of proteins by X-ray Crystallography.

Transcriptomics: Study of variations in the expression level of different genes under different environmental conditions.

Proteomics (functional genomics) study of all proteins – 1278 families of proteins doing all the work in cells.

Proteomics is center stage for new drug discovery.

Metabolomics deals with metabolizing enzymes: Over 50 cytochrome P450 enzymes determine the fate of drugs in the body. Biological networks with cybernetic relationship in cellular, biochemical and metabolic reactions.

System Biology: Biological switch boards with differential combinations of homodimers helirodimers and heterodimers initiating signaling and cell activation in several systems.

Metabolic phenotyping in health and disease: The human metabolome Database contains 41500 entries including water soluble and lipid soluble metabolites, 5680 genes and protein sequences and 440 human metabolic and disease pathways. For instance, the multiple genes and their poly morphisms in metabolic syndrome with their SNPs, are now known.

Epigenetics and transcriptional gene silencing

Irinotecan (UGTQ, A128 allele) Valproic acid (PULG mutation) Warfarin (VKD RCIrs 9923231 allele)8 Marcia Angel M.D. former editor of NEJM, in “The truth about drug companies: how they deceive us and what to do about it”. Random House 2004, observed that the pharmaceutical industry is corrupted by easy profits and greed. $35 billion are spent on “promotion of drugs” in doctors- marketing masquerading as education. She has given guidance for the mission to make drugs better, safer and more affordable.

EHR AND COMPUTERIZED PRESCRIPTIONS

In my book “Computers in Medicines: Progress in Medical informatics (Tata McGraw Hill 2005, 3rd reprint 2009). I have given action plans for introducing electronics Health Record and computerized prescriptions in India. Dr. N. J. Rao (Hyderabad), Dr. Anil Vij (Delhi), and Dr. Rohini Chougulay (Mumbai) have developed them successfully.

Med Docket – TM clinic management software developed Dr. Rohini Chouguley has following features 1.

Linkage of drug names to diagnosis

2.

More than 1200 generic drug names and drug trade names

3.

Alerts for drug interactions

4.

Pregnancy and lactation alerts

5.

Alerts for drug allergies

6.

Automatic dose calculations based on age, gender, body surface area

7.

Auto calculation of total drug quantity prescribed based on dose, pregnancy and duration

Nutrigenomics – Nutrition gene interactions Future drug delivery systems: Site specific, pathophysiology – driven optimizing pharmacokinetic and pharmacodynamic and pharmacogenetics responses tailored to meet individual therapeutic responses.

It should be mandatory to provide readable package inserts regarding safety risks and precautious in using the drug. Millions of patients suffer because Pharma Companies and doctors fail to forewarn about drugs side effects. Pharmaco vigilance for every drug old or new, should be a continuous process. Drug related deaths can occur during clinical trials for which adequate insurance cover is mandatory.7

Mobile phones now carry adequate information about drug – drug interactions, and reminders for appropriate changes in drug dosage in such situations. Every written prescription should have at the bottom in bold letters this printed caution: If you notice any untoward reaction stop the drug and report to your doctor immediately.

Forewarned is forearmed.

CHECKLISTS

Sometimes rare but important adverse drug reactions (ADRs) are not detected in randomized controlled drug trials prior to FDA’s drug approval e.g. Troglitazone’s hepatotoxicity or viovax’s adverse effect on CAD. The internet now makes available a wide range of information about ADRs almost instantaneously. CDIC (clinical pharmacogenetics implementation consortium) gives pharmacogenetics information in the package inserts eg.

Dr. Atul Gawande in his book “The checklist Manifesto – How to get things right” states – “Clinicians now have at their disposal some six thousand drugs and four thousand medical and surgical procedures, each with different requirements, risks and considerations. Major complications for surgical patients in all hospitals fell by 36% after the introduction of checklists, deaths fell by 47%, infections fell by almost half. A checklist is a simple solution that makes the entire surgical team working towards solving a problem. Despite this doctors around the world resist checklists.

Abacavir (HLAB5701)

How to handle death?

Capecitabine

1009

Dr. Atul Gawande in his famous book “Being mortal”

CHAPTER 218

Tissue transcription profiling will be routine for planning appropriate treatment of cancers.

Carbamazepine (HLAB 1502, 3101)

BEYOND MEDICINE

1010

Table 2: Examples Genetic determinates of responses to drugs Polymorphism of drug metabolizing enzymes

Mechanism

Consequences

TPMT (Thiopurine S-methyl transferase)

(Inactivation of azathioprine and 6 mercaptopurine) = full activity enzyme EM : extensive metabolism deficient activity enzyme PM : Poor metabolism

PM phenotype patients show Excessive bone marrow toxicity with “Usual” dose EM phenotype patients show under treatment with” usual” dose of azathioprine.

NAT-2 (n-acetyl transferase)

Acetylation of isoniazid, Slow acetylators likely to produce hydralazine, sulfonamides, INAH neuropathy procainamide etc. “slow” rapid” and “intermediate” acetylators

Cytochrome P450 mono oxygenases

Isoforms with different substrate specificities multiple pathways EM (extensive metabolizers) PM (poor metabolizers) IM (intermediate metabolizers)

Range of activity can vary tenfold between individuals on same dose. e.g. chlorpromazine

CYP2D6 antiarrhythmic drugs

Metabolic pathway for exaggerated drug effect B blockers, tricyclic antidepressants, neuroleptic drugs, selective serotonin reuptake inhibitors

PM phenotypes show on same dose of B blockers can be identified by test drug debrisoquine

CYP2C19

Catalyzes omeprazole Proguanil, diazepam and etalopram

EM genotype patients show only 29% cure rate for eradicating H. Pylori Vs 100% cure rate in PM genotype for same dose 20 mg omeprazole

CYP2C9

Metabolism of warfarin and phenytoin, loss of catalytic function in PM phenotype causes bleeding even with low warfarin dose.

100-200-fold difference in clearance of mephentoin between EM and PM phenotype increased toxicity in PM phenotype.

Genes coding ion channel proteins

Mutant genes, remain sub clinical until challenged by drugs such as quinidine which prolong action potentials

Prolonged QT and Polymorphic VTachycardia

has observed that doctors are trained how to keep their patients alive as long as possible but they are never taught how to prepare people to die. The last 8 days of a terminally ill patient in the hospital ICU can mean complete financial ruin for the entire family. A trusting doctor patient relationship will allow the doctor to explain to the relatives of the patient of the futility of heroic measures which only prolong his suffering. It is more humane for the terminally ill patient to die at home with his family around, rather than in the ICU. In 1991 Greyon Thompson, a critical care specialist posed 4 questions to his patients.

1.

Do you want to be resuscitated if your heart stops?

2.

Do you want aggressive life support such as intubation and mechanical ventilation?

3.

Do you want antibiotics?

4.

Do you want gastric tube or intravenous feeding if you cannot eat on your own?

The written answers made management decisions easier and brought down end of life costs to half the national

average. In the words of Mahatma Gandhi – “Death is the truest of friends, delivers us from agony”.

REFERENCES

1.

R.D. Lele. Ayurveda & Modern Medicine. 2nd edition 2001.

Bharatiya Vidya Bhavan 2. R.D. Lele. Homeopathy & Modern Medicine 2015, National Book Depot 3. R.D. Lele Clinical Science & Clinical Research. 2nd edition 2008, National book depot 4. R.D. Lele Clinical Approach 3rd edition 2015, National Book Depot 5. R.D. Lele How to ascertain drug-related deaths during clinical trials. JAPI 2013; 61:49-53 6. R.D. Lele Computers in Medicine: Progress in Medical Informatics. Tata Mc Graw Hill 2005 .3rd reprint 2009.

7. Marcia Angell The truth about the drug companies. How they deceive us and what to do about it. 2004 Random House 8. Pai SA, Kshirsagar NJ. Clin Pharmacol 2016; 10:1002 9. Atul Gawande: “The Check List Manifesto. How to get things right” 10. Atul Gawande: Being Mortal

Doctor-Patient Relationship

C H A P T E R

219

Ambika Prasad Mohanty

INTRODUCTION

Doctors and patients interact; it demands respect, and if the doctor also displays compassion, sets the scene for the development of trust. Physicians must never forget that patients are individual human beings with problems that all too often transcend their physical complaints. They are not “cases” or “admissions” or “diseases.” Patients do not fail treatments; treatments fail to benefit patients.

Most patients are anxious and fearful. Physicians should instill confidence and offer reassurance but must never come across as arrogant or patronizing. The doctor– patient relationship is in itself therapeutic; a successful consultation with a trusted doctor will have beneficial effects irrespective of any other therapy given. The doctor–patient relationship is multilayered, dynamic and bilateral. On considering a relationship that is based on mutual participation of two individuals, the term “relationship” refers to neither structure nor function but rather an abstraction compassing the activities of two interacting systems or persons. The apparent, intrinsic quality of this unique doctor-patient relationship allows two people, previously unknown to each other, to feel at ease with variable degree of intimacy. This relationship, in time, may develop to allow the patient to convey highly personal and private matters in a safe and constructive environment. A professional attitude, coupled with warmth and openness, can do much to alleviate anxiety and to encourage patients to share all aspects of their medical history. Empathy and compassion are the essential features of a caring physician. The physician needs to consider the setting in which an illness occurs— in terms not only of patients themselves but also of their familial, social, and cultural backgrounds. The ideal patient-physician relationship is based on thorough knowledge of the patient, mutual trust, and the ability to communicate.

HISTORY OF DOCTOR-PATIENT RELATIONSHIP

The doctor-patient relationship has been dependent on the medical and social scenes of following periods. These are: (a) Ancient Egypt (approximately 4000 to 1000 B.C.), (b) Greek enlightenment (approximately 600 to 100 B.C.),

Table 1: Types of doctor–patient relationship Patient control

Doctor control

Doctor control

Low

High

Low

Default

Paternalism

High

Consumerist

Mutuality

(c) Medieval Europe (approximately 1200 to 1600 A.D.), (d) The French revolution (late 18th century), (e) Doctorpatient relationship 1700-to present day. In ancient Egypt healers were as much magicians and priests as they were doctors and magic was an integral part of care. Treatment was largely limited to external. It seems likely that in ancient Egyptian medicine the activity-passivity type relationship existed. The Greeks developed a system of medicine based on an empirico-rational approach, such that they relied more on natural observation. The Hippocratic Oath established a code of ethics for the doctor, whilst also providing a ‘Bill of Rights’ for the patient. In Medieval Europe there was deterioration of the doctor-patient relationship. The magico-religious beliefs were revived and became widely accepted. The events that led to the French Revolution brought an end to an era in which the mentally ill and socially underprivileged were incarcerated in dungeons. There was change in the doctor-patient relationship from an activity-passivity approach to a guidance-co-operation model. During the 18th Century symptom-based model of illness ensured the preservation of patient dominance throughout the period.

Later the hospitals emerged as places to treat patients who were underprivileged. Doctors provided treatment to those who were more passive. The hospital became the cornerstone of medical care and along with rapid growth of microbiology, surgical skills and pathology a new Medicine developed which required the examination of the patient’s body to formulate a diagnosis resulting in an activity-passivity (paternalistic) model.

TYPES OF DOCTOR–PATIENT RELATIONSHIP

Different forms of doctor-patient relationship arise from differences in the relative power and control exercised by doctors and patients (Table 1). In reality, these different models perhaps do not exist in pure form, but nevertheless most consultations tend towards one type.

PATERNALISTIC RELATIONSHIP

A paternalistic (or guidance–cooperation) relationship, involving high physician control and low patient control, where the doctor is dominant and acts as a ‘parent’ figure who decides what he or she believes to be in the patient’s best interest. This form of relationship traditionally characterized medical consultations and, at some stages of illness, patients derive considerable comfort from being able to rely on the doctor in this way and being relieved of burdens of worry and decision making. However, medical consultations are now increasingly characterized

1012

Table 2: Duties of a good doctor Patients must trust doctors with their life and death. To justify that the Doctor must show respect for human life.

Knowledge, skills and performance • Make the care of your patient the first concern.

• Provide a good standard of practice and care.

BEYOND MEDICINE

Safety and quality • Protect and promote the health of patients.

• Take prompt action for patient safety, dignity.

Communication, partnership and teamwork • Treat patients as individuals and respect their dignity.

• Respect patient’s right to confidentiality.

• Work in partnership with patient • Work with colleagues in the ways that best serve patient’s interests Maintaining trust • Be honest and open and act with integrity • Never discriminate unfairly against patients or colleagues • Never abuse your patient’s trust by greater patient control and relationships based on mutuality.

MUTUALITY RELATIONSHIP

A relationship of mutuality is characterized by the active involvement of patients as more equal partners in the consultation and has been described as a ‘meeting between experts’, in which both parties participate as a joint venture and engage in an exchange of ideas and sharing of belief systems. The doctor brings his or her clinical skills and knowledge to the consultation in terms of diagnostic techniques, knowledge of the causes of disease, prognosis, treatment options and preventive strategies, and patients bring their own expertise in terms of their experiences and explanations of their illness, and knowledge of their particular social circumstances, attitudes to risk, values and preferences.

CONSUMERIST RELATIONSHIP

A consumerist relationship describes a situation in which power relationships are reversed; with the patient taking the active role and the doctor adopting a fairly passive role, acceding to the patient’s requests for a second opinion, referral to hospital, a sick note, and so on.

DEFAULT RELATIONSHIP

A relationship of default can occur if patients continue to adopt a passive role even when the doctor reduces some of his or her control, with the consultation therefore lacking sufficient direction. This can arise if patients are not aware of alternatives to a passive patient role or are timid in adopting a more participative relationship.

Different types of relationship, and particularly those characterized by paternalism and mutuality, can be viewed as appropriate to different conditions and stages of illness. For example, in emergency situations it is generally necessary for the doctor to be dominant, whereas in other situations patients can be more actively involved in treatment choices and other decisions regarding their care.

DIFFICULTIES IN THE DOCTOR–PATIENT RELATIONSHIP

Regardless of experience and skill, it is inevitable that, at some point in a doctor’s career, the doctor–patient relationship will break down. There can be many reasons for this; sometimes, these are beyond the control of the clinician, but often conflict arises when there is a genuine or perceived failure of the doctor to meet one or more of the duties outlined in (Table 2). It is important to recognize a breakdown in the relationship quickly and, whenever possible, identify the reason. If patients are unhappy with an aspect of their care, they are entitled to a prompt, open, constructive and honest response that includes an explanation and, if appropriate, an apology.

It is also important to reassure the patient that the issues raised will not adversely affect their future care. Often, an acknowledgement that something is wrong and demonstration of a desire to put things right are sufficient to rectify any conflict. However, the longer one takes to address a problem, the more difficult it becomes to resolve. The patient may continue to be dissatisfied with the doctor and it may be most appropriate for another colleague to take over their care. It is important to reflect on such incidents, to identify whether one would approach a similar challenge differently next time.

DOCTOR-PATIENT COMMUNICATION

Effective communication between doctor and patient is a central clinical function that cannot be delegated.

Most of the essential diagnostic information arises from the interview, and the doctor’s interpersonal skills also largely determine the patient’s satisfaction and positively influence health outcomes. Such skills, including active listening are qualities of a doctor most desired by patients.

When a patient sees a doctor, he has some expectations and hopes. He expects the doctor to be interested in him as an individual. He wants to be listened, so that his fears can be expressed and his burdens shared. To be able to meet these expectations the doctor must develop certain skills. He should have the patience to listen to the patient’s complaints and try to understand what is trying to convey.

There is considerable healing power in the doctor-patient alliance. The bond of trust between the patient and the doctor is vital to the diagnostic and therapeutic process. It forms the basis for the doctor-patient relationship. In order for the doctor to make accurate diagnosis and provide optimal treatment recommendations, the patient must be able to communicate all relevant information about an illness. Doctors are obliged to refrain from divulging confidential information. This duty is based on accepted codes of professional ethics which recognize the special

Table 3: Some Barriers to Good Communication in Health Care The Doctor • Authoritarian or dismissive attitude • Hurried approach • Use of jargon • Inability to speak first language of the patient • No experience of patient’s cultural background The patient • Anxiety • Misconceptions • Conducting sources of information • Cognitive impairment • Hearing/speech/visual impairment nature of these medical relationships. Some barriers to good communications in health care is given in Table 3.

CONTEMPORARY ISSUES

In India, the doctor-patient relationship has remained far more constant than in Western societies. A paternalistic approach still dominates, and doctors have a high status in society. Litigations rates of doctors are far lower in India in comparison to Western countries. Another contemporary effect on the doctor-patient relationship has been the exponential increase in the use of the internet by the patients. This means that the patients are better informed, especially in the more affluent society, and this has facilitated the patient-centered approach to health care that predominates today. While better patient education has obvious advantages for the doctor-patient relationship, there are concerns that information on the internet might not always be accurate and reliable. This poses a new challenge for the medical professional – that of revising any misinformation the patient has found him- or her-self. In some countries doctors have a poor reputation and inequity of care and un virtuous circle of referral and kickbacks may destroy any chance of a trusting relationship with their patients.

CONCLUSION

Previously, patients were most often considered to be too ignorant to make decisions on their own behalf.

CHAPTER 219

• Reluctance to discuss sensitive or trivial issues

Doctors felt comfortable in making decisions on behalf 1013 of their patients. Later on doctors became separated from their patients politically, economically and socially.

The distance between doctor and patient widened and the doctor-patient relationship became impersonal and remote. Today however there is a new alliance between the doctor and patient, based on co-operation rather than confrontation, in which the doctor must “understand the patient as a unique human being”. Thus patientcentered care has replaced a one-sided, doctor-dominated relationship in which the exercise of power distorts the decision-making process for both parties. The primary objective of the doctor is to listen to the patient in order to identify what is the ‘real’ problem actually is instead of simply eliciting symptoms and signs. Shared decision making between the doctor and the patient will determine the most appropriate and best course of action for an individual patient. The doctor in this patient-centered model is ideally placed to bridge the gap between the world of medicine and the personal experiences and needs of his patients. The significance of the intimate personal relationship between physician and patient cannot be too strongly emphasized, for in an extraordinarily large number of cases both the diagnosis and treatment are directly dependent on it. One of the essential qualities of the clinician is interest in humanity, for the secret of the care of the patient is in caring for the patient.

REFERENCES

1.

Walker BR. Davidson’s Principles & Practice of Medicine, 22nd ed. El sevier,2014: 1-4.

2.

Longo DL. Harrison’s Principles of Internal Medicine, 19th ed. Mc Graw Hill, 2015: 4-7.

3.

Tato P. The Doctor’s Communication Handbook, 6th ed.

BYWORDBOOKS, 2010: 1-186.

4.

Troug RD. Patients and Doctors- The evolution of a relationship. New Eng J Medicine 2012; 366:585.

5.

Wong SYS, Lee A. Communication Skills and Doctor Patient relationship. The Hongkong Medical Diary 2006; 3:7-9

6.

Mendoza MD, Smith SG, Mickey M, Hickner JH. The Seventh Element of Quality: The Doctor-Patient relationship. Fam Med 2011; 43:83-9.

7.

Berger D. Corruption ruins the doctor-patient relationship in India. BMJ 2014; 348:1-2.

8.

Kaba R, Sooriakumaran P. The evolution of the doctorpatient relationship. International J of surgery 2007; 5:57-65.

C H A P T E R

220

Democratizing Knowledge to Improve Care for the Underserved: Project ECHO

THE ECHO STORY

Launched in 2003, at the University of New Mexico Health Sciences Center, Project ECHO (extension for Community Healthcare Outcomes) grew out of a need for rural and underserved patients in New Mexico, USA to have better access to specialty care. While treating patients with the hepatitis C virus (HCV), Project ECHO Director and founder, Dr Sanjeev Arora, recognized that the volume of patients needing specialized HCV care in his clinic far exceeded capacity. In addition, many patients had to travel very long distances to access care, resulting in lost work time and income, and travel costs. These obstacles negatively affected patient care, compliance and outcomes, as patients would often delay seeking care (and experience increased complications) or not seek treatment at all.

In response, Dr Arora developed a solution to the problem of inadequate access to specialty care. Using technology and clinical management tools, he developed Project ECHO, an innovative learning platform designed to dramatically expand specialty expertise in traditionally underserved areas.

This low-cost, high-impact intervention is accomplished by linking expert interdisciplinary specialist teams located at academic medical centres (hubs) with healthcare workers in rural and underserved areas through teleECHO clinics, where experts mentor and share their expertise via case-based learning, enabling primary care clinicians to develop the ability to treat patients with complex conditions in their own communities. The ECHO model is not telemedicine where the specialist assumes the care of the patient, but instead a guided practice model where the primary care clinician retains responsibility for managing the patient.

MECHANICS OF THE ECHO MODEL

The model is based on 4 key principles: •

Use of technology (multipoint videoconferencing and the internet) to leverage scarce healthcare resources in a telementoring modality

•

Dissemination of clinical best practices across disparate care sites to reduce disparities

•

Case-based learning, so that learners receive guided practice and support from a multidisciplinary expert team and master issues of complexity

•

Evaluation of outcomes

Sanjeev Arora, Kumud Rai, Sunil Anand

In addition to these four key principles, the ECHO model focuses on an all teach – all learn model, whereby the hub and the spoke or primary care clinicians are members of the same team and all learn from each other. The ECHO model fosters peer-to-peer mentoring and creates a cross pollination of idea sharing and mentoring among the different spoke sites. This is achieved through: a) casebased learning, b) knowledge networks, and c) learning loops. Knowledge networks consist of regularly scheduled teleECHO clinics that bring together expert interdisciplinary specialists and community-based partners.

At the spoke sites, each clinician presents their cases following a prescribed algorithm and case presentation form. The multidisciplinary team of experts at the hub site, which usually includes a disease specialist(s), pharmacist, and behavioral health expert, and the spoke participants discuss the case and share their recommendations.

Partners learn best practices through learning loops in which they are mentored to treat diverse patients in real world situations and practice. Over time, these learning loops create deep knowledge, skills and self-efficacy.

Many studies have shown the value of the ECHO model in improving physician satisfaction, particularly among rural and isolated clinicians, as they feel less isolated and more connected to the community of practice.

The goal of the ECHO model is to create ‘force multiplication’, to logarithmically improve the capacity to deliver specialty care—up to 10 to 100 times more capacity. Project ECHO provides the right knowledge at the right place at the right time, allowing millions of people access to specialty they otherwise would not have access to.

EVALUATION AND IMPACT OF THE ECHO MODEL

Project ECHO believes that tracking and evaluation of project results is critical. ECHO regularly evaluates teleECHO clinic attendance and uses pre- and postsurveys to evaluate participant learning, self-efficacy, and satisfaction with the ECHO model as a learning and community building tool, along with a few key patient metrics. A prospective cohort study published in the New England Journal of Medicine (June 2011), comparing treatment of HCV at the University of New Mexico clinic to treatment by primary care clinicians in rural New Mexico, demonstrated that treatment for HCV using the ECHO model is as safe and effective as treatment at an academic medical centre. Since then 45 publications have been published and document the value of ECHO

1015

CHAPTER 220

Fig. 1: Global Map of ECHO Replication Sites as of 10/1/16

ECHO SPREAD

NATIONAL INSTITUTE FOR MENTAL HEALTH AND NEUROSCIENCES (NIMHANS) – BANGALORE, INDIA

Project ECHO has established a technical assistance arm that supports the replication of Project ECHO programs around the world. Replication is achieved by enabling partners to create ECHO hubs, in which sites or spokes connect through teleECHO clinics, gaining specialty expertise and knowledge. Project ECHO supports rapid global scaling of the ECHO model by providing robust training in the best practices for replication, which includes monthly Introduction, Orientation and Immersion training sessions and many other outreach events that are offered at the ECHO Institute in Albuquerque, NM, USA, http://echo.unm.edu/start-an-echo/orientation-events/ .

NIMHANS currently runs four teleECHO clinics for mental health and drug addiction, mental health care during pregnancy and postpartum, and the road to recovery for patients with substance use disorders. They are also running a special clinic for the State of Bihar, which connects 9 district hospitals and will soon be expanding to include 22 additional district hospitals to address addiction and mental health. To date, NIMHANS has trained a total of 1,000 doctors and 440 allied healthcare workers.

Currently, the ECHO Institute conducts teleECHO clinics for over 20 conditions such as chronic pain, integrated addictions and psychiatry, rheumatology, HIV, complex care, epilepsy, tuberculosis (TB), bone health, and endocrinology. ECHO is being adopted as an effective model for capacity building and care delivery all over the world by leading academic medical centres and international organizations. At this juncture, there are 93 hub replication partners globally, including 60 sites in the U.S., and an additional 28 programs operating in 16 countries, covering 50 distinct complex conditions.

INASL operates a teleECHO clinic from the Postgraduate Institute of Medical Education and Research Chandigarh (PGIMER) in support of the Punjab Government’s elimination of HCV program. This teleECHO clinic connects a total of 22 district hospitals and over the last four months has registered and begun treatment for 12,000 new patients.

ECHO IN INDIA

The ECHO Model is quickly spreading throughout India and the ECHO India Trust office has been established, under the directions of Drs Sunil Anand and Kumud Rai to provide support to Indian partners. A brief summary of the work of each of the Indian replicating partners has been included below.

INDIAN NATIONAL ASSOCIATION FOR THE STUDY OF THE LIVER (INASL)

INSTITUTE OF LIVER AND BILIARY SCIENCES (ILBS) – NEW DELHI, INDIA

The ILBS has a long-running ECHO for primary care clinicians for liver diseases and currently runs two clinics: one on liver diseases, and a second that connects 10 medical colleges across India to train physicians in how to treat liver diseases.

KARUNA TRUST – BANGALORE, INDIA

The Karuna Trust is utilizing the ECHO model with

1016 Community Health Workers (CHWs) to teach primary

care clinicians and CHWs throughout their seven large hospitals and dozens of community health clinics.

BEYOND MEDICINE

POST GRADUATE INSTITUTE OF MEDICAL EDUCATION AND RESEARCH (PGIMER) – CHANDIGARH, INDIA

REFERENCES

1.

Arora S, Kalishman S, Dion D, Som D, Thornton K, Bankhurst A, Boyle J, Harkins M, Moseley K, Murata G, Komaramy M. Partnering urban academic medical centers and rural primary care clinicians to provide complex chronic disease care. Health Affairs 2011; 30:1176-84.

PGIMER has recently launched an HCV and HCB teleECHO clinic, and has received both funding and a collaborative agreement from the state of Punjab to recruit and enable Punjabi primary care clinicians into this liver care teleECHO clinic. The PGI Chandigarh teleECHO clinic connects 14 different prisons in Punjab to the Department of Hepatology at PGI Chandigarh.

2.

Arora S, Kalishman S, Thornton K, Dion D, Murata G, Deming P, Parish B, Brown J, Komaromy M, Colleran K, Bankhurst A. Expanding access to hepatitis C virus treatment—Extension for Community Healthcare Outcomes (ECHO) project: disruptive innovation in specialty care. Hepatology 2010; 52:1124-33.

3.

MDT TB PROGRAM (MUTLI-DRUG RESISTANCE PROGRAM AT DELHI)

Arora S, Thornton K, Komaromy M, Kalishman S, Katzman J, Duhigg D. Demonopolizing medical knowledge.

Academic Medicine 2014; 89:30-2.

4.

Arora S, Thornton K, Murata G, Deming P, Kalishman S, Dion D, Parish B, Burke T, Pak W, Dunkelberg J, Kistin M. Outcomes of treatment for hepatitis C virus infection by primary care providers. New England Journal of Medicine 2011; 364:2199-207.

5.

Chand P, Murthy P, Gupta V, Kandasamy A, Jayarajan D, Sethu L, Benegal V, Varghese M, Komaromy M, Arora S. Technology Enhanced Learning in Addiction Mental Health: Developing a Virtual Knowledge Network: NIMHANS ECHO. InTechnology for Education (T4E), 2014 IEEE Sixth International Conference on 2014 Dec 18 (pp. 229-232). IEEE.

6.

Hariprasad R, Mehrotra R. Cancer Screening Program Using Technology Assisted Learning. Journal of Global Oncology 2016; 2(3 suppl):23s-.

7.

Zhou C, Crawford A, Serhal E, Kurdyak P, Sockalingam S. The Impact of Project ECHO on Participant and Patient Outcomes: A Systematic Review. Academic Medicine 2016; 91:1439-61.

The ECHO India Trust office is planning a program to connect four Drug Resistance TB Centres to 25 District TB Officers, State Tuberculosis Officers, the New Delhi TB Centre and the Central TB Division to conduct a teleECHO clinic for the management of MDR TB. Additionally, a new clinic will be started around the Control Access Program for Bedaquiline (new TB drug) that will include: the National Institute of research in Tuberculosis, Chennai; Government Medical College, Guwahati; Sewrie /KEM Hospital Mumbai; BJ Medical College, Ahmedabad; National Institute of Tuberculosis and Respiratory Diseases, New Delhi; and Rajan Babu Institute of Pulmonary Diseases and Tuberculosis, New Delhi.

More than 15 additional programs are planned and will launch within the coming year to include cancer, diabetes, cervical cancer prevention and many other areas. Additionally, an introduction, orientation and immersion training will be held in India in November for those signed partners.

C H A P T E R

221

ADVANCE to ADVANCE on: The First Evidence of Legacy Effect in the Management of Hypertensive Diabetic Patients Sanjay Kalra

INTRODUCTION

Diabetes mellitus is associated with chronic macro and micro-vascular complications, which impair duration as well as quality of life. One of the main goals of diabetes care is to prevent and delay these complications.

A comprehensive approach, focusing on control of glycaemia, blood pressure, lipids and weight is followed to achieve this aim.

VASCULAR HEALTH

Advances in understanding of the pathology and natural history of non-enhanced communicable disease have contributed to enhanced importance of non-glycemic parameters in diabetes management.

The INTERHEART study, for example, revealed that dyslipidemia (odds ratio [3.25]), hypertension (1.91), and obesity (1.62) are as important determinants of the risk of myocardial infarction as diabetes (2.37) is. Similarly, in INTERSTROKE, hypertension (3.89), dyslipidemia (1.89), and obesity (1.65) were found to be more important than diabetes (1.36) in increasing the risk of stroke.

diabetes, irrespective of initial blood pressure levels or the use of other blood pressure lowering drugs. A multinational trial, ADVANCE was conducted in 215 collaborating centers in 20 countries. After a 6-week active run-in period, 11 140 patients with type 2 diabetes were randomized to treatment with a fixed combination of perindopril and indapamide or matching placebo, in addition to current therapy. The primary endpoints were composites of major macro vascular and microvascular events, defined as death from cardiovascular disease, non-fatal stroke or non-fatal myocardial infarction, and new or worsening renal or diabetic eye disease.

The beneficial impact of glucose-lowering and lipidlowering on diabetes- related outcomes has been known for long. UKPDS and FIELD have shown reduction in cardiovascular outcomes with intensive glucoselowering strategies. The legacy effect of these strategies, i.e., persistence in cardiovascular benefit has also been reported recently.

After a mean of 4.3 years of follow-up, 73% of those assigned active treatment and 74% of those assigned control remained on randomized treatment. Compared with patients assigned placebo, those assigned active therapy had a mean reduction in blood pressure of 5.6 / 2.2 mm Hg. The relative risk of a major macrovascular or microvascular event was reduced by 9% (861 [15.5%] active vs 938 [16.8%] placebo; hazard ratio 0.91, 95% CI 0.831.00, p=0.04). The separate reductions in macrovascular and microvascular events were similar but were not independently significant (macro vascular 0.92; 0.81-1.04, p=0.16; microvascular 0.91; 0.80-1.04, p=0.16). The relative risk of death from cardiovascular disease was reduced by 18% (211 [3.8%] active vs 257 [4.6%] placebo; 0.82, 0.680.98, p=0.03) and death from any cause was reduced by 14% (408 [7.3%] active vs 471 [8.5%] placebo; 0.86, 0.750.98, p=0.03).

While the phenomenon of glycemic legacy is wellknown, the concept of ‘vascular legacy ‘or blood pressure lowering legacy’ has not been discussed adequately.

Though preclinical and clinical studies have suggested the feasibility of such a legacy, clinical data to prove this has been lacking till recently. This chapter reviews and analyses the findings of the ADVANCE and ADVANCE ON trials. Based upon this evidence, it proposes a pragmatic approach to utilize the vascular legacy of perindopril + indapamide combination.

The ADVANCE study therefore proved the cardiovascular and the renal benefit of a perindopril + indapamide combination, administrated as routine therapy, irrespective of baseline blood pressure, to all patients with type-2 diabetes. This study demonstrated that both primary prevention and secondary prevention of cardiovascular and renal events could be achieved with perindopril + indapamide combination. In this regard, the ADVANCE results were an improvement over the results of MICRO HOPE, which included only high risk patients.

VASCULAR LEGACY

THE ADVANCE STUDY

The ADVANCE study assessed the effects of the routine administration of an angiotensin converting enzyme (ACE) inhibitor-diuretic combination (perindopril + indapamide) on serious vascular events in patients with

THE ADVANCE ON STUDY

The ADVANCE researchers assessed the long term outcomes of intensive intervention in ADVANCE. They invited surviving participants, who had previously been assigned to perindopril + indapamide or placebo and to

BEYOND MEDICINE

1018 intensive or standard glucose control (with the glucose-

control comparison extending for an additional 6 months), to participate in a post-trial follow-up evaluation. The primary end points were death from any cause and major macrovascular events. The baseline characteristics were similar among the 11,140 patients who originally underwent randomization and the 8494 patients who participated in the post-trial follow-up for a median of 5.9 years (blood pressure lowering comparison) or 5.4 years (glucose-control comparison). Between group differences in blood pressure and glycated hemoglobin levels during the trial were no longer evident by the first post-trial visit.

The reductions in the risk of death from any cause and of death from cardiovascular causes that had been observed in the group receiving active blood-pressure–lowering treatment during the trial were attenuated but significant at the end of the post-trial follow-up; the hazard ratios were 0.91 (95% confidence interval [CI], 0.84 to 0.99; P=0.03) and 0.88 (95% CI, 0.77 to 0.99; P=0.04), respectively.

No differences were observed during follow-up in the risk of death from any cause or major macro vascular events between the intensive-glucose control group and the standard-glucose-control group; the hazard ratios were 1.00 (95% CI, 0.92 to 1.08) and 1.00 (95% CI, 0.92 to 1.08), respectively.

The ADVANCE ON trial showed that the benefits with respect to mortality that had been observed among patients originally assigned to blood pressure lowering therapy were attenuated but still evident at the end of follow-up. There was no evidence that intensive glucose control during the trial led to long-term benefits with respect to mortality or macrovascular events. Thus, it proved a vascular legacy effect in diabetes care, provided appropriate therapy is instituted early on in the course of the disease. This legacy is effective in both macro and micro-vascular beds.

DISCUSSION

ADVANCE was a landmark trial in diabetes care, as it established the cardiovascular benefit of perindopril + indapamide in all persons with type-2 diabetes, irrespective of blood pressure status. The ADVANCE and ADVANCE ON trial reveal better effects on cardiac, as compared to the cerebrovascular, and on renal, as opposed to the retinal vasculature. This discordance is similar to that seen with ramipril, empagliflozin and liraglutide in their studies. In spite of this limitation, the results of ADVANCE and ADVANCE ON support the universal use of perindopril + indapamide, as a preventive and therapeutic strategy, in type-2 diabetes.

Based upon their data, a target blood pressure of approximately 144/80mm Hg appears safe in the long run. A perindopril+indapamide combination can be used in any type-2 diabetes person in conjunction with all commonly used cardiovascular drugs, including other

blood pressure lowering drugs, statins and anti-platelet drugs, irrespective of age, gender, history of hypertension / microvascular disease / macro vascular disease, or degree of glycemic control. Thus, ADVANCE supports the use of this combination as standard of care in not only hypertensive, but normotensive persons with type2 diabetes as well. It must be noted that the incidence of cough is much lower with perindopril as compared to other ACE inhibitor.

ADVANCE ON adds strength to this contention, as it proves the long term advantages of perindopril + indapamide on cardiovascular and renal outcomes, even after the extra initial blood pressure lowering effect as compared to placebo has been lost. However, the drugs should not be used along with other ACE inhibitors or thiazide diuretics. The robust results of these randomized controlled trials support the use of the active study drug, as opposed to angiotensin receptor blockers (ARBs) and other ACE inhibitors, which do not enjoy such evidencebased backing.

REFERENCES

1.

Patel A, ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. The Lancet 2007; 370:829-40.

2.

Zoungas S, De Galan BE, Ninomiya T, Grobbee D, Hamet P, Heller S, MacMahon S, Marre M, Neal B, Patel A, Woodward M. Combined effects of routine blood pressure lowering and intensive glucose control on macrovascular and microvascular outcomes in patients with type 2 diabetes new results from the ADVANCE trial. Diabetes Care 2009; 32:2068-74.

3.

Heller SR, ADVANCE Collaborative Group. A summary of the ADVANCE trial. Diabetes Care 2009; 32(suppl 2):S35761.

4.

Zoungas S, Chalmers J, Neal B, Billot L, Li Q, Hirakawa Y, Arima H, Monaghan H, Joshi R, Colagiuri S, Cooper ME. Follow-up of blood-pressure lowering and glucose control in type 2 diabetes. New England Journal of Medicine 2014; 371:1392-406.

5.

Brugts JJ, Arima H, Remme W, Bertrand M, Ferrari R, Fox K, DiNicolantonio J, MacMahon S, Chalmers J, Zijlstra F, Caliskan K. The incidence and clinical predictors of ACEinhibitor induced dry cough by perindopril in 27,492 patients with vascular disease. International Journal of Cardiology 2014; 176:718-23.

6.

DiNicolantonio JJ, Lavie CJ, O’Keefe JH. Not all angiotensin-converting enzyme inhibitors are equal: focus on ramipril and perindopril. Postgraduate medicine. 2013 Jul 1;125(4):154-68.

7.

Ferrari R, Rosano GM. Not just numbers, but years of science: Putting the ACE inhibitor—ARB meta-analyses into context. International Journal of Cardiology 2013; 166:2868.

Laughter is the Best Medicine

C H A P T E R

222

Anil Chaturvedi

Your body cannot heal without play.

Your mind cannot heal without laughter.

Your soul cannot heal without joy.

-- Catherine Rippenger Fenwick Laughter is the biological reaction of humans to moments or occasions of humor. It is an outward expression of amusement. Laughter is the behavioral response to humor.1 The American Association for Therapeutic Humor (AATH) defines therapeutic humor as: “any intervention that promotes health and wellness by stimulating a playful discovery, expression or appreciation of the absurdity or incongruity of life’s situations. This intervention may enhance health or be used as a complementary treatment of illness to facilitate healing or coping, whether physical, emotional, cognitive, social, or spiritual.”2 Gelotology (from the Greek root gelos (to laugh), is a term coined in 1964 by Dr. Edith Trager and Dr. W.F. Fry to describe the scientific study of laughter.3

FACTS AND FIGURES

•

On average, a child laughs 300 times a day while an adult laughs only 17 times a day.

•

The majority of men report that their laughter is a chuckle, and the majority of women report that theirs is a giggle.

•

Adults between the ages of 18 and 34 report laughing the most.

•

Most laughter does not come from listening to jokes; it comes from spending time with family and friends.

•

People tend to laugh more when in groups. People should surround themselves with others who laugh, because laughter is contagious.

•

Smiling is a mild, silent form of laughing.

•

Babies start to laugh at about four months of age.

THE MECHANISM

There are four potential mechanisms by which humor might influence physical health. First, physiological changes in the body may result from vigorous laughter, the results being relaxed muscles, improved respiration, enhanced circulation, increased production of endorphins, and decreased production of stress-related hormones.

Second, a positive emotional state may increase pain tolerance, enhance immunity, and undo cardiovascular

ill-effects. Third, using humor a moderating adverse effects of stress. Finally, humor may provide another indirect benefit to health by increasing one’s level of social support.

PSYCHOLOGICAL AND PHYSIOLOGICAL BENEFITS OF HUMOR

There are enumerable psychological and physiological benefits of humor.

Psychological benefits of humor 1.

Reduces anxiety

2.

Reduces tension

3.

Reduces stress

4.

Reduces depression

5.

Reduces loneliness

6.

Improves self-esteem

7.

Restores hope and energy

8.

Provides a sense of empowerment and control

Physiological benefits of laughter 1.

Improves mental functioning

2.

Exercises and relaxes muscles

3.

Improves respiration

4.

Stimulates circulation

5.

Decreases stress hormones

6.

Increases immune system defenses

7.

Increases production of endorphins

THE HEALTH BENEFITS OF HUMOR AND LAUGHTER

Humor used therapeutically can enhance a patient’s well-being. Norman Cousins, a patient diagnosed with ankylosing spondylitis in 1964, was the first to formally study how it affects the quality of life. He developed his own therapy program including humor to treat himself when suffering with pain. He discovered a cumulative decrease in his inflammation. Further, he found he could enjoy two hours of pain-free sleep after ten minutes of sustained laughter. After his recovery, Cousins joined the staff at UCLA Medical School to establish a Humor Research Task force to purse clinical research on humor.4

The following are some of the researched benefits of laughter •

Blood Pressure – People, who laugh heartily, on a regular basis, have a lower standing blood pressure

BEYOND MEDICINE

Maryland Medical Center. The study, which is the first to indicate that laughter may help prevent heart disease, found that people with heart disease were 40 percent less likely to laugh in a variety of situations compared to people of the same age without heart disease.9

than does the average person. When people have a good laugh, initially the blood pressure increases, but then it decreases to levels below normal.5

1020

•

Hormones – Laughter reduces at least four of the neuro-endocrine hormones associated with stress.

These are epinephrine, cortisol, dopamine, and growth hormone.

•

Immune System – Clinical studies by Lee Berk at Loma Linda University have shown that laughter strengthens the immune system by increasing infection-fighting antibodies.6

•

Muscle Relaxation – Belly laughs result in muscle relaxation. While you laugh, the muscles that do not participate in the belly laugh relax. After you finish laughing, those muscles involved in the laughter start to relax. Therefore, the action takes place in two stages.7

•

Pain Reduction – Laughter allows a person to “forget” about pains such as those associated with aches, arthritis, etc. In 1987, Texas Tech psychologist Rosemary Cogan used the discomfort of a pressure cuff to test the medical benefits of laughter on pain management. Subjects who watched a 20-minute Lily Tomlin routine could tolerate a tighter cuff than those who had watched an informational tape or no tape at all.8

•

•

•

Brain Function – Laughter stimulates both sides of the brain to enhance learning. It eases muscle tension and psychological stress, which keeps the brain alert and allows people to retain more information.

Respiration – Frequent belly laughter empties your lungs of more air than it takes in, resulting in a cleansing effect – similar to deep-breathing. This deep breathing sends more oxygen-enriched blood and nutrients throughout the body.

The Heart – Laughter, along with an active sense of humor, may help protect you against a heart attack, according to a study at the University of

HUMOR AND THE HEALTH PROFESSIONAL

There is immense value of humor for health care professionals. Humor helps doctors and nurses deal with the stress of caring for patients who are in pain. It also fosters good working relationships among colleagues and improves morale. Having a positive attitude at work can extend to colleagues and support staff, and health care workers who greet colleagues with a smile usually get one in return. One must not forget that smile is the shortest distance between the two people. By blending with humor and laughter we can bring health, happiness and harmony within ourselves and our patients.10

REFERENCES

1.

Howard J. Bennett, MD Southern Medical Journal 2003; 96:12.

2.

Fry, W. The biology of humor. International Journaol of Humor 1994; 111-126.

3.

Kuhn C. Stages of Laughter. Journal of Nursing Jocularity 1994; 4:34-35.

4. Cousins N. Anatomy of an illness (as perceived by the patient). N Engl J Med 1976; 1458-1463.

5.

Martin, R. Is Laughter the best medicine? Humor, laughter, and physical health. Current Directions in Psychological Science 2002; 11:217-219.

6.

Martin, R. Sense of Humor and physical health: Theoretical issue, recent findings and future directions. Humor: international Journal of Humor Research 2004; 17:1-19.

7.

Buxman K, LeMoine A, editors. Nursing perspectives on humor. Staten Island (NY): Power Publications; 1995.

8.

Wooten P. Humor: an antidote for stress. Holist Nurs Pract 1996; 10:49-56.

9.

Robinson VM. Humor and the Health Professions.

Thorofare, NJSlack, Inc., 1991, ed 2.

10. Chaturvedi A. Laughter the Best Medicine. Clinical Medicine Update 2015; 607-611.

C H A P T E R

223

Medicine is a Serious Business?

Arulrhaj, Aarathy Kannan, Ajinkya Borhade, Sachin Babhalsure

ABSTRACT

Practice of medicine is viewed by young doctors as stressful and even dangerous. This perspective has resulted in the younger generation shying away from independent medical practice. The current ambience of consumer litigation, criminal prosecution and violence on doctors has not helped either. The soul of the medical profession was violated when the Hon Supreme Court retitled the patient as a consumer. A score of ambulance lawyers and defensive medical practices were the gain to the society.

The law makers and the judiciary have chosen to characterise healthcare as an industry thus relegating the profession to a secondary role. The trade unions conjured to de enforce a parliamentary decision to nullify a Supreme Court verdict calling health care an industry.

The current impasse is an inevitable gravitation directly traceable to mindless legislation flowing out of such layman’s perspective.

The identity crisis of medical profession is complete as to whether it is still a profession as the fraternity claims or is it a trade or industry as the courts and governments insist.

This dichotomy is the reason for the doctors and hospitals being taxed and regulated as an industry while the public expectations hover around services rendered in a highly ethical and professional manner. The resultant stress on the system is squarely borne by the medical fraternity.

HEALTHCARE SHOULD NEVER BE TARGETED AS INDUSTRY

Then Industrial ethics will preveal which is dangerous to Public Healthy Life.

Let all the stake holders of health come together, restore the nobility of the profession & make medicine as a worshipful often wanted profession.

INTRODUCTION

Medicine is a noble profession. But today viewed as a serious business by doctors & Youth. Why this seriousness? Why this Traders culture & consumerism?

What is the role of doctor, public, media & government in restoring the nobility of the profession. Let us analyze the above iteneries & arrive at the way forward.

WHY SERIOUS ?

Serious is defined as having an important and dangerous outcome and needing lot of attention and energy. Medicine is a career one is expected to make zero mistakes, the toll of which is borne by the poor doctor. One of the sociology professor in Delhi comments, “a doctor will always find

the sword of Damocles hanging over his neck”. When Death knocks at the door the Doctor is looked upon as a God. When he accepts the challenge he is looked upon as an Angel. When he cures the patient he is looked upon as a common man. When he asks for his fee he is looked upon as a devil.

The fear one feels as a doctor should be because of missing a differential diagnosis, not that one will be beaten up if the patients’ condition worsens. Assault on doctors and hospitals is on increase. Death, treatment failure and perceived high treatment cost evoke violence. Doctors and hospital staff are beaten up and even murdered1.

Hospitals are smashed violently. No wonder practice of medicine has moved over to a serious high risk category.

BUSINESS ?

Business is defined as enterprise, agency or entity involved in provision of goods or services to customers. Modern world has approached health care as an industry and a high voltage business. The phenomenon of doctors establishing small hospitals typically called nursing homes is unique to South Asia and South east Asia. Most of them provide primary and scondary care. They provide scientific care at affordable cost with the homely ambience of the family doctor. Technology and laboratory are used appropriately and minimally. The art of clinical medicine sustains them.

The bludgeoning Tertiary care hospitals provide cutting edge technology and run on evidence based medicine.

The art of clinical medicine is disappearing throughout the world. Evidence based medicine is in the forefront for doctors & society. Needless to say these tertiary care hospitals are for profit institutions and are accountable to their share holders. Without the corporate investment the type of tehcnology made available for patient care would be non existent. The expanding frontiers of modern medicine would grind to a halt. It will be unrealistic to expect these hospitals not to take a business approach.

The idea of patient as a commodity is complete. The dilemma of the medical profession begins here. Where does the profession end and industry start? Where is the boundary where the medical profession’s ethics ends and business ethics begins ?

THE VERSION FROM DOCTORS (FIGURE 1)

The contract between a doctor and a patient isn’t that the doctor promises to cure the patient of the ailment, but that (s)he will do her/his utmost best for the patient, to diagnose the problem, and chart out a treatment line best suited for the patient; “curing” rarely, more often despensing “care”

profession in India unless you are really passionate about it and you are ready to face up the challanges that you will face as you progress through the profession”.

1022

On the whole the whole profession is under siege.

Something drastic needs to be done to revive the confidence and body language of the profession.

WHAT THE YOUNG ASPIRANTS SAY?

“When I joined MBBS I thought of saving many lives.

Now I think of saving only one life, that is my life”.

BEYOND MEDICINE

Ref: An anonymous Indian Doctor Medical profession is labeled as business that to serious life endangering business. Why venture into it? Doctors Feel.

Who are all the stake holders of health?

Government, MCI, Media, Politicians, Public & Physicians

THE VIEW FROM OTHER STAKE HOLDERS OF HEALTH

Fig. 1: Self assessment of doctor: A thought process and doing his best to teach and facilitate the patient to live with the incurable chronic diseases they have: diabetes, high blood pressure, COPD, cardiac illness, etc., What do doctors feel ?

•

Doctors and hospitals feel unsafe in todays’ atmosphere

•

Patient is viewed as a litigant and multiple forums have taken a toll.

•

Patients and bystanders either do not understand the illness, treatment, the cost involved or feign ignorance

•

Doctors are over worked and stressed out

•

Multiple laws on the profession and hospitals2

•

The expectations of the patients are often illogical and unrealistic

•

Moderate remuneration

By the end of this year, it is estimated that 300 physicians will commit sucide. While depression amongst physicians is not new, sheer unhappiness and work stress amongst physicians is on the rise3.

One doctor who is a successful cardiologist in one of the famous corporate hospitals confides, “ I would not do it again, and it has nothing to do with the money. I get too little respect from patients, physician colleagues, and administrators, despite good clinical judgment, hard work, and compassion for my patients. There are so many other ways I could have made my living and been more fulfilled. The sad part is we chose medicine because we thought it was worthwhile and noble.

One budding physician in a two tier town revealed, “ I would never really advise anyone to takeup this

Politicians do not respect doctors; neither do the media.

The public, thankfully, still trust and appreciate doctors, but that relationship is constantly put to test. The society feels doctors are arrogant, often superficial and live a life secluded from the mainstream society. A section of doctors availing forwarding commission from hospitals, scan centres and laboratories have not helped to bridge the trust gap.

“Almost everybody in the contry has been a victim of some form of graft or malpractice-be it inflated bills, wrong diagnosis or substandard treatment”, Down to earth, a science magazine, declared last year4.

The government feels doctors are extracting money from poor patients. They also feel doctors and hospitals are under regulated.

THE MISMATCH

The mismatch of the society and governement regulating hospitals as industry and trade but expecting value added services as a profession has done heavy damage.Thes dichotomy has to end.The strain borne by the profession can be traced to this dichotomy . Earlier this contradiction is settled, the better for the society and the profession.

FALL OUT

One of the direct fall out of this dichotomy is that small and medium hospitals especially run by doctors are disappearing at an alarming rate. Corporate hospitals and for profit hospitals are filling up this space. It will be a sad day when primary and secondary care would be provided by corporate giants. Small and medium private hospitals are a national asset5. They are holding the health care cost down.They provide quality service in local mileu and in a friendly ambience. They are eminently accessible. Losing them will create a frankenstein which does not serve the purpose.

DOCTOR IS THE TEAM LEADER

To change the current scenario doctors as the team leaders

Associations and organisations who have the responsibilty and duty towards their members to see that they get an environment conducive to the practice of ethical and clean medicine.

CONCLUSION

The whole relationship of the medical profession vs the society and medical profession verses healthcare industry should be renegotiated and redefined. So long as the patient is centre of all care, medical ethics should be the only defining parameter. All other dimensions should be reset. Medical ethics being a dynamic concept has to be revised and revitalised in space and time. Any industry or institution based on patient care should only follow medical ethics. This may have realtime implications on the hospitals. The services that require a business approach can be channelised through outsourcing. Another alternative would be to create a separate category of hospitals for the ones which are actually an extended practice. They can be called ‘ professional hospitals ‘. Therefore profit hospitals can be defined as the “health care industry”.

Probably primary and secondary care hospitals will fit into professional hospitals. Tertiary care to healthcare industry.

One of the key privileges to be conceded to doctors is exemption from criminal prosecution. Profession based

hospitals should be provided financial and non financial 1023 incentives. There certainly is a strong case for national dislogue on the status of doctors,hospitals and healthcare industry. Afterall we are a nation in making. We should develop an unique model incorporating our strengths.

“By any standards that one may adopt, medicine is and ought to be a profession and not a mere career or just an income earning activity. This can be no different even when the professional activity becomes more and more organized and assumes larger dimensions. The dividing line between professions and mere careers is getting blurred increasingly, we do hence find laws and regulations increasingly entering into zones which were left to the sound discretion of the professionals in yesteryears. Ethical professional standards and not the mere stipulations of law must provide the beacon light for any conscientious professional”. Justice R Basant.

Medicine is always a noble profession. Medicine profession is a knowledge profession. Healthcare industry is a business. Understanding and implementing this concept will make medicine a loving profession for all the stakeholders.

REFERENCES

1.

Assaults on doctors Article in British journal 1(6127):1621-2 · July 1978 DOI: bmj.1.6127.1621-c ·

medical 10.1136/

2.

Ethical and legal issues in medical practice. Indian J Urol 2009; 25:335–336.doi: 10.4103/0970-1591.56191.

3.

Hyposkillia, Deficiency of Clinical Skills Herbert L. Fred, MD Professor, Department of Internal Medicine, The University of Texas Health Science, Center at Houston.

4.

2004Trust in the Medical Profession: Conceptual and Measurement Issues Article in Health Services Research 37(5):141939 · November 2002 DOI: 10.1111/14756773.01070.

5.

Bureau of Economics and statistics, Government of Kerala, Report on Private Medical Institutions in Kerala for the years 1986, 1995, 2004.

CHAPTER 223

have to take the initiative. Doctors should be competent, communicative, compassionate and offer scientific medical care. Public should understand that cure is not always possible and have to learn to accept death.They have to budget for health and understand that medical treatment shall incur a certain level of expenses.The press and media should bridge the gap between doctors and society and notwiden it. Healthcare must be regulated through a single window with soft laws. Healthcare should get promotional incentives like education in the form of soft loan, low taxes, incentive for rural postioning etc.

C H A P T E R

224

Saga of Man, Microbiome and P4 Bedside Medicine

1958 : Nobel Prize for Medicine and Physiology was awarded to 32 year old Microbiologist, Joshua Lederberg, USA. His ideas enunciated later are hot topics today.

‘Microbiome’, then emerged in a collaborative humanmirobiome “superorganism” study launched by National Institutes of Health, USA and European MetaHit consortium. What is Microbiome? Lederberg proposed that it was the sum total of all microbes (commensals and pathogenic) residing in human body mostly the gut, outnumbering 100 trillion, weighing approximately 2 Kg. Till recently they were regarded as essentially hostile to human hosts, thought to be perennial enemies, inviting “rampant” antibiotics. Our understanding has undergone a sea-change as we now know human genome contains 30,000 coding proteins-genes. This composite of microbial genome is 100 times larger. Together with 100 trillion microbes, their composite genes and our 30,000 constitute Metagenome. This emerging science has transformed our notions as we now begin to understand this “ecosystem”

Prakash Pispati

within us that profoundly influences our health vis-à-vis disease.

Add to it, dynamic environmental factors and we will appreciate how microbiome can determine predisposition, manifestations of veritable diseases and consequently our treatment strategies.

CAUSE - EFFECT PHENOMENA

To prove, Koch’s postulates must be convincingly addressed. A major stumbling block was inability to culture approximately 80% of all bacteria in our microbiome. However, DNA sequencing technology has revolutionized studies in Molecular Biology.

Simultaneously, advances in Computational Biology along with Bioformatic tools have enabled us decipher the complexity of such microbial host-environmental interaction within us. (Figure 1)

CLASSIC EXAMPLE: HLA B27 PREDISPOSITION TO ANKYLOSING SPONDYLITIS (AS)

The association of HLA B27 gene and AS is far too well known. In Caucasians the gene is present in about 95%, in Asians about 70 – 75% of AS patients. The organisms most commonly implicated are gram negative, bacilli, eg.. Klebsiella, Shigella, Salmonella. Near identical mirror image cell surface antigenic structures of these bacilli and HLA B27 gene is a fine example of molecular mimicry.

This can incite and signal to activate Th and TREGG pathways of the immune system complex signaling, inducing remote sacroiliitis as in AS, or reactive arthritis in HLA B27 patients (Figure 2).

Some subsets of HLA B27 are known to be predisposed to AS eg.27:02, 27:04, 27:05 and other subsets protect the host against AS eg. 27:06, 27:09. The Africans seem protected against AS, the Caucasians seem vulnerable.

TARGETED AND TAILORED P4 MEDICINE

Fig. 1: Diagrammatic representation of microbes - rheumatoid arthritis link

Now many hospitals in India offer genetic profiling in an attempt to predict later disease manifestations. So far our thrust is to diagnose diseases and treat as per their organ involvement. eg. Angioplasty and CABS for episodes of myocardial infarction. About 90% of our investment in medical research and treatments seems towards attacking fully manifested diseases rather as they unfold, or predicted even before. Evidence Based Medicine (EBM) relies on data collection through a variety of studies localized or multicentric in specific, well defined disease subsets of patients with elaborate criteria of inclusion and exclusion. Conclusions if any are then extrapolated

1025

CHAPTER 224

Fig. 2: AS HLA B27 positive patient with marked bilateral sacroiliitis and hip joint narrowing.

Fig. 3: Genetic, epigenetic, environmental predisposition to disease into general recommendations presented commonly as ‘guidelines’, or algorithms. Such presumptions and premises are expected to be valid for any patient anywhere by the attending doctor who follows such guidelines to write standardized prescription, that is how most of us are prone to practice medicine daily … through generalized treatment regimes naturally with highly variable treatment outcome.

A distinguished Immunologist Professor Leroy Hood, who won the prestigious Lasker Award in the U.S. and many more the world over, propagated the concept of P4 Medicine. He advocates that medicine should be Predictive, Preventive, Participative and Personalized. He further writes that new technologies available for studies in microbiome, genetics, metabolomics (metabolic end product of host microbe interaction) and meta-genomics can help predict diseases to come and install strategies to prevent. (Figure 3). He forecasts arrival of ‘Wellness Clinics’ with a thrust on preventive and a holistic approach to individuals with targeted and tailor-made treatments.

He believes that this will result in not only high strike rates of treatment outcome but also heavy reduction in treatment budgets minimizing need of high-end, high cost procedures such as organ transplants, bypass or even joint replacement surgeries.

P4 MEDICINE FOR THE MASSES

Computational Biology centres with high capability to collate mass data, dissect and analyze mathematically into reproducible observations, treatment outcome is on the anvil. An individual patient and / or his physician can log in symptoms / signs, investigated reports into a Computational Biology centre to generate and transmit prescriptions. Already 15% of Rheumatoid Arthritis patients in the U.S. have gone a step further and asked for prescribed drug delivery at their doorstep online… sparking a debate on the merits and inherent risks.

MEDICINE AND THE TELECOM REVOLUTION

Taking microbiome, meta-genomics and P4 medicine to the masses allow democratization of Medicine perhaps akin to ‘Obamacare’… via mini gadgets such as smart phones. I have had some patients even from remote villages showing before and after pictures of diseases they or their folks suffer from on their cell-phones. Are not laboratory reports shown to us on ‘WhatsApp’? Don’t increasing number of patients located elsewhere expect “cellular” treatment advice ?

Isn’t telemedicine eroding and cutting down clinic visits of patients? Aren’t ‘Dr. Apple’ and Dr. Google (Figure 4).

Surely for surgical patients this is inevitable despite robotic surgery. As for physicians we have got to adopt, adapt, be adept and accept these new turns and twists of science if we insist that patients must visit us at our clinics …. in their interest … and ours.

1026

A MISSING GAP

BEYOND MEDICINE

Today, such new technologies are invented by a new generation of scientists in their laboratories of physics, mathematics, engineering, bioengineering and computer sciences. Are they alive to the needs of our patients? Are we in a position to open a dialogue with them at the start and not at finish? When will our medical conferences, our textbooks and medical curricula incorporate courses of these nascent sciences heavily influencing our ways of medicine and life ? Are we ready for this brave new world of relentless march of science ? Will we be swept off our feet or ride the change?

Fig. 4: Doctor Apple & Google

REFERENCES

1.

‘Dr. Google’ taking charge of some of our medical practices? Isn’t the traditional Holy Grail.

Scher JU. Abramson SB. The Microbiome. The Rheumatologist 2011; 5:31-35

2.

Doctor-patient relationship in peril?

Ermann J. Landmarks & Advances in Understanding HLA-B27. The Rheumatologist 2016; 7:11-15

3.

Cruz-Tapias P. Castiblanco J. Anaya JM. HLA Association with Autoimmune Diseases In. Anaya JM, Shoenfeld Y, Rijas-Villarraga A, Levy RA, Cervera R. Ed. Autoimmunity from Bench to Bedside. Bogota: Crea, 2013 : 271-28

4.

Hood Leroy. Brogaard K. Price ND. A vision for 21st Century Healthcare. Bastjr RC. Hong WK, Kufe DW et al In: 9th edition, John Wiley & Co., London K and Hoboken USA. 1-10.

5.

Alvin T. Future Shock. New York, N.Y. : Random House Inc: 1970

6.

Aldous Huxley. Brave New World. New York. : Harper and Brothers 1960

This relentless march of technology is impacting our patients and us doctors every day. This surely facilitates our daily work. eg. scanned reports are transmitted right away on our gadgets from imaging centres. That’s good for us; but what when patients expect our prescriptions and advice to be sent on their tools or download direct from internet without having to visit us? Don’t we see abuse, misuse, falsehoods and serious errors in medical practice by gullible patients, as we lose our authority to treat our patients ourselves? Is there still room for patients to visit us for that healing touch? In the era of driverless taxis are ‘doctorless’ clinics in the offing?

C H A P T E R

225

Nuclear Medicine as a Problem Solver in Diagnosis and Therapy

Nuclear medicine is the modality which uses radioisotopes to study the function of different organs of the body.

Radiolabeled compounds which can trace metabolic pathways, enzyme functions, receptors, perfusion etc. are injected into the body and with the help of special equipment called gamma cameras the passage of tracer in the body is imaged. Important information about normal and altered physiological functions in health and disease are obtained with this technique. 2 technologies; SPECT or Single Photon Emission Computed Tomography, nowadays combined with a CT scanner (SPECT-CT) and PET-CT or Positron Emission Tomography combined with CT are routinely available. PET-CT uses very short lived isotopes of 11C, 13N, 14O,18F produced in a cyclotron and labelled with various compounds to give quantitative information about body processes. Combination of physiological information and anatomical structural information make SPECT-CT and PET-CT very powerful tools in diagnosis and management of various diseases.

Nuclear scans, both SPECT and PET-CT are invaluable in management of several diseases and many times act as problem solvers in difficult diagnostic situations. Nuclear medicine is also increasingly used in the therapeutic arena, with successful therapies with radioisotopes available for many diseases.

Vikram R Lele

uptake in the salivary glands, conforming diagnosis of Graves’ disease (Figure 2).

In 10% of cases of thyrotoxicosis, what clinically appears as Graves’ disease may turn out to be thyroiditis. A thyroid scan is very valuable in making the correct diagnosis and planning therapy.

Case 3

77 yr. old male patient presented with slowness in movement and imbalance since 2 months. Parkinsonism was suspected and a TRODAT scan was asked for (Figure 3). 99mTc-TRODAT scan showed normal uptake of tracer in both caudate nuclei and both putamen excluding Parkinson’s disease. In Parkinson’s disease there is deficiency of Dopamine in the dopaminergic neurons projecting to the caudate nuclei and putamina. There is also deficiency of the presynaptic dopamine transporter (imaged by TRODAT scan). This scan shows asymmetrical reduction in dopamine transporter in the putamen opposite to the involved limb with tremor or rigidity in Parkinson’s disease and will be normal in essential tremor and drug induced parkinsonism.

Case 4

Specific examples of clinical situations helped by Nuclear medicine are also discussed later.

50 yr. old male on antipsychotic medication demonstrated clinical features of parkinsonism. The clinical question was whether he had Parkinson’s disease or was manifesting drug effects. A TRODAT scan was asked for which clearly showed deficient uptake in the left putamen, confirming dopaminergic deficit and excluding diagnosis of drug induced parkinsonism (Figure 4).

CASE EXAMPLES

Case 5

Tables 1, 2 & 3 summarize the diagnostic utilities of SPECT, PET-CT and Therapy respectively.

Case 1

21 yr. old male presented with history of palpitations and weight loss. T3, T4 raised. TSH low. An isotope thyroid scan was asked for to confirm Graves’ disease.

Isotope scan showing absent tracer uptake in the thyroid gland with normal uptake in the salivary glands. Diagnosis of Graves’ disease was excluded and Thyroiditis was diagnosed, changing the management completely (Figure 1).

Case 2

A 35 yr. old female presented with history of irritability, nervousness, weight loss and reduced appetite. T3, T4 elevated, low TSH. Isotope scan was advised: Isotope scan with 99mTc-pertechnetate scan showing increased intense uptake in the Thyroid gland with no

22 yr. old male presented with cough and weight loss.

X-ray chest showed lung lesions. A PET-CT was asked for. It showed extensive lung metastases and abdominal lymph nodal metastases. A careful review of images showed a small testicular lesion which was picking up the isotope (Figure 5). A diagnosis of testicular cancer with lung and nodal metastases was made, confirmed on orchiectomy. On chemotherapy there was good response with disappearance of all metastatic lesions.

This case demonstrates the utility of FDG PET-CT in detection of occult malignancy, staging of malignancy and demonstrating response to treatment.

Transaxial (left and middle column) and MIP (right column) images of whole body PET-CT with 18F-FDG. Upper row shows fused PET-CT images, lower row CT images.

1028

Table 1: Utility of SPECT, SPECT-CT Radiopharmaceutical

Clinical situation

Information obtained

Nervous system Tc-ECD

99m

Tc-TRODAT

BEYOND MEDICINE

99m

Memory loss

Presence of Alzheimer’s disease vs Fronto temporal degeneration

Temporal lobe epilepsy

Localization of seizure focus

Parkinsonism

Diagnosis of dopaminergic deficit. Differentiate Parkinson’s disease from essential tremor and drug induced Parkinsonism

Thyroid and parathyroid Tc-pertechnetate

Thyrotoxicosis

Differentiate between Graves’ disease and thyroiditis.

Diagnose autonomous toxic nodule

Tc-MIBI

Hyperparathyroidism

Localize parathyroid adenoma

99m

99m

Heart Tc-Tetrofosmin/MIBI Ischemic heart disease

99m

Diagnose myocardial ischemia, extent and severity Physiological significance of angiographic coronary stenosis Gatekeeper function to decide medical management vs intervention (angioplasty/bypass surgery)

Lung Tc-MAA

99m

Pulmonary embolism

Exclude pulmonary embolism in dyspneic patient

Gastrointestinal system Tc-Sulfur colloid

99m

Tc-labelled RBCs

99m

Gastroparesis

Measurement of gastric emptying times in patients with bloated sensation, diabetics

Gastro esophageal reflux (GER)

Document presence of GER

Occult GI bleeding

Identify site of gastrointestinal bleeding

And response to therapy

Kidneys Tc-EC/DTPA/DMSA

99m

Hydronephrosis/hydroureter

Diagnose /exclude obstructive uropathy

Renal failure

Document accurate GFR Renal donor evaluation

Transplant

Diagnose Acute tubular necrosis, rejection, urinoma, lymphocele

Urinary infection

Diagnose cortical scarring

Hypertension

Diagnose physiologically significant renal artery stenosis

Musculoskeletal system Tc-MDP

99m

Bone pain

Diagnose stress fracture, metastases, metabolic bone disease, osteomyelitis

Joint pains

Diagnose joint inflammation

Lymphatic system Tc-sulfur colloid

99m

Lymphedema

Confirm lymphatic obstruction as cause for limb edema

Sentinel node in breast cancer Identify sentinel node in stage 1 breast cancer Hepatobiliary system Tc-Mebrofenin

99m

Upper abdominal pain

Gall bladder ejection fraction, sphincter of oddi dysfunction, acute cholecystitis, biliary atresia Document predicted

Future remnant liver function remnant liver function in planned hepatic resections for tumors and transplants

1029

Table 2: Utility of PET-CT Radiopharmaceutical

Clinical situation

Information obtained

Oncology Occult malignancy

Detect occult cancer

F-FLT

Staging of cancer

Map out extent of cancer

F-FET

Detection of recurrence

Detect relapse/recurrence

Response to therapy

PERCIST criteria for metabolic response to chemotherapy

Recurrence vs necrosis/edema

Differentiate recurrence from response to therapy

Neuroendocrine tumors

Gold standard scan for diagnosing neuroendocrine tumors (carcinoids, pheochromocytomas, insulinomas, gastrinomas etc.)

18 18

Ga-DOTATATE

68

Response to therapy, recurrence Ga-PSMA

68

Prostate cancer

Diagnosis of prostate cancer in patients with elevated PSA Staging of prostate cancer Detection of recurrence Response to therapy

Neurology F-FDG

18

Dementia

Differentiate Alzheimer’s disease from other dementias Parkinson’s plus syndromes (Progressive Supranuclear Palsy, Multi System Atrophy, Cortico Basal Degeneration)

F-FET (Fluoro Ethyl Tyrosine)

18

Paraneoplastic syndromes

Detection of occult malignancy as cause of paraneoplastic syndromes

Tumors

Detection of recurrence of brain tumors after therapy

Cardiology N-Ammonia

13

Ischemic heart disease

Absolute myocardial flow quantification

Rubidium

82

F-FDG

18

Coronary flow reserve estimation Myocardial viability

Detecting viable myocardium in patients with low LEVF post myocardial infarction

Myocardial sarcoidosis

Detection of active myocardial sarcoidosis

Fever of Unknown Origin F-FDG

18

Investigation of choice in prolonged fevers

There are extensive metastatic lesions in the lungs along with metastatic abdominal lymphadenopathy. A small focus of neoplasm is seen in the right testicle.

Pre and post orchiectomy and chemotherapy MIP images showing complete resolution of metastatic disease indicating successful therapy (Figure 6).

Case 6

A 55 yr. old male with hypertension, dyslipidemia and

Focus of occult infection, infection or neoplasm

strong family history of ischemic heart disease suffered myocardial infarct in January 2011. He underwent coronary bypass surgery post infarction with arterial revascularization (LIMA to LAD, radial to OM-PDA). He presented in a year post bypass with angina and dyspnea.

A myocardial perfusion scan with 99mTc-Tetrofosmin was performed (Figure 7).

Myocardial perfusion images in short axis (upper 4 rows from apex to base of heart. Upper row: stress images,

CHAPTER 225

F-FDG

18

1030

Table 3: Utility in therapy Radiopharmaceutical

BEYOND MEDICINE

131

Iodine

Clinical situation

Utility

Thyrotoxicosis (Graves’ disease, Autonomous Functioning Toxic Nodule)

Effective ablation of toxic thyroid gland. High cure rate

Thyroid cancer

Post thyroidectomy remnant ablation, metastatic disease ablation

177

Lu- DOTATATE

Metastatic neuroendocrine cancer

Effective arrest or regression of disease in 80% of patients

177

Lu-PSMA

Metastatic prostate cancer

Powerful potential therapy in castrate and chemotherapy resistant metastatic disease

153

Samarium, 89Strontium

Painful skeletal metastases

Effective, lasting relief of metastatic bone pain

90

Yttrium-theraspheres/sirspheres

Metastatic hepatic disease

Effective reduction in tumor burden in hepatic metastases

Iodine-Lipiodol, 188Rhenium Lipiodol

Metastatic hepatic disease

Effective reduction in tumor burden in hepatic metastases

Painful joints

Effective radio synovectomy with pain relief

131

Yttrium,188Rhenium,169Erbium, Holmium

90

166

Fig. 1

Fig. 3

Fig. 4 Fig. 2

following row: rest images.), row 5,6 vertical long axis slices from septum (left) to lateral wall (right) (row 5 post stress, row 6, resting) row 7,8 horizontal long axis slices from inferior wall to anterior wall.

1031

CHAPTER 225

Fig. 5

DIAGNOSIS

Fig. 7 Myocardial perfusion imaging is vital to 1) diagnose myocardial ischemia 2) document extent and severity of ischemia, 3) to risk stratify patients into those who should be managed medically (low to intermediate risk scan pattern) and those who should undergo interventional revascularization (high risk scan pattern).

In conclusion, Nuclear medicine is an invaluable tool in diagnosis and management of several conditions enumerated in the above tables and illustrative cases.

Fig. 6 Images show significant global hypoperfusion on stress images, with stress induced left ventricular dilatation and right ventricular uptake, with complete normalization on resting images. These findings indicate a “high risk scan� pattern. Angiography was advised which showed left main ostial stenosis and a right coronary artery ostial stenosis with graft occlusion.

REFERENCES

1.

R.D. Lele: Principles and Practice of Nuclear Medicine, 3rd edition, 2010 Arnold Heinemann.

2.

Mettler and Guiberteau, Essentials of Nuclear Medicine Imaging, 6th edition, 2012, W.B. Saunders.

3.

R. Wahl, Principles and Practice of PET and PET-CT, 2nd edition, 2008, Wolters Kluwer.

C H A P T E R

226

Does Modern Medicine Increase Life-expectancy: Quest for the Moon Rabbit?

Sundeep Mishra

“What is the goal of medical treatment: Is it alleviating discomfort or lengthening lives?”

ABSTRACT

The search for elixir of immortality has yielded mixed results. While some of the interventions like PCI and CABG have been a huge disappointment at least as far as prolongation of life is concerned: their absolute benefit is meager and that too in very sick patients. Cardiac specific drugs like statins and aspirin have fared slightly better, being useful in patients with manifest CAD, particularly in sicker populations although even their usefulness in primary prevention is rather low. The only strategies of proven benefit in primary/primordial prevention are pursuing a healthy life-style and its modification when appropriate: like cessation of smoking, weight reduction, increasing physical activity, eating a healthy diet and bringing blood pressure, serum cholesterol and blood glucose under control.

INTRODUCTION

Mortality has tormented human consciousness since time immemorial and humankind has perpetually searched for a therapy that extends life, the so called Philosopher’s Stone. In this quest the human race has been only partially successful; the life expectancy has certainly increased but only upto a certain point. “Nobody has yet achieved even modest life extension beyond the apparent upper limit of about 120 years.” Thus along this road there have been some successes but mostly disappointments. Typically, when a “new therapy” is introduced there is a lot of hope but as its use increases, its side-effects also become apparent, which starts a whole new drive towards next generation of this therapy which is safer and more effective, but then even newer side-effects come up again and this cycle goes on and on; something like “Carrot and the Horse.” Further, the effects of a new therapy are more remarkable when disease has already occurred (secondary prevention) and already reduced life expectancy as a result of this disease; the more severe / serious the disease, the greater possible benefit of the therapy. However, although effective therapy may reduce the mortality arising of this disease but practically never brings it back to normal, “the Zenos’s Paradox.” Recently, advanced technology has provided us with two highest-profile treatments for coronary artery disease (CAD): coronary artery bypass grafting (CABG) and percutaneous coronary interventions (PCI). Each intervention in itself promised

a lifesaving relief and consequently was embraced enthusiastically by physicians and even lay public. Both these techniques indeed often provide rapid, dramatic reduction of the alarming pain associated with angina.

Yet, when it comes to prolonging life, their track-record is near dismal providing little or no improvement in survival rates over standard medical and lifestyle therapies except in the sickest of the patients. Further, these procedures are also associated with significant side-effects. “Doctors generate better knowledge of efficacy than of risk, and this skews decision making,” says David Jones Ackerman professor of the culture of medicine.1 But why blame only physicians, even “patients are wildly enthusiastic about these treatments,” he says. “There’ve been focus groups with prospective patients who have stunningly exaggerated expectations of efficacy. Some believed that angioplasty would extend their life expectancy by 10 years! Angioplasty can save the lives of heart-attack patients. But for patients with stable coronary disease, who comprise a large share of angioplasty patients? It has not been shown to extend life expectancy by a day, let alone 10 years—and it’s done a million times a year in this country.”

So are any interventions at all which can increase the expectancy of life particularly in context of cardiovascular conditions?

HISTORY OF INCREASE IN LIFE-EXPECTANCY

Worldwide life-expectancy at birth was 30.9 years in 1900, 46.7 in 1940, 61.13 in 1980.2 As seen there was a dramatic improvement in life-expectancy after 1940 which could be attributed to three factors: 1.

A wave of global drug and chemical innovations; penicillin, streptomycin, vaccines, discovery of DDT etc.

2.

Spread and availability of medical and public health technology to all, including poorer countries.

3.

Change in international status (value) of health which practically became a “right,” upgraded from mere “desirable.”

While early improvement in life-expectancy was a result in control of infectious diseases, subsequent improvement occurred as a consequence of focus on life-style diseases.

From 1991 to 2004 life-expectancy in US improved by 2.33 years mostly by medical innovation (discovery and

availability of new drugs) but also addressing problems like smoking and obesity. 3 In context of CVS diseases mortality from heart disease in the US fell by more than half between 1950 and 1995, with a resultant increase in life expectancy of approximately 3½ years, half to twothirds of which has been attributed to coronary care units, treatment of hypertension, and medical and surgical treatment of coronary artery disease. 4, 5

APPROACHES TO IMPROVING LIFE EXPECTANCY

Improvement of life-expectancy with any maneuver essentially depends on;

Duration for which intervention is applied – age of the patient

PRIMORDIAL PREVENTION – HEALTHY INDIVIDUAL

Caloric restriction

Caloric restriction is the only consistently reproducible experimental means of extending mean and maximum lifespan. Laboratory experiments show markedly decreased morbidity in laboratory mammals that are fed to only 80% full.6 Indirect human proof comes from Okinawa, a region in Japan which boasts one of the longest life expectancies for its population in the world as also having a significantly large population of centenarians (living within the region) despite being one of the poorest regions in the country (being the bottom ranked in socioeconomic indicators for Japan). This is attributed to diet, high levels of physical activity, and strong cultural values that include good stress-coping abilities. Among the peculiarities of culture Okinawa culture embraces Hara Hachi Bu, which means to eat only until 80% full. 7 Further, studies on the oldest living natural population in the world, the Seventh Day Adventists living in California, support these findings. 8 Long-term human trials of CR are now being done. More recent work reveals that the effects long attributed to caloric restriction may be obtained by restriction of protein alone, and specifically of just the sulfur-containing amino acids cysteine and methionine.9,10

Increased Physical Activity

Undertaking regular exercise (jogging) increases the life expectancy of men by 6.2 years and women by 5.6 years, as per data from the Copenhagen City Heart study presented at the EuroPRevent2012 meeting. It showed that between one and two-and-a-half hours of jogging per week at a “slow or average” pace delivered optimal benefits for longevity. 11

Metformin

A study by Bannister and co-workers revealed that patients with type 2 diabetes mellitus (DM) initiated with metformin monotherapy not only had 38% better survival

Geroprotectors

Experimental proof of this class of drugs comes from rapamycin. It is an immune-modulator (also the drug in drug-eluting stent) which was found to lengthen the mices’ lives by up to 14 per cent. Likewise, everolimus was found to partially reverse the immune deterioration that normally occurs with age in a pilot trial in people over 65 years old. The drug acting by inhibiting a protein called mTOR (interestingly mTOR also seems to be affected by calorie restriction) improved participants’ immune response and is involved in sensing the level of nutrients available within cells, shifting cells into energyconserving mode, which has anti-ageing effects, including that on the immune system.13 In addition to rapamycin analogs, resveratrol, found in grapes, and pterostilbene, a bio-available substance, found in blueberries have also shown favorable response.14 Scientists estimate that these drugs could increase lifeexpectancy by 10 years.

Senolytics

Investigators from The Scripps Research Institute, Mayo Clinic and other institutions have identified a new class of drugs that in animal models dramatically slows the aging process, alleviating symptoms of frailty, improving cardiac function, and extending a healthy lifespan.

The 2 drugs are dasatimib (an anti-cancer drug) and quercetin (a natural compound found in many fruits, vegetables, leaves and grains), an antihistamine and antiinflammatory — can kill senescent cells. Senescent cells have stopped dividing and accumulate with age, are a non-productive burden on the total cell population, accelerating the aging process.15

Genome Sequencing

Geneticist Craig Venter announced he is pursuing a goal of extending and enhancing the healthy and high performance life-span by employing the power of human genomics, informatics, next-generation DNA sequencing technologies and stem cell advances.

Maintaining Ideal Cardiovascular Health

In the middle ages of human life-history, the major diseases limiting the life-expectancy are cerebro-vascular diseases and cancer. Thus it is not surprising that attempts to prevent the occurrence of CVS diseases (primordial prevention) would have an impact on increasing lifeexpectancy. The best way to do that seems to be to remain at a level of health which does not permit risk factors to appear (As defined by American Heart Association [AHA]). It has been suggested that community-based primordial prevention is capable of reducing cardiac deaths by 90% and prolonging life-expectancy by 10

CHAPTER 226

Severity of disease – Baseline mortality is the most important factor operative on lifespan-gain from any procedure. Diseases with a higher baseline annual mortality rate demonstrated more lifespan gained. Thus therapeutic maneuvers provide more survival benefit in secondary prevention than primary or primordial prevention.

than those with DM and treated with sulphonylurea (0.62, 1033 0.58–0.66), but unexpectedly survived 15% longer than even matched, non-diabetic controls (0.85, 95% CI 0.81– 0.90).This brings out an interesting prospect of metformin as first-line therapy and may imply that metformin may confer benefit in non-DM.12

1034

Table 1: Reduction of Life-expectancy with risk factor

BEYOND MEDICINE

Risk Factor

Reduction in LifeExpectancy (years)

Smoking

13.9

Obesity

4

Physically inactive in leisure time

3.6

High Blood Pressiure

2.4

Vegetable / Fruit intake <5 / day

1.3

years.16,17 It involves following health behavioral lifestyle characteristics:18 1.

Not smoking or quitting over 1 year ago.

2.

Table 2: Improvement in Life-expectancy with control of risk factor Risk Factor Reduction

Improvement in LifeExpectancy (years)

Male Smoking Cessation

2.3

DBP reduction ≤ 88 mm Hg

1.1-5.3

Total Cholesterol ≤ 200 mg/dl

0.5-4.2

Reduction of Weight

0.7-1.7

Female Smoking Cessation

2.8

A body mass index≤ 25 kg/m2.

DBP reduction ≤ 88 mm Hg

0.9-5.7

3.

Exercising at a moderate intensity ≥150 minutes (or 75 minutes at vigorous intensity) each week.

Total Cholesterol ≤ 200 mg/dl

0.4-6.3

4.

Eating a “healthy diet”: adhering to four to five important dietary components - sodium intake, 1.5 g/day; - sugar-sweetened beverage intake,36 oz weekly; - 4.5 cups of fruits and vegetables/day; - three 1 oz servings of fiber-rich whole grains/day; - two 3.5 oz servings of oily fish/week.

Reduction of Weight

0.5-1.1

5.

Maintaining total cholesterol ≤200 mg/dL.

6.

Keeping blood pressure≤ 120/80 mmHg.

7.

Maintaining fasting blood glucose ≤100 mg/dL.

PRIMARY PREVENTION OF CAD

Risk Factor Modifications

Mere presence of risk factors leads to reduction in lifeexpectancy (Table 1). Thus, logically correction of risk factors will be expected to lead to at least partial restoration of life-expectancy (Table 2). Measures used in primary prevention customarily include smoking cessation, diet modification, physical activity, weight management and correction of high blood pressure. Since the reduction of life-span is maximum with smoking, smoking cessation is likely to benefit most and it has been estimated that the risk attributable to smoking returns to baseline (nearly 14 year gain in life-expectancy) after 5 year of smoking cessation.19 Likewise a 10mm drop in systolic blood pressure may reduce cardiovascular mortality by upto 40%.20 Another study noted that on average, male smokers would gain 2.3 years from quitting smoking; males with hypertension would gain 1.1-5.3 years from reducing their diastolic blood pressure to 88 mm Hg; men with serum cholesterol levels exceeding 200 mg/dl would gain 0.5-4.2 years from lowering their serum cholesterol level to 200 mg/dl; and overweight men would gain an average of 0.7-1.7 years from achieving ideal body weight. Corresponding projected gains for at-risk women are 2.8 years from quitting smoking, 0.9-5.7 years from lowering blood pressure, 0.4-6.3 years from decreasing

serum cholesterol, and 0.5-1.1 years from losing weight.21 Eliminating coronary heart disease mortality is estimated to extend the average life expectancy of a 35-year-old man by 3.1 years and a 35-year-old woman by 3.3 years.22

Statins

Statins have been hailed by many as “wonder drugs”, with some physicians suggesting mass treatment of population. Dr John Reckless, chairman of Heart UK and a consultant endocrinologist at Bath University went as far as suggesting they should be added to the water supply.

Some advocate it being put in table salt like “Iodine.” The question is whether statins are really the wonder drugs they’ve been made out to be? Particularly in context of primary prevention (what to talk of primordial prevention) their role is controversial. While early trials predicted a modest reduction in mortality and a meta-analysis (14 randomised control trials{RCT}; 34,272 participants) demonstrated an all-cause mortality reduction of 16% (RR 0.84, 95% CI 0.73 to 0.96), the analysis was criticized because many of the trials included diabetics and patients with micro-albuminuria (now considered CAD equivalents) and so these trials were not purely of primary prevention. 21 On the other hand another meta-analysis of 11 RCTs involving 65 229 individuals completely free from CVD at baseline demonstrated that use of statins in this high-risk primary prevention setting was not associated with a statistically significant reduction (risk ratio, 0.91; 95% confidence interval, 0.83-1.01) in the risk of all-cause mortality.23 Likewise an NNT review for Statin Drugs Given for 5 Years for Heart Disease Prevention (Without Known Heart Disease) revealed that no life was saved consequent to their use.24

Aspirin

The role of aspirin (ASA) in primary prevention of CAD is also controversial. While use of ASA is definitely of use in prevention of CAD, the balance between vascular

Table 3: Risk-benefit analysis of ASA in primary prevention Primary Prevention

Harm (Number of patients in whom a major GI bleeding event is caused per 1000/year)

Men at lowto-high cardiovascular risk

1–3

1–2

Essential hypertension1

2

1–2

events avoided and major bleeds caused by aspirin is substantially uncertain. A recent meta-analysis shows that for individuals without pre-existing vascular disease, the reduction of cardiovascular events after adding longterm aspirin are likely to be of similar magnitude as the hazards Table 3.25,26

STABLE CAD

Statins

There’s little doubt that statins are effective in reducing mortality and heart attacks in patients with manifest CAD. Several large controlled trials including 4S, CARE, LIPID, HPS, TNT, MIRACL, PROV-IT and A to Z have shown relative risk reductions between 7% on the low end (in MIRACL) and 32% on the high end (in 4S), with an average relative risk reduction of about 20%. However, the sobering aspect is that absolute risk reductions are much more modest. They range from 0.8% in MIRACL on the low end to 9% in 4S on the high end, with an average of 3%. A meta-analysis of data from 90 056 participants in 14 randomized trials of statins found that across all the RCTs, statin treatment was associated with a statistically significant 12% reduction in all-cause mortality (RR 0.88, 95% CI: 0.84, 0.91, p<0.0001). On the flip-side, majority of patients saw no benefit at all and only 1 in 83 had their lifespan extended (was saved from a fatal heart attack).27,28

Aspirin

The classic Antiplatelet Trialists’ Collaboration (an analysis of RCTs of anti-platelet therapy among more than 54 000 high-risk patients with prior evidence of cardiovascular disease) revealed that aspirin therapy reduced by about ¼ the risk of composite of nonfatal MI, nonfatal stroke, and vascular death (vascular event). Practically, this benefit translated to reduction of 1 vascular event out of 50 patients treated for 1 year.29

Renin Angiotensin System

Nishino and co-workers investigated the effect of angiotensin-converting enzyme inhibitors (ACE-I) / angiotensin receptor blockers (ARB) on survival benefits in patients with stable CAD (CAD but without MI).

They found that all-cause (5.2% vs. 5.6%, P=0.56) and cardiovascular (3.2% vs. 3.0%, P=0.23) mortality were similar regardless of whether ACEI/ARB were used or not.30 On the other hand HOPE study showed that ACEI

Beta Blockers

A post-hoc analysis of CHARISMA trial revealed that in known CAD but without MI, β-blocker use was not associated with lower ischemic outcomes, but rather a trend toward a higher stroke risk (3.5% versus 1.5%; hazards ratio, 2.13; 95% confidence interval, 0.92–4.92; P=0.079).32

Coronary Artery Bypass Grafting

First successful CABG procedure was performed by Rene Favaloro of the Cleveland Clinic in 1968. Favaloro’s report fired the imagination of many surgeons, initially operating on stable patients but as skill was acquired on ever-sicker patients, and even during MI. By 1977 cardiac surgeons were performing 100,000 bypass procedures per year based only on case reports with no single trial available to justify its usefulness. “Surgeons said trials were totally unnecessary, as the logic of the procedure was self-evident, you have a plugged vessel, you bypass the plug, you fix the problem, end of story.” But there was a ‘a fly in the ointment,’ The first RCT of CABG, from Veterans Administration hospitals, published in 1977 revealed that there was no survival benefit in most patients who had undergone CABG versus those receiving standard medication. During this time there were two other separate multicenter, RCTs: the European Coronary Surgery Study and the Coronary Artery Surgery Study which showed however, that in some high risk sub-set of patients of CAD; significant obstruction of the left main coronary artery, triple-vessel CAD and left ventricular (LV) systolic dysfunction, and two-vessel CAD plus proximal left anterior descending coronary artery disease there could be a benefit.33-35 However, even this survival advantage vanished on longer term follow up (12 years or more).36 On the other hand a recent network analysis evaluating 95 trials and 93 553 [patients did reveal that CABG reduced an all cause mortality by 20% (rate ratio 0.80, 95% credibility interval 0.70 to 0.91). Thus the current evidence shows that CABG may improve survival for a few patients with the most severe forms of CAD, but for most others while it relieves symptoms but may not improve life-expectancy.

Percutaneous Coronary Angioplasty

The issue with PCI is even more contentious. Like CABG, PCI rates went from zero to 100,000 procedures in no time with no clinical trial to assess long-term outcomes: based just on the logic of the procedure and patients’ reports of how much better they felt. Yet the first clinical trials, which appeared around early 1990s, showed no survival benefit of elective angioplasty as compared with medication.

However, here the physicians took a different approach, because by the time trial results came (negative results)

CHAPTER 226

Benefit (Number of patients in whom a major vascular event is avoided per 1000/year)

therapy may reduce SCD mortality in those with CAD, 1035 stroke, peripheral vascular disease, or diabetes and at least one other cardiovascular risk factor. Over a mean follow-up period of five years, the relative risk of SCD was reduced by approximately 40%, although the absolute risk was low in both treatment and control groups (0.8 vs.

1.3%, respectively).31

Table 4: Drugs improving life-expectancy in heart failure Drug

Mortality Reduction %

Other Benefits

ACE-I

17-37

Symptomatic benefit

ARB

Similar to ACE-I

Symptomatic benefit

Beta Blockers

34-65

Reduce hospitalizations, risk of sudden death, improve LV function, exercise tolerance; and reduce heart failure functional class

BEYOND MEDICINE

1036

Aldosterone Antagonists

15-30

Reduction in hospitalizations and sudden death

Hydralazine/ Nitrates

43% in African Americans

Symptomatic benefit

Digoxin

No Benefit, No harm

Symptomatic benefit, Reduce hospitalization

the interventionists claimed that they had moved to nextgeneration devices, on the other hand the now evaluated procedure was already out-dated and therefore the trial meaningless. However, the matter-of-fact is that there are several small trials in stable CAD patients comparing PCI with medical therapy (with both single and multivessel disease). While most have reported only limited follow-up data they do show that PCI significantly improved angina relief and short-term exercise tolerance, but did not significantly reduce death, MI, or need for subsequent revascularization.37-39 In fact a meta-analysis of six RCTs comprising 1,904 patients revealed that the only outcome measure that favored PCI (compared with medical therapy) was angina relief (OR 0.70; 95% CI 0.50 to 0.98). However, for death, MI, and need for repeat revascularization the ORs trended strongly in favor of medical therapy (29% to 42%) versus PCI. Further, the need for subsequent CABG was nearly 60% higher with PCI, although the situation may be slightly different when newer generation of drug eluting stents is used.40,41 On positive side, like CABG there are certain subsets of patients where there may survival advantage with PCI particularly primary PCI. A comparative-effectiveness study of CABG surgery in a population of real-world patients (105 156 propensity score-matched Medicare patients) has shown that CABG surgery may be associated with approximately 19 days increase in life-expectancy versus PCI.42 On the other hand, a study Berger and coworkers revealed that in those high–risk anatomic subsets in which survival is prolonged by CABG versus medical

therapy, revascularization by PTCA and CABG also yielded equivalent survival over seven years.43

ACS / AMI

Statins

RIKS-HIA Study demonstrated that early statin (started before or at the time of hospital discharge) therapy could lead to a 25% reduction in 1-year mortality (relative risk, 0.75; 95% CI, 0.63-0.89; P = .001) in hospital survivors of AMI.44 Even in individuals with elevated CRP (a marker of inflammation / ACS) statin therapy could lead to a gain of life expectancy; 6.6 months in male and 6.4 months in female.45

Aspirin

In the ISIS-2 study, the use of aspirin (162 mg chewed) in AMI was associated with nearly 1/4th reduction of vascular mortality.46 In other ACS (Non MI) aspirin use has been associated with reduction in fatal or nonfatal MI by 50–70% during the acute phase and by 50–60% at 3 months to 3 years.47,48

Beta Blockers

Several prospective RCTs trials of beta-receptor blockade therapy after AMI have demonstrated an improvement in survival, primarily due to a decreased incidence of SCD.4951 The benefit was notable right from the beginning (in the first few months) and persisted on long-term follow-up (even up to 6 years). At follow-up, beyond a year, these studies show a 30–45% relative reduction in SCD, with an absolute sudden death incidence reduction of 1.3– 6.2%. On the other hand, CHARISMA Trial showed that β-blocker use in patients with prior MI but no heart failure was associated with a lower composite cardiovascular outcome driven but no reduction in mortality. 32 The ACC/ AHA committee on chronic stable angina recommends beta-blockers as the first-line therapy in post-MI patients based on evidence of improved mortality.52

Renin Angiotensin System

CREDO-Kyoto PCI/CABG registry cohort-2 investigators studied nearly 12,000 patients undergoing first PCI and demonstrated that patients with MI, treated with ACEI/ ARB had a survival advantage: 3-year all-cause mortality (6.6% vs.11.7%, P<0.0001). However, this benefit was not manifest in non MI patients.53

Thrombolysis

The Fibrinolytic Therapy Trialists’ Collaborative Group evaluated 9 trials including 58,600 patients and demonstrated highly significant absolute mortality reductions of about 30 per 1000 for those presenting within 0-6 h and of about 20 per 1000 for those presenting 7-12 h from onset but a (statistically) uncertain benefit of about 10 per 1000 for those presenting at 13-18 h. The benefit was observed both among patients presenting with ST elevation or bundle-branch block--irrespective of age, sex, BP, heart rate, or previous history of MI or diabetes-and was greater, the earlier the treatment began.54 The temporal effect on survival was demonstrated in other studies as well; in a retrospective subgroup analysis of

1037

Table 5: Disease stage and impact of various therapies in prolongation of life Intervention

Primary Prevention

Stable CAD

Unstable CAD

CHF

End-stage Heart Disease

Life-style intervention

+

++

+++

+++

+++

NA

Statins

­­

±

+

++

NA

NA

ASA

­­

±

+

++

NA

NA

ACE-I / ARB

­­

­­

+

++

+++

NA

Beta-blockers

­­

­­

±

+

+++

NA

Aldosterone Antagonists

­­

­­

­­

­­

++

±

+

+

+

+

±

+

­­

+

ICD

­­

CRT

­­

­­

Cardiac Assist Devices CPR

­­

­­

Mechanical Ventilation

A meta-analysis of 10 randomized trials demonstrated the superiority of PTCA over thrombolytic therapy in preventing death and other adverse clinical outcomes; a reduction of mortality by more than 1/3rd (34%, P= 0.02), an absolute risk reduction for death of approximately 2%, death or nonfatal AMI (11.9% vs. 7.2%, P< 0.001), all stroke (2.0% vs. 0.7%, P= 0.007), and hemorrhagic stroke (1.1% vs. 0.1%, P< 0.001).56

CONGESTIVE HEART FAILURE

As life-span decreases, as a consequence of severity of disease, several therapeutic interventions may aid in bringing down the mortality.

Drugs

Several drugs may be effective in this situation and the mechanism may involve either preventing the development of lethal heart rhythms or by limiting the on-going damage to heart muscle Table 4.57 1. ACE-I. 2.

ARBs .

3.

Beta-blockers.

4.

Aldosterone receptor antagonists (but not other diuretics which can improve symptoms but do not improve survival.)

5. Hydralazine/Nitrates Beta-blockers, bisoprolol, metoprolol, and carvedilol have been shown to reduce total mortality in several studies.58-60 The effect seems to be predominantly due to reduction of mortality from SCD (42% with bisoprolol in CIBIS II, an absolute risk reduction of 2.7% over a mean follow-

­­

­­

­­

Percutaneous Coronary Angioplasty

­­

­­

­­

patients in GISSI-1 trial showed that patients randomized to streptokinase (or control treatment) within 1 hour of symptom onset there was a 51% reduction in mortality (studied at 21 days).55

­­

­­

­­

­­ ­­

­­

­­

­­

­­ ­­

+

up period of 1.3 years) but the effect may also be due to reduction in ischemia.61 The mechanism of mortality reduction with ACE- I is under scrutiny. The CONSENSUS trial showed a 31% reduction of total mortality at 1 year in the enalapril (vs. the placebo group) but no reduction in sudden death.62 On the other hand in the TRACE study, trandolapril significantly reduced the risk of SCD in post MI patients with LV dysfunction, a 22% relative decrease and a 3.2% absolute decrease in SCD over a 4-year period.63 Even, aldosterone antagonists seem to significantly reduce mortality in patients with severe heart failure by reducing arrhythmic deaths. In the RALES study, over a 2-year period, the relative risk of SCD was reduced by 29%, and absolute risk reduced by 3%.64

Devices

COMPANION trial was a RCT comparing standard heart failure drug therapy alone, or in combination with either cardiac resynchronization therapy (CRT) or CRT plus implantable cardioverter‐defibrillator (ICD) in heart failure patients - NYHA class III–IV with LVEF ≤35% and QRS width ≥120 ms. They found that mortality was reduced equally in both the device arms (with no significant improvement of mortality with combined device; CRT/ICD (combo device). Thus use of a combo device in this situation should be based on the indications for ICD therapy.65

Surgery

Heart transplantation is the therapy of choice for the treatment of end stage heart failure and has been shown to improve not only life-span but also exercise capacity and quality of life.66 In patients of dilated cardiomyopathy, heart failure and significant mitral regurgitation, there is some data which suggests that mitral valve surgery may be associated with reduction in mortality as well as improvements in quality of life.67

CHAPTER 226

Primordial Prevention

BEYOND MEDICINE

1038

LIFE-SUSTAINING THERAPIES

Life-sustaining therapy is any intervention, technology, or treatment that forestalls the moment of death or simply those therapeutic maneuvers withholding or withdrawing them would lead to termination of life.

Thus by definition these interventions have the effect of increasing the life span of the patient. Many “therapies” may qualify this category: mechanical ventilation, cardio-pulmonary resuscitation, vasoactive agents, dialysis, artificial nutrition, hydration, antibiotics, blood replacement products as well as those specific for cardiac condition such as ICDs (for secondary prevention of SCD), pacemakers (for bradyarrhythmias), and cardiac mechanical assist devices (for advanced decompensated heart failure).68

DRUGS OR LIFE-STYLE MODIFICATION

The efficacy of either strategy depends on the stage medical science intervenes (Table 5). Since life-style diseases now account for nearly 2/3rd of all serious diseases world-wide, a strategy targeted towards these diseases is likely to yield most results.69 Drugs are powerful, indispensable weapons against CVD once it develops. However, its value in prolongation of life may not be that impressive in stable conditions: In stable CAD absolute reduction of mortality with drugs is in range of 1%. The benefit of therapeutic interventions (drugs and devices), increase with severity of disease, in range of 5-10% absolute risk reduction in ACS and in the range of 10% with CHF. However, because these strategies are expensive, they certainly have at least some side effects, alone they may be not sufficient. In contrast, a healthy lifestyle is inexpensive, safe and effective.

In primary prevention risk factor modification can be a very effective strategy contributing to absolute mortality reduction in the range of 5% with a combination of all these strategies. On the other hand role of drugs (in this subset), if at all is controversial and a matter of on-going debate.

In a perfectly healthy individual (primordial prevention) the only maneuvers which seem to help are adhering to a level of health which does not permit risk factors to appear (an ideal life style), a strategy capable of reducing cardiac deaths by 90% and prolonging life-expectancy by 10 years. However, while life-style modifications are effective they are not simple to implement. It requires change and persistence (adherence to change). Thus, going beyond mere medical care, psychological and nutritional counseling, social and family support may also be required to manifest a life-time behavior modification.

CONCLUSIONS

The inevitability of death has been instrumental in search for therapy that extends life, the “elixir of life.”

Over the course of eons several interventions have been discovered which help in prolonging life but in a special circumstance. In general the more severe the disease and the longer the time life-saving intervention is applied the greater the benefit. PCI and CABG are more useful in

sicker patients with CAD while statins, aspirin and ACEInhibitors are clearly beneficial in any CAD, although magnitude of benefit is still small, if any, when used in primary prevention.

REFERENCES

1.

Jones DS. Broken Hearts: The Tangled History of Cardiac Care (Johns Hopkins). http://www.amazon.com/BrokenHearts-Tangled-History- Cardiac/dp/1421408015/ref=sr_1 _1?ie=UTF8&qid=1360790266&sr=8-1&keywords=Broken+ Hearts%3A+The+Tangled+History+of+Cardiac+Care

2.

Acemoglu D and Johnson S. Disease and Development: The Effect of Life Expectancy on Economic Growth. Journal of Political Economy 2007; 115:925-85.

3.

Bunker JP. The role of medical care in contributing to health improvements within societies. International Journal of Epidemiology 2001; 30:1260-1263.

4.

Goldman L, Cook EF. The decline in ischemic heart disease mortality rates: an analysis of the comparative effects of medical interventions and changes in lifestyle. Ann Intern Med 1984; 101:825–36.

5.

E. Hunink MGM, Goldman L, Tosteson ANA et al. The recent decline in mortality from coronary heart disease, 1980–1990: the effect of secular trends in risk factors and treatment. JAMA 1997; 277:535–42.

6.

Willcox, C, Willcox, B, Hidemi, T, Curb, D, Suzuki, M, 2006. Caloric restriction and human longevity: what can we learn from the Okinawans? (Online) accessed: 15/12/09 via ProQuest.

7.

Holloszy JO; Fontana L. “Caloric restriction in humans”. Exp Gerontol 2007; 42:709–12. doi:10.1016/j.exger.2007.03.009.

PMID 17482403.

8.

Fraser, G, Shavlik, D, 2001. ten years of life, is it a matter of choice?, (Online) Vol. 161, accessed: 11/01/09 via Google scholar.

9.

Altered dietary methionine differentially impacts glutathione and methionine metabolism in long-living growth hormone-deficient Ames dwarf and wildtype mice”. Longevity & Healthspan 3 (10). 2014. doi:10.1186/2046-2395-3-10.

10. H. Sparing of methionine requirements: evaluation of human data takes sulfur amino acids beyond protein”. J Nutr 2006; 136 (6 Suppl): 1676S–1681S. 11. European Society of Cardiology (ESC). “Regular jogging shows dramatic increase in life expectancy.” ScienceDaily.

ScienceDaily, 3 May 2012. <www.sciencedaily.com/ releases/2012/05/120503104327.htm>.

12. Bannister CA, Holden SE, Jenkins-Jones S, et al. Can People With Type 2 Diabetes Live Longer Than Those Without?

A Comparison of Mortality in People Initiated With Metformin or Sulphonylurea Monotherapy and Matched Non-diabetic Controls. Diabetes Obes Metab 2014; 16:11651173.

13. Blagosklonny MV. Prospective treatment of age-related diseases by slowing down aging. American Journal of Pathology 2012; 181:1142-1146.

14. Kaeberlein, Matt (2010). “Resveratrol,pterostilbene and rapamycin:are they anti-aging drugs?”. BioEssays 32 (2): 96–99. doi:10.1002/bies.200900171.

15. Zhu Y, Tchkonia T, Pirtskhalava T, Gower AC, Ding H et al.

The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 2015; 14:644–658.

16. Capewell S, Ford ES, Croft JB, Critchley JA, Greenlund KJ, Labarthe DR. Cardiovascular risk factor trends and potential for reducing coronary heart disease mortality in the United States of America. Bull World Health Organ 2010; 88:120–130.

17. O. Lloyd-Jones DM, Leip EP, Larson MG, et al. Prediction of lifetime risk for cardiovascular disease by risk factor burden at 50 years of age. Circulation 2006; 113:791–798.

enzyme inhibitors/angiotensin II receptor blockers in 1039 revascularized coronary artery disease patients according to history of myocardial infarction. Circ J 2013; 77:1242-52.

31. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients: The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000; 342:145–153.

32.

19. Bakhru A, Erlinger TP. Smoking cessation and cardiovasacular disease risk factors: Results from the third National Health and Nutrition Examination Survey. PLoS Med 2005; 2:e160.

34. Detre KM, Takaro T, Hultgren H, Peduzzi P. Longterm mortality and morbidity results of the Veterans Administration randomized trial of coronary artery bypass surgery. Circulation 1985; 72:V84–9.

20. Burt VL, Cutler JA, Higgins M, et al. Trends in the prevalence, awareness,treatment, and control of hypertension in the adult US population. Data from the health examination surveys, 1960 to 1991. Hypertension 1995; 26:60–69.

21. Taylor F, Ward K, Moore TH, Burke M, Davey Smith G, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 2011; (1):CD004816.

22.

Tsevat J, Weinstein MC, Williams LW, Tosteson ANA, Goldman L. Expected Gains in Life Expectancy From Various Coronary Heart Disease. Risk Factor Modifications.

Circulaton 1991; 83:1194-1201.

23. Ray KK, Seshasai SRK, Erqou S, Sever P, Jukema JW, et al. Statins and All-Cause Mortality in High-Risk Primary Prevention. A Meta-analysis of 11 Randomized Controlled Trials Involving 65 229 Participants. Arch Intern Med 2010; 170:1024-1031.

24. Statin Drugs Given for 5 Years for Heart Disease Prevention (Without Known Heart Disease). Therapy (NNT) Reviews – Cardiology. ww.thennt.com/nnt/statins-for-heart-diseaseprevention-without-prior-heart-disease/ 25. Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, Peto R, Buring J, Hennekens C, Kearney P, Meade T, Patrono C, Roncaglioni MC, Zanchetti A. Antithrombotic Trialists’ (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.

Lancet 2009; 373:1849–1860.

26. Patrono C. Low-dose Aspirin in Primary Prevention.

Cardioprotection, Chemoprevention, Both, or Neither? Eur Heart J 2013; 34:3403-3411.

27. CTT Collaborators. Efficacy and safety of cholesterollowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins.

Lancet 2005; 366:1267-1278.

28. Z. Statins Given for 5 Years for Heart Disease Prevention (With Known Heart Disease). Therapy (NNT) Reviews – Cardiology. http://www.thennt.com/nnt/statins-for-heartdisease-prevention-with-known-heart-disease/ 29. Antiplatelet Trialists Collaboration. Collaborative overview of randomized trials of antiplatelet treatment, I: prevention of vascular death, MI and stroke by prolonged antiplatelet therapy in different categories of patients. Br Med J 1994; 308:235-246.

30. Nishino T1, Furukawa Y, Kaji S, Ehara N, Shiomi H, et al. Distinct survival benefits of angiotensin-converting

33. Bangalore S, Bhatt DL, Steg G, Weber MA, Boden WE, et al. β-Blockers and Cardiovascular Events in Patients With and Without Myocardial Infarction. Post Hoc Analysis From the CHARISMA Trial. Circ Cardiovasc Qual Outcomes 2014; 7: 872-81.

35. Varnauskas E. Survival, myocardial infarction, and employment status in a prospective randomized study of coronary bypass surgery. Circulation 1985; 72:V90–101.

36. Passamani E, Davis KB, Gillespie MJ, Killip T. A randomized trial of coronary artery bypass surgery. Survival of patients with a low ejection fraction. N Engl J Med 1985; 312:1665–71.

37. The Veterans Administration Coronary Artery Bypass Surgery Cooperative Study Group. Eleven-Year Survival in the Veterans Administration Randomized Trial of Coronary Bypass Surgery for Stable Angina. N Engl J Med 1984; 311:1333-1339.

38. Windecker S, Stortecky S, Stefanini GG, daCosta BR, Rutjes AW, et al. Revascularisation versus medical treatment in patients with stable coronary artery disease: network metaanalysis. BMJ 2014;348:g3859 doi: 10.1136/bmj.g3859 39. Henderson RA, Pocock SJ, Clayton TC, et al. Seven-year outcome in the RITA-2 trial: coronary angioplasty versus medical therapy. J Am Coll Cardiol 2003; 42:1161–70.

40. Parisi AF, Folland ED, Hartigan P. A comparison of angioplasty with medical therapy in the treatment of single-vessel coronary artery disease. Veterans Affairs ACME Investigators. N Engl J Med 1992; 326:10–6.

41. RITA-2 Trial Participants. Coronary angioplasty versus medical therapy for angina: the second Randomised Intervention Treatment of Angina (RITA-2) trial. Lancet 1997; 350:461–8.

42. Al. Bucher HC, Hengstler P, Schindler C, Guyatt GH. Percutaneous transluminal coronary angioplasty versus medical treatment for nonacute coronary heart disease: meta-analysis of randomised controlled trials. BMJ 2000; 321:73–7.

43. Hlatky MA, Boothroyd DB, Baker L, et al. Comparative effectiveness of multivessel coronary bypass surgery and multivessel percutaneous coronary intervention. Ann Intern Med 2013. Available at: http://annals.org.

44. Berger PB, Velianou JL, Vlachos HA, Feit F, Jacobs AK, et al. Survival Following Coronary Angioplasty Versus Coronary Artery Bypass Surgery in Anatomic Subsets in Which Coronary Artery Bypass Surgery Improves Survival Compared With Medical Therapy. Results From the Bypass Angioplasty Revascularization Investigation (BARI). J Am Coll Cardiol 2001; 38:1440 –9.

45. Stenestrand U, Wallentin L; for the Swedish Register of Cardiac Intensive Care (RIKS-HIA). Early Statin Treatment

CHAPTER 226

18. Lloyd-Jones DM, Hong Y, Labarthe D, et al. American Heart Association Strategic Planning Task Force and Statistics Committee. Defining and Setting National Goals for Cardiovascular Health Promotion and Disease Reduction: The American Heart Association’s Strategic Impact Goal Through 2020 and Beyond. Circulation 2010; 121:586–613.

Following Acute Myocardial Infarction and 1-Year Survival. JAMA 2001; 285:430-436.

1040

46. Ap. Blake GJ, Ridker PM, Kuntz KM. Projected lifeexpectancy gains with statin therapy for individuals with elevated C-reactive protein levels. J Am Coll Cardiol 2002; 40:49-55.

BEYOND MEDICINE

47.

“Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group,”. The Lancet 1988; 2:349–360.

48. Lewis Jr. HD, Davis JW, Archibald Jr. DG, et al., “Protective effects of aspirin against acute myocardial infarction and death in mean with unstable angina. Results of a Veterans Administration Cooperative Study,”. New England Journal of Medicine 1983; 309:396–403.

49. Cairns JA, Gent M, Singer J, et al., “Aspirin, sulfinpyrazone, or both in unstable angina. Results of a Canadian Multicenter Trial,”. New England Journal of Medicine 1985; 313:1369–1375.

50. A randomized trial of propranolol in patients with acute myocardial infarction. I. Mortality results. J Am Med Assoc 1982; 247:1707.

51. Reduction in mortality after myocardial infarction with long-term beta-adrenoceptor blockade. Multicentre international study: supplementary report. Br Med J 1977; 2(6084):419.

52. Pedersen T.R. (1985) Six-year follow-up of the Norwegian multicenter study on timolol after acute myocardial infarction. New Engl J Med 1985; 313:1055.

53. Gibbons RJ, Chatterjee K, Daley J, et al. ACC/AHA/ACPASIM guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Patients With Chronic Stable Angina). J Am Coll Cardiol 1999; 33:2092–197.

54. Nishino T, Furukawa Y, Kaji S, Ehara N, Shiomi H, on behalf of the CREDO-Kyoto PCI/CABG registry cohort-2 investigators. Distinct Survival Benefits of AngiotensinConverting Enzyme Inhibitors/Angiotensin II Receptor Blockers in Revascularized Coronary Artery Disease Patients According to History of Myocardial Infarction.

Circ J 2013; 77:1242–1252.

55. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Fibrinolytic Therapy Trialists’ (FTT) Collaborative Group. Lancet 1994; 343:31122.

56. White HD, Van de VERF HJJ. Thrombolysis for Acute Myocardial Infarction. Circulation 1998; 97:1632-1646 57. Weaver WD, Simes RJ, Betriu A, et al. Comparison of primary coronary angioplasty and intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review. JAMA 1997; 278:2093-8.

58. Controlling Heart Failure and Improving Clinical Outcome.

UCLA Heart Failure Practice Guidelines SUMMARY 2005. https://www.google.co.in/url?sa=t&rct=j&q=&esrc=s&s ource=web&cd=9&cad=rja&uact=8&ved=0ahUKEwjB8c Db0eLJAhVYBo4KHV6xAosQFghkMAg&url=http%3A %2F%2Fwww.med.ucla.edu%2Fchamp%2FCHFmg05a. doc&usg=AFQjCNHRBJSNkEoaQUp1n8-SyqIeMCl46w 59. Bna. The Cardiac Insufficiency Bisoprolol Study II (CIBISII). A randomised trial. Lancet 1999; 353:9.

60. Bnb. Packer M., Bristow M.R., Cohn J.N., et al.(1996) The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. US Carvedilol Heart Failure Study Group [see comments]. New Engl J Med 1996; 334:1349.

61. Bnc. MERIT-HF. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure. Lancet 1999; 353:2001.

62. Bnd. Anderson J.L., Rodier H.E., Green L.S. Comparative effects of beta-adrenergic blocking drugs on experimental ventricular fibrillation threshold. Am J Cardiol 1983; 51:1196.

63. Bne. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure.

Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) New Engl J Med 1987; 316:1429.

64. Bnf. Kober L., Torp-Pedersen C., Carlsen J.E., et al.

A clinical trial of the angiotensin-converting enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group. New Engl J Med 1995; 333:1670.

65. Bng. Pitt B., Zannad F., Remme W.J., et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators New Engl J Med 1999; 341:709.

66. Hunt S A. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol 200546e1–82.82 Current ACC/AHA practice guidelines including comprehensive overview of the literature until 2005, together with references 1 and 2 67. Hosenpud J D, Bennett L E, Keck B M. et al The registry of the International Society for Heart and Lung Transplantation: sixteenth official report–1999. J Heart Lung Transplant 199918611–626.626.

68. Bq. Geha A S, El‐Zein C, Massad M G. Mitral valve surgery in patients with ischemic and nonischemic dilated cardiomyopathy. Cardiology 200410115–20.20.

69. Br. Wiegand DLM, Kalowes. Withdrawal of Cardiac Medications and Devices. AACN Advanced Critical Care 2007; 18:415–425.

70. SUS - Ministério da Saúde Brasil. Mortes por doenças cardiovasculares caem 20,5% no Brasil. http://portal.saude. gov.br/portal/aplicacoes/noticias/default.

C H A P T E R

227

The Heart and Lung cannot Live without Each Other

The heart and lung are intimately associated with each other. I will be presenting a series of cases that highlight their interplay.

These can be divided into situations where the interplay is purely anatomic and those where the physiologic dependence is predominant. I am leaving out complex congenital heart disease where in the presence of asplenia and hyposplenia there may be associated lung and tracheo-bronchial pathologies as well, since this is not a subject for this meeting.

PHYSIOLOGIC

Pulmonary edema

Patients with left sided cardiac dysfunction typically have interstitial or frank pulmonary edema, which manifests with effusions, septal thickening and ground-glass attenuation. This may simulate interstitial lung disease or lymphangitis carcinomatosis, but the ability to pick up LV or LA dilatation or other clues that point to cardiac disease helps in establishing the diagnosis.

Bhavin Jankharia

Anomalous pulmonary venous drainage and associated syndromes like the hypogenetic lung syndrome also affect the heart and the pulmonary arteries causing plethora and other associated lung changes such as hypoplasia

ANATOMIC

Direct extension of disease

Tumors and infection that affect the lung and mediastinum can directly affect the heart and the pericardium.

Lymphoma, bronchogenic carcinoma and tuberculosis do this commonly (Figure 1).

Granulomatous cardiomyopathy

This refers to patients who have monomorphic ventricular tachycardia along with lymphadenopathy and possible lung lesions with myocardial fibrosis or edema on cardiac

Pulmonary hypertension

Pulmonary hypertension may be related to cardiac disease to pulmonary disease, to shunts or may be idiopathic.

When it is related to cardiac disease, there is pulmonary edema and pulmonary hypertension.

PH also affects the right ventricle and right atrium causing pressure and volume overload that can be seen on CT scan.

PH due to pulmonary thromboembolism can present with lung infarcts and effusion along with cardiac changes.

Fig. 2 (A,B): Lymphoma. End-diastolic four-chamber (A) and short-axis (B) images in a 52-years old man show nodular thickening of the LV and RV myocardium (arrows). This eventually turned out to be lymphoma

Fig. 1: Squamous cell carcinoma of lung. End-diastolic axial cine images show a squamous cell carcinoma of the left hilum involving the left pulmonary artery

BEYOND MEDICINE

1042

Fig. 3 (A-C): Sarcoidosis. End-diastolic cine short axis series (A) shows dilatation of the LV. Delayed enhanced short axis (B,C) images show abnormal mid-myocardial, epicardial and subendocardial enhancement in different LV segments (arrows) MRI. Sarcoidosis and tuberculosis present in this manner (Figure 2)

Metachronous / synchronous disease

Metastases, lymphoma and conditions like amyloidosis can simultaneously affect the heart and the lungs and mediastinum (Figure 3).

C H A P T E R

228

New Approach to Management of Erectile Dysfunction in 2017

Erectile dysfunction (ED), defined as the inability to achieve and or maintain an erection adequate for intercourse, it is the most common sexual complaint of men presenting to their health care providers. ED is an issue that greatly impacts a patient’s quality of life and can have detrimental effects on his relationship with his partner. ED is not just his problem its their problem.

ED is most commonly classified as psychogenic, organic, or mixed etiology. Organic ED encompasses neurogenic, endocrinologic, vasculogenic, and medication, substanceinduced. Risk factors for CVD such as hypertension, diabetes, smoking, obesity, and dyslipidemia are also well established risk factors for ED. The 2012 Princeton III Consensus addresses the evaluation and management of CV risk factors in men with ED and no CVD. In men with ED and CVD, there are various risk categories for morbid events related to sexual activity.

Not surprisingly, highly active men appear to have a decreased risk of major adverse cardiac events (MACE) following episodic physical or sexual activity.

Deepak K Jumani

of these one-third are in India either at diabetic or prediabetic stage. India and China are two countries in the world where diabetes is an explosive epidemic1. In fact India and China, let us call it Chindia, are the diabetes capital of the worlds. Men and women with diabetes have sexual problems. The commonest complication of diabetes seen in Indian men is erectile dysfunction, low sexual desire and ejaculatory disorders. In diabetic women we observe vaginal dryness, hypoactive sexual desire disorders and depression. In diabetes certain infections which affect sexual functions & which are very common are balanoposthitis in males and vulvovaginitis, candidiasis in females.

Sexual dysfunctions in men include mainly erectile dysfunction, low sexual desire and ejaculatory disorders.

In Diabetics we see Angiopathy

Macroangiopathy (rarely): Iliac arteries Microangiopathy Microcirculation

(frequently);

Penile

arteries

and

Sexual activity is equivalent to 3-5 metabolic equivalents of task (METs), as is walking one mile on flat terrain in 20 minutes or climbing two flights of stairs in 10 seconds.

Exercise tolerance should be assessed prior to initiation of ED therapy in all men regardless of CV risk. As Per the Princeton III panel algorithm, if a man can exercise to 3-5 METs, he should be able to engage in sexual activity. In a patient with questionable cardiac health, the management of CV issues should always supersede and precede management of ED.

Polyneuropathy Somatic nervous system: Pudendal and dorsal penile nerve

In men with hypertension, it is well established that the prevalence of ED is increased in hypertensive men compared to normotensive ones. The reported prevalence of ED in the hypertensive patient ranges from 15-46%, depending on the study population. Some antihypertensive medications are associated with some degree of ED. The agents associated with the most significant prevalence of ED include diuretics, centrally acting sympatholytics, aldosterone receptor antagonists, and beta-blockers. On the other hand, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II (ATII) receptor blockers appear to have no significant negative effects on erectile function.

Impairment of prostanoid synthesis (Prostacyclin: PGI2, PGE1)

Diabetes is the biggest health tsunami of our century.

There are 387 million diabetics across the globe and

Autonomic nervous system: Parasympathetic  pelvic and cavernous nerves (Impairment of erection) Sympathetic  pelvic and cavernous nerves (Loss of emission and ejaculation)

Impairment of Neurotransmitter synthesis/release

Endothelial and smooth muscle cell dysfunction Impairment of eNOS (NO)

Upregulation of arginase (NO) Upregulation of protein kinase C (PKC) ß II Impairment of KATP-channels (additionally enhanced by sulfonylurea antidiabetics) Upregulation of insulin-like growth factor binding protein 3 (IGFBP-3) precursor Downregulation of estrogen ß-receptor expression Upregulation of α1-adrenoceptors Glycosylated hemoglobin C-induced decrease of NOrelease.

1044

Basic Pathogenesis of Erectile Dysfunction.

Penile erection is a neurovascular phenomenon that depends upon neural integrity, a functional vascular system, and healthy corpora cavernosal tissues.

Normal erectile function involves 3 synergistic and simultaneous processes:

BEYOND MEDICINE

A neurologically mediated increase in penile arterial inflow, relaxation of cavernosal smooth muscle, and restriction of venous outflow from the penis.

MOLECULAR BASIS OF ERECTILE DYSFUNCTION

Molecular basis of Neurogenic Erectile dysfunction

During radical prostetectomy even if its nerve sparing surgery there are chances of the nerves getting damaged and at a molecular level, cavernosal nerve transection profoundly decreases DNA content in the cavernosal tissue. This is accompanied by up-regulation of apoptotic genes. In caners its well known that it’s the turning off the genes which triggers apoptosis. Another mechanism of cell death is when the cell percieves decreased signalling as seen in patients with spinal cord injury. All these molecular level changes not only decrease the weight of the penis but also the size and girth. All this is due to nerve disruption-induced apoptosis and hypoxiainduced damage to the corpora, leading to smooth muscle atrophy.

Molecular basis of Vasculogenic Erectile Dysfunction

Smoking, trauma, atheroscleoris lead to arterial insufficiency. This leads to many changes in the penile morphology and gene expression. The diminished blood supply to the penile nerves lead to decrease in the diameter of myelinated and demyelinated nerve fibers, which ultimately leads to depletion of the myofilaments.

Additionally there are fewer endothelial cells and less nitric oxide production, ultimately leading to less corpora smooth muscle relaxation.

Another cause is venous leak which allows the blood to flow out after sexual stimulation and hence there is no rigid erection. The probable etiology is that it’s the Androgen deficiency which leads to corpora smooth muscle atrophy. Testosterone also is known to stimulate the vascular endothelial growth factor, and hence Testosterone deficiency in men not only causes diminished sex drive but also induces ED at cellular level.

Molecular basis of Diabetes induced Erectile Dysfunction

Hyperglycaemia leads to generation and impaired clearance of oxygen-derived free radicals. This is oxidative stress in the microvasculature leads toproduction of Advanced Glycated end products (AGE), AGEs are products formed by non-enzymatic Maillard reactions between a protein’s primary amino group and carbohydrate-derived aldehyde groups. AGEs bind with a receptor, RAGE, which mediates binding of AGEs to endothelial cells, thereby inhibiting endothelial-mediated smooth muscle relaxation via a nitric oxide pathway.

The end result of this molecular cascade is impaired vasodilatation in any microvascular area, ranging from

coronary vasculature to the retina to the penis.

ATP binding cassette transporters(ABC) viz A1, ABCG1 and Cholesterol 27-hydroxylase are Reverse Cholesterol transport proteins(RCT), that facilitate removal of macrophages and constitute a first line of defense against atherosclerosis, Studies revealed that ABC1 ABCG1 are identified to be suppressed by AGE. AGE also promote lipid overload through enhancing expression of proteins that facilitate lipid uptake and through suppressing reverse cholesterol transport proteins like Cholesterol 27 hydoxylase.

A new hypothesis has emerged and sounds very true is that instead of turning off the genes required for smooth muscle relaxation, there is a new pathway of calcium channeling called the Rho/Rhokinase which is turned on which leads to vasoconstriction and chronic detumescence. This is observed in diabetic rats. So if this RhoA/Rhokinase factor is inhibited the patients can get enhanced erection.

Lastly apoptosis has a critical role in diabetes induced Erectile dysfunction. Researchers have found in diabetic rats that there is a deficiency of anti-apoptosis gene βcl-2.

The deficiency of this gene leads to a shift in homeostasis and cell death and organ degeneration.

Molecular basis of Testosterone on Erectile Dysfunction

Over 20 percent of men with erectile dysfunction have low testosterone. There is a clear correlation between low testosterone and severity of erectile dysfunction. In animal models it is studied that adequate androgen levels are essential for expression of NOS gene in the penis. It is also noted in these models that intra cavernosal pressure was reduced in hypo gonad models and reversed by androgen replacement therapy.

Research also suggests that there is a possible down regulation of both the production and activity of nitric oxide in the absence of testosterone in the rat, thus diminishing the response to peripheral stimulation via the nitric oxide pathway.

Several other mechanisms of hypogonadism induced ED include smooth muscle cell degeneration and increase in apoptotic activity due to diminished androgen stimulation with associated fibrosis of the corpus cavernosum. An enhanced response to mediators of vasoconstriction such as α-adrenergic stimuli is also suggested to occur in the hypogonadal environment.

A New Strategy

VEGF is a multifunctional protein, stimulating angiogenesis, inhibiting apoptosis, and increasing vascular permeability. The hypothesis is that, since endothelial cells synthesize nitric oxide, increasing the quantity of endothelial cells in the target organ will increase nitric oxide production and subsequent vasodilatation. This can prevent ischemia in the heart and, similarly, might improve erections in the penis.

Using this fact a new strategy to increase nitric oxide levels through enhancing the penile vasculature, using

recombinant vascular endothelial growth factor (VEGF) are currently being tried by transfection of VEGF into the rat penis to reverse vasculogenic ED via an increase in the levels of eNOS and inducible nitric oxide synthase (iNOS).

Christ and associates tried transfer humanhslo/maxi-K gene as this is responsible for increasing the response of smooth muscle to minimal levels of endogenous muscle relaxants such as nitric oxide in the corpora cavernosa of patients with ED. In 2017 we shall see an amazing era of medicine and a great breakthrough in the therapeutic management of erectile dysfunction. Truly the study of human genome sequencing has made a revolutionary change in our understanding of the molecular basis of the pathology of erectile dysfunction and have paved a new road map to curative strategies.

Novel emerging molecular targets for treatment of Erectile Dysfunction:

Many men do not respond to the first line of therapy for Erectile dysfunction i.e. PDE5 inhibitors. Thus emerged the thirst for novel therapeutic drug and treatment targets.

Research suggests that endothelial microparticles, myeloperoxidase and haem oxygenase -1, are newer emerging molecular targets to treat vasculogenic ED. Endothelial derived MPs (Endothelial Mirco-particles, EMP,) released in response to cellular damage or dysfunction as expressed by the marker CD144 were found to be elevated in diabetic patients with coronary artery disease and elevated EMP’s

MANAGEMENT OF ED

Approach to a patient of ED

Making the basic sexual assessment a routine clinical practice, would have clear benefits in improving the overall health status, The fact of erectile dysfunction, being an early sign of cardiovascular risk, supports the practice of routine assessment of sexual function, in clinical practice.

A well-elicited sexual history which includes onset, duration and severity of the ED, a detailed history of the stages of male sexual response which is desire, arousal, orgasm and resolution, morning erections and gender orientation, ensures appropriate clinical judgment and diagnosis, and also identifies possible co- existence of sexual disorders, for appropriate management.

A psychosocial history eluding to anger, depression, guilt,

A validated questionnaire which we use are IEF (International Index of Erectile Function) is a commonly used questionnaire for evaluation. Others include Sexual Health Inventory for Men (SHIM), Brief Male Sexual Functioning Inventory (BMSFI), etc. However these are not the alternatives to good detailed history taking.

A detailed physical examination from top to bottom is mandatory with examination of the reproductive organs for any local pathology, femoral pulses, varicocele hernia, hydrocele, phimosis, paraphimosis, herpes, peyronies disease, micropenis all signs of secondary sexual charactersticks and signs of hypogonadism, etc. Lastly a digital rectal examination has been proven to help us evaluate the status of benign enlargement of prostates in elderly males.

Ask every diabetic in your history do you have problems in making love ?

Ask history of morning erections. (If a patient is less than 40 years and gets morning erections even once a week, he has psychogenic or situational ED) This patient doesn’t need any medications he only needs proper counseling.

Advice: Smoking, diet, exercise Blood pressure: < 130/80 mm Hg Cholesterol : TC <150, LDL<100 HDL >40 Diabetes control : HbA1c ≤ 7% Eye examination : Annual examination Feet examination : Everytime the patient walks in your clinic.

Guardian drugs : Aspirin, ACEI, statins Heart risk score : UKPDS, Framingham, Hormones.

Impotence Rx : Drugs, Injectables, etc..

Other tests include •

Serum Testosterone Free and Total

•

Sex Hormone Binding Globulin

•

Free T3 T4 and TSH

•

Serum FSH, LH Prolactin.

•

USG of Scrotum and Doppler studies

•

Serum PSA Free and Total

•

DRE(Digital Rectal Examination)

•

Questionaaires like IIEF (International Index of Erectile Dysfunction)

•

One sophisticated tests which is now almost obsolete is Nocturnal Penile Tumuscence Rigidity (NPTR) Tests. 2 Electrodes are tied at the base and tip of the penis which are connected to Rigiscan and these are connected to a computer, Rigiscan detects nocturnal erections during REM sleep which are

CHAPTER 228

It was found that there was an increase intra cavernosal pressures after transfecting recombinant VEGF via an adenovirus vector. They also noted an increase in regeneration of penile smooth muscle and nerves as well as endothelial cell hypertrophy and hyperplasia. In a more recent application, VEGF was demonstrated to inhibit apoptosis after intra cavernous injection, effectively restoring pressure in diabetic rat penile crura.

addictions, financial insecurities, extramarital affairs, 1045 body image issues, etc needs to be assessed.

plotted on the computer. Presence of erections indicates pyschogenic or situational ED.

1046

•

Instead of the above tests a roller of stamp can be advised to be put on the shaft of the penis and if it breaks it indicates psychogenic or situational ED.

Novel Approach to Erectile Dysfunction

BEYOND MEDICINE

In a recent study a relationship between the ratio of platelet count and absolute lymphocyte count (PLR) was studied as a marker of severity of Erectile dysfunction.

PLR value increased depending on the severity of ED. Mean PLR values were 108 in mild ED, 116 in Moderate ED and 130 in Severe ED groups.

The plateletelymphocyte ratio value is increased in moderate and severe erectile dysfunction compared with the control group (p Z 0.04 and p < 0.001).

Treatment of ED

So for a good enough erection one has to see that the endothelium has to be normal functional, adequate nitric oxide, guanylate cyclase activators and stimulators, cGMP to be present in more bioavailabale form to maintain tumusence and lastly something to block the PDE5 enzyme.

The first line of treatment is Oral Drugs and Counselling.

The second line of treatment is intracavernous injection of papaverine and largactil and prostaglandin, vaccum therapy and intraurethral drugs like prostaglandin, along with counselling.

The third line of therapy is Surgical treatment with Implants and counseling.

So Counselling forms the mainstay of treatment of ED The Oral Drugs are Phosphodiesterase 5 Inhibitors (PDE5 inhibitors) (Table 1)

To understand the treatment of ED one must understand that a normal vascular and neuronal endothelium produces endothelial nitric oxide synthase and neuronal nitric oxide synthase. eNOS and nNos initate the NO to enter in the corpora cavernosa spony tissue and converts Guanosine Monophosphate to Cyclic Guanosne Monophosphate with the help of an enzyme Gyanylate Cyclase. This Cyclic GMP is the main chemical which relaxes the smooth muscle cell of the Corpora and allows the blood to flow in penile vasculature. This cGMP also decreases the Calcium influx through specific protein kinases and allows the smooth muscle relaxation and erections.

These drugs block the conversion of Cyclic Guanosine Monophosphate(CGMP) to 5,Guanosine Monophosphate and make CGMP more bioavailable which relaxes the smooth muscles and allows the blood to flow in the intracavernosal vasculature. (Figure 2)

But soon cGMP gets hydrolysed to 5 Guanosine monophosphate with the help of a enzyme Phosphodiastrase 5.

• Dizziness

140 135 130 125 120 115 110 105 100 95 90

The three PDE5 inhibitors available in our country are Sildenafil Citrate,Tadalafil and Udenafil.

Side Effects of PDE5 inhibitors include •

Facial flushing

• Headache •

Nasal congestion

136

116 104

105

NoED (n:175)

Mild (n:64) p=0.38

Moderate (n:115) p=0.04

Severe (n:83) p<0.001

Severity of erectile dysfunction

Fig. 1: Platelet / lymphocyte ratio value

Fig. 2: Mechanism of action of PDE5I

Table 1: PDE5 inhibitors Parameter

Sildenafil

Tadalafil

Udenafil

Doses available

25mg,50mg,100mg

5mg, 20mg

100mg

Adminstration

Taken 90-120 mins prior the act

Taken at least 120 mins prior to act

Taken at least 60 mins prior to act

Food Interaction

Avoid Fatty meals

None

None

Mean time to peak concentration (C Max)

60 min

120 min

60 mins

T1/2

3-5 hours

17.5 hours

10-12 hours

The other non invasive treatment available is low intensity 1047 extra corporal shock wave therapy improves ED through angiogenesis.

• Dyspepsia •

Visual disturbance (blue halo)

• Priapism •

Contraindications include

•

Recent cardiovascular event

• Nitrates • Hypotension •

Anatomical deformity

•

Angulation, cavernosal fibrosis, Peyronie’s

•

Predisposition to prolonged erection

-

Sickle cell disease

-

Multiple myeloma

-

Leukaemia

PDE 6 enzyme inhibition is less with Udenafil compared to Sildenafil - no Visual Abnormality PDE 11 enzyme inhibition with Udenafil is less than Tadalafil – No myalgia.

Now we also have mouth dissolving films of Sildenafil and Tadalafil which have faster onset of action and lesser side effects.

The newer oral drugs which shall soon be available are avanafil, mirodenafil, lodenafil carbonate and SLX2101.

The second line of treatment is Injection of papaverine and largactil with or without prostaglandin available as bimix or trimix self filled injection. Always caution the patient of priapism. The site of injections which shouldbe avoided are 12oclock position as it can damage the neurovascular bundle and 6 oclock position of the shaft of the penis as this can damage the urethra.

Vaccum devices can be advised to patients who have undergone Prostatectomy or elderly diabetics Though this devise is non invasive drug free and cost effective it is cumbersome, sometimes pts complain of pain and numbness and delayed ejaculations.

MUSE is medicated urethral insertion of drugs with the help of a device and prostaglandin pellets are introduced in the urethra.

Some observations in my practice is that many young adults have low sexual desire and have low free testosterone and high SHBG, these patients were put on testosterone replacement therapy did develop azoospermia. Many adults who had long standing co morbid conditions if put on testosterone replacement therapy did develop cardiovascular outcomes.

So the dilemma is what have to be done to improve the sexual desire of diabetics who have hypo androgenism.

Its imperative to give them something which has a testosterone like effect and also does not have adverse effects of testosterone.

According to Masters and Johnsons male sexual response, one has to have a desire to get a proper arousal and if the desire is inadequate (Figure 3).

We have only focused on erection and ignored the desire which is the first to be in a male sexual response. So there exists a therapeutic gap in treatment of hypoactive sexual desire disorders in men with diabetes. But we now have a novel neutraceutical which has a tremendous effect of improving the sexual desires of our diabetic men. These neutraceuticals have L arginine which is a proven nitric oxide donor and ingredients combined with it are Saponised Fenugreek which has been studied to improve free testosterone levels to almost double and do not have any adverse side effects like synthetic testosterone. These neutraceuticals also have zinc which helps in spermatogenesis and also magnesium which has a relaxing effect and pyridoxine which helps in absorbtion of zinc and magnesium. There are many phytoneutraceuticals which have L Arginine combined with Pyknogenol, Safed Musli, Terrestris Trichuris, Asparagus adscendens,Withania somnifera, Mucuna pruriens, Ginesing and Ginkgo biloba.

These combination with L Arginine help in improving the sexual desire and not give any side effects like synthetic testosterone.. We have a ongoing study of this neutraceutical and it has been showing us a promising future.

The Newer Therapies are Regenerative therapies

Guanalyl Cyclase Activators and Stimulators as these increase the cellular cGMP concentration via the direct

CHAPTER 228

Fig. 3: Male Sexual Response

The surgical treatment of ED is insertion of penile prosthesis or implants. The cheapest implant is made by Dr Rupin Shah which is a implant which is non inflatable and has a differential rigidity. Today we have 2 piece implants and 3 piece implants and the most widely recommended is three piece implant as these are totally concealed in body. Device is inflated to provide rigidity and deflated for concealment. Erection longevity is controllable. When deflated, the cylinders are soft and flaccid and they do expand the penis in girth.

1048 activation of sGC, which results in both vasorelaxation

and inhibition of platelet aggregation.

BEYOND MEDICINE

Rho- Kinase Inhibitors: Inhibition of the calcium sensitization pathway with Rho-kinase inhibitors offers a therapeutic option for the treatment of ED that does not involve the direct targeting of the NO/sGC/cGMP pathway.

Sonic Hedgehog Shh is a secreted protein important for formation of penile structures in the embryonic and early postnasal period and also for maintaining the sinusoids in aduts. Clinical evidence suggest that Shh is reduced in the penis of diabetic rats and human, and administration of exogenous Shh increased vascular endothelial growth factor and Nitric Oxide Synthase. Schwann cells in the penile nerual tracts contained abundant Shh. So Nanofiber aligned along the crushed nerve fibers during surgery observed enhanced regeneration of nerve fibres as seen on electron microscopy.

Gene Therapy: An adenoviral vector constructed to introduce a gene coding for a protein has been useful for improving ED. Mesenchymal Stem Cell Therapy: Increasing evidences suggest the presence of penile endogenous Stem Cellss, with the regenerative potential that rely on endogenous Stem Cells/progenitor cells thus offer new insights into ED therapy.

Nano technology : Primarily this technology applies for topical delivery of drugs for on demand erectile function, Injectable gels into the penis to prevent morphology changes post prostatectomy, Hydrogels to promote CN regeneration/neuroprotection and Encapsulation of drugs to increase erectile function (primarily of PDE5i) So a Ideal Prescription for a Diabetic having ED should be OHA/Insulin, Statin, Aspirin,Antihypertensive preferably ARBs, Nebivalol or Indepamide. Low dose Tadalafil 5mg, L-Arginine Plus, and low dose testosterone if he has low Free Testosterone.

Even though we prescribe the medicines for cure, emotional bonding makes the process faster. Talk about your fears and insecurities with your partner. Do not live under the stress for performance as for women, intercourse is all about emotional attachment. Enhance the emotional aspect and share your heart’s worries with your partner. One important message which I would like to convey is that it is proven beyond doubt that ED is the earliest marker of myocardial ischemia. So if a physician just asks a simple question to every male above 30 years of age that whether he has a problem in making love….

This shall open a Pandora’s box and give a physician a window of opportunity and a window of curability to work up this patient and save him from impending fatal cardiac problems. Lastly Diabetes is not an option, Not for anyone. It is how gracefully we handle the process and how lucky we are as the process handles us, and today if we are able to improve the metabolic imbalance by controlling diabetes, hypertension, dyslipidaemia we

have lots of avenues to offer our patients a cure for erectile dysfunction.

REFERENCES

1.

N.C.C. Impotence. NIH consensus development panel on impotence. JAMA 1993; 270:83–90.

2.

Uckert S, Mayer ME, Stief CG, et al. The future of the oral pharmacotherapy of male erectile dysfunction: Things to come. Expert Opin Emerg Drugs 2007; 12:219– 28.

3.

Gandaglia G, Briganti A, Jackson G, et al. A systematic review of the association between erectile dysfunction and cardiovascular disease. Eur Urol 2014; 65:968–78.

4.

Hodges LD, Kirby M, Solanki J, et al. The temporal relationship between erectile dysfunction and cardiovascular disease. Int J Clin Pract 2007; 61:2019-2025.

5.

Patatsoris AG, Korantzopoulos PG. Hypertension, antihypertensive therapy, and erectile dysfunction.

Angiology 2006; 57:47-52.

6.

Melman A, Gingell JC. The epidemiology and pathophysiology of erectile dysfunction. J Urol 1999; 161:5– 11. [PubMed]

7.

Melman A, Rehman J. Pathophysiology of erectile dysfunction. Mol Urol 1999; 3:87–102. [PubMed]

8.

El-Sakka AI, Morsy AM, Fagih BI, Nassar AH. Coronary artery risk factors in patients with erectile dysfunction. J Urol 2004; 172:251–254. [PubMed]

9.

User HM, Zelner DJ, McKenna KE, McVary KT. Microarray analysis and description of SMR1 gene in rat penis in a post-radical prostatectomy model of erectile dysfunction. J Urol 2003; 170:298–301. [PubMed]

10. Corona G, Mannucci E, Mansani R, et al. Aging and pathogenesis of erectile dysfunction. Int J Impot Res 2004; 16:395–402. [PubMed] 11. Aversa A, Isidori AM, De Martino MU, et al. Androgens and penile erection: evidence for a direct relationship between free testosterone and cavernous vasodilation in men with erectile dysfunction. Clin Endocrinol (Oxf) 2000; 53:517–522. [PubMed] 12. Marin R, Escrig A, Abreu P, Mas M. Androgen-dependent nitric oxide release in rat penis correlates with levels of constitutive nitric oxide synthase isoenzymes. Biol Reprod 1999; 61:1012–1016. [PubMed] 13. Baba K, Yajima M, Carrier S, et al. Delayed testosterone replacement restores nitric oxide synthase-containing nerve fibres and the erectile response in rat penis. BJU Int 2000; 85:953–958. [PubMed] 14. Traish AM, Munarriz R, O’Connell L, et al. Effects of medical or surgical castration on erectile function in an animal model. J Androl 2003; 24:381–387. [PubMed] 15. Aversa A, Isidori AM, Greco EA, et al. Hormonal supplementation and erectile dysfunction. Eur Urol 2004; 45:535–538. [PubMed] 16. Yoshino O, Matsuno H, Nakamura H, et al. The role of Fas-mediated apoptosis after traumatic spinal cord injury. Spine 2004; 29:1394–1404. [PubMed] 17. Fraiman MC, Lepor H, McCullough AR. Changes in penile morphometrics in men with erectile dysfunction after nerve-sparing radical retropubic prostatectomy. Mol Urol 1999; 3:109–115. [PubMed] 18. Siroky MB, Azadzoi KM. Vasculogenic erectile dysfunction:

newer therapeutic strategies. J Urol 2003; 170:S24– S29. discussion S29–S30. [PubMed] 19. Gongora Castillo C, Alvarez Gomez de Segura I, Bonet Furgeri H, de Miguel del Campo E. Impotence of arterial origin: experimental models and evaluation of sexual behavior in rats. J Urol (Paris) 1993; 99:122–126. [PubMed] 20. Lue TF. Penile venous surgery. Urol Clin North Am 1989; 16:607–611. [PubMed] 21. Muller SC, Hsieh JT, Lue TF, Tanagho EA. Castration and erection; an animal study. Eur Urol 1988; 15:118– 124. [PubMed]

23. Yamagishi S, Takeuchi M, Inagaki Y, Nakamura K, Imaizumi T. Role of advanced glycation end products (AGEs) and their receptor (RAGE) in the pathogenesis of diabetic microangiopathy. Int J Clin Pharmacol Res 2003; 23:129–134. [PubMed] 24. Bivalacqua TJ, Champion HC, Usta MF, et al. RhoA/Rhokinase suppresses endothelial nitric oxide synthase in the penis: a mechanism for diabetes-associated erectile dysfunction. Proc Natl Acad Sci U S A 2004; 101:9121– 9126. [PMC free article] [PubMed] 25. Alici B, Gumustas MK, Ozkara H, et al. Apoptosis in the erectile tissues of diabetic and healthy rats. BJU Int 2000; 85:326–329. [PubMed] 26. Yamanaka M, Shirai M, Shiina H, et al. Diabetes induced erectile dysfunction and apoptosis in penile crura are recovered by insulin treatment in rats. J Urol 2003; 170:291– 297. [PubMed] 27. Ferber D. Gene therapy: repair kits for faulty genes. Science 2001; 294:1639. [PubMed] 28. Magee TR, Ferrini M, Garban HJ, et al. Gene therapy of erectile dysfunction in the rat with penile neuronal nitric oxide synthase. Biol Reprod 2002; 67:1033–1041. [PubMed] 29. Magee TR, Ferrini MG, Davila HH, et al. Protein inhibitor of nitric oxide synthase (NOS) and the N-methyl-D-aspartate receptor are expressed in the rat and mouse penile nerves and colocalize with penile neuronal NOS. Biol Reprod 2003; 68:478–488. [PubMed] 30. Hedman M, Hartikainen J, Syvanne M, et al. Safety and feasibility of catheter-based local intracoronary vascular endothelial growth factor gene transfer in the prevention of postangioplasty and in-stent restenosis and in the treatment of chronic myocardial ischemia: phase II results of the Kuopio Angiogenesis Trial (KAT). Circulation 2003; 107:2677–2683. [PubMed] 31. Lin CS, Ho HC, Chen KC, et al. Intracavernosal injection of vascular endothelial growth factor induces nitric oxide synthase isoforms. BJU Int 2002; 89:955–960. [PubMed] 32. Rogers RS, Graziottin TM, Lin CS, et al. Intracavernosal vascular endothelial growth factor (VEGF) injection and adeno-associated virus-mediated VEGF gene therapy prevent and reverse venogenic erectile dysfunction in rats. Int J Impot Res 2003; 15:26–37. [PubMed] 33. Yamanaka M, Shirai M, Shiina H, et al. Vascular endothelial growth factor restores erectile function through inhibition of apoptosis in diabetic rat penile crura. J Urol 2005; 173:318–323. [PubMed]

35. Krenn-Pilko S, Langsenlehner U, Thurner EM, Stojakovic T, Pichler M, Gerger A, et al. The elevated preoperative platelet- to-lymphocyte ratio predicts poor prognosis in breast cancer patients. Br J Cancer 2014; 110:2524e30.

36.

Raungkaewmanee S, Tangjitgamol S, Manusirivithaya S, Srijaipracharoen S, Thavaramara T. Platelet to lymphocyte ratio as a prognostic factor for epithelial ovarian cancer. J Gynecol Oncol 2012; 23:265e73.

37. Unal D, Eroglu C, Kurtul N, Oguz A, Tasdemir A. Are neu- trophil/lymphocyte and platelet/lymphocyte rates in patients with non-small cell lung cancer associated with treatment response and prognosis? Asian Pac J Cancer Prev 2013; 14: 5237e42.

38. Ciftci H, Gumus K, Yagmur I, Sahabettin S, Celik H, Yeni E, et al. Assessment of Mean Platelet Volume in men with vas- culogenic and nonvasculogenic erectile dysfunction.

Int J Impot Res 2015; 27:38e40.

39. La Vignera S, Condorelli RA, Burgio G, Vicari E, Favilla V, Russo GI, et al. Functional characterization of platelets in patients with arterial erectile dysfunction. Andrology 2014; 2:709e15.

40. Esposito K, Ciotola M, Giugliano F, et al. Endothelial microparti- cles correlate with erectile dysfunction in diabetic men. Int J Impot Res 2007; 19:161-6.

41. Sildenafil treatment of women with AntidepressantAssociated Sexual Dysfunction. JAMA 2008; 300:395-404 42. Giuliano FA, Rampin O., Benoit G., Jardin A.. Neural control of penile erection. Urol Clin North Am 1995; 22:747– 766.

43. Kedia, Stefan Ückert, Farhang Assadi-Pour, Markus A. Kuczyk and Knut Albrech. Avanafil for the treatment of erectile dysfunction: initial data and clinical key properties 2013 5: 35 originally published online 21 November 2012 Therapeutic Advances in Urologty George T. 44. Shehzad B, Andrea Coelle, et al Adverse Events Associated with testosterone Administration. New Engl Jor Medic 2010; 365:2 45. Potentials of Phtyto therapeutic treatment of Erectile Dysfunction by Guillome Abouma, Claudine Mannirfasha.. et all 10, 57172, 57174 Department of Biomedical Sciences, Faculty of health and wellness, Cape Peninsula, University of Tech. Bellville, South Africa 46. Pyknogenol and Erectile Dysfunction: Int J Impot Res. 2008 Mar-Apr;20(2):173-80. Epub 2007 Aug 16, Stanislavov R, Nikolova V, Rohdewald P. 47. Recruiting Endogenous stem cells: A novel therapeutic approach for treatment of Erectile Dysfunction. Zhong Chen Xin, Yong De Xu, Guiting Lin, Tom, F Lue, Asian Journal of Andro. 2015 17,1-6.

48. Mesenchymal Stem Cell therapy for treatment of Erectile Dysfunction. Mohit Khera, Marten Albersen, John Mulhall 49. Evaluation of Efficacy and Safety of once a day daily dosage of Tadalafil 5mg A randaomised Multicentric double blind placebo control trial: European Journal of Urology 50-2006351-359.

50. Can Low Intensity Extracorporal Shock wave therapy improve Erectile dysfunction? Europen Journal 58(2010) 241-249.

CHAPTER 228

22. Cartledge JJ, Eardley I, Morrison JF. Advanced glycation end-products are responsible for the impairment of corpus cavernosal smooth muscle relaxation seen in diabetes. BJU Int 2001; 87:402–407.[PubMed]

34. Christ GJ. Frontiers in gene therapy for erectile 1049 dysfunction. Int J Impot Res 2003; 15(suppl 5):S33–S40.

[PubMed]

1050 51. Efficacy and Safety of Lodenafil Carbonate in the Treatment of Erectile Dysfunction in Patients With Diabetes. Multicentric Study Clinical Trials.gov Identifier:NCT01180283, March-2013.

54. Emerging Molecular targets for treatment of Erectile Dysfunction Vascular and Regenerative therapies on the Horizon. Inger Stallmann-Jogerson and R Clinton Webb Current Drug Targets 2015-16, 427-441.

52. All Diabetic Men are Testosterone Deficient. Eric L. Ding, BA; Y. Song MD et al. Sex Differences of Endogenous Sex Hormones and Risk of Type 2 Diabetes. JAMA 206; 295:1288-99.

55. US National Library of Medicine Gene therapy using adenovirus vector.

BEYOND MEDICINE

53. ED and L-Arginine Chen J, Wollman Y, Chernichovsky T, Iaina A, Sofer M, Matzkin H. BJU Int 1999; 83:269-73

56. Nanotechnology for ED. Topical delivery of drugs for on demand EF Han G, Tar M, Kuppam DSR, Friedman A, Melman A, Friedman J, Davies KP. J Sex Med 2014; 7:224233.

C H A P T E R

229

Chronic Fatigue Syndrome

INTRODUCTION

Chronic fatigue syndrome (CFS) is a disorder characterized by persistent , incapacitating fatigue of sudden or definite onset unrelieved by rest with associated symptoms which is not explained by any medical or psychiatric illness.

The term ‘chronic fatigue syndrome’ and the criteria for diagnosing the disease were introduced in 1988, however over the past two centuries, illnesses presenting with outbreaks of chronic fatigue, and constellation of other symptoms similar to this disease were identified as neurasthenia, myalgic encephalomyelitis, ‘Raggedy Ann syndrome’, Royal Free disease and chronic infectious mononucleosis.

EPIDEMIOLOGY

In U. S. the prevalence rates in adults vary between 0.2 – 0.4%. A study from UK reported a 9% prevalence whereas V. Patil et al reported 10% prevalence in women in their study done in Goa. Common age of presentation is between 30 -40 years although it has been reported in children and adolescents too. Cases are reported from all parts of the world. More common in females, in less educated and low socioeconomic strata.

ETIOPATHOGENESIS

The exact etiology and pathogenesis of chronic fatigue syndrome is still an enigma. There is a complex interplay between predisposing, perpetuating and precipitating factors which may vary from individual to individual.

Various hypotheses have been given for understanding the pathogenesis. These are based on clinical studies focussing on one or more factors associated with this condition. However these are statistical associations and a consistent causal relationship with any factor has not been established in large proportion of cases. Following factors have been identified -

Genetic

Clustering of CFS cases can occur in a single family but it has not been proven contagious. Twin studies indicate a familial predisposition but no gene /genes responsible have been identified.

Immunologic

Jalees Fatma

None of these are present as a consistent feature in most patients nor does it correlate with severity of disease.

Infections

Multiple infectious agents have been linked to CFS. Borna disease virus, parvovirus B19,glandular fever, Enterovirus, human herpesviruses 4, 6, and 7, Nipah virus encephalitis, Infectious Mononucleosis, Q fever and Lyme disease. The latter three have been associated in a high percentage of cases. While antecedent infections are associated with CFS, a direct causal relationship with any microbial infection has not been established.

Endocrine/Metabolic •

Hypothalamic hypoactivity

-

pituitary

-

adrenal

(HPA)

•

Higher chronic adrenocorticotropic (ACTH) autoantibody levels

•

Low magnesium level,

•

Low arachidonic acid level,

•

Low l-carnitine level and

•

Low cortisol levels. (poorer response to CBT)

hormone

Neurological - Neuroimaging studies have revealed •

Glucose hypometabolism in the frontal cortex and brain stem, with

•

Decreased number and or affinity for the receptor protein for serotonin in the hippocampus and

•

Decreased grey matter volume (in population study)

PSYCHOLOGICAL AND PSYCHOSOCIAL FACTORS

Factors Predisposing to CFS

Obsessional type of personality,

High parental mental stress Childhood and adult neglect, abuse and maltreatment Increased level of stress Pre morbid psychiatric illness

•

Modest elevation of ANA

Perfectionist attitude and personality

•

reduced immunoglobulin levels,

Factors Perpetuating CFS

•

Abnormal natural killer cell cytotoxicity,

•

increase immune activation markers,

•

greater numbers of CD16+/CD3− natural killer cells

Disordered sleep

Family illness burden Non-acknowledgment by physician

1052

Table 1: Conditions which should be excluded before making a diagnosis of CFS Medical Illnesses

Psychiatric disorders

Miscellaneous

Anaemia

Major Depressive disorder

Alcohol abuse

Type 2 diabetes

Bipolar Disorder

Substance abuse

BEYOND MEDICINE

Hypothyroidism Schizophrenia Connective tissue disorders

Anorexia Nervosa

Myopathies

Bulimia Nervosa

Morbid obesity BMI (>40)

Myasthenia gravis and other myasthenia syndromes

Table 2: Diagnostic criteria for Chronic Fatigue Syndrome 1. Persistent, Severe, debilitating fatigue for 6 months or more 2. Fatigue is not lifelong, it has a new or definite onset 3. Fatigue is unexplained by/unrelated to physical exertion or organic disease 4. Not substantially relieved by rest 5. Fatigue results in a significant reduction in previous social, occupational, educational and personal activity levels 6. Four or more of the following additional symptoms lasting for >6 consecutive months a. Impaired memory or concentration, b. Sore throat, c. Tender cervical or axillary lymphadenopathy, d. Myalgias,

Chronic Heart failure

e. Pain in several joints,

Chronic obstructive pulmonary diseases

g. Post exertional (physical or mental) malaise, (which may be delayed in onset with prolonged extreme exhaustion)

Chronic Renal failure Chronic liver disease Multiple sclerosis Neoplastic Disease Excessive significance given to symptoms & catastrophic thinking about disease Fear of fatigue Avoidance of physical activity Lack of social support Self- efficacy to do things despite the problems.

Over-vigorous activity alternating with resting for long periods

DIAGNOSIS

Chronic fatigue syndrome is a diagnosis of exclusion. This is often challenging to the physicians as fatigue is a part of many diseases. Detailed history and thorough clinical examination is a must to rule out disorders causing fatigue (Table 1). Tachycardia is often present. CFS has a considerable overlap with fibromyalgia.

Laboratory tests

No specific test can diagnose CFS. Tests are done to exclude medical illnesses causing fatigue. Extensive testing is not productive. Investigations should be planned judiciously guided by clinical clues.

f. Headache of new onset, type or increased severity ,

h. Un-refreshing sleep.

For the diagnosis of CFS, various diagnostic criteria have been made. The most commonly used diagnostic criteria for clinical and research purpose is the United States CDC (centre for disease control) criteria. This is also called Fukuda criteria and is based on Holman 1988 scoring system.

The Fukuda criteria of CFS are shown in (Table 1).

Exclusion Criteria

Medical, psychiatric and other conditions explaining fatigue (Table 1).

Certain other points need attention Cognitive Dysfunction: Significant decrease of cognitive functions is seen in many cases of CFS. The affected domains are attention, memory , information processing and reaction time and this impairment is reflected in day-to-day activities. There is difference in actual and perceived cognition. Motor speech, language, reasoning and intelligence are unaltered.

Severity of disease: CFS can be mild, moderate or severe.

Patients with mild CFS are mobile, can care for themselves and can do light domestic tasks with some difficulty.

Patients with moderate CFS have reduced mobility and are restricted in their activities of daily living. They may have peaks and troughs in their daily activities. Patients with severe CFS are incapacitated and are able to do minimal tasks only.

Phases of Disease & The triggering event?: The four fennel phases of the disease are described as crisis, stabilization, resolution and integration. Most patients describe an infection, a flu like illness or infectious mononucleosis,

somatic events like pregnancy, injury, child birth & surgery as the triggering event. Serious life events and stressors may also precipitate it.

Medications to reduce pain, discomfort, fever 1053 (when present)

•

Medications to treat anxiety and depression

•

Relaxation and stress-reduction techniques such as:

–

Biofeedback

–

Deep breathing techniques

–

Hypnosis

Psychological problems are common (irritability, mood swings, anxiety, panic attacks).

–

Massage therapy

–

Meditation

MANAGEMENT

–

Muscle relaxation techniques

–

Yoga

Other Symptoms: Irritable bowel, nausea, diarrhoea or dyspepsia, chills and night sweats, Brain fog, chest pain, shortness of breath, chronic cough, visual disturbances, Allergies or sensitivities to foods, odours, chemicals, medications or noise, orthostatic instability, irregular heartbeat, dizziness, balance problems or fainting.

Management is often difficult and response is variable.

It may take a long time. Functional disability, phase & severity of disease should be assessed. The subjectivity can be eliminated by questionnaire based evaluation.

Physician must not negate the presence of symptoms, as this can lead to aggravation of disease.

Three main forms of treatments Cognitive behavioural therapy (CBT) is a psychotherapeutic approach directed at helping the patient understand the nature of disease, suggestions to change lifestyle to improve symptoms, changing the perception of patient regarding fatigue and exertionrelated concerns, reducing a focus on symptoms, and develop coping mechanisms. The patient is encouraged to restore sleep hygiene, to remain as active as possible, and to gradually return to previous levels of exercise and other activity. CBT typically consists of 12–14 sessions spread over 6 months & improves symptoms.

Graded Exercise therapy (GET): GET usually consists of an exercise program based on simple activities like walking or cycling that continues for 3–5 months. Exercise is gradually increased, with set goals for maximal heart rates. The target is to improve upon deconditioning and gradual recovery of exercise intolerance.

CBT and GET appear to improve fatigue primarily by changing the patient’s perception of the fatigue and also by reducing the focus on symptoms. Among these two, CBT is more effective.

Pacing: The basic concept is that the energy available to a particular patient is fixed and its expenditure throughout the day may be planned so that the daily activities are accomplished without precipitation of fatigue. Therefore, after each scheduled activity a period of rest or relaxation is introduced.

Other Treatment Interventions •

Healthy diet

Prognosis

About half of the patients of CFS show some improvement, and about 30% continue to remain disabled. Recovery rates of adult CFS have been shown in the range of 5% but are better for children and adolescents. Return to work ranges from 8% to 30% among the patients with CFS. Mortality due to CFS is rare.

REFERENCES

1.

Wessley S. The history of chronic fatigue syndrome. In: Straus S, editor. Chronic Fatigue Syndrome. New York: Mark Dekker; 1994. p. 41-82.

2. Christley Y, Duffy T, Everall IP, Martin CR. The neuropsychiatric and neuropsychological features of chronic fatigue syndrome: Revisiting the enigma. Curr Psychiatry Rep 2013; 15:353.

3. Afari N, Buchwald D. Chronic fatigue syndrome: A review.

Am J Psychiatry 2003; 160:221-36.

4. Reynolds NL, Brown MM, Jason LA. The relationship of Fennell phases to symptoms among patients with chronic fatigue syndrome. Eval Health Prof 2009; 32:264-80.

5. Alraek T, Lee MS, Choi TY, Cao H, Liu J. Complementary and alternative medicine for patients with chronic fatigue syndrome: A systematic review. BMC Complement Altern Med 2011; 11:87.

6. Patel V., Kirkwood B R. Weiss H, Pednekar S, Fernandes J,Pereira B, et al Chronic fatigue in developing countries: population based survey of women in India. BMJ 2005; 330:1190 7.

Lorusso L, Mikhaylova SV, Capelli E, Ferrari D, Ngonga GK, Ricevuti G. Immunological aspects of chronic fatigue syndrome. Autoimmun Rev 2009; 8:287-91.

8. Bhui KS, Dinos S, Ashby D, Nazroo J, Wessely S, White PD. Chronic fatigue syndrome in an ethnically diverse population: the influence of psychosocial adversity and physical inactivity. BMC Med 2011; 9:26.

9. Abbi B, Natelson BH. Is chronic fatigue syndrome the same illness as fibromyalgia: Evaluating the “single syndrome” hypothesis. QJM 2013; 106:3-9.

CHAPTER 229

•

Reducing Breast Cancer: Risks and Options

C H A P T E R

230

Karthik Ghosh, Amit K Ghosh

INTRODUCTION

Breast cancer is amongst the commonest cancers among women in India1-3. An analysis of breast cancer cases among women in Delhi, Mumbai, Chennai and Bangalore between 1982 to 2005 performed by the Indian Council of Medical Education and Research, revealed that the number of breast cancer cases have more than doubled in the last 10 years3. Although the incidence of breast cancer among women in India is low, the number of women with breast cancer is quite high (In a report by the Globocan Project in 2012, it was estimated that 144,937 women were diagnosed with breast cancer and 70,218 died of breast cancer in 20122. In 2012, cancer statistics showed 226,870 women will be diagnosed with breast cancer in the US compared to nearly 145,000 in India; 39,510 will

Table 1: Factors that Influence Breast Cancer Risk Risk Factors

Effect on breast cancer risk

Age

Increase with increasing age

Family History

Increases based on number and degree of relationship, and age of affected relative

Benign Breast disease

Atypical hyperplasia increases risk

Breast density

Dense breasts increases risk

Genetics

Hereditary breast cancer: BRCA 1 and 2, TP53, CDH1, PTEN

Chest wall radiation for Hodgkinâ&#x20AC;&#x2122;s disease

Increases risk

Exercise*

Lowers risk

BMI*

High BMI increases risk

Alcohol*

Excess use increases risk

Diet*

High fat diet increases risk

Post-menopausal hormone use*

Prolonged use of estrogen and progesterone increases risk

Smoking*

Increased risk

Reproductive factors such as breast feeding, age at first childbirth*

Lactation lowers risk; early age at first parity reduces risk

* Modifiable or potentially modifiable risk factor

die of breast cancer in the US compared to almost 71,0000 India1,4. Mortality rates are higher likely due to multiple factors related to lack of awareness, screening, early diagnosis and treatment options.

The cause for the increase in breast cancer risk is likely multifactorial due to known associations of multiple risk factors with breast cancer. Reports have suggested that the increase in incidence of breast cancer in urban Indian women may be related to lifestyle changes such as the adoption of a western diet, higher alcohol use and increased obesity. Moreover, rapid urbanization and improvements in the Indian economy have led the working woman to postpone childbearing, have fewer children and decreased breast feeding practices; practices that may increase breast cancer risk by prolonged exposure to estrogen3. Population based studies are needed to determine if specific risk factors are more relevant to the population in India. In this report, we discuss known and potential factors that influence risk and strategies that can reduce breast cancer risk.

BREAST CANCER RISK FACTORS

While there is evidence that some known risk factors for breast cancer such as age, family history, age at menarche, age at menopause, age at first live birth, and proliferative breast biopsy findings, others such as lifestyle may modify risk but research is still ongoing to understand them5-7.

Some of these risk factors are non-modifiable such as age and family history. However, other suspected risk factors such as diet rich in fat, excess use of alcohol, prolonged use of post-menopausal hormone therapy and smoking also increase risk (risk factors known and potential are listed in Table 1.

Several reports demonstrate that the risk of breast cancer increases with increasing age4,5. While breast cancer is rare in women younger than age 20 years, the probability of breast cancer increases as women age4. Family history of breast cancer puts a woman at increased risk, but the number, degree and age of affected relatives influences the extent of risk6,7. Hereditary breast cancer occurs in association with gene mutations such as BRCA 1 and 2, and with evolving research, other genes such as TP53, CHD1 and PTEN are also now being associated with breast cancer risk8-12. Reproductive factors such as early menarche and late menopause results in prolonged estrogen exposure and are associated with a small increase in risk13. Early child birth and prolonged lactation on the other hand, reduces breast cancer risk7,14. Postmenopausal hormone therapy with combined estrogen and progesterone has

Table 2: Strategies to Reduce Breast Cancer Risk Specific Measures/ Agents

Lifestyle interventions

Exercise, maintain a healthy weight/ BMI, low fat diet, avoid or minimize alcohol use

Medications

Tamoxifen, Raloxifene, Exemestane

Surgical Options

Bilateral mastectomies; Bilateral Salpingooophorectomies

been shown to increase breast cancer risk (HR: 1.27; 95%CI, 0.91-1.78)15. Women who have benign breast biopsies showing atypical hyperplasia are also at elevated risk (RR 4.2; 95% CI: 3.26-5.41) and the risk persists for at least 25 years after the biopsy16. Women who receive chest wall radiation therapy for Hodgkinâ&#x20AC;&#x2122;s lymphoma are at 3-fold increased risk of breast cancer (standardized morbidity ratio 8.5% for women younger than 30 years to 1.2% for those 30 and older at radiation therapy)17. With increasing use of screening mammography, studies demonstrated that the finding of dense breasts on mammogram increases breast cancer risk. Women with dense tissue comprising over 60-75% of the mammogram have a four to six fold increased risk than women with non-dense breasts18-20. Gathering accurate risk factor information from the patient can facilitate risk stratification efforts so that resources for breast cancer screening and risk reduction can be appropriately directed.

STRATEGIES FOR REDUCING BREAST CANCER RISK

Research studies on breast cancer risk reduction have been directed at reducing the known risk factors for breast cancer. In general, these strategies can be classified into lifestyle modifications to reduce breast cancer risk, use of risk reducing medications and risk reducing surgeries (Table 2).

LIFESTYLE MODIFICATIONS

Several lifestyle factors have been described that are associated with reduced breast cancer risk and can be incorporated into an individualâ&#x20AC;&#x2122;s lifestyle. These include regular exercise, healthy diet, maintaining a healthy weight, limiting alcohol and avoidance of prolonged postmenopausal combined hormone therapy.

Physical activity has been associated with reduced breast cancer risk in multiple prior reports especially in postmenopausal women21-23. Moreover, physical activity in adolescence and young adulthood is associated with reduced breast cancer risk (RR 0.81 95% CI 0.73-0.89)24.

General recommendations include at least 150 minutes of moderate intensity or 75 minutes of vigorous intensity activity each week for adults, and limiting sedentary behavior such as sitting or lying down25.

Studies to assess the relationship between dietary factors and breast cancer risk showed positive associations with

Increased body weight/ body mass index is a known risk factor for breast cancer27. In a meta-analysis study, obesity increased the risk of estrogen receptor positive postmenopausal breast cancer (relative risk 1.39) especially in women who did not use postmenopausal hormone therapy27. The Nursesâ&#x20AC;&#x2122; Health Study showed that postmenopausal women who lost 10kg or more of their weight reduced their breast cancer risk by 56% (95% CI 0.21-0.86; p=0.01)28. Moreover, studies have also shown that weight gain after age 18 associated with increased postmenopausal breast cancer incidence29. Hence, we recommend that regular exercise, healthy diet and a healthy body weight should be strongly encouraged when aiming for breast cancer risk reduction.

Several prior studies have demonstrated a consistent association between alcohol and breast cancer risk30-33. A meta-analysis study showed that women consuming >45 gm (>3 drinks) daily had 1.5 times increased risk than non-drinkers31. Moreover, the risk has been shown to be dose-dependent31. Limiting alcohol to less than a serving a day is a practical approach25.

Post-menopausal hormone therapy with estrogen and progesterone over 5 years was found to be associated with increase in incident breast cancers34. However, the risk was not increased in women who only received estrogen without progesterone following hysterectomy.

Therefore, women need to be informed of benefits and the risks of these medications when used to manage menopausal symptoms. In addition, this information should be reassessed on a yearly basis while she is on the medication with a plan to avoid long term use.

MEDICATIONS TO REDUCE RISK

Studies with anti-estrogen therapy have consistently demonstrated reduction in breast cancer risk35-38.

These agents including the selective estrogen receptor modulators (SERM), tamoxifen and raloxifene, as well as the aromatase inhibitors exemestane and anastrozole, have demonstrated definite benefits but also side-effects from therapy and are options for the high-risk population.

Additionally, factors such as the cost and availability of the medication are also important when making a choice of taking the medication. Tamoxifen is the only agent that can be used for pre-menopausal women whereas all three agents can be used for post-menopausal women.

Tamoxifen is a SERM that continues to be been used for adjuvant therapy of estrogen receptor positive breast cancer. Subsequently, tamoxifen was studied for breast cancer prevention showing reduction in the risk after 5 years of use35. A meta-analysis of tamoxifen trials showed that after 5 years of use, tamoxifen reduced invasive breast cancer risk by 33% (relative risk reduction 0.67; 95%CI

CHAPTER 230

Strategies

excess intake of calories, high saturated fat, and excess 1055 alcohol while inconclusive findings were noted on the association between dietary fiber, fruits and vegetables, soy and vitamin supplements26. A healthy low fat diet that is rich in fiber, fruits and vegetables is encouraged for breast cancer risk reduction.

1056 0.52 to 0.86)23. Side-effects of the medication include hot

BEYOND MEDICINE

flashes, vaginal concerns, and weight gain similar to all anti-estrogens, but also the risk, albeit small, of deep vein thrombosis, pulmonary embolism, stroke and uterine cancer.

Raloxifene is a SERM that has been used for osteoporosis treatment for many years39. In the second breast cancer prevention trial, the STAR trial, raloxifene was demonstrated to reduce breast cancer risk similar to tamoxifen in postmenopausal women36. In a metaanalysis of raloxifene trials, the medication taken for 4 to 8 years, reduced estrogen receptor positive breast cancer by 59%(relative risk reduction 0.41;95% CI,0.27 to 0.62)23.

While the side-effects of hot flashes, vaginal concerns, and weight gain were similar to tamoxifen, there were fewer events in terms of deep vein thrombosis, pulmonary embolism, stroke and uterine cancer.

Exemestane, an aromatase inhibitor, is an option for reducing risk for postmenopausal women at elevated breast cancer risk. In an international, randomized, placebo-controlled trial of exemestane for breast cancer prevention in post-menopausal women, this agent resulted in 65% reduction in risk of invasive breast cancer (risk ratio 0.35; 95% CI 0.18 to 0.7;p0.002) at a median follow up of 35 months37. Side effects include menopausal symptoms of hot flashes, insomnia and arthralgias, and reduced bone mineral density.

Anastrozole is another aromatase inhibitor that more recently was shown to reduce breast cancer risk when used in postmenopausal women. In an international, randomized, double blind, placebo controlled trial of high risk women from 18 countries, anastrozole taken for 5 years was associated with reduced risk ((hazard ratio 0·47, 95% CI 0·32–0·68, p<0·0001)38.

RISK REDUCING SURGERY

In women who are at very high risk of breast cancer such as BRCA 1 or 2 mutation carriers, prophylactic surgeries may be performed to reduce their breast cancer risk. However, these are patient-driven decisions that should be undertaken following extensive education and counseling to ensure that the patient understands the pros and cons of each decision. Risk reducing mastectomies have shown breast cancer risk reduction by 90% to 95%40,41. Risk reducing salpingo-oophorectomies (RRSO) have also been shown to reduce risk of ovarian as well as breast cancer and is an option for women at very high risk such as BRCA 1 and 2 mutation carriers42. Additional benefits of risk reducing procedures include reduction in anxiety and detection of occult malignancies but the side effects include menopausal symptoms (with RRSO), body image and sexuality issues, and the risks of surgical intervention.

SUMMARY

Prior reports have shown the association between variety of factors and development of breast cancer. Lifestyle modifications can be recommended to women to reduce breast cancer risk. These measures have multiple health

advantages and can be safely recommended to women irrespective of their risk status. Chemoprevention with agents such as tamoxifen or raloxifene, exemestane or anastrozole may be considered in select situations for women at high risk. Risk reducing surgery is an option for women at highest risk.

The above discussions detail several measures that can reduce breast cancer risk based on the current known information. Additionally, educating the population about breast awareness and advice to seek medical attention earlier for breast concerns, can potentially impact the growing problem of breast cancer in India.

REFERENCES

1.

Torre LA, Goding Sauer AM, Chen Jr MS. Et. al. Cancer statistics for Asian Americans, native Hawaiians, and pacific islander, 2016. CA Cancer J Clin 2016; 66:182-202.

2.

Torre LA, Bray F, Siegel RL, et al. Global Cancer statistics, 2012. CA Cancer J Clin 2015; 65:87-108.

3.

Shetty P. India faces growing breast cancer epidemic. Lancet 2012; 379:992-993.

4.

Siegel R, Naishadam D, Jemal A. Cancer Statistics 2012; 62:10-29.

5.

Hulka BS, Moorman PG. Breast cancer: hormones and other risk factors. Maturitas 2001; 38:103-13;

6.

Evans D, Lalloo F, Shenton A, Boggis C, Howell A. Uptake of screening and prevention in women at very high risk of breast cancer. Lancet 2001; 358:889-90.

7.

Key TJ, Verkasalo PK, Banks E. Epidemiology of breast cancer. Lancet Oncol 2001; 2:133-40.

8.

Couch FJ, Nathanson KL, Offit K. Two decades after BRCA: setting paradigms in personalized cancer care and prevention. Science 2014; 343:1466-70.

9.

Silwal-Pandit L, Langerød A, Børresen-Dale AL. TP53 Mutations in Breast and Ovarian Cancer. Cold Spring Harb Perspect Med 2016 Nov 4. pii: a026252. doi: 10.1101/ cshperspect.a026252.

10. Yadav P, Masroor M, Tanwer K, Mir R, Javid J, Ahmad I, Zuberi M, Kaza RC, Jain SK, Khurana N, Ray PC, Saxena A. Clinical significance of TP53 (R72P) and MDM2 (T309G) polymorphisms in breast cancer patients. Clin Transl Oncol 2016; 18:728-34.

11. Bubien V, Bonnet F, Brouste V, Hoppe S, et al. High cumulative risks of cancer in patients with PTEN hamartoma tumour syndrome. J Med Genet 2013; 50:255-63.

12. Berx G, Becker KF, Höfler H, van Roy F. Mutations of the human E-cadherin (CDH1) gene. Hum Mutat 1998; 12:22637.

13. Brinton LA, Schairer C, Hoover RN, Fraumeni JF. Menstrual factors and risk of breast cancer. Cancer Invest 1988; 6:245254.

14. Collaborative Group on Hormonal Factors in Breast Cancer.

Breast cancer and breast feeding: collaborative reanalysis of individual data from 47epidemiological studies in 30 countries, including 50302 women with breast cancer and 96973 women without the disease. Lancet 2002; 360:187-95.

15. Heiss G, Wallave R, Anderson GL. Health risks and benefits 3 years after stopping Randomized Treatment With Estrogen and Progestin. JAMA 2008; 299:1036-1045.

16. Hartmann LC, Sellers TA, Frost MH, Lingle WL, Degnim

AC, Ghosh K, Vierkant RA,Maloney SD, Pankratz VS, Hillman DW, Suman VJ, Johnson J, Blake C, Tlsty T,Vachon CM, Melton LJ 3rd, Visscher DW.Benign breast disease and the risk of breast cancer. N Engl J Med 2005; 353:229-37.

17. Wahner-Roedler DL, Nelson DF, Croghan IT, Achenbach SJ, Crowson CS, Hartmann LC, O’Fallon WM.Risk of breast cancer and breast cancer characteristics in women treated with supradiaphragmatic radiation for Hodgkin lymphoma: Mayo Clinic experience. Mayo Clin Proc 2003; 78:708-15.

19. Vachon CM, Brandt KR, Ghosh K, Scott CG, Maloney SD, Carston MJ, Pankratz VS, Sellers TA. Mammographic breast density as a general marker of breast cancer risk. Cancer Epidemiol Biomarkers Prev 2007; 16:43-9.

20. Ghosh K, Vachon CM, Pankratz VS, Vierkant RA, Anderson SS, Brandt KR, Visscher DW, Reynolds C, Frost MH, Hartmann LC. Independent association of lobular involution and mammographic breast density with breast cancer risk. J Natl Cancer Inst 2010; 102:1716-23.

21. Mahoney MC, Bevers T, Linos E, et al. Oportunites and strategies for breast cancer prevention through risk reduction. CA Cancer J Clin 2008; 58:347-371.

22. McTiernan A, Kooperberg C, White E, Wilcox S, Coates R, Adams-Campbell LL, Woods N, Ockene J; Women’s Health Initiative Cohort Study. Recreational physical activity and the risk of breast cancer in postmenopausal women: the Women’s Health Initiative Cohort Study. JAMA 2003; 290:1331-6.

23. Cummings SR, Tice JA, Bauer S, Browner WS, Cuzick J, Ziv E, Vogel V, Shepherd J, Vachon C, Smith-Bindman R, Kerlikowske K . Prevention of breast cancer in postmenopausal women: approaches to estimating and reducing risk. J Natl Cancer Inst 2009; 101:384-98.

24. Lagerros YT, Hsieh S-F, Hsieh C-C. Physical activity in adolescence and young adulthood and breast cancer risk: a quantitative review. Europ J Cancer Prev 2004; 13:5-12.

25. American cancer Society guideline on exercise and cancer risk prevention: http://www.cancer.org/healthy/ eathealthygetactive/acs guidelines on nutrition physical activity for cancer prevention/acs-guidelines-on-nutritionand-physical-activity-for-cancer-prevention-summary (Website verified on December 4, 2016) 26. Thomson CA. Diet and breast cancer:understanding risks and benefits. Nutr Clin Pract 2012;27:636-50.

27. Munsell MF, Sprague BL, Berry DA, Chisolm G, TrenthamDietz A. Body Mass Index and Breast Cancer Risk According to Postmenopausal Estrogen-Progestin Use and Hormone Receptor Status. Epidemiol Rev 2014; 36:114–136.

28. Chlebowski RT, Pettinger M, Stefanick ML, Howard BV, Mossavar-Rahmani Y, McTiernan A. Insulin, physical activity, and caloric intake in postmenopausal women: breast cancer implications. J Clin Oncol 2004; 22:4507-13.

29. Huang Z, Hankinson SE, Colditz GA, Stampfer MJ, Hunter DJ, Manson JE, Hennekens CH, Rosner B, Speizer FE, Willett WC. Dual effects of weight and weight gain on breast cancer risk. JAMA 1997; 278:1407-11.

31. Hamajima N, Hirose K, Tajima K, et al. Alcohol, tobacco and breast cancer--collaborative reanalysis of individual data from 53 epidemiological studies, including 58,515 women with breast cancer and 95,067 women without the disease.

British Journal of Cancer 2002; 87:1234-1245.

32. Key J, Hodgson S, Omar RZ et al. Meta-analysis of studies of alcohol and breast cancer with consideration of methodological issues. Cancer Causes Control 2006; 17:759770.

33. Allen NE, Beral V, Casabonne D, Kan SW, Reeves GK, Brown A, Green J; Million Women Study Collaborators.

Moderate alcohol intake and cancer incidence in women. J Natl Cancer Inst 2009; 101:296-305.

34. Chlebowski RT, Hendrix SL, Langer RD, Stefanick ML, Gass M, Lane D, Rodabough RJ, Gilligan MA, Cyr MG, Thomson CA, Khandekar J, Petrovitch H, McTiernan A; WHI Investigators.Influence of estrogen plus progestinon breast cancer and mammography in healthy postmenopausal women: the WHI randomized trial. JAMA 2003; 289:324353.

35. Fisher B, et al. Tamoxifen for prevention of breast cancer: report of the BSABP P-1 study. J Natl Cancer Inst 1998; 90:1371-1388.

36. Vogel VG et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive brast cancer and other outcomes.

JAMA 2006; 295:2727-2741.

37. Goss PE, Ingle JN, et al. Exemestane for breast cancer prevention in postmenopausal women. NEJM 2011; 364:2381-91.

38. Cuzick J, Sestak I, Dowsett M, et al. Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial. Lancet 2014; 383:1041–48.

39. Shah A, Cohen FJ, Bjarnason NH, et al. Long-term Effects of Raloxifene on Bone Mineral Density, Bone Turnover, and Serum Lipid Levels in Early Postmenopausal Women. Arch Intern Med 2000; 160:3444-3450.

40. Hartmann LC, Sellers TA, Schaid DJ, Frank TS, Soderberg CL, Sitta DL, Frost MH,Grant CS, Donohue JH, Woods JE, McDonnell SK, Vockley CW, Deffenbaugh A, CouchFJ, Jenkins RB.. Efficacy of bilateral prophylactic mastectomy in BRCA1 and BRCA2 gene mutation carriers. J Natl Cancer Inst 2001; 93:1633-7.

41. Rebbeck TR, Friebel T, Lynch HT, Neuhausen SL, van_t Veer L, Garber JE, Evans GR, Narod SA, Isaacs C, Matloff E, Daly MB, Olopade OI, Weber BL. Bilateral Prophylactic Mastectomy Reduces Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers: The PROSE Study Group 2004;22:1055-62.

42. Domchek SM, Friebel TM, SingerCF, Evans G, Lynch HT, Isaacs C, Garber JE, NeuhausenSL, MatloffE, Eeles R, Pichert G, Van t’veer L, Tung N, Weitzel JN, Couch FJ, Rubinstein WF, Ganz PA, Daly MB, Olopade OI, Tomlinson G, Schildkraut J, Blum JL, Rebbeck TR. Association of RiskReducing Surgery in BRCA1 or BRCA2 Mutation Carriers with Cancer Risk and Mortality. JAMA 2010; 304:967–975.

CHAPTER 230

18. McCormack VA, Silva IS. Breast Density and Parenchymal Patterns as Markers of Breast Cancer Risk: A Meta-analysis.

Cancer Epidemiol Biomarkers Prev 2006; 15:1159-1169.

30. Smith-Warner SA, Spiegelman D, Yaun SS, van den Brandt 1057 PA, Folsom AR, Goldbohm RA, Graham S, Holmberg L, Howe GR, Marshall JR, Miller AB, Potter JD, Speizer FE, Willett WC, Wolk A, Hunter DJ. Alcohol and breast cancer in women: a pooled analysis of cohort studies. JAMA 1998; 279:535-40.

C H A P T E R

231 MAGNITUDE OF THE PROBLEM

A Rational Approach to Cancer Pain Management PN Jain

CLASSIFICATION OF PAIN

In India, about 1 million new cancer patients are diagnosed every year. A stastistical data suggest that approximately 60-80% patients, when they are diagnosed, are advanced cases & hence incurable. Often, their major symptom is moderate to severe pain. According to present estimates, about 56% cancer patients require relief of symptoms (palliative care) at any given time in India, however, only 28% are provided some sort of palliative care before they die. There is an immediate need to address this issue at all levels. Clinicians should reassure patients & their families that most pain can be relieved throughout the course of illness. Health professionals should encourage patients to be active participants in pain management.

State regulatory bodies should not hamper the supply & collaborate with patients and their families taking the costs of the drugs & technologies into accounts in selecting pain management strategies.

Nociceptive

PREVALENCE OF PAIN

Bone pain is the most common kind of pain caused by cancer. Upto 85% of patients dying from breast, prostate or lung cancer demonstrate bone involvement at autopsy.

Bone pain affects 28% hospice in-patients, 34% in cancer pain clinic & 45% advanced patients at home. The gold standard treatment is radiotherapy.

1

A systematic review (2007) of 6000 patients including 54 studies during 1964-2005 found following prevalence of cancer pain. Despite clear world health organization guidelines (1986) pain still is a major problem.

•

Pain after curative treatment, 33%

•

Pain during active anticancer therapy 59%

•

During advanced disease 64%

•

At all disease stages 53%

•

>33% patients grade their pain as moderate or severe

IMPORTANCE OF CONTROLLING CANCER PAIN

Pain control merits high priority for two reasons. First under-relieved pain causes unnecessary suffering.

Because pain diminishes activity, appetite, and sleep, it can further weaken an already debilitated patient. The psychological effect of cancer pain can be devastating.

Pain is defined as ‘an unpleasant sensory & emotional experience associated with actual or potential tissue damage or described in terms of such damage. The perception of pain is modulated by the patient’s mood, morale & the meaning of the pain for the patient. Pain in cancer may be caused by the cancer itself or by its treatment (radiation, chemotherapy & surgery) or its related debility or concurrent disorder.

•

Functional (physiological e.g. cramp, myofascial pain, colic)

•

Organic (pathological e.g. trauma, cancer)

•

Somatic pain arising from the covering of the body, i.e. skin, subcutaneous tissue

•

Visceral pain arises from viscera.

Non-Nociceptive (Neuropathic) •

Nerve compression (e.g. sciatica)

•

neural injury

•

peripheral (e.g. post herpetic neuralgia)

•

central sympathetically maintained pain

BONE METASTASES

Neuropathic Pain: Defined as pain arising due to lesion or disease in the somatosensory nervous system. It can be caused by cancer directly invading the nervous system or cancer treatment itself causing pain e.g chemotherapy induced peripheral neuropathy (CIPN), radiotherapy induced pain or pain caused by surgery i.e. phantom limb pain. Neuropathic cancer pain is caused by cancer directly while neuropathic pain in cancer is caused by treatment or due to co-morbid conditions e.g diabetic neuropathy, post herpetic neuralgia. Now treatment guidelines have been released by the International neuropathic pain group.2

PRINCIPLES OF PAIN MANAGEMENT

Relief of pain may be achieved by the following methods: • Explanation •

Modification of pathological process

•

Elevation of pain threshold

•

Interruption of pain pathways

•

Modification of lifestyles & immobilization

GOALS OF PAIN MANAGEMENT

•

Relief at night

•

Relief at rest during the day

•

Relief on movement (this is not always completely possible)

rectally, intramuscularly as well as by topical 1059 applications and are the first line agents for mild to moderate cancer pain. There is increasing evidence to suggest that these drugs may have unique role in management of certain kinds of pain from bone metastases. Side effects of NSAIDs should be carefully monitored. Cox-2 NSAIDs (e.g. Celecoxib, Etoricoxib) have been introduced in practice, which are considered relatively safe in terms of gastric mucosa and platelets.

PAIN ASSESSMENT

II.

Opioids: They are the mainstay treatment in moderate to severe cancer pain because of their effectiveness, ease of titration & favorable risk-tobenefit ratio. Opioids do not have a ceiling effect to their analgesic efficacy & will not reverse or antagonise the effects of other opioids within this class given simultaneously. Side effects include constipation, nausea, vomiting, itching, urinary retention, confusion, sedation & rarely respiratory depression if patient is not opioid naïve. Drug tolerance, physical dependence, addiction are no more big clinical issues.

Morphine is the most commonly used opioid for moderate to severe pain because of it’s availability in a wide variety of dosage and forms.

It has well characterized pharmacokinetic & pharmacodynamic profile & relatively low cost.

Recommended starting dose is usually 10 mg 4 hourly.

If a drug falls to relieve, move up the ladder. Do not move laterally in the same efficacy group.

Guidelines for the use of opioids in the management of cancer pain

“For the individual”-The right dose of an analgesic is the dose that relieves the pain.

1.

Start with a specific drug for a specific type of pain.

2.

Know the pharmacology of the drug prescribed very well.

3.

Adjust the route & dose of the drug as per patient’s need & comfort.

4.

Use drug combination for additive effects & reduce side effects.

5.

Anticipate & treat the side effects aggressively.

6.

Prevent acute withdrawal by slowly tapering doses.

7.

7.

Anticipate & manage complications like overdose, seizures & myoclonus etc.

III.

Adjuvant Drugs:

Adjuvants play a major role for pains that are insensitive to opioids. They are also useful in counteracting the side effects of the pain medications like nausea, vomiting, itching, dyspepsia, constipation etc. The mainly used adjuvants are as follows:

PHARMACOTHERAPY OF PAIN: WHO LADDER APPROACH

Use of analgesics:

“By the mouth”-The oral route is the preferred route for analgesics, including morphine.

“By the clock”- Persistent pain relief requires preventive therapy. This means that analgesics should be given regularly & prophylactically. “ As needed” medication is irrational & inhumane.

“By the ladder”-use a three-step WHO analgesic ladder: Step 1: non narcotics (NSAIDS) Step 2: mild opioids (Codeine,pentazocine) Step 3: strong opioids (morphine)

“Monitored treatment”-The response to treatment must be monitored to ensure that benefits of treatment are maximized & adverse effects minimized.

“Use adjuvant drugs”-A laxative is almost always necessary with an opioid: > 50% of patients need an antiemetic.

ORAL ANALGESICS3

Oral analgesics are the mainstay of therapy for cancer pain. An estimated 70-90% of patients can be rendered relatively free of pain, when rational principles of pharmacological management are applied in a thorough & careful manner. The World Health Organization has adopted a ‘ladder’ approach to cancer pain management that relies exclusively on the administration of oral analgesia.4 I.

Non-opioid (Non-narcotic) analgesics: These agents are effective when administered as the sole drug treatment for mild pain. They may be combined with opioids to treat moderate to severe pain.

Paracetamol is a safe step 1 WHO ladder analgesics.

NSAID’s have analgesic, anti-inflammatory & antipyretic activity. They can be given orally,

1. Corticosteroids 2.

Antidepressants (amitryptyline)

3.

Anticonvulsants (gabapentin)

CHAPTER 231

Assess relief in relation to each pain. Whether pain is somatic, visceral or neuropathic or mixed assess different components of each pain. If marked anxiety and/or depression, it may take 2-4 weeks to achieve optimum results. pain score should be assessed on 0-10 numerical rating scale (NRS), where 0 is “no pain” and 10 is “worst possible pain”. Reassessment is a continuing necessity.

Various QOL scales are available e.g. Mc Gill Pain questionnaire, Brief pain inventory (BPI).

1060 4.

Other drugs: Antacids, H2 blockers, laxatives, stool softeners, antiemetics, antihistaminics & antipsychotic drugs etc. Radiopharmaceutical agents like bisphosphonates may be used in once a week infusion in bone metastasis with good relief. Inj calcitonin also has a role in pain relief due osteolytic lesions.

REFERENCES

BEYOND MEDICINE

1.

van den Beuken-van Everdingen MH, de Rijke JM, Kessels AG, Schouten HC, van Kleef M, Patijn J. Prevalence of pain in patients with cancer: a systematic review of the past 40 years. Ann Oncol 2007; 18:1437-49.

2.

Nanna B Finnerup, Nadine Attal, Simon Haroutounian, Ewan McNicol, Ralf Baron et al Pharmacotherapy for neuropathic pain in adults: a systematic review and metaanalysis. Lancet Neurology 2015; 143:162–173.

3.

Bennett MI, Rayment C, Hjermstad M, Aass N, Caraceni A, Kaasa S. Prevalence and aetiology of neuropathic pain in cancer patients: a systematic review. Pain 2012; 153:359-65.

4.

Zech DF, Grond S, Lynch J, Hertel D, Lehmann KA. Validation of World Health Organization Guidelines for cancer pain relief: a 10-year prospective study. Pain 1995; 63:65-76.

C H A P T E R

232

Smartphone Applications in Clinical Medicine Shriram V Kulkarni, Sagar Sinha, Adhar Kulkarni, Chitra S Kulkarni, Vivek Redkar, Swaraj S Devlalkar, Sayali S Devlalkar, Aditya S Kulkarni, Arun Kurhe, Om Kulkarni

INTRODUCTION

The digital industry including computers, smartphones and the world of social media has seen a tremendous upsurge in the recent years especially due to marked internet connectivity.

According to TRAI, India is an upcoming super power in the world telecommunication sector marked by improved mobile connectivity, smartphones and internet use at a reasonable cost. The urban rural divide is getting patched up and the rate of growth is quite significant.1 Despite such a large advancement on the technical front, medical practioners especially physicians have not fully used its potential. Only a small section comprising of residents and students are using them frequently.A cross sectional multicentre study revealed that mobile phone apps use has become almost universal in academic & clinical settings improves point of care decision making . 2 A very good review article by Andrew Bucholz deals with beilefs, benefits & barriers of smartphone use.3,4,5 There are currently around 165,000 health-related apps available for either Apple or Android phones and it’s been predicted that the global revenue from these products will reach $21.1 billion by 2018. Globally, digital health start ups attracted $5.8 billion in funding in 2015. As on today 190 million smartphones are used in India maximum users is of Android system 60 % & only 7% use Apple IOS, it is expected that we will have 651 million smrt phones in use by 2019,(QUORA).

MOBILE MEDICAL APPS (MMA)

Mobile apps are software programs that run on smartphones and other mobile communication devices.

They can also be accessories that attach to a smartphone or other mobile communication devices, or a combination of both. Points to consider (for doctors) 1.

Developer: Rely on known developers who have the experience. Eg. Medical organizations,

2.

Content: Type of content- knowledge/resources/ tools,

3.

Accessibility: Familiarity with use of smartphones is a must and the app features should be explored,

4.

Purpose: Primarily being used as reference tool, aid clinical decisions, improving patient-care,

5.

Cost: Free vs. paid apps. Does the cost over time confer sustainability?

Points to consider (for recommending to patients) 1.

Integration: Patient generated data as a verification tool,

2.

Electronic presence: 2nd opinion, symptom checker, use in life-threatening situations including AMI/ hypoglycaemia/stroke/poisoning etc.

3.

Patient-doctor relationship: Improving team-based and evidence generated medical care,

4.

Two very elaborate text books written by Dr. R.D. Lele 5 envision the scenario which has come true after almost after 28 years & suppoted by stalwarts like Eric Topol recently.6

Outcome: basic principle is to improve patient health,

5.

Cost and accessibility: Feasibility of use, especially older population and cost are major factors.

Few review articles published in API Medicine update 20147, 201618 & RSSDI update 20159 add to valuable information on technology in medicine & diabetes in India.

The rate at which the physician prescribes an app & the actual uses it, is variable the download rate is about 60 -70 % and retention rate is 20 – 50 %.

Mobile and internet technology should be seen as the means to address India’s deficit of doctors through innovations in technology and telemedicine. A smartphone is a basic tool of communication and with the help of internet connectivity can substantially change the quality and outcome of health care; which has been confirmed by many clinical studies.10

OTHER CONSIDERATIONS

Technology access: both in terms of smartphone (costing around Rs.5-50,000) and internet connection around Rs. 500 monthly with capability to platforms and operation systems (IOS and Android) along with technology and language literacy will determine further use in upcoming years. Some smartphones are now available for senior citizens which pronounce the name of the caller, with a panic button and improve access to counter the issues of

1062 touch and dexterity of a small screen.

Guide, Disease Guide (Free access to The Merck Manual), Newsfeed, Interaction analyzer, Pill identifier, and dosing calculators. One can access essential, free specialty resources from trusted in the app which offers 300+ premium resources in 35+ medical specialties, integrated into a seamless, cross-indexed collection.

Further financial hardships should be avoided since a few apps are free initially but may cost later. Patient motivation is seen adequately with younger age group and educated care givers. But the same may lack in patients staying alone in villages or in an old age home.

BEYOND MEDICINE

Privacy, confidentiality and burden of unnecessary advertisements are going to be major challenges of this digital age. Other issues to consider are app overload, addiction and new terms like ‘selfie disorder’ and ‘trolls’.

1.

Advanced bundled apps: These are designed to provide information at the point of care Medscape from WebMD which is supported across all devices.

Medscape is the leading medical resource used by healthcare professionals for clinical information, highest rated, fastest growing free mobile app with over 4 million registered users. Initial log is required (free).

The components include: Medical News: across 30+ specialties, covering FDA announcements, thought leader perspectives, conference news, important journal articles.

Drug Information and Tools: adult and pediatric drug dosing information in seconds, check drug interactions, access drug dosing calculators.Disease & Condition Information: clinical presentation, workup, and treatment information for 4,400+ diseases and conditions (Authored and reviewed by expert physicians).Medical Calculators: 129 medical calculators covering formulas, scales, and classifications, drugs integrated dosing calculators.

Drug Formulary Information.Continuing Medical Education Courses: Complete accredited CME/CE courses for professional development and to fulfil licensure.Offline Access: can be accessed without an internet connection when you select the option to download the clinical reference database.

Epocrates is used by 1 million health care professionals worldwide. Highlights include: drug prescribing and safety information, drugdrug interactions among up to 30 drugs at a time, medical news and research information, perform hundreds of calculations and coordinate care securely. It also has disease information, clinical practice guidelines, alternative medications, lab guides, coding and more content is available by upgrading to an Epocrates Plus subscription.

UpToDate is the leading clinical decision support resource with evidence-based clinical information – including drug topics and recommendations that clinicians rely on at the point of care. It has been the subject of over 30 research studies confirming that widespread usage of UpToDate is associated with improved patient care and hospital performance.

Omnio (formerly Skyscape) has healthcare professional’s clinical workflow in mind with Drug

2.

Other clinical reference tools

Access Medicine: has eBooks on internal medicine, cardiology, genetics, pharmacy, diagnosis and management, basic sciences, patient care, and a repository of medical knowledge from all specialities ,all databases have latest editions of selected medical titles.

DynaMed plus clinical reference tool, written by a world-class team of physicians and researchers who synthesize the evidence and provide objective analysis. Based on clinical evidence and the content is updated multiple times each day to ensure information they need to make decisions at the point of care, includes overviews and recommendations, graphics and images, precise search results every time, expert reviewers, specialty content and mobile access. Cost ($395).

3.

Apps for Medical students & learning

Many apps now cater to the medical student population and can give them and can open their worlds to many horizons. Examples: LabGear for Lab Reference, RENOTE for academic note taking and referencing- Clinical Skills: Medical History taking and clinical exam, Cranial Nerves: Functional Mapping of cranial nerves, Physiology Guru, Anatomy apps.

4.

Professional enhancements uses .

These integrated platform apps can smoothen one’s clinical practice including appointments, recordkeeping and are the future of e-health.

Lybrate provides an online and app-based doctor consultation platform. Similarly Practo provides healthcare solutions for healthcare providers and consumers. Practo Search lets patients to browse through doctor profiles online and book appointments, while Practo Ray serves as a practice management solution for healthcare providers to manage patient data and digital healthcare records.

PlexusMD is professional network for doctors and healthcare organizations Profile, can find and connect with their alumni and colleagues, share and read interesting cases, read the latest news and apply to high quality jobs, courses and fellowships across leading institutions. Regular updates of the latest developments in your specialty from BMJ, Lancet, NEJM and associations like WHO, AHA, ESH, IMA, MCI and all other top sources Find and apply instantly to jobs, courses and fellowships across leading institutions. major conferences and

events across specialties. Share interesting cases, presentations, articles and grow your follower base.

For patients & caregivers

1 mg and Netmeds are licensed online pharmacists offering prescription medicines. MyChart allow you to access your medical records on your phone at any time. You can quickly see which vaccinations you’ve had and when at a glance, along with the last time you visited the doctor and which prescriptions you’re taking. You can even send a non-urgent message to your clinic and receive a response schedule visits from directly within the app, and request prescription refills. Physiotherapy apps, medical procedure explanation apps add value to patient care as a whole.

6.

Medical Journals, Organisations in App format.

The Journal of Association of Physicians of India has free access via myJAPI app and is an important source for consultants and physicians for practice guide-lines and for Indian literature for postgraduate students. Most of other journals are very costly. Website of API is another value addition for the Indian physicans.

7

Indian scenario- Swasthya Slate

This is a powerful device that allows Android Tablets and Phones to conduct 33 diagnostic tests on the mobile device, includes specialized applications that help users perform a variety of screenings and health analysis protocols, allows users to deliver fast and accurate care at home, in clinics and just about anywhere. Also contains decision support tools to enable users to deliver quality recommendations.

Stores electronic medical records both locally on the phone/tablet and also pushes the data onto our cloud. This allows offline/online operations and doctor on call services. CDAC, Chandigarh has developed many Indian health apps.

CONCLUSION

Smartphone apps are going to be the mainstay of health care of next generation.11 In future How Big Data Will Change Healthcare ? New ways to mine data analytics will enable new avenues of research, identifying new

REFERENCES

1.

Telecom Regulatory Authority of India, The Indian Telecom Services Performance Indicators, January - March, 2016, New Delhi, India, 5th August, 2016, Pages1-24.

2.

Jamal A., Mobile phone use among Medical Residents, A cross sectional multicentre survey in Saudi Arabia, JIMR Mhealth Uhealth, 2016 May 19;e 61.

3.

Andrew Buchholz, , Brittany Perry, , Lucia Beck Weiss, Danielle Cooley-, Smartphone Use and Perceptions among Medical Students and Practicing Physicians, Journal MTM 5:1:27–32, 2016.

4.

Ozdalga E, Ozdalga A, Ahuja N, The Smartphone in Medicine: A Review of Current and Potential Use Among Physicians and Students J Med Internet Res 2012; 14:e128.

5.

Lele R.D., Computers in Medicine , 1988 Institute of engineers, , 01-Feb-2005. Lele R.D.Computers in Medicine & progress in Medical Informatcs, 1 st edition, Tata McGraw-Hill Education, 2005, Pages92-111, 521-527.

6.

Eric J. Topol, MD, Steven R. Steinhubl, MD; Ali Torkamani, PhD, Digital Medical Tools and Sensors JAMA 2015; 313:353-354.

7.

Joshi Shashank R., Editor-Medicine Update Vol.24-1, 2014, Amitabh sagar, Smartphone , Tablets, phablets-Utilizing technology optimally in Medicine.Pg 490-495.

8.

SV Kulkarni, Sagar Sinha, Adhar Kulkarni, Aditya Kulkarni, Gurpreet S. Wander, KK Pareek. Smartphones in Medicine:Augmenting Bedside Clinical Skills & Beyond.

Editors-Medicine Update 2016-2, progress in Medicine 2016, Chapter 358- Pg.1868-1873.

9.

Kulkarni SV, Gokharal K, Arun Kurhe, Adhar Kulkarni, Kulkarni C. In Social Media in Diabetes Management in India, RSSDI update 2015, Editor Sarita bajaj_Jaypee Publications.

10. Smith R, Menon J, Rajeev JG, et al. Potential for the use of mHealth in the management of cardiovascular disease in Kerala: a qualitative study. BMJ Open 2015; 5:e009367.

11. Ali EE, Chew L, Yap KY Evolution and current status of mhealth research: a systematic review BMJ Innovations Published Online First: 05 January 2016.

CHAPTER 232

5.

patients prior to acute episodes looking at healthcare 1063 data differently, provide new sources of data and research models, in population health it will give decision support for the best outcomes to improve efficiency of management. The ultimate step is to improve population health.

C H A P T E R

233

Air Ambulance Services Transport of Critically Sick Patients Munish Prabhakar, Geeta Kampani, Ashok Chandna

Transport of critically sick patients has always remained a challenge since time immemorial. The sick used to be carried by surface ambulances from the war zones to military hospitals and primary to tertiary care centres causing significant increase in morbidity and mortality.

Most of the times transport by surface ambulance was not possible due to shear logistical nightmare of time involved, non availability of critical care equipments for such a long duration and deterioration of patients during transport.

The excessive morbidity and mortality of soldiers during wars lead to the concept of air ambulance services for saving valuable lives and decreasing morbidity. The first recorded use of an aircraft for evacuation of soldiers was during the first world war when an Italian soldier who required amputation of both legs in a remote war zone with no medical facilities was evacuated to tertiary care centre on a flight taking 3 hours, while the surface journey would have taken 6 days to reach the same hospital. With increasing requirement of transferring patients to save life and provide best medical care, Air medevac has become a part of the emergency medical services system.

There is need to provide comprehensive emergency and critical care to all types of patients during rescue operations aboard helicopter or fixed wing aircrafts. The services are extremely advanced ICU in air and life saving for many who are evacuated from extremely hostile terrains and remote places completely devoid of medical facilities.

HISTORY OF AIR AMBULANCE SERVICES

The helicopters for use of Medevac dates back to use in Burma in 1944 and subsequently in the prolonged and bloody war of Vietnam and US. The first fixed wing aircraft was used in world war for an Italian patient in 1917 but well equipped air ambulances were used during second world war, where the air ambulances were used not only for transfer of patients to the hospital but also for in flight treatment and minor surgeries performed in the air. Obviously it was use during wars and requirement to transfer patients from hostile war zones to safe havens of tertiary care hospitals was instrumental in developing the concept of air ambulance services which was logically extended to civilian populations. The use has expanded to a fully equipped ICU in the air with all modalities of treatments being given in Air and patients being transferred on ventilators, pacemakers and aortic balloon pumps. Advanced countries like Switzerland have air ambulance services not only for human beings but for injured animals specially cows.

POTENTIAL RISKS AND CHALLENGES DURING AIR AMBULANCE TRANSFERS

Atmospheric/ Avionic Physics

Atmospheric physics potentially affect all air travellers regardless of the aircraft and more so the patients being evacuated in compromised status. As planes ascend through the first 30,000–40,000 feet, the temperature decreases linearly at an average rate of 2°C/ 305 m. If sealevel temperature is 16°C, the outside air temperature is approximately −57°C at 35,000 feet. Pressure and humidity also decline, and patients are also exposed to radiation, vibration and acceleration forces also known as “g” forces. Cabin humidity usually ranges from 10 to 20 % and this is completely unavoidable as air at high altitude is completely devoid of humidity. It causes drying effect on airway passages, skin and cornea specially those using contact lenses. Demons and Cook monitored anxiety levels of patients and noted that anxiety levels are usually very high in anticipation of the flight and possible outcome due to non availability of standard medical care during periods of difficulties or complications.

Pressurization of Aircrafts

There are special issues with respect to pressurization of the aircraft. Not all aircraft and helicopters used as air ambulances have pressurized cabins, and others are pressurized to only 10,000 feet above sea level. In many case the flight need to be operated at pressures maintained at sea levels when flying at 15000 feet. These pressure changes require advanced knowledge by flight staff with respect to the specifics of aviation medicine, including changes in physiology and the behaviour of gases. There are effects of gas expansion at higher altitudes, the effect of hypoxia and anxiety, potential for complications during movement of patients. The helicopters have stricter weather conditions that they can operate in and commonly do not fly at altitudes over 10,000 feet above sea level. We need to discover and prevent various adverse physiological responses to hostile biologic and physical stresses encountered in the aerospace environment.

Hypoxia at high altitude

Hypoxia can be an extremely serious issue during Medevacs. Fixed wings propeller aircrafts fly at 15000 feet while jets fly at35-40000 feet above the sea levels.

Barometric pressure progressively decreases from 760 mm of Hg at sea level to140 mm of Hg at 40,000 feet. Partial pressure of inspired oxygen decreases proportionately to increasing altitude. Since the water vapour pressure

The physiologic response to decreased PiO2 is hyperventilation, caused by increase in the tidal volume and increased cardiac output caused primarily due to tachycardia. This increase in cardiac output is proportional to drop in oxygen saturation. Hypoxia is also a stimulus for atrial arrhythmias and premature ventricular beats.

The increased sympathetic nervous system activity during air ambulance flights is additional factor predisposing to cardiac arrhythmias.

Expansion of Gases at high altitude

We have all studied Boyelâ&#x20AC;&#x2122;s law during our class 12 which states that the volume to which a given quantity of gas is compressed is inversely proportional to surrounding pressures. Any gas trapped in an enclosed space expands by 40 percent going from sea level to 10 thousand feet of altitude. It can potentially cause severe pain and perforation of ear drums if Eustachian tubes are blocked or stretching of suture lines after recent abdominal surgeries. This is a definite concern in patients of pneumothorax as the expansion of gases cause desaturation or hemodynamic compromise if it becomes tension pneumothorax. Expansion of gasses in hollow obstructed viscera may expand and cause rupture of viscera. Air in endotracheal tubes expands and may cause trauma to the trachea, requiring adjustments in the cuff pressure. We need to use IV bags rather than bottles as expanded gas in the bottles can increase the flow rates and if medicines are included than overmedication may happen. There is a need to use infusion pumps rather than open line to control the doses of critical medications and the quantity of fluids being administered.

Aircraft life support systems such as oxygen, heat and pressurization are the first line of defence against most of the hostile aerospace environment. Higher performance aircraft will provide more sophisticated life support equipment to help the body resist acceleration, and pressure breathing apparatus. In compromised patients there is elevation in risk of sudden incapacitation, such as a tendency towards myocardial infarction, epilepsy or worsening of diabetes and expansion of abdominal and pulmonary gases which may lead to hazardous condition at higher altitude. Barodontalgia, commonly known as tooth squeeze and previously known as aerodontalgia, is

pain in tooth caused by a change in atmospheric pressure. 1065 The pain usually ceases at ground.

Operational challenges

Availability of Planes/helicopters is not a problem but in absence of dedicated air ambulance, different types of planes are chartered hence the compatibility of equipment and the stability during the flights can be a problem especially during turbulences. Different configuration and types of planes donâ&#x20AC;&#x2122;t provide similar space and equipment handling comfort. Oxygen supply when not available in standard fit cylinders causes need to carry additional oxygen bottles against the rules of flight safety which needs fixed oxygen cylinders. Where the service provider company has a dedicated plane for air ambulance services, the compatibility of equipment and fixed oxygen is not a problem The conversion time of plane to air ambulance decreases and compatibility of equipment and safety is ensured. The dedicated aircraft can be converted from a chartered plane to Air Ambulance in 45 minutes time while more time may be required sometimes for organizing various other permissions.

Equipment and interiors

Air ambulances, are equipped for advanced life support and have interiors that reflect this. The challenges in most air ambulance operations, particularly those involving helicopters, are the high ambient noise levels and limited amount of working space, both of which create significant issues for the provision of ongoing care. While equipment tends to be high-level and very conveniently grouped, it may not be possible to perform some assessment procedures while in flight. In some types of aircraft, the design means that the entire patient is not physically accessible in flight.

The specialized stretchers where all equipment can be secured and stability with oxygen supply are imported and very expensive as very few companies in the world are manufacturing them. Special patient loading equipment, vacuum mattresses, ventilators driven by oxygen only, IV fluid dispensing equipment, monitors, defibrillators, syringe and infusion pumps need to be fully secured with the stretcher to avoid instability during turbulences, so are specially made for Air ambulance hence more expansive. A typical air ambulance is a complete ICU in the air. Specialized ambulances also carry aortic balloon pumps.

Accidents

Beginning in the 1990s, the number of air ambulance crashes in the United States mostly involving helicopters, began to climb. By 2005, this number had reached a record high because when a life was at stake, air ambulances would often operate on the very edge of their safety envelopes, going on missions in conditions where no other civilian pilot would fly. These pilots must have a great deal of experience in piloting the aircraft because the conditions of air ambulance flights are often more challenging. After a spike in air ambulance crashes in the United States, the U.S. government stepped up the

CHAPTER 233

at normal body temperature is 47 mm of Hg regardless of altitude, PiO2 at 40,000 feet is incompatible with human life. In order for humans to fly at such altitudes the aircrafts are pressurised at 8-10,000 feet levels. PiO2 decreases from 150mm of Hg at Sea level to 107 mm of Hg at cabin pressure of 8,000 feet. For a normal traveller it causes decrease of PaO2 from 98 to 55mmof Hg and leads to a small decrease in Oxygen saturation but in a compromised patient with cardio-pulmonary disorder, it could lead to significant drop of oxygen saturation requiring the patient to be flown in air ambulance with Cabin pressures reduced to sea levels, which is not only very expensive but technically very difficult to maintain and very few air ambulances are equipped to handle this technically and operationally.

1066 accreditation and air ambulance flight requirements,

BEYOND MEDICINE

ensuring that all pilots, personnel, and aircraft meet higher standards.

In 2006, the United States National Transportation Safety Board concluded that many air ambulances crashes were avoidable eventually leading to the improvement of government standards and CAMTS accreditation. Many crashes were due to extreme weather conditions and trying to save lives but were counterproductive as many lives of crew, medical professionals and patients on board were lost.

Air Fields and Landing requirements: Non-availability of helicopter landings even in the major metros and towns make the service nonexistent in our country for serious emergencies as the helicopter evacs are quite common all over the world. Many of the remote areas are not having operational air fields or require military clearances if some are available. Majority of the airfields are dawn to dusk hence the availability is limited during those hours leading to loss of crucial time. Regulations being nonexistent for medevac, the flight clearances can take enormous time and the staff in many small airfields are available for few hours as they cater to occasional flights. Poor communication facilities in those area cause enormous delays in acquiring permissions. Military control of airfields can cause many hours of delay for security clearances especially when foreign nationals are involved or in high security operational area.

Cost-effectiveness

The service is very cost effective if the value of life saved is calculated but remains prohibitively expensive in our country. Whilst some countries have effective methods of funding as in the UK and Europe the Insurance systems are available to make it cost effective.. Most of European countries, US and Canada provide insurance for air evacuation during emergencies to travellers all over the world and this concept of insurance cuts down the cost of air evacuations especially for those who are travelling to remote areas for tourism or adventure sports.

Emergencies during national disasters are covered mostly by government funds.

Despite of various challenges and nascent stage of air ambulance services in India, the service is growing and there is a need to kick start it for local populace by meeting all the challenges that can be overcome if the government of the day has the will, insurance companies start the services, the corporate pitch in their resources and charity starts contributing. The improvement of this industry can be a major boost to tourism and quality healthcare at right time in our country.

REFERENCES

1.

Branas CC, MacKenzie EJ, Williams JC, Schwab CW, Teter HM, Flanigan MC et al. “Access to trauma centers in the United States.”. JAMA 2005; 293:2626–33. doi:10.1001/ jama.293.21.2626. PMID 15928284.

2.

Burney RE, Hubert D, Passini L, Maio R “Variation in air medical outcomes by crew composition: a two-year followup.” Ann Emerg Med 1995; 25:187–92. PMID 7832345.

3.

Meier, B, Saul, S. Fatal crashes provoke debate on safety of sky ambulances. New York Times, February 28, 2005.

4.

Isakov AP. “Souls on board: helicopter emergency medical services and safety.”. Ann Emerg Med 2006;47:357–60. doi:10.1016/j.annemergmed.2005.12.020. PMID 16546621.

5.

Lam DM. “To Pop A Balloon: Air Evacuation During The Siege of Paris, 1970.” Aviation, Space, & Environmental Medicine, 59(10): 988-991, October 1988.

6.

Bearl, Spc. Daniel. “MEDEVAC Unit Stays on Alert to Save Injured Comrades.” US Military News via army.mil/-news, February 9, 2007. Retrieved: December 4, 2010.

7.

“First in the Nation - Celebrating 37 Years of Air Medical Transport!” Flight for Life, 2006. 8 “Governor O’Malley Announces New Additions to Maryland’s World-Class Emergency Response.” Maryland State Police Aviation Command via mspaviation.org, October 20, 2010.

Medical Personnel

In most cases, an air ambulance staff has to be considerably more skilled than a typical paramedic so as to permit them to exercise more medical decision-making attitude.

Assessment skills need to be considerably higher, and permit inclusion of functions such as reading x-rays, scans and interpretation and performance of critical and important lab results. This allows for planning, consultation with supervising physicians, and issuing contingency orders during flight. In seriously ill patients the inclusion of respiratory therapists/intensivists experienced in aviation medicine is becoming more prominent. They also need training in such areas such as intubation, chest tube insertion, surgical airways, securing patient cervical spine through use of spine boards in flight which can be very difficult due to lack of space and manoeuvrability.

C H A P T E R

234

Recent Management of Lymphoedema

1067

SB Gogia

Early diagnosis is important since treatment is most effective when lymphedema is diagnosed at the earliest stage. Diagnostic tests for lymphedema come under the following categories: •

History and physical examination

•

Soft tissue imaging

•

Lymph vessel and lymph node imaging helps mapping of lymph flow. Injected nuclear dye (Lymphoscintiscan), and Flouroscent dye (Indo Cyanine green) is mapped through special cameras.

Dyes traceable though MRI are not yet available in India.

•

Measures of volume done traditionally through water displacement techniques is now replaced by perimetry and computer software,

•

Changes in electrical conductance

•

Changes in biomechanical properties

•

Genetic testing

•

Other vascular imaging Ultrasound Doppler helps to identify venous problems which frequently may occur as a cause or effect. MRI also helps distinguish excessive fat (lipedema) as a cause.

•

Blood tests for other conditions that can look like lymphedema. Lymphedema has no cure but can be successfully managed when properly diagnosed and treated. Long term management programs like for any other chronic disease are required.

The most dreaded components which worsen the disease are repeated attacks of cellulitis also called adeno dermal lymphangitis (ADLA). Skin care, control of fungus, as well as antibiotics especially penicillin are needed to prevent as well as prevent such episodes,

Complete decongestive therapy (CDT) (also called combined, complex or comprehensive decongestive therapy) is considered the “gold standard” of treatment.

Effects of CDT are to decrease swelling, reduce the risk of cellulitis, increase lymph drainage from the congested areas, reduce skin and subdermal fibrosis, enhance patient’s functional status, relieve pain and discomfort, improving quality of life.

Fig. 1: Progress of Lymphoedema

CHAPTER 234

True lymphedema is swelling caused by abnormality in the lymphatic system. Lymphedema can also co-exist with other medical and swelling conditions. Correct diagnosis of lymphedema may require evaluation by a physician.

The initial lymphoedema caused by filariasis is reversible with filaricidal drugs but once secondary infection has set in, the disease enters a chronic irreversible stage.

Lymphedema due to other causes like cancer and venous disease follows similar common pathway (Figure 1).

BEYOND MEDICINE

1068 Components of CDT are:

1.

manual lymph drainage (MLD)

2.

multi-layer, short-stretch compression bandaging

3.

lymphatic exercise

4.

skin care

5.

education in lymphedema self-management, and elastic compression garments

6.

Intermittent Pneumatic Compression Therapy (IPC) is also used as an adjunct.

CDT programs should be individualized based on the presence of other medical conditions or patient abilities. Patients with wounds, scars, or musculoskeletal conditions; palliative care patients; or patients with postradiation fibrosis may require adaptations of CDT. If

there is limited mobility of the body part with or near the swelling, the patient may require other therapies, such as scar massage or myofascial therapy, in addition to CDT, to have a benefit from CDT. Surgery for lymphedema is not curative, but it has been used in specific circumstances for control of a severe condition. Circumstances where surgery may be considered are: reducing the weight of the affected limb, minimizing the frequency of inflammatory attacks, improving cosmetic appearance, or fitting the limb into garments. Many surgical procedures available that have been used for lymphedema: (a) excisional operations, including debulking and liposuction, (b) tissue transfers, and (c) microsurgical lymphatic reconstruction. Only few surgeons perform these procedures. Conjunction with CDT is almost mandatory.

C H A P T E R

235

Sahaja Yoga for Management of Stress & Life Style Diseases Sandeep Rai, Madhur Rai, Yashoda Kattimani, Vishesh Agarwal

ABSTRACT

The changes of rapid globalization are putting heavy stress on people and taking a heavy toll of their health and lives. Only a century ago the primary threats to human life were infections, but now days most humans die of diseases like diabetes heart attacks and stroke in which stress plays a major role. Diseases like angina, heart attack and diabetes which only struck in elderly age groups are now claiming, as their victims, as young as 30 yrs old. It may not be an easy task to change the present day stressors of competitive, aggressive fast paced lives, but certainly a change can be brought in an individual’s perceptions and coping abilities to combat negative effects of stress on health and diseases. In fact, new research reveals that simple 20 minutes of Sahaja Yoga meditation a day now can keep you free of stress.

INTRODUCTION

When stress takes hold, the brain is bathed in chemicals; the sympathetic nervous system gets a jump-start.

Glucose and fats flood the bloodstream and our cardiovascular and respiratory systems rev up, all to give us the armaments we need to deal with the stress. These changes would make sense if we were running for our lives or rescuing our child from a fire. But when everything from taxes to television news triggers a reactive response, stress becomes toxic. As it is not possible to change the style or pace of our modern life, we need to discover suitable mechanisms to cope with daily stress.

Psychological stress plays an important role in the causation of essential hypertension, which is one of the most important public health problems in developed, and developing countries. Recently, it has been reported that emotional stress and anxiety can precipitate overt ischemic heart disease and cause sudden death. Modulation of stress can in turn lead to improvement in numerous life style diseases like, diabetes, hypertension, ischemic heart disease and host of other psychosomatic diseases, the proof of which already exists in scientific literature.

At present considerable evidence exists for the place of mind body medicine in maintaining and improving psychological health. Ten million American adults now say they practice some form of meditation regularly, twice as many as a decade ago. “For 30 years meditation research has told us that it works beautifully as an antidote to stress,” says Daniel Goleman, author of Destructive Emotions. “But what’s exciting about the new research is how meditation can train the mind and reshape the brain.

Sahaja Yoga is a unique form of meditation technique

developed by Dr Nirmala Devi Srivastava, (Hon PhD in Cognitive Science from Romania University), popularly known as Shri Mataji Nirmala Devi in the year 1970.

Through this process, an inner transformation takes place by which one becomes energized and de- stressed. It offers a practical method of understanding your own energy system and tapping into this powerful force. Scientific studies have proved beyond doubt that SYM (sahaja yoja meditation) acts by reducing sympathetic activity (Stress) and promoting parasympathetic activity (Relaxation).

Studies comparing experienced SY meditators compared to controls or short-term meditators have demonstrated physiological changes during meditation suggestive of a wakeful hypo metabolic state that is characterised by decreased sympathetic nervous activity, important for fight and flight mechanisms involved in stress reactions, and increased parasympathetic activity, important for relaxation and rest. Sahaja Yoga Meditation, has been shown to reduce autonomic activity in short- and longterm practitioners compared to controls. This included a reduction in heart, respiratory and pulse rates, systolic blood pressure and oxygen metabolism, and reduction of urinary vanilly mandelic acid (VMA) a break down product of Stress Hormone Adrenalin and increases of Skin Resistance1 reflecting a de stressed state.

These physiological alterations are indicators of deep parasympathetic activation and therefore physiological relaxation that have been related to stress relief and may have a role in the prevention of stress-related illness, most notably, hypertension and other cardiovascular diseases.

Electro-physiological (EEG) studies comparing the brain activation of long-term Sahaja Yoga practitioners have been able to find specific brain activation patterns corresponding to a relaxed state of mind & subjective feelings of happiness and have also shown on sophisticated EEG studies of better interconnectivity of different brain regions2,3 An interesting study investigating the neural correlates of emotional reactivity of long-term Meditators compared to controls showed reduced psychological, physiological and electrophysio-logical reactivity to stressful stimuli, providing for the first time in the World the neurophysiologic evidence to support the hypothesis that Sahaja Yoga Meditation leads to ‘‘detachment’’ and greater emotional resilience to stressful life events.4 Rigorous randomized trials on SY Meditation using active control groups have demonstrated significant effects on depressive mood and work stress in full-time workers.5 In other studies, on SY Meditation, promising effects have been shown in depression & anxiety,6 on enhanced Quality

1070 of life7 and on improving Psychological health in a diverse

BEYOND MEDICINE

group of population consisting of different nationalities and age groups.8 In fact, the same physiological effects achieved with Sahaja Yoga Meditation in healthy individuals, could also be achieved in patients with asthma, hypertension, epilepsy and Diabetes, after few weeks of Meditation training, which furthermore were related to the significant reduction of Blood pressure, attacks of epilepsy & asthma & improvements in Diabetes Control& ADHD in children.6,9,10,12,13-16 Two large controlled studies recently completed in the Physiology & Medicine Department of MGM Institute of Health Sciences, Navi Mumbai by the authors on effects of Sahaja Yoga meditation on endothelial function, oxidative stress, serum cortisol, perceived stress levels and HRV found a very significant improvement in heart rate variability, endothelial function and serum cortisol levels and found significantly decreased oxidative stress and perceived stress levels in long term Sahaja Yoga meditators as compared to general healthy population who were not practicing any meditation.17

provocation of myocardial ischemia in patients with coronary artery disease. In the present study, Serum Nitrite was measured in both the groups for an indirect assessment of Nitric Oxide (NO) levels in the body. NO levels correlate very well with the endothelial function of the body. Our study showed, that the Mean value of Serum Nitrite in SYM Yoga Group were significantly more than in the Non Yoga Group. This indicated a Better Endothelial Functioning in The long term Sahaja Yoga Meditators.

HEART RATE VARIABILITY

•

Perceived Stress: PSS is the most widely used scale for assessing stressfulness of events, physical and psychiatric diseases and stress management programs. Meditation not only improves one’s subjective ability to cope, but also one’s behavioral ability to cope through reduced reactivity to external stimuli and quicker response to stressor. In our study the perceived scores in SYM group were significantly less compared to that in the Non Yoga healthy group. Thus it was clearly evident that the SYM group was overall all less stressed and their Perceived stress levels were found to be lower in as compared to non yoga group.

•

Serum Cortisol levels (a biological marker of stress) was measured in the long term SY meditators and compared it to the Healthy non meditators. Most previous studies have found that urine and plasma cortisol levels are decreased during meditation.

This release of cortisol in response to an acute stressor is believed to be involved in promoting survival functions, such as increasing blood pressure and blood sugar levels and promoting analgesia. However, despite their protective effects during times of stress, chronic elevations of glucocorticoids can have damaging effects on the body over time, particularly when acute responses to stress becomes chronic. In our study SYM Group showed lower Cortisol levels. Higher serum Cortisol values in the Non Yoga group indicated higher stress levels in them.

The heart is also where researchers discovered the body’s best biological indicator of stress: heart rate variability. Heart rate variability is the cutting edge of current cardiology research. In essence, HRV provides a picture of the interplay between the sympathetic and parasympathetic branches of ANS. Cardiovascular disease (CVD) is the leading cause of death and disability worldwide. Autonomic imbalance, characterized by a hyperactive sympathetic system and a hypoactive parasympathetic system, is associated with various pathological conditions. Over time, excessive energy demands on the system can lead to premature aging and diseases. Therefore, autonomic imbalance may be a final common pathway to increased morbidity and mortality from a host of conditions and diseases, including cardiovascular disease. Substantial evidence exists to support the notion that decreased HRV precedes the development of a number of risk factors. Studies have shown that Work stress has shown to decrease HRV, which is in itself is a major risk factor for cardiovascular morbidity and mortality. The effects of modifiable risk factors might be prevented or minimized by engaging in behaviors that might increase HRV. In healthy individuals, acute increases in HF-HRV generally occur in response to positive-emotion induction, relaxation and meditation.

Our study showed the mean LF/HF ratio of the SYM Group was significantly lower than the Non Yoga Group.

The lower LF/HF ratio in Yoga Group indicated a better Sympathovagal Balance in Yoga subjects. Also higher levels of HF which were recorded in the Yoga Group Indicated a Parasympathetic Dominant (Relaxed) State in Sahaja Yoga Meditation Subjects. It is now amply clear that autonomic imbalance might be the final common pathway linking a host of disorders and conditions to death and disease. Thus, changes in Life style & behaviors like incorporating Sahaja Yoga Meditation in daily life can alter this autonomic imbalance toward a more salubrious profile may serve to prevent or at least minimize the effects of certain factors on the risk for cardiovascular disease and death.

•

ENDOTHELIAL FUNCTION: Nitric oxide is a soluble gas continuously synthesized by the endothelium. This substance has a wide range of biological properties that maintain vascular homeostasis. Diminished nitric oxide bioactivity may cause constriction of coronary arteries during mental stress and exercise and can contribute to

The Possible Mechanisms, Mammals, including humans, have over millions of years evolved the ability to deal rapidly and reflexively with perceived threats to survival and this ability has conferred a considerable survival advantage to this group of animals. In humans however, the same stress response can be triggered in situations

HOW YOGIC MEDITATION REDUCES STRESS?

which, while they do not necessarily threaten survival, occur fairly frequently. Such a typical situation is in the daily live hassles as meeting deadlines. Repeated activation of the stress response is thought to result in dysregulation of physiology which leads to the body‘s own survival mechanisms and this in turn damages health.

Sahaja Yoga Meditation is now a central feature in corporate wellness and youth development programs globally and is increasingly being prescribed by doctors as a part of Holistic health recommendations. It is non intrusive and self regulating in nature. SYM has been extensively researched upon in India and abroad It is taught free of charge at all the Sahaja Yoga Centers in more than 157 countries around the world. For her significant contribution to understanding of subtle energy systems H.H Shri Mataji Nirmala Devi received numerous Awards and recognition from around the Globe. She has received United Nations Peace Prize and has been twice nominated for Nobel Peace Prize. The simple technique of Sahaja Yoga can be learnt free from internet also.

For learning Sahaja Yoga Meditation or for any more information visit site -www.freemeditation.com, or write to doctorsandeeprai@gmail.com

ACKNOWLEDGEMENTS

We thank the Hon’able Vice Chancellor, Respected Dean & Head of Departments of Physiology & Medicine,of the MGM institute of Health Sciences , Navi Mumbai, the entire team of dedicated doctors of the International Sahaja Yoga Health Centre, Navi Mumbai, Dr Ramesh Manocha, Lecturer in Psychiatry, Sydney Medical School, Australia, Dr Sheng Chia, Asst Prof of Epidimiology at the London School of Epidemiology, Dr Usha Panjwani –Professor, Defence Institute of Physiology and Allied Sciences, New Delhi, Dr Deepak Chug, Senior Consultant Neurologist in Los Angeles, USA, Prof Katya Rubia, Dept Of Cognitive Neuroscience, Institute of Psychiatry, Kings College University London, Dr Ashish Pradhan, Medical Director, Pfizer, USA, Prof Medicine, MGM, Mumbai, and last but not the least, all the Volunteers for all their cooperation & valuable contributions.

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

U. Rai, S. Sethi, and S. Singh, ―Some effects of Sahaja Yoga and its role in the prevention of stress disorders, Journal of International Medical Sciences 1988; 19–23.

Aftanas, L.I., Golocheikine, S.A. Human anterior and frontal midline theta and lower alpha reflect emotionally positive state and internalized attention: highresolution EEG investigation of meditation. Neuroscience Letters 2001; 310:57–60.

Aftanas, L.I., Golocheikine, S.A. Linear and non-linear concomitants of Altered state of consciousness during meditation: high resolution EEG investigation. International Journal of Psychophysiology 2002a; 45:158–1158.

Aftanas, L., Golosheykin, S. Impact of regular meditation practice on EEG activity at rest and during evoked negative emotions. International Journal of Neuroscience 2005; 115:893.

R. Manocha, G. B. Marks, P. Kenchington, D. Peters, and C. M. Salome, ―Sahaja Yoga in the management of moderate to severe asthma: a randomized controlled trial, Thorax, 2002; 57:110–115.

Morgan D- “Sahaja Yoga: an ancient path to modern mental health?” Transpersonal Psychology Review 2001; 4:41–49.

Sheng-Chia Chung, Maria M. Brooks, Madhur Rai, Judith L. Balk, MD, MPH and Rai Sandeep, -Effect of Sahaja Yoga Meditation on Quality , of Life, Anxiety, and Blood Pressure Control. The Journal of Alternative aznd Complementary Medicine 2012; 18:589–596 Rai S, Sharma RC, Singh CB, Shaunak A. Ajinkya, -Effect of higher state of consciousness Thoughtless awareness on psychological health ,Neuroscience Research, ISSN: 09768866 & E-ISSN: 0976-8874, Vol. 1, Issue 1, 2010, PP-01-08.

Chugh, D, 1997. The effects of Sahaja Yoga in bronchial asthma and essential hypertension. New Delhi Medicos N13 5 (4), 46–47 Panjwani U, Selvamurthy W, Singh SH. ―Effect of sahaja yoga practice on seizure control and EEG changes in patients of epilepsy. Indian J Med Res 1996; 103:165Harrison, L., Manosh, R., Rubia, K. Sahaja Yoga Meditation as a family treatment program for attention deficit hyperactivity disorder children. Journal of Clinical Psychology and Psychiatry 2004; 9:479–497.

Peters RK, Benson H, Peters JM. ―Daily relaxation response breaks in a working population: II effects on blood pressure. Am J Pub Health 1977; 67:954-9.

Rubia K, - The neurobiology of Meditation and its clinical effectiveness in psychiatric disorders. Biological Psychology 2009; 82:1–11.

Panjwani U, Gupta HL, Singh SH, U. Rai, ―Effect of Sahaja yoga practice on stress management in patients of epilepsy.

Indian J Physiol Pharmacol 1995; 39:111-6.

L. J. Harrison, R. Manocha, and K. Rubia, ―Sahaja Yoga Meditation as a family treatment programme for children with attention deficit-hyperactivity disorder. Clinical Child Psychology and Psychiatry 2004; 9:479–497.

R. Manocha, D. Black, J. Sarrs, and C. Stough, ―A randomized, controlled trial of meditation for work stress, anxiety and depressed mood in full-time workers, Evidence-171 Based Complementary and Alternative Medicine, vol. 2011, Article ID 960583, 8 pages, 2011. View at Publisher • View at Google Scholar MD Thesis-A.Vishesh - RCT To Evaluate The Role Mind Body Technique of Sahaja Yoga Meditation in Stress reduction. MD Thesis, MGM University of Health Sciences, Navi Mumbai, 2013.

1071

CHAPTER 235

One very popular view is that the physiological changes achieved by SYM are characterized by the relaxation response—Psychophysiological studies of Sahaja Yoga, suggest that in reality it does elicit a relaxation response.

It is hypothesized that this subtle energy (kundalini) actualizes in limbic system of the brain and therefore by its effects on the limbic system, it modulates the emotional response of an individual. Also limbic system has rich connections with hypothalamus and through this route it exerts its effect on autonomic nervous system.

The limbic system also acts on the HPA axis and there by modulates the release of various hormones released in response to stress. Modulation of Stress can in turn lead to improvement in numerous life style diseases like, Diabetes, Hypertension, Ischemic Heart disease and host of other psychosomatic diseases, the proof of which already exists in scientific literature

REFERENCES

C H A P T E R

236

Important Drug Interactions Every Physician Must Know Sumeet Singla, AK Agarwal, RK Singal

Todayâ&#x20AC;&#x2122;s physician has to choose from a bewildering array of drugs. New drugs are formulated and introduced into the market every year. Any given patient is being treated with a multitude of drugs. The reasons for this are many; longer life spans, clustering of diseases in a patient, mushrooming of sub-specialities and the incessant promotional campaigns by pharmaceutical companies. All of this exposes patients to deleterious side effects of polypharmacy. Also, many of the commonly used drugs have clinically important interactions when used together. These interactions can decrease or enhance the efficacy of either of the two interacting drugs and predispose the patient to lower therapeutic efficacy or drug toxicity, respectively. An attempt is being made to generate awareness among physicians about important drug interactions. It is not possible to enumerate all such interactions; however, interactions of the commonly prescribed drugs viz. anti-diabetics, anti-hypertensives, cardiovascular drugs, anti-tubercular, anti-epileptic,

warfarin, newer oral anticoagulants, and anti-infectives have been presented in tabular form. The detailed mechanisms of these interactions have not been discussed as we want this chapter to be a desktop, ready-reckoner for the busy physician to be used in the clinic. A summary of the very important and must-remember drug interactions is given in the end.

ANTI-DIABETIC, ANTI-HYPERTENSIVE AND CARDIOVASCULAR DRUGS

Patients with type 2 diabetes mellitus often require multifactorial pharmacological treatment due to different co-morbidities. Relevant drug interactions are predominantly related to sulfonylureas, thiazolidinediones and glinides. Metformin has a very low interaction potential. With the exception of saxagliptin, dipeptidyl peptidase-4 (DPP-4) inhibitors also show a low interaction potential. Incretin mimetics and sodiumâ&#x20AC;&#x201C;glucose cotransporter-2 (SGLT-2) inhibitors

Table 1: Drug interactions of Anti-diabetic Drugs Antidiabetic Drug

Interacting Drug

Clinical Effect

Clinical Relevance Clinical Management

Sulfonylureas

Fluconazole, H2-antagonists, sulfonamides, clarithromycin, verapamil

Increased efficacy of sulfonylureas, hypoglycemia

Moderate

Dose reduction of sulfonylurea, blood glucose monitoring

Rifampicin, phenytoin, carbamazepine

Decreased efficacy of sulfonylureas, hyperglycaemia

Moderate

Increase dose of sulfonylurea, blood glucose monitoring

Non-selective betablockers

Decreased efficacy of sulfonylureas, hyperglycemia

Moderate

Blood glucose monitoring

Iodinated contrast media

High risk of contrast High induced nephropathy

Contraindicated 48 hours prior and 48 hours after use of contrast media

Thiazolidinediones Calcium channel blockers, NSAIDs

Fluid retention, heart failure

High

Avoid combination, close monitoring

DPP-4 inhibitors*

Diltiazem, Atazanavir, ritonavir, clarithromycin

Increased efficacy of DPP-4 inhibitors, hypoglycemia

Moderate

Dose reduction of DPP-4 inhibitor, blood glucose monitoring

Rifampicin

Decreased efficacy of DPP-4 inhibitors, hyperglycemia

Moderate

Increase dose of DPP-4 inhibitor, blood glucose monitoring

GLP-1 analogues

Increased risk of pancreatitis

Moderate

Avoid use together

Metformin

* Especially for Saxagliptin

1073

Table 2: Drug Interactions of Anti-hypertensive Drugs Drug

Interacting Drug

Beta-blockers

Clinical Management

Verapamil, Diltiazem Additive bradycardia, AV block

High

Avoid using together, monitor heart rate, BP and ECG

Antidiabetic drugs, Suppression of including insulin and neuroglycopenic GLP-1 analogues symptoms tremor, sweating, palpitations (hypoglycemia unawareness)

High

Monitor blood sugars

Bronchodilators

Decreased bronchodilator activity, bronchial spasm

Moderate

Avoid use in asthma, COPD. Use selective beta-blockers

Increased digoxin levels, digoxin toxicity (mainly with verapamil)

High

Avoid use together, decrease digoxin dose by upto 50%, monitor digoxin levels

Diuretics

ACEIs, ARBs

Carvedilol, Metoprolol

Hepatic interaction Moderate leading to high blood levels of Verapamil

Use atenolol, bisoprolol or nebivolol (also when using potent hepatic enzyme inducers or inhibitors)

Digoxin

Increased digoxin toxicity due to hypokalemia

High

Monitor blood potassium levels

Aspirin (with thiazide diuretics)

Increased blood uric acid levels

Moderate

Monitor blood uric acid levels

NSAIDs

Lowering of antiModerate hypertensive effect of loop diuretics

Monitor BP, avoid use of NSAIDs, use acetaminophen

Steroids

Hypokalemia, lowering of antihypertensive effect due to sodium retention

Moderate

Avoid use together, monitor serum potassium levels and BP, supplement potassium

Aminoglycoside antibiotics

Ototoxicity (when used with loop diuretics)

Moderate

Avoid use together, monitor for ototoxicity

Diuretics

Additive hypotensive action

Moderate

Monitor BP closely, do not use together in volume depleted patients

Potassium sparing diuretics

Hyperkalemia when used together

High

Monitor blood potassium levels, avoid use together in renal function derangement Contd...

CHAPTER 236

Clinical Relevance

Verapamil, Diltiazem Digoxin

Clinical Effect

1074

Table 2: Drug Interactions of Anti-hypertensive Drugs

BEYOND MEDICINE

Drug

Clonidine

Interacting Drug

Clinical Effect

Clinical Relevance

Clinical Management

ACEIs, ARBs

Hyperkalemia when used together

High

Monitor blood potassium levels, avoid use together in renal function derangement

NSAIDs

Reduced Moderate antihypertensive action due to sodium and fluid retention

Avoid use together

High-dose aspirin

Reduced Moderate antihypertensive action due to sodium and fluid retention

Avoid use together

Centrally acting depressant agents (hypnotics, tranquillizers, neuroleptics, antiepileptics, some anti-depressants, H1-anti-histaminic agents, alcohol)

Additive sedative effects

Avoid use together, instruct patient to avoid driving, use machinery, prevent falls

High

ACEIs - Angiotensin Converting Enzyme Inhibitors, ARBs- Angiotensin Receptor Blockers, HR - Heart Rate, BP Blood Pressure, NSAIDs - Non-Steroidal Anti-Inflammatory Drugs, HIV - Human Immunodeficiency Virus

Table 3: Drug interactions of commonly used cardiovascular drugs Drug

Interacting Drug

Clinical Effect

Clinical Relevance

Clinical Management

Atorvastatin

Verapamil, clarithromycin itraconazole, fluconazole, ciclosporine

Rhabdomyolysis

High

Avoid use of macrolides and azoles, use rosuvastatin

Clopidogrel

Proton Pump inhibitors

Decreased efficacy of clopidogrel

Moderate

Avoid use of PPIs with clopidogrel, add aspirin or use prasugrel

Amiodarone

Digoxin

Increased digoxin concentration, Digoxin toxicity

High

Avoid use together, decrease digoxin dose by upto 50%, monitor blood digoxin levels and for clinical digoxin toxicity

Sildenafil

Nitrates

Severe hypotension

High

Contraindicated for use together

Amiodarone, itraconazole

Increased plasma sildenafil level

Moderate

Avoid use together

Clarithromycin, ciclosporine, itraconazole

Increased digoxin concentration, Digoxin toxicity

High

Avoid use together, decrease digoxin dose by upto 50%, monitor blood digoxin levels and for clinical digoxin toxicity

Digoxin

comprise a very low interaction potential and are therefore recommended as an ideal combination partner from the clinicalâ&#x20AC;&#x201C;pharmacologic point of view.

The vast majority of hypertensive patients are treated with antihypertensive drugs for many years. Other therapeutic agents are frequently used simultaneously, thus giving

1075

Table 4: Drug Interactions of Warfarin Drugs with moderate to high risk of increased INR and/or bleeding tendency when used concomitantly with warfarin Clinical Management

Metronidazole

Monitor INR when starting Methylsalicylate (topical) or stopping, decrease dose of warfarin by 30% when adding metronidazole

Monitor INR when starting or stopping, avoid use together

Amiodarone

Monitor INR when starting Ranitidine or stopping, decrease dose of warfarin by 25% when adding amiodarone

Monitor INR when starting or stopping, use alternative (famotidine)

Aspirin (> 6 gms/day), NSAIDs

Use lower doses of aspirin, monitor for bleeding, use COX-2 inhibotors

Rosuvastatin

Monitor INR when starting or stopping, decrease dose of warfarin by 20% when adding rosuvastatin, use atorvastatin

Clopidogrel

Monitor for bleeding

Sulfamethoxazole (with or without trimethoprim)

Severe interaction, Monitor INR, decrease dose of warfarin by 25% when adding sulfamethoxazole

Ciprofloxacin, levofloxacin

Monitor INR when starting Tramadol or stopping, decrease dose of warfarin by 15% when adding ciprofloxacin

Monitor INR when starting or stopping, decrease dose of warfarin by 20% when adding tramadol

Phenytoin

Lactulose Initially INR is increased, later on with long term use it is decreased - monitor INR, use alternative antiepileptic drug

Monitor INR when starting or stopping

Clarithromycin

Monitor INR when starting Fenofibrate or stopping, decrease dose of warfarin by 15% when adding clarithromycin

Monitor INR when starting or stopping, decrease dose of warfarin by 15% when adding fenofibrate

Lansoprazole

Monitor INR when starting Fluconazole or stopping

Monitor INR when starting or stopping, decrease dose of warfarin by 20% when adding fluconazole

Leflunomide

Monitor INR when starting Isoniazid or stopping

Monitor INR when starting or stopping, decrease dose of warfarin by 15% when adding isoniazid

Levothyroxine

Monitor INR when starting Itraconazole or stopping

Monitor INR when starting or stopping, decrease dose of warfarin by 25% when adding itraconazole

rise to the possibility of drug-drug interactions. The potential for drug-drug interactions increases with rising age, since elderly patients receive larger number of drugs, but also because the renal excretion of several therapeutic agents is impaired in the elderly, as a result of diminishing kidney function. Tables 1, 2 and 3 summarise drug interactions of common anti-diabetic, anti-hypertensive and cardiovascular drugs.

Drug

Clinical Management

DRUG INTERACTIONS OF WARFARIN

Warfarin has been the mainstay of oral anticoagulant therapy for the past 60 years and it is most commonly used to treat or prevent thrombosis or thromboembolism in patients with venous thromboembolism, atrial fibrillation and prosthetic heart valves. However, this drug is efficacious only when the dosage is maintained within a narrow therapeutic index, measured by the international normalized ratio (INR). Multiple challenges exist in appropriately achieving and maintaining therapy

CHAPTER 236

Drug

1076

Table 5: Drug Interactions of Warfarin

BEYOND MEDICINE

Drugs with moderate to high risk of decreased INR and/or clotting tendency when used concomitantly with warfarin Drug

Clinical Management

Drug

Clinical Management

Azathioprine

Monitor INR when starting or stopping; 2 to 3 fold higher dose of warfarin may be required

Rifampicin

Monitor INR when starting or stopping; increase dose of warfarin by 25-50% when adding rifampicin

Carbamazepine

Monitor INR when starting or stopping, increase dose of warfarin by 50% when adding carbamazepine

Sulfasalazine

Monitor INR when starting or stopping; may need to increase dose of warfarin by 50%

Methimazole

Monitor INR when starting or stopping

Propylthiouracil Monitor INR when starting or stopping

Table 6: Clinically important Drug Interactions of Anti-epileptic Drugs What AEDs do to other drugs AED

Interacting drug

Clinical effect

Carbamazepine, Phenytoin

Oral Contraceptives (OCP) (estrogen containing)

Loss of contraceptive High efficacy

Avoid use together, use OCP with high dose oestrogen, use alternative method of contraception, use AEDs which do not interact with OCPs*

Carbamazepine

Warfarin**

Loss of warfarin efficacy, lower INR

Moderate

Avoid use, monitor INR, increase dose of warfarin, use levetiracetam, oxcarbazepine

Phenytoin

Warfarin**

Unpredictable effect, INR may increase or decrease

Moderate

Avoid use, monitor INR, use levetiracetam, oxcarbazepine

Carbamazepine, Phenytoin

Cortisol, dexamethasone, hydrocortisone, methylprednisolone, prednisolone

Reduced serum concentrations of steroids

Moderate

Monitor clinically for loss of efficacy

Carbamazepine, Phenytoin

Amiodarone, atorvastatin, digoxin, metoprolol, nifedipine, nimodipine, verapamil

Carbamazepine, Phenytoin

Doxycycline, itraconazole, metronidazole, albendazole

Valproic acid

Amitriptyline, meropenem, imipenem

Reduced serum concentrations of interacting drugs

Increased serum concentration of interacting drugs

Clinical relevance

Clinical management

Moderate

Monitor clinically for loss of efficacy

Moderate

Avoid use together

Contd...

1077

Table 6: Clinically important Drug Interactions of Anti-epileptic Drugs What AEDs do to other drugs AED

Interacting drug

Clinical effect

Clinical relevance

Clinical management

What other drugs do to AEDs Interacting drug

Clinical effect

Clinical relevance

Clinical management

Phenytoin

Rifampicin

Lower serum phenytoin levels

Moderate

Avoid use together, monitor serum phenytoin levels

Phenytoin

Clarithromycin, fluconazole, fluoxetine, isoniazid

Phenytoin toxicity

High

Avoid use together, monitor serum phenytoin levels

Phenytoin

Allopurinol, amiodarone, diltiazem, omeprazole

Phenytoin toxicity

Moderate

Avoid use together, monitor serum phenytoin levels

Carbamazepine

Rifampicin

Lower serum Moderate carbamazepine levels

Carbamazepine

Dextropropoxyphene Carbamazepine toxicity

Carbamazepine

Haloperidol, Risperidone, fluoxetine

Carbamazepine

Avoid use together, monitor serum carbamazepine levels

High

Avoid use together

Moderate

Avoid use together

Carbamazepine Clarithromycin (NOT Azithromycin), toxicity fluconazole, isoniazid, metronidazole

High

Avoid use together

Carbamazepine, lamotrigine, phenytoin, valproic acid

Sertraline

AED toxicity

Moderate

Avoid use together

Valproic acid

OCP, Meropenem

Loss of efficacy of Valproic acid, seizures No effect on OCP efficacy

Moderate

Avoid use together, increase dose of valproic acid

Lamotrigine

OCP

High Loss of efficacy of lamotrigine, seizures May lead to loss of OCP efficacy at doses > 300mg/day

Avoid use together, increase dose of lamotrigine Use other AEDs which do not interact with OCPs*

Lamotrigine

Rifampicin

Lamotrigine toxicity

Dose reduction of lamotrigine by 50%, slow up-titration of lamotrigine

Carbamazepine toxicity

Moderate

What AEDs do to other AEDs AED

Interacting drug

Clinical effect

Clinical relevance

Clinical management

Valproic acid

Lamotrigine

Lamotrigine toxicity

Moderate

Dose reduction of lamotrigine by 50%, slow up-titration of lamotrigdine Contd...

CHAPTER 236

AED

1078

Table 6: Clinically important Drug Interactions of Anti-epileptic Drugs

BEYOND MEDICINE

What AEDs do to other drugs AED

Interacting drug

Clinical effect

Clinical relevance

Clinical management

Valproic acid

Carbamazepine

Carbamazepine toxicity

Moderate

Monitor serum levels of affected AEDs

Carbamazepine, Phenytoin

Benzodiazepines, lamotrigine, pregabalin, topiramate, valproic acid

Reduced serum concentration of interacting AEDs, Loss of efficacy of AED, breakthrough seizures

High

Monitor serum levels of affected AEDs

*Levetiracetam, pregabalin, gabapentin, valporate, and topiramate at doses < 200 mg/day do not interact with OCPs ** Oxcarbazepine and Levetiracetam have not been reported to interact with warfarin. Valproic acid may increase bleeding tendency by interfering with platelet function and clotting factor disturbances ;

Table 7: Drug Interactions of Anti-tubercular Drugs ATT Drug

Interacting Drug

Clinical Effect

Clinical Management

Rifampicin

Verapamil, Amlodipine, Nifedipine, diltiazem

Reduced levels of calcium channel blockers

Monitor BP, increase dose of calcium channel blockers, use alternative anti-hypertensive

Beta- blockers (NOT Atenolol)

Reduced levels of betablockers

Monitor BP, increase dose of beta-blockers, use atenolol

Sulfonylureas

Decreased efficacy of sulfonylureas, hyperglycaemia

Monitor blood sugar, add other drugs

Phenytoin, carbamazepine, Lower serum levels of valproic acid, AEDs, breakthrough benzodiazepines seizures

Monitor serum levels of AEDs

Digoxin

Reduced serum digoxin levels

Monitor clinically and serum digoxin levels

OCPs

Reduced efficacy of oestrogen and progesterone containing OCPs

Avoid use together, use additional method (barrier), injectable progesterone may be used

Corticosteroids

Reduced efficacy of steroids

Increase dose of steroids

Cyclosporine

Reduced efficacy of ciclosporine

Increase dose of ciclosporine

Itraconazole, fluconazole, macrolides

Marked reduction in blood Use higher doses of antilevels of anti-fungals fungals

Isoniazid

Phenytoin, Carbamazepine Marked rise in blood levels of phenytoin and carbamazepine, AED toxicity

Monitor clinically and blood AED levels, reduce dose

Pyrazinamide

Zidovudine

Increase dose of pyrazinamide, avoid use of zidovudine (use Tenofovir)

Decreased levels and efficacy of pyrazinamide, loss of efficacy in HIV-TB co-infected patients

Contd...

1079

Table 7: Drug Interactions of Anti-tubercular Drugs

Quinolones

Reduced levels of ciclosporine

Increase dose of ciclosporine

Thiazide diuretics

Increased uric acid levels in blood

Increase dose of allopurinol

Calcium, Iron containing oral preparations, antacids

Reduced absorption of Quinolones

Space out the drugs by 2-4 hours

Drugs that prolong QT interval**

Further QT prolongation, risk of TDP

Avoid use together, monitor by ECG, Moxifloxacin is contraindicated

Amiodarone

Increased risk of arrhythmia

Avoid use together

**Drugs that prolong QT interval: Imidazoles, tricyclic antidepressants, atypical antipsychotics, amiodarone & other anti-arrhythmics, some antidepressants (citalopram, escitalopram, fluoxetine, mirtazapine, paroxetine, sertraline, trazodone, venlafaxine) alfuzosin, chlorpromazine & domperidone, galantamine, haloperidol, indapamide, lithium, methadone, quinine sulphate, tamoxifen, tizanidine, co-trimoxazole. Other Non-drug risk factors for prolonged QT interval: Family history, electrolyte abnormalities (hypokalaemia, hypocalcaemia, hypomagnesaemia), cardiac ischaemia, cardiomyopathies, hypothyroidism and hypoglycaemia.

Table 8: Drug Interactions of common Anti-infective agents Anti-infective Drug

Interacting Drug

Clinical Effect

Clinical Management

Clarithromycin, Azithromycin

Atorvastatin

Risk of rhabdomyolysis

Avoid use together, use rosuvastatin

Warfarin*

Increased INR, bleeding tendency

Monitor clinically and by INR

NOACs - Dabigatran, Rivaroxaban, Apixaban

Increased risk of bleeding

Monitor clinically

Phenytoin, carbamazepine

Increased blood levels of AED with clarithromycin and erythromycin, AED toxicity

Avoid use together, monitor clinically and blood AED levels, use Azithromycin

Drugs that prolong QT interval**

Further QT prolongation, risk of TDP

Avoid use together, monitor by ECG

Warfarin*

Increased INR, bleeding tendency

Monitor clinically and by INR

Methotrexate

Methotrexate toxicity

Monitor clinically for signs of liver and haematological toxicity

Amiodarone

Increased rosk of arrhythmia

Avoid use together

Atorvastatin

Risk of myopathy

Avoid use together

Warfarin

Increased INR, bleeding tendency

Monitor clinically and by INR

NOACs - Dabigatran, Rivaroxaban, Apixaban

Increased risk of bleeding

Not recommended, Monitor clinically

Drugs that prolong QT interval**

Further QT prolongation, risk of TDP

Avoid use together, monitor by ECG

Linezolid

Rifampicin

Low blood levels of linezolid, therapeutic failure

Increase dose of linezolid, use alternative antibiotic

Meropenem

Valproic acid

Reduced blood levels of valproic acid, loss of seizure control

Contraindicated

Trimethoprim and Cotrimoxazole

Itraconazole, Fluconazole

NOACs - Newer Oral AntiCoagulants, TDP - torsades de pointes, INR - International Normalised Ratio, PPIs - Proton Pump Inhibitors; *Penicillins and cephalosporins are preferred drugs when patients are on warfarin and NOACs

CHAPTER 236

Cyclosporine

1080

Table 9: Very Important Drug Interactions of the “Red Alert” Drugs - Summarised Drug

Comments

Warfarin

Monitor INR and patient closely when adding metronidazole, ciprofloxacin, cotrimoxazole, clarithromycin, doxycycline, fluconazole, azathioprine, rifampicin, isoniazid, carbamazepine, phenytoin, sulfasalazine, amiodarone Adjust dose of warfarin, at the outset, when adding these drugs Switch to LMWH or UFH

BEYOND MEDICINE

Atorvastatin

Do not use with verapamil, clarithromycin, itraconazole, fluconazole, ciclosporine Monitor CPK levels Switch to rosuvastatin (with warfarin, atorvastatin may be better) when adding any of these drugs

Clarithromycin

Do not use with atorvastatin, digoxin, warfarin, dabigatran, rivaroxaban, apixaban, colchicine, phenytoin, carbamazepine and drugs that prolong QT interval May use azithromycin or other antibiotic in patients taking any of these drugs

Itraconazole, Fluconazole Do not use with atorvastatin, dabigatran, rivaroxaban, apixaban, digoxin Use carefully with warfarin, carbamazepine, phenytoin, rifampicin Digoxin

Do not use with clarithromycin, itraconazole, ciclosporine, verapamil, diltiazem Use carefully with diuretics, amiodarone, rifampicin, phenytoin, carbamazepine

Rifampicin, Isoniazid

Use carefully with hepatotoxic drugs Use carefully with phenytoin, carbamazepine, warfarin, digoxin, calcium channel blockers, oral contraceptives, corticosteroids, sulfonylureas, macrolide antibiotics, azole antifungals

Carbamazepine, phenytoin

Do not use with clarithromycin, oral contraceptive pills

Amiodarone

Use carefully with digoxin, warfarin, carbamazepine, phenytoin and drugs that prolong QT interval

Sildenafil

Do not use with nitrates

Allopurinol

Do not use with azathioprine

Use carefully with warfarin, itraconazole, isoniazid, rifampicin

LMWH - Low Molecular Weight Heparin, UFH - UnFractionated Heparin, CPK - Creatine Phospho-Kinase within this narrow index. Recent data have identified genetic variants that may reduce a person’s requirement for warfarin.Furthermore, once a suitable dosage of warfarin has been established, control of therapy can be affected by changes in intake of vitamin K, development of acute medical conditions (e.g., fever, diarrhea), changes in certain chronic medical conditions (e.g., heart failure) and interactions with prescription, nonprescription and herbal products. Tables 4 and 5 list important interactions of warfarin with other drugs.

CLINICALLY IMPORTANT DRUG INTERACTIONS INVOLVING ANTI-EPILEPTIC DRUGS (AEDS)

Patients with difficult-to-treat epilepsy benefit from combination therapy with two or more antiepileptic drugs (AEDs). Additionally, virtually all epilepsy patients will receive, at some time in their lives, other medications for the management of associated conditions. In these situations, clinically important drug interactions may

occur. Carbamazepine and phenytoin induce many cytochrome P450 (CYP) and glucuronyl transferase (GT) enzymes, and can reduce drastically the serum concentration of associated drugs which are substrates of the same enzymes. Valproic acid may cause clinically relevant drug interactions by inhibiting the metabolism of selected substrates, most notably lamotrigine and carbamazepine. Compared with older generation agents, most of the recently developed AEDs are less likely to induce or inhibit the activity of CYP or GT enzymes.

Levetiracetam, gabapentin and pregabalin have not been reported to cause or be a target for clinically relevant pharmacokinetic drug interactions. The interactions listed below are not complete and may be variable in each individual patient. Hence, close clinical monitoring and measurement of serum levels of the affected drug is warranted. Table 6 lists the important interactions of antiepileptic drugs.

ANTI-TUBERCULAR DRUGS AND THEIR INTERACTIONS

DRUG INTERACTIONS OF COMMONLY USED ANTIINFECTIVE DRUGS

Antibiotics and antifungals are prescribed very commonly and on top of many other drugs which the patient is already consuming. Therefore, drug interactions are bound to occur and patient may have adverse consequences.

Listed below (Table 8) are some of the commonly used antibiotics and anti fungal drugs and their important drug interactions.

MANAGING DRUG INTERACTIONS

Because of the variability in individual metabolism, many interactions will not be obvious in most individuals, but when an interaction occurs, it may lead to considerable morbidity, or mortality. The usual way to manage the potential interaction is through conscientious monitoring and general awareness of the clinical symptoms of toxicity.

If a new medicine has been added and a new symptom occurs, be suspicious of an interaction, not just an adverse effect. When about to prescribe a potentially interacting medicine (see red alert drugs and Table 9 below), one should ask the following questions: 1.

Is the combination really necessary—what are the alternatives?

2.

What are the likely adverse effects of high dosages of the target medicine (how hazardous)?

3.

What clinical monitoring does the patient need to know about to report back to you?

What objective monitoring needs to be done, and 1081 when?

THE “RED ALERT” DRUGS

The following medicines should ‘ring alarm bells’ as having important interactions: •

Warfarin

•

Statins - atorvastatin

•

Macrolide antibiotics - clarithromycin, azithromycin

•

Calcium channel blockers - verapamil, diltiazem

•

Azole antifungals - itraconazole, fluconazole

•

SSRIs - fluoxetine

•

Amiodarone

•

Digoxin

•

Rifampicin, Isoniazid

• Antiepileptic medicines particularly carbamazepine, phenytoin; less so valproate

REFERENCES

1. Perucca E. Clinically relevant drug interactions with anti epileptic drugs. Br J Clin Pharmacol 2005; 61:246-55.

2.

Arbex MA, Varella MCL, Siqueira HR, et al. Antituberculosis drugs: Drug interactions, adverse effects, and use in special situations. Part 1: First-line drugs. J Bras Pneumol 2010; 36:626-40.

3.

Johannessen SI, Landmark CJ. Antiepileptic Drug Interactions - Principles and Clinical Implications. Curr Neuropharmacol 2010; 8:254-67.

4.

May M, Schindler C. Clinically and pharmacologically relevant interactions of antidiabetic drugs. Ther Adv Endocrinol Metab 2016; 7:69–83.

5.

Triplitt C. Drug Interactions of Medications Commonly Used in Diabetes. Diab Spectr 2006; 19:202-11.

6.

Zwieten PA. Interactions between antihypertensive agents and other drugs. European Society of Hypertension Newsletter 2003; 4:1-2.

7.

Bryant L, Fishman T. clinically important drug–drug interactions and how to manage them. J Pr Health Care 2009; 1:150-3.

CHAPTER 236

The most well-known drug interaction of anti-tubercular drugs is amongst themselves - hepatitis - caused by combined hepatotoxic potential of isoniazid, rifampicin, and pyrazinamide. When one considers the drugs used for the treatment of tuberculosis, the important interactions are almost exclusively caused by rifampicin.

Rifampicin is a potent liver enzyme inducer that increases the activity of the microsomal enzymes so that the pace of metabolism and excretion of other drugs metabolised by the same enzyme system is increased. Isoniazid is an enzyme inhibitor. Ethambutol and pyrazinamide have few significant drug interactions. Table 7 enumerates the common and important interactions of anti-tubercular drugs.

4.

C H A P T E R

237

Knowledge Management: Bringing About A New Era in Medicine

ABSTRACT

Healthcare is an incredibly dynamic field that requires an equally dynamic school of thought-sharing in order to maximize the benefits that organizations bring to patients. Knowledge management (KM) is the process of creating, sharing, using and managing the knowledge and information of an organization The principles of knowledge management are thoroughly applicable in medicine. Tacit knowledge, which is at the center of knowledge sharing, is very potent in its ability to cause miscommunications when not properly shared within an organization. If it is shared in an open forum that is very accessible however, it can also help organizations in building up their knowledge base by sharing the experiences of long-time employees. By taking the time to learn about knowledge management, workers in medicine and healthcare can position themselves and their organizations to be successful for many years to come. Healthcare organizations and leaders in these organizations should take the time to learn more about knowledge management, assess the knowledge gaps in their organizations, build new knowledge sharing initiatives, foster the culture of a learning organization, and communicate successes from the new initiatives early and often. By taking the time to build a learning culture, one that values knowledge management, organizations will be prepared to quickly adapt, regardless of whatever changes that come in the future.

INTRODUCTION

Healthcare is an incredibly dynamic field, with rapid changes and new technologies being introduced to the fold seemingly every week. In order for workers in healthcare to keep up with all of these changes, it is important to consider how information is circulated amongst members within healthcare organizations to optimize efficiency. With all of the information that is out there, clear communication and sharing of ideas is essential in order to help streamline the organizational learning process. For this reason, the practice of knowledge management and how to successfully implement it within an organization has been the subject of much interest recently. Knowledge Management (KM) is quickly coming to the forefront as the next innovative frontier for organizational management. Although healthcare has been heavily invested in evidence-based methodology, many in the medical field are beginning to recognize the role knowledge management is playing in bringing about a new era in medicine. By learning about

Aditya Ghosh, Amit K Ghosh

knowledge management, how to create and foster a culture of knowledge sharing, how each of us can become a knowledge worker, and how to evaluate organizational knowledge management, we will be prepared to help usher in this new age of medicine. In this review we will learn about knowledge management, creating a culture of knowledge management, how to measure the effectiveness of knowledge management and ultimately how to become a KM worker.

WHAT IS KNOWLEDGE MANAGEMENT?

Healthcare is a very evidence-focused field, requiring that any given hypothesis be thoroughly backed up with data before any given action can be taken. It has been suggested that this way of thinking, though effective and time-tested, is why knowledge management as a field of study has lacked serious academic interest from many in the medical community until recently.1 Knowledge management (KM) is the process of creating, sharing, using and managing the knowledge and information of an organization.2 Increasingly, these teams are beginning to understand that effective practice of organizational knowledge management lead to everyone having a better understanding of their teams’ visions. The first step to understanding knowledge management is to understand the definition of knowledge. Ackoff’s hierarchy describes both how knowledge is derived from both data and information and how knowledge leads to understanding and wisdom.3 In Knowledge Management in Healthcare, Ackhoff’s hierarchy is described within the context of healthcare.4 Data can be described as “patient and family history, basic physiologic monitors, medication history...”, which is then used and compared to standard evidence- based values of normal baselines to help create information. This information helps a doctor obtain a better sense of his or her patient’s current state of health.4 Medical information is than used by the doctor in conjunction with his or her knowledge to create a plan of care. Knowledge in the context of healthcare refers to a clinician’s understanding of “disease process, clinical experience, knowledge of the patient and his or her preferences, familiarity with practice guidelines, and practice alerts”.4 To this end, knowledge is subjective as it is born from on one’s own experiences. By using knowledge to create a plan of action, the doctor has now gained an understanding of the patient’s current situation.

After attaining understanding, a clinician can graduate to the final level of wisdom after they have helped the patient come up with “subsequent decisions about care including discussion of preventative actions to ensure

health”. Central to this entire process is the concept that knowledge is created from an individual’s experiences.4 These experiences take the form of the clinician’s past medical training and cases seen, which after using as a reference to the patient’s current condition, help the clinician move forward with a decisive plan of how to best help the patient.

A CULTURE OF KNOWLEDGE MANAGEMENT

Fostering a culture of knowledge management can drastically improve the outcomes of knowledge management initiatives. Especially during a time when healthcare organizations are getting larger and changes are occurring at a rapid rate, the importance of effective knowledge management practices is paramount.4 As organizations in healthcare make steps towards improving overall quality of the care and regulatory agencies enforce more strict policies to ensure higher levels of patient quality are met, this reinforces the cultures of knowledge

In order to create a learning organization, one in which frequent knowledge sharing is encouraged and the ability to effectively do so is optimized, Garvin et. al.7 describe three essential pillars that are required. These are a “supportive learning environment, concrete learning processes, and leadership that reinforces learning”.7 The supportive learning environment is essential as it ensures that everyone feels comfortable asking questions to their colleagues, and any organizational uncertainties can be quickly cleared up. Concrete learning processes are very important in knowledge management, as it ensures that those in the organization who are creating the protocols and those in the organization who are trying to learn from the protocols are both on the same page.

It makes the entire process of distributing knowledge more efficient by decreasing the overall variability and ambiguity of organizational learning processes. Finally, it is very important that the leadership in any organization encourages this learning environment. If leaders in the organization do not aid in the reinforcing of knowledge management, the top-down effect will be less success in any knowledge sharing initiative. As Zipperer describes in her textbook on 'Knowledge Management in Healthcare', “A learning culture develops when leaders decide that new patterns to thinking and acting are essential for the organization . . . Leaders should engage others to create organizations ... where employees excel at creating, acquiring and transferring knowledge”.4 Learning organizations must partake several activities to successfully engage in knowledge management.

These activities include, systematic problem solving; experimentation with new approaches; learning from their own experience and past history; learning from the experiences and best practices of others; and transferring knowledge quickly and efficiently throughout the organization.8 When partaking in organizational problem-solving, it is very important that a system is in place and closely followed as this will ensure that in the future, if similar problems are encountered, workers in an organization can effectively glean from the wisdom and experience of their colleagues. On the same token, experimentation with new approaches is important in learning organizations as there is a constant influx of new knowledge that can be applied to organizational practices to make them more efficient. Overall, learning organizations are best geared to carry out new knowledge management initiatives because the systems that they have in place encourage rapid transfer of knowledge throughout the organization.

Organizational leaders should lead the initiation of knowledge management initiatives and foster the learning culture. To do so, these leaders must have a particular set of personal characteristics to encourage this transformation in the organization. Balik and Gilbert

CHAPTER 237

Knowledge itself comes in three types: explicit knowledge, implicit knowledge, and tacit knowledge.5 Explicit knowledge is defined as “knowing what”, and usually manifests as data that is easily understandable. Implicit knowledge is “knowing how and being able to talk about it”, as it influences action and is shared through common experiences. Tacit knowledge is “knowing how but not being able to explain it”, and is practical knowledge that is conveyed through clinical experiences.4 In the context of knowledge management, it is the last category of knowledge, tacit knowledge that is suggested to yield the highest benefits if sharing of this type of knowledge is optimized within an organization.6 If sharing of tacit knowledge is not optimized within an organization, the team can be compromised with turnover in the workforce occurs. Equally problematic to inefficient sharing of tacit knowledge within healthcare are both a lack of understanding regarding what knowledge management entails from a resource perspective and an incomplete comprehension of the terms that define knowledge management.4 To mitigate this problem, organizations can implement “mental models” that “...sustain [knowledge management initiatives] and create the culture to support them”.4 Especially in organizations that are beginning to value the importance of tacit knowledge, the shared mental models are essential to successful practice of knowledge management. By standardizing knowledge and the sharing of it, those within the organization can feel confident that they are moving forward in a unified direction towards an agreed-upon vision. These mental models are also a way of organization-wide standardization of communication regarding initiatives aimed at improving safety. Mental models ensure that the organization has a shared understanding that new initiatives are being implemented to benefit patients, and not to point blame on others within the organization. By attaining a better sense of the types of knowledge and how to implement shared mental models, organizations can make moves to start fostering frequent practice of knowledge management.

sharing. This will help to assure the proper protocols are 1083 shared throughout organizations, thereby improving their ability to keep up with any organizational or personnel changes that may occur.

BEYOND MEDICINE

1084 together describe four characteristics that enable leaders

to create change: “1) A personally hold passion for healthcare. 2) Consistency in words and actions, authentic, humble. 3) Intelligence, eager to learn, reflective. 4) A genuine concern and trust in others”.9 Tangible passion in leaders is essential, as their passion for healthcare trickles down through the organization and fuels interest among employees in incorporating organizational changes, to better deliver quality care. Consistency amongst leaders in their words and actions is crucial when leading any knowledge management initiative, as this enables the quick transfer of knowledge that comes with these initiatives. The ability for leaders to quickly learn and reflect is essential as it ensures that they will be able to adapt to new information and adjust the organizationwide messaging to reflect this new knowledge in a way that puts everyone on the same page. The capacity of a leader to trust others is imperative when leading a learning organization and fostering a learning culture, as a leader’s confidence empowers employees with their own feelings of confidence, enabling them to more quickly be able to learn and adapt to new knowledge. The following are success factors that transformational healthcare leaders introduce to their organizations: “A constant focus on patient care combined with disciplined action; an ability to challenge the status quo while maintaining a future orientation; an eagerness to engage everyone; an atmosphere of teamwork and problem solving; an ability to develop the talents of others”.4 These factors all culminate in an organization that is poised with a culture that encourages knowledge sharing. Altogether, while leaders are important in kick starting efforts to create learning organizations, the success of new knowledge management initiatives is dependent on the entire organization’s ability to efficiently share knowledge in a systematic fashion.

STARTING KNOWLEDGE MANAGEMENT INITIATIVES

For organizations to start knowledge management initiatives, equally important to fostering a culture of knowledge sharing is attaining an understanding of how to effectively start knowledge management initiatives.

If not done properly these initiatives may fail to take off and, though well-intentioned, can result in organizations shutting off further interest to any potential future knowledge sharing initiatives. The following section provides a thorough look into how to build successful knowledge management programs that shape how organizations conduct knowledge sharing.

As has been explored in earlier sections, without proper knowledge management programs in place, organizations have tendencies to exhaust resources through inefficient policies. These result in delays of delivering services, as employees are met with similar problems that previous employees have faced, but information on these lessons has not been appropriately communicated. In a hospital setting, it is even more imperative that proper knowledge sharing initiatives are installed, as the stakes are arguably even higher than in

other institutions. As Zipperer mentions, “In a hospital, the delay in improvement, or possible worsening of care due to a lack of optimizing ‘what the knowers know,’ could adversely impact those who have entrusted their lives or the lives of their loved ones to the organization”.4 This highlights a very important aspect of knowledge management, by optimizing the care a hospital provides by implementing “what the knowers know” into new initiatives for healthcare, hospitals and their doctors are adhering to their missions of providing the best possible quality of care to the patients who are dependent on their services. With a proper understanding of the importance and the scope of knowledge management programs, organizations can go about planning and starting these programs with the right mindset.

Part of the mindset that organizations must adopt when starting up new knowledge management initiatives is that there is a level of complexity when trying to implement them. One of the biggest contributors to this complexity, especially in the realm of healthcare, is that employees have become accustomed to frequent new initiatives aimed at improving different aspects of the organization.

Without proper communication of the reasoning behind the initiatives, employees are tasked with immediately changing the way to conduct certain practices. When done in combination with infrequent updates on the results of such changes, results in employees feeling discouraged and often frustrated with any new initiative that is introduced.10 In a setting such as healthcare, doctors, nurses, and administrative staff all want to feel that their day to day efforts and cooperation with new programs is leading to improvements in the ability of their hospital to provide high quality care to the patient population. In order to prime an organization for the maximal benefit of a knowledge management initiatives, Zipperer noted, “participants must understand the context of the requested change. New initiatives need to be distinguished from past programs in order to demonstrate why the new initiative will be successful in contrast to former failed attempts”.4 In the case of knowledge management programs, proper communication needs to be relayed as to the importance of knowledge management towards optimizing delivery of new information, and the overall ability for the organization to deliver its services to its customers. Employees should also understand how these new initiatives will help them. This includes citing examples of how knowledge sharing can serve as a way to help people encountering similar problems communicate solutions to one another. Ultimately, while fatigue from implementation of new programs can add complexity to starting new knowledge sharing initiatives, proper communication throughout the organization as to the reasoning behind these new initiatives can ameliorate much of this complexity.

This leads us into the key strategies for starting knowledge management initiatives. In a healthcare setting, when starting communications about the need for knowledge management initiatives, Riege describes that need for knowledge sharing improvements should

After steps have been taken to conduct an intake of the current gaps in knowledge and priorities for new knowledge management initiatives have been set, creating the right team to carry out the implantation of the program is essential.12 Zipperer outlines strategies that can be utilized towards building this team, “1) Engaging leadership, 2) Identifying champions, and 3) Trumpeting early findings/successes”.4 First, by connecting knowledge management initiatives to the organization’s mission statement and relating the potential results of effective knowledge sharing to potential improvement in the organization overall, leaders throughout the organization will be interested to offer their support and encourage others to support the movement. Second, it is important to identify champions in the organization who can help

possess the necessary knowledge of organizational 1085 procedures, can point out the flaws of certain new initiatives, and can help build out the context of these initiatives within the values of the organization.13 Third, it is important to relay early findings and successes to the entire team. This can help motivate people in the organization who have not yet contributed to the initiative to start helping out.14 By showing to the entire organization on a consistent basis that the knowledge sharing initiatives are yielding benefits, more people will be excited to join the cause. As Zipperer writes, “Even the most emergent successes should be broadly shared with champions through the organization and, when appropriate, more publicly. Storytelling can serve as an effective tactic to spread news of success”.4,15 This approach of spreading successes to the team as soon as they occur will be very helpful in engaging the support of the organization and get everyone excited about the possibilities that future knowledge sharing initiatives can bring. Building out a team of champions and using them to engage the support of the entire organization will ultimately greatly improve the chances of successful implementation of knowledge management initiatives.

CHAPTER 237

be communicated within the context of benefiting patient safety and quality of care.11 After the initial communication has gone out, organizations should take some time collecting and receiving input from employees as to how to shape the programs and what initiatives should be prioritized. It is very important that organizations take as much time as needed to fully determine the current knowledge sharing state, as this will determine how they build their knowledge management initiatives. Zipperer outlines three essential steps that organizations should follow when identifying the current knowledge sharing state: 1) Determining what exists and where the gaps are, 2) Considering and collecting real-life examples, and 3) Defining and recognizing context.4 First, it is important for organizations to get an understanding of how communication of current protocols and any new revisions is being handled, within the different departments and divisions. This involves surveying employees regarding both the forum through which procedural updates come (i.e. email, memos, or during meetings), as well as any current problems they have with the current system of problem-solving. By finding where the gaps in knowledge sharing are most prevalent, organizations can quickly pinpoint which areas knowledge management initiatives need to prioritize. Second, once the initial survey has gone out and adequate responses have been collected, it is important for organizations to highlight to their employees what their own colleagues have identified as needed areas of improvement. By providing these examples, people throughout the organization can attain an understanding of the importance of implementing effective knowledge management initiatives. Third, in order to effectively assess the current knowledge management state, it is important to recognize the context and define it in a way that the entire organization can understand. Zipperer outlines that “Conducting group interviews, conducting a team-focused assessment, and employing social network analysis tools” can all be effective ways of doing this.4 These methods can be effective in establishing the context of how organizational knowledge sharing occurs, which similar to before, can help organizations in determining how to best allocate resources when starting new knowledge management initiatives.

As organizations determine champions who can work to engage the entirety of the organization in joining the new initiatives, it is important to make sure that the team is a multidisciplinary team that is a manageable size and has members who appreciate working with one another. After determining who will be a part of the core team, leading the integration of knowledge sharing programs, it is important that the members of this team are appropriately assigned a focus for their contributions.16 The three methods of how these assignments can be made in order to improve the odds of the team successfully creating and implementing knowledge management programs: 1) Building a mental model around what a team is, 2) Partnering with Human Resources, and 3) Articulating requirements needed to get the job done. First, when building a mental model of what a team is, it is essential that every member of the team has bought into the mission of the focus group; everyone should be fully cooperative and enthusiastic to create new knowledge management procedures and integrate them into the workplace. This is very important to the success of the team, as everyone should feel that their viewpoint is valid and should be motivated to contribute their thoughts towards building out the best possible knowledge sharing programs.

Second, partnering with Human Resources (HR) can be incredibly helpful in successfully implementing knowledge sharing programs as HR can create specific requirements that make sure that people are using knowledge sharing procedures in their work, ensuring that employees in an organizations are accountable for their adoption of knowledge management, and by creating policies that ultimately encourage knowledge sharing.4 Third, it is important that the team clearly defines the what is needed to successfully complete the creation of knowledge management initiatives. By taking the time to collect thoughts on the knowledge gaps that exist in

BEYOND MEDICINE

1086 the current organization, teams can prioritize which

knowledge sharing programs should be focused on and implemented in the shorter term. Here, the teams can also determine which programs would be easier to implement and which could be introduced at a quicker rate than others. Engaging in these discussions will make sure that resources are properly allocated and that the knowledge sharing initiatives can be rolled out and implemented in a timely manner, keeping with the expectations of everyone within the team and the organization at large.4 Altogether, building a multidisciplinary team ensures that knowledge management initiatives take multiple views into consideration and are built in ways that can maximize their chances for success.

After taking the time to assess the current knowledge sharing state, and building a multidisciplinary team of champions that can engage others in the organization, the last phase of developing successful knowledge management initiatives is developing methods for knowledge sharing that utilize a communication tool that works for everyone in the organization. Zipperer outlines three main points to consider when building the communication process, “1) Identifying and committing to a sharing process that has minimal impact on daily work, 2) Selecting tools that make sense, and 3) Leveraging an existing wiki or intranet site”.4 By creating a sharing process that has minimal to no impact on an employee’s daily work, the chances of knowledge management being successfully practiced increases exponentially. When taken with the above point that employees eventually become weary after multiple new programs and initiatives that can be time-consuming and distracting to comply with, the welcome change of a program that brings benefits with minimal distractions from work can be enticing for many. In line with this point is the importance of selecting a communication tool that is easily accessible to all employees. The more unwieldy a tool is for someone to use, the less likely they are to use it. Especially in the case of hospital work, where buy-in of clinicians will be essential, simplifying the tools they need to use is very important.17 When unveiling any new technology that has been deemed necessary for the success of a new knowledge management initiative, proper guidance on how to use the technology has to be relayed to the entire team, as well as communication as to how exactly the technology fits into the context of better, organization-wide knowledge sharing. Finally, leveraging an organizational intranet site as the central location to display all of the success stories that were discussed earlier can be highly effective as a communication tool. This can be the method of connecting the entire organization with updates on how the knowledge management initiatives have been going, and keep everyone in the loop as to improvements that have been recorded as a result of the new programs. This can again serve as motivation for employees in all levels of the organization to get involved, as excitement builds on the potential that better knowledge sharing brings to everyone. Creating places on the intranet for discussion forums regarding the implementation of knowledge

management programs can help the entire organization feel additionally invested, as everyone has a chance to feel that his or her voice has been heard and contributed to an aspect of the new initiative. Ultimately, by adopting a top down approach and recognizing the importance of engaging people at all levels of the organization in implementing new knowledge sharing initiatives, these programs can be successfully built and implemented in ways that benefits everyone involved.

HOW TO MEASURE KNOWLEDGE SHARING EFFECTIVENESS

One of the most important aspects highlighted above when starting knowledge management programs is building effective methods of measuring the effects that these programs have on the ability of employees within the organization to communicate new knowledge and updates on protocol with one another, as well as their effect on the overall productivity of the organization. It is imperative that the correct approach is taken when trying to measure the effectiveness of knowledge management programs, as incorrect information can make employees wary that the program itself may be inefficient. The information provided to the organization, measuring the effectiveness of new knowledge sharing initiatives, should be relayed in a way that is credible and easily understandable by everyone who reviews it. The following is a detailed account into how organizations should properly assess the success of any knowledge sharing initiative.

The first point that is important for organizations to understand when beginning to measure how well a new knowledge management initiative is performing is that the process itself can be very difficult for a number of reasons, many due to the nature of tacit knowledge itself which is at the core of knowledge management. Tacit knowledge, by its nature, is intangible and difficult to measure upon initial inspection. Zipperer has described, “Tacit Knowledge, which represents the social and adaptable knowledge vital to collaboration and patientcentered care, is harder to quantify and capture”.4 In order for knowledge sharing to be measured, it requires that organizations to think outside of the box when creating innovative methods.18 Part of what makes tacit knowledge difficult to measure is the fact that it is passed on through many different forums of communication. Tacit knowledge is exchanged through more observable actions and not articulated ones, such as both “experientially driven behavior” or “expression of thought through language”.19 This contributes to the elusive nature of tacit knowledge and to the difficulty of engaging in discussions about knowledge management. It is therefore essential that tacit knowledge is well defined within organizations. In order to do this, tacit knowledge must first be translated into “written verbal or observed processes so that it becomes explicit, tangible, transferable, and measurable”.4 This ensures that communication about tacit knowledge is clear organization-wide, contributing to the consistent and clear messaging that will be delivered to the team.

A way to successfully translate tacit knowledge into more

Another important aspect of tacit knowledge is to keep in mind that it is deeply rooted in the social interactions between colleagues. Because of the social nature of knowledge management, the appropriate channels should be leveraged when trying to build an understanding of how knowledge sharing occurs between people. There are three forums for knowledge sharing which can be used when measuring knowledge management: 1) social networks, 2) knowledge harvesting, and 3) communities of practice.4 When assessing social networks, Liebowitz has suggested using social network analysis tools such as questionnaires, surveys, and interviews, as well as utilizing the services of actors, in order to understand how organization-wide communication is handled.20 This also helps build an understanding of which leaders within the organization are considered to be the chief disseminators of knowledge. Based on feedback from social network analysis, certain people and groups of interest can be pinpointed as needing improvement in their sharing of knowledge. Knowledge harvesting, on the other hand, makes tacit knowledge more tangible through the use of interviews that can serve to highlight key aspects of the day-to-day knowledge sharing that occur, which are difficult to pick up from normal questionnaires.

These interviews are usually conducted with long-term employees who are leaving the organization, as a way to make sure that their knowledge is appropriately documented and their thoughts can be distilled for the rest of the organization to use.21 This is beneficial to the entire organization as knowledge is appropriately shared and it prevents a potential “brain drain” if the employee eventually does leave the organization. The third method way to record knowledge sharing by leveraging the social aspect of tacit knowledge is through communities of practice (CoP). CoPs are groups, that can be a variety of sizes, who share and create knowledge that is shared quickly throughout the group. The benefits of having such groups has been shown to improve the delivery of

care in hospital settings.22 Zipperer describes how CoPs 1087 are effective when trying to measure knowledge sharing in an organization as:‘CoPs provide opportunity and means for researchers to disseminate findings quickly to interested individuals who in turn apply the research in the real world. Results from implementation then inform further research elements of open communication, mutual interest, negotiation, and trust contribute to the success or failure of the process. This method accelerates the research to practice and practice-informed research paradigms, while providing valuable data from research, funding, real-world application and outcomes measurement.4 In order to build a thorough understanding of the knowledge sharing status within the organization, three knowledge discovery tools should be utilized. namely content analysis, text mining, and ontology application.4 Content analysis refers to building context of knowledge based on analysis of words used in reports.23 This allows researchers to discover the specific terminology that is used when conducting knowledge sharing, and allows them the opportunity to find areas for improvements in relaying of information. Text mining, on the other hand, delves even deeper by determining the number of times certain terms are used and giving them value-weighted numbers based on the which terms are used more than others. Text mining is effective in capturing context and experience in healthcare.24 Lastly, ontology application is a third very useful tool for knowledge discovery. Ontologies themselves are terms that are used to group separate concepts together under one umbrella. By applying ontologies into knowledge management initiatives, organizations can help take tacit knowledge and connect it to other concepts in ways that are “collectively accessible” and “applicable”. This is very important, especially in the realm of medicine and healthcare, as tacit knowledge that is not properly distinguished to an entire care team can result in miscommunication or inefficiencies that affect quality of patient care. Ontologies, when applied in this example, can help unify the team in their understanding of different concepts related to the delivery of patient care.25 Altogether, knowledge discovery can be successfully practiced when content analysis, text mining, and ontology application are used in tandem to help build out a team’s understanding of how knowledge sharing is conducted and the effects that new initiatives are having on the ability of a team to perform knowledge management.

HOW TO BECOME A KNOWLEDGE WORKER IN HEALTHCARE

The most empowering aspect of knowledge management is that, while it tends to be introduced in organization-wide initiatives, everyone has the ability to start engaging in knowledge sharing and becoming knowledge workers. As long as employees have an understanding of the steps that are required to practice knowledge management, they can start actively participating as knowledge workers within their organizations. It is important however that people who work in healthcare organizations also understand the interactions between tact knowledge and healthcare.4

CHAPTER 237

measurable explicit knowledge form is through the use of a knowledge audit.4 Zipperer outlines four key aspects of organizational knowledge sharing that a knowledge audit is able to determine 1) the current state of knowledge sharing pertaining to how widespread is organizationwide sharing; 2) Who are the experts that have most of the knowledge that needs to be disseminated, and how well have they done is spreading what they know; 3) are there sizeable gaps in the current state of knowledge within an organization, and if so, within what specific areas of the organization do those gaps exist; and 4) how can followup measurements of knowledge sharing be effectively coordinated. While carrying out this sort of knowledge audit is very useful when collecting information on the knowledge sharing status during the creation phase of new knowledge management initiatives, it can be even more effective when deployed soon after the new initiative has been implemented as a way to get back data on whether knowledge sharing has indeed improved since the new programs have been integrated into the organization.

1088 It is very helpful to take the time to explore how different

BEYOND MEDICINE

people within healthcare organizations can engage in knowledge sharing, as their experiences can help build the platform for others to similarly engage in the practice of knowledge management. In this section, we will focus primarily on the roles of Case Managers, Hospitalists, Nurses, and Patients as knowledge workers, but by the end of this section, you should have an understanding of how anyone who is involved in the healthcare industry can effectively practice knowledge sharing.

Case Managers play a very important role in healthcare as knowledge workers. They work as advocates for the patients in identifying their needs and serving as a hub for the patient’s care, connecting patients to a variety of healthcare practitioners as well as entities related to their care that exist outside the realm of healthcare (i.e. financial institutions, social workers, and insurance providers).4 Because of their multifaceted roles in the healthcare delivery process, they possess unique knowledge built from the time they have spent both with the patients and with the rest of the healthcare industry. They have the ability to help patients decide what is the best course of action based on their conditions and necessary medical care. For this reason, it is important that Case Managers share their knowledge both with other Case Managers, as well as others who they interact with.

Hospitalists have tremendous roles to play in engaging with knowledge sharing practices. They manage a patient’s care after the patient has been admitted to the hospital for any number of conditions or medical problems.

They work with other clinicians, engage in the reading and interpretation of the patient’s past medical charts, and take charge in determine the patient’s medical plan.

Hospitalists will engage in sharing of knowledge when the patient is discharged from the hospital, as they help explain to the patient the prescribed medical treatment plan. These instructions must be given using terminology that the patient understands, while also helping the patient become accustomed to the medical terminology of their current or treated medical condition.4,26 Because of their position, working within multidisciplinary teams and coordinating many different types of healthcare workers, hospitalists can serve as the ideal knowledge worker, helping to engage everyone in making sure that communication is clear and knowledge is being properly shared amongst all necessary channels.

Nurses serve a crucial role in knowledge sharing within a healthcare setting because of their close interactions with both the patients and the physicians. They can observe every day where miscommunications are occurring and possess an acute understanding of how this miscommunication can result in frustrations on both sides. It has been seen that because of their close interactions with patients, “the perception of trust and shared vision by nurses has been shown to positively influence knowledge sharing”.4,27 This makes sense because if patients feel comfortable with their nurses and trust them, they will be more likely to engage in sharing

of knowledge with their nurse that can help in ensuring that the best care is delivered.

It can be empowering to learn that patients themselves play a very large role in knowledge management within healthcare organizations. For this reason, patients must be sure that they ask all of the necessary questions, clear up anything they do not understand with their nurses and doctors, and make sure that they are getting the most out of their healthcare experience. Patients should feel that they are “in the loop” so to speak when care is being delivered. This helps ensure that the patient’s needs are held first and foremost as the highest priority when care is being delivered. For this reason, the patient must make sure that they elucidate, in their own words, exactly what they are going through, and the physician must make sure to document the patient’s description of their present condition in exactly those same words. This ensures that the knowledge has been properly shared and the doctor has a good understanding of what the patient is going through.

In total, the though four roles have only been covered in this section, healthcare itself has many different roles, where everyone should feel empowered to begin working as a knowledge worker. By taking extra time to make sure that goals are properly communicated, assignments are clearly worded, and different terminology for similar concepts are cleared up, organizations can make dramatic improvements before starting massive organization-wide knowledge management initiatives.

CONCLUSION

The principles of knowledge management are thoroughly applicable in medicine. Tacit knowledge, which is at the center of knowledge sharing, is very potent in its ability to cause miscommunications when not properly shared within an organization. If it is shared in an open forum that is very accessible however, it can also help organizations in building up their knowledge base by sharing the experiences of long-time employees. By taking the time to learn about knowledge management, workers in medicine and healthcare can position themselves and their organizations to be successful for many years to come. By taking the time to build a learning culture, one that values knowledge management, organizations will be prepared to quickly adapt, regardless of whatever changes that come in the future. Learning the important role that each one of us plays in a knowledge management-based system empowers everyone, especially in healthcare organizations where uniting every team member’s focus ensures the highest quality of care is given to patients.

Healthcare is an incredibly dynamic field that requires an equally dynamic school of thought-sharing in order to maximize the benefits that organizations bring to patients. Healthcare organizations and leaders in these organizations should take the time to learn more about knowledge management, assess the knowledge gaps in their organizations, build new knowledge sharing initiatives, foster the culture of a learning organization, and communicate successes from the new initiatives early

and often. If done well, knowledge management initiatives can empower everyone within the organization, and improve the organization’s service-providing capacity moving forward.

REFERENCES

1.

2.

Wilson TD. The nonsense of ‘knowledge management.

Information Research, 8 (1) (2002) (paper no. 144) Available at http://www.informationr.net/ir/8-1/paper144.html.

Retrieved on Nov, 6, 2016

3.

Ackoff RL. From data to wisdom. Journal of applied systems analysis 1989; 16:3-9

4.

Barnard P, Napier J, Zipperer L. What is Knowledge?

Knowledge Management in Healthcare 2014:1.

5.

Bohmer RM. Designing care: aligning the nature and management of health care. Boston, Massachusetts; Harvard Business Press 2009; 2013 Mar 29.

6.

Davison G, Blackman D. The role of mental models in the development of knowledge management systems.

International Journal of Organizational Behavior 2005; 10:75769.

7.

Garvin DA, Edmondson AC, Gino F. Is yours a learning organization? Harvard business review 2008; 86:109.

8.

Garvin DA. Building a learning organization. Org Dev & Trng, 6E (Iae). 1985;274.

9.

Balik, B. and Gilbert, J., 2010. The heart of leadership: Inspiration and practical guidance for transforming your health care organization. Chicago, IL: American Hospital.

Association Press

10. Gollop R, Whitby E, Buchanan D, Ketley D. Influencing skeptical staff to become supporters of service improvement: a qualitative study of doctors’ and managers’ views. Quality and Safety in Health Care 2004; 13:108-14.

11. Riege A. Three-dozen knowledge-sharing barriers managers must consider. Journal of knowledge management. 2005; 9:18-35.

12. Davenport TH, De Long DW, Beers MC. Successful knowledge management projects. MIT Sloan Management Review 1998; 39:43.

13. Swinglehurst D, Greenhalgh T, Russell J, Myall M. Receptionist input to quality and safety in repeat prescribing in UK general practice: ethnographic case study. BMJ 2011; 343:d6788.

15. Denning S. Effective storytelling: strategic business narrative techniques. Strategy & Leadership 2006; 34:42-8.

16. Collins JC. Good to great: Why some companies make the leap... and others don’t. New York, NY: Harper Business; 2001.

17. Campbell EM, Guappone KP, Sitting DF, Dykstra RH, Ash JS. Computerized provider order entry adoption: Implications for clinical workflow. J Gen Intern Med 2008; 24:21-26.

18. Liebowitz J, Suen CY. Developing knowledge management metrics for measuring intellectual capital. Journal of intellectual capital 2000; 1:54-67.

19. Delen D, Al-Hawamdeh S. A holistic framework for knowledge discovery and management. Communications of the ACM 2009; 52:141-5.

20. Liebowitz J. Linking social network analysis with the analytic hierarchy process for knowledge mapping in organizations. Journal of knowledge management. 2005; 9:76-86.

21. De Brún C. ABC of knowledge management. National Library for Health: Knowledge Management Specialist Library. 2005.

22. Ranmuthugala G, Cunningham FC, Plumb JJ, Long J, Georgiou A, Westbrook JI, Braithwaite J: A realist evaluation of the role of communities of practice in changing healthcare practice.

Implement Sci 2011; 6:49-10.

23. Ruben BD. What patients remember: a content analysis of critical incidents in health care. Health Communication 1993; 5:99-112.

24. Raja U, Mitchell T, Day T, Hardin JM. Text mining in healthcare. Applications and opportunities. J Health Inf Manag 2008; 22:52-6.

25. Casellas N. Legal ontologies. InLegal Ontology Engineering 2011 (pp. 109-169). Springer Netherlands.

26. Shekelle PG, Pronovost PJ, Wachter RM, Taylor SL, Dy SM, Foy R, Hempel S, McDonald KM, Ovretveit J, Rubenstein LV, Adams AS. Advancing the science of patient safety.

Annals of Internal Medicine 2011; 154:693-6.

27. Chang CW, Huang HC, Chiang CY, Hsu CP, Chang CC. Social capital and knowledge sharing: effects on patient safety. Journal of advanced nursing 2012; 68:1793-803.

CHAPTER 237

Girard, John P.; Girard, JoAnn L. “Defining knowledge management: Toward an applied compendium”. Online Journal of Applied Knowledge Management 2015; 3:1–20.

14. Kotter, J.P. Leading change: Why transformation efforts 1089 fail. Harvard Business Review 1995; 73:59-67

Prognostication – A Lost Skill in Medicine

C H A P T E R

238 Prognosis (“foretelling, foreseeing”) is a term for predicting the likely outcome of one’s current standing.

One of the earliest written works of medicine is the Book of Prognostics by Hippocrates, written around 400 BC. This work opens with the following statement: “It appears to me a most excellent thing for the physician to cultivate prognosis; for by foreseeing and foretelling, in the presence of the sick, the present, the past, and the future, and explaining the omissions which patients have been guilty of, he will be the more readily believed to be acquainted with the circumstances of the sick; so that men will have confidence to entrust themselves to such a physician.”

For 19th century physicians, particularly those following the French school of medicine, the main aim of medicine was not to cure disease, but rather to give a medical diagnosis and achieve a satisfying prognosis of the patient’s chances. Only several decades later did the focus of efforts in Western medicine shift to curing disease.

At the end of the nineteenth century prognostication took up approximately ten percent of medical textbooks, by 1970 this had fallen to nearly zero. An article on prognostication in Lancet from 1934 reads: “Of the three great branches of clinical science – diagnosis, prognosis, and treatment – prognosis is admittedly the most difficult.

Whilst precise predictions of the future are obviously not possible, relatively simple mathematical modeling techniques can make reasonable estimates of likely outcomes for individual patients. Patient’s prognosis not only depends on their age and primary diagnosis, but also on the severity of their illness, their functional capacity both prior to and during the illness and the number of comorbidities they are suffering from.

THE COMMON SCENARIO

Imagine you are receiving an unconscious patient on ventilator. On examination, you find out that the patient, a chronic smoker with 40 pack years, k/c/o HT/CAD & DM on treatment for the past 10 years, recently diagnosed right lung cancer on chemotherapy for 8 weeks, developed one episode of GTCS, revived post cardiac arrest in another hospital and connected to ventilator and on inotropic support. CT Brain taken shows multiple metastases. Patient’s family members are called by the doctor to inform the condition. After Doctor’s detailed explanation, the very next common question asked by the family members is “AUR KUCH PROBLEM NAHI HAI KYA?”.

M Raveendran

PROGNOSTICATION

“Doctor, if I am dying, don’t use these machines on me.”

This sentence is repeatedly heard by physicians. How are we to know that someone “is dying?”. Most physicians are willing to forego useless medical interventions when a patient is near death or to shape a plan of care so that it reflects an unavoidably grim prognosis. To accomplish that, physicians need a number of skills and tools, including accurate ways of estimating survival prospects.

In this article we review current efforts in that regard and evaluate the challenges and opportunities they present to practitioners and patients.

The day, one is born, not only he is growing in age and size; he is also marching towards death. The organ/organ system which has started its functioning slowly starts to fail also. One is growing day by day, means dying day by day. We know that, the patho-physiology for any disease should be congenital / traumatic/ infection/inflammation/ or malignancy. Add one more organ failure.

Every person who is born has to die one day. Date of manufacture/ date of expiry are not only for man made products, but also for man. Every organ which is functioning in our body today will malfunction or stop functioning one day.

How to predict? Are there any biomarkers? Any formula? Any signs /symptoms? Any scoring system?

Any prognostication?

End of Life

Most doctors are over optimistic when giving prognosis.

They tend to overstate how long the patient may survive.

For patients who are critically ill, especially in an ICU, there are plenty of prognostic scoring systems which are more accurate; the most famous of these is APACHE II scale. Knowing the prognosis helps to decide on treatment modalities or to withhold them, which plays an important role in the end of life decisions? Prognostic scoring is also used for cancer outcome predictions.

Estimators that are commonly used are 1.

Prognosis-free survival - Length of time during and after medication or treatment during which the disease being treated does not get worse.

2.

Survival rate - % of people in treatment group who are alive for a period of time after diagnosis.

Most doctors are over optimistic when giving prognosis. They tend to overstate

3. the patient Survival time -For The remaining duration life from events such as pneumonias and falls), and the nature of 1091 how long may survive. patients who are critically ill,of especially in an ICU, time of scoring diagnosis. the assistance available (medical, nursing, and family there are plenty the of prognostic systems which are more accurate; the most famous care) will allow a prediction of how long the walk will go.

Can Be Accomplished Objective Estimates of theseWhat is APACHE II scale.

Knowing the With prognosis helps to decide on treatment

of Survival?

Thethem, best which that can withrole high-quality modalities or to withhold playsbeandone important in the end of PROGNOSTIC life INDICES

Only a few decades ago, all physicians had to offer for prognostication was descriptions of the survival experience of a large group of persons who were defined

3. Survival time - The remaining duration of life from the time of diagnosis.

Disease Severity Duration of illness Extent/staging of disease Disease identification time

PROGNOSTICATION

TRIAD

Treatment Drugs Effects/side effects Efficacy of Drugs Consultants’ Expertise

Extraneous factors co morbidities Age/sex Genetic factors Environmental influence

Table 1: Karnofsky performance scale (KPS) %

Criteria

100 Normal; no complaints; no evidence of disease

CHAPTER 238

measures on a large population will not reveal the day when a person will die, and it probably will not limit the range of days to the next few, except in cases of persons Estimators thatsurviving. are commonlyThis used are barely is because the pace of dying is affected survival by many factors a substantial period of 1. Prognosis-free - Length of over time during and after medication or time (Figure 1). Prognosticating will always be inescapably treatment during which the disease being treated does not get worse. difficult. Dying can be seen as a walk on a long tightrope.

2. Survival rate - % of people in treatment group who are alive Measures of a walker’s skill (the illness and the body’s for a response), period of timethe aftergustiness diagnosis. of the wind (the rate of external decisions? Prognostic scoring is also used for cancer outcome predictions.

90

Able to carry on normal activity; minor signs or symptoms of disease

80

Normal activity with effort; some signs or symptoms of disease

70

Cares for self; unable to carry on normal activity or to do active work

60

Requires occasional assistance but is able to care for most personal needs

50

Requires considerable assistance and frequent medical care

40

Disabled; requires special care and assistance

30

Severely disabled; hospitalisation is indicated, although death not imminent

20

Very sick; hospitalisation necessary; active support treatment is necessary

10

Moribund; fatal processes

0 Fig. 1: Prognostication Triad What Can Be Accomplished With Objective Estimates of Survival?

Dead

Table Palliative performance scale measures (PPS) on a large population will The best2:that can be done with high-quality

not reveal the day when a person will die, and it probably will not limit the range of days

Estimated median survival in days

%

Ambulation

Activity level Evidence Self-care of disease

Intake

Level of consciousness

100

Full

Normal No disease

Full

Normal

Full

90

Full

Normal Some disease

Full

Normal

Full

80

Full

Normal with effort Some disease

Full

Normal or reduced

Full

70

Reduced

Cant do normal job or work Some disease

Full

As above

Full

145

60

Reduced

Cant do hobbies or housework Significant disease

Occasional assistance needed

As above

Full or confusion

29

4

50

Mainly sit/lie

Cant do any work Extensive disease

Considerable assistance needed

As above

Full or confusion

30

11

40

Mainly in bed

As above

Mainly assistance

As above

Full or drowsy or confusion

18

8

30

Bed bound

As above

Total care

Reduced

As above

5

E

20

Bed bound

As above

As above

Minimal

As above

4

2

10

Bed bound

As above

As above

Mouth care only

Drowsy or coma

1

1

0

Death

(a) NA

(b)

(c)

NA 108

41

6

1092

Table 3: Palliative Prognostic Index Variable

Table 4: The Palliative Prognostic Score (PnP) Partial Score Value

PPS 10-20

4

30-50

2.5

60+

0

BEYOND MEDICINE

2.5

Moderately Reduced

1.0

Normal

0 1.0

Absent

0

Dyspnea at Rest Present

3.5

Absent

0 4.0

Absent

0

Total Score

PPV

NPV

0.83

0.71

by one characteristic: perhaps those newly diagnosed with a deadly illness or those who had reached a certain stage of such an illness. With the recent introduction of better computing and statistical tools, dramatically improved objective estimates of prognosis have become available.

A statistical model that relies on computer analysis can often weigh the elements more accurately and usefully than projections that rely on the average experience of mixed groups or clinicians’ personal experience. A careful consideration of both individual diseases and diseased individuals is required for the restoration of prognosis to the same status as diagnosis and treatment.

PROGNOSTICATION TOOLS

Prognostication index is a global measurement of patients’ functional capacity which includes the following scores/ indices.

Only 10 % of patients with < 50 % score survive > 6 months.

PPS is a modification of KPS (Tables 1 and 2).

PPI > 6.0 , survival < 3 weeks ( Sensitivity – 80% Specificity – 85 %) (Table 3).

Cardinal Symptoms Predicting Survival

No Yes

0 1

Anorexia

No Yes

0 1.5

≥3 10-20

0 2.5

> 12 11-12 7-10 5-6 3-4 1-2

0 2 2.5 4.5 6 8.5

≤8.5 8.6 - 11 >11

0 0.5 1.5

20-40% 12-19.9% <12%

0 1 2.5

30 DAY SURVIVAL >70% 30-70%

TOTAL SCORE 0-5.5 5.6-11 11.1-17.5

Lymphocyte Percentage

6-week survival

>4

Dyspnea

Total WBC (x109/L)

Delirium Present

Partial Score

Clinical Prediction of Survival (weeks)

Edema Present

Assessment

Karnofsky Performance Slatus

Oral Intake Severely Reduced

Criterion

National Hospice study data revealed 5 cardinal symptoms that predict survival - Dyspnea, Anorexia, Weight loss, Dry mouth and Dysphagia. Asthenia, Confusion, Drowsiness and Delirium have also been shown to have prognostic values in advanced cancer cases. Dyspnea predicts < 30 days, Anorexia < 58 days, Dry mouth < 50 days, Dysphagia < 30 days and Confusion

RISK GROUP A B C

< 38 days. In general, greater the number of symptoms, worse is the prognosis (Table 4).

BIOLOGIC PARAMETERS FOR PREDICTING POOR PROGNOSIS

•

Low serum Na+ - Persistent hyponatremia in spite of corrective measures.

•

Low serum Albumin – denotes long standing malnutrition/DCLD

•

High TC / Low lymphocyte % - denotes immunosuppressive state of the patient.

•

Thrombocytosis – negative prognostic indicator in multiple cancers.

•

High serum Bilirubin – denotes active liver failure or sepsis.

•

High Alk.Phosphatase – metabolic state at present.

•

High LDH – indicating high cell metabolism.

•

High CRP – increased metabolism / cell turnover.

•

Vit B 12 >600pmol/L - Hematologic disorders like chronic myelogenous leukemia, promyelocytic leukemia, polycythemia Vera, hyper eosinophilic syndrome, acute hepatitis, cirrhosis, hepatocellular carcinoma and metastatic liver disease.

•

Uric Acid >7.2/dl – denotes high cell turnover and hyper metabolism.

denotes

increased

Table 5: Illnesses with Poor Prognosis

•

Malignant Hypercalcemia metastatic disease.

in bone tumor/

Cardiac failure requiring inotropic support, Progressive renal failure, Repeated hospital admissions.

CRF

Poor compliance for dialysis, Severe hyperkalemia without treatment

COPD

Respiratory failure

CANCER

Multiple metastases, Refractory hypercalcemia, Bleeding tumor, Bone marrow failure.

OTHERS

Sepsis, Massive CVA, Hypoxic encephalopathy, Coma

help avoid burdensome treatments.

Hippocratic writers characterized the physician’s role thus: “Declare the past, diagnose the present, foretell the future; practice these arts.”

GSF Prognostic Indicator guidance (gold standards framework)

Earlier identification of people nearing the end of their life and inclusion on the register leads to earlier planning and better coordinated care.

It has three steps

IDENTIFY  ASSESS  PLAN

IDENTIFY patients in their last year and what stage are they.

“Life is short, the art long, opportunity fleeting, experience treacherous, and judgment difficult.”

REFERENCES

1.

Hipócrates, Hippocrates; with an English Translation WHS Jones. 1979: William Heinemann

2.

Hancock K, Clayton JM, Parker SM, Wal der S, Butow PN, Carrick S, et al. Truth-telling in discussing prognosis in advanced life-limiting illnesses: a systematic review. Palliat Med. 2007; 21: 507-517.

3.

Evans LR, Boyd EA, Malvar G, Apatira L, Luce JM, Lo B, et al. Surrogate decision-makers’ perspectives on discussing prognosis in the face of uncertainty. Am J Respir Crit Care Med. 2009; 179: 48-53.

4.

Parker SM, et al. A systematic review of prognostic/end-oflife communication with adults in the advanced stages of a life-limiting illness: patient/caregiver preferences for the content, style, and timing of information. Journal of pain and symptom management. 2007; 34: 81-93.

5.

Stone PC, Lund S. Predicting prognosis in patients with advanced cancer. Ann Oncol. 2007; 18: 971-976.

6.

Mack JW1, Smith TJ . Reasons why physicians do not have discussions about poor prognosis, why it matters, and what can be improved. J Clin Oncol. 2012; 30: 2715-2717.

7.

Barnett MM. Does it hurt to know the worst?-psychological morbidity, information preferences and understanding of prognosis in patients with advanced cancer. Psychooncology. 2006; 15: 44-55.

8.

Teno JM, Weitzen S, Fennell ML, Mor V. Dying trajectory in the last year of life: does cancer trajectory fit other diseases?

J Palliat Med. 2001; 4: 457-464

9.

Murray SA, et al. Illness trajectories and palliative care.

International Perspectives on Public Health and Palliative Care. 2013; 30.

ACCESS Current and future clinical and personal needs.

PLAN Planning the treatment asper the patient / his family’s decision Patients with cancer have sharp decline in functional status and quality of life in the last months of life.

Identifying where the patient lies in the course of disease is important (Figure 2).

These models are not dictators, but only tools. They will be most helpful when well understood and thoughtfully applied, and their use warrants careful evaluation.

Adjectives such as rarely and usually are notoriously ambiguous whereas numbers are clear and compact. The strongest argument for prognostic indices is that they facilitate professional communication. Some illnesses are associated with a diagnosis that virtually carries a poor prognosis like pancreatic cancer, biliary tract cancer and metastatic adenocarcinoma of unknown primary and untreated small cell lung cancer. There are circumstances that have a very poor prognosis in specific illnesses, given in Table 5.

CONCLUSION

Doctors face two challenges in prognosticating near the end of life: formulating accurate predictions and communicating them. If Doctors are better able to anticipate death, they will be likely to help the patient and his family to make judicious use of medical treatments.

Increased accuracy of prognosis helps patients and family to make directive decisions, allow for preparations and

10. Maltoni M, Pirovano M, Scarpi E, Marinari M, Indelli M, Arnoldi E, et al. Prediction of survival of patients terminally ill with cancer. Results of an Italian prospective multicentric study. Cancer. 1995; 75: 2613-2622.

CHAPTER 238

Fig. 2: Cancer Trajectory, Diagnosis to Death

CCF

1093

C H A P T E R

239 •

Assessment of Uncounsious Patient

Coma is a state of unconsciousness caused by temporary or permanent impairment of the ascending reticular system in the brainstem, or both cerebral hemispheres.

The key components of the neurological examination of the comatose patient are: •

level of consciousness

•

the pattern of breathing

•

size and reactivity of the pupils

•

eye movements and oculovestibular responses

•

motor responses (tone, reflexes and posturing)

•

meningism and signs of the underlying cause

Saurabh Jain

skull base fractures.

•

Cranial scars, drains, ICP monitors and VP shunts

•

Track marks and drug paraphernalia

•

Infusions (e.g. Sedatives, vasopressors)

•

Ventilator (evidence of spontaneous breaths)

IMPORTANT SIGNS AND DIAGNOSTIC CONSIDERATIONS

Vital Signs •

Hypertension- Pheochromocytoma, eclampsia, calcineurin inhibitor toxicity, drug ingestion (amphetamines, arsenic, cocaine, phencyclidine).

•

Hypotension - Addison disease, sepsis, drug ingestion (β blockers, calcium channel blockers, arsenic, barbiturates, cyclic antidepressants, lithium, methanol, opioids, organophosphates, phenothiazine, sedative-hypnotics)

•

Hypothermia - Hypothyroidism, hypoglycemia, environmental exposure, drug ingestion (barbiturates, opioids, sedative-hypnotics, phenothiazine)

•

Hyperthermia - Infection, drug ingestion (amphetamines, cocaine, tricyclic antidepressants, phencyclidine, salicylates), malignant catatonia, neuroleptic malignant syndrome

•

Tachycardia – Infection, drug ingestion (alcohol, amphetamines, cocaine, ethylene glycol, arsenic, cyclic antidepressants, phencyclidine, phenothiazine)

•

Bradycardia - Uremic coma, myxedema coma, drug ingestion (β blockers, opioids)

•

Tachypnea - Diabetic ketoacidosis, drug ingestion (ethylene glycol, salicylates, amphetamines, methanol)

Systemic causes can sometimes have focal signs (e.g.

Todd’s paresis, hemiparesis due to hypoglycemia)

•

Dyspnea – ACS, Drug ingestion (alcohol, barbiturates, opioids, sedative-hypnotics

GENERAL EXAMINATION

Odour

In particular, assessment of asymmetry for the presence of focal neurological deficits is vital.

CAUSES OF COMA

While stabilizing the ABCs ,watch for any focal deficit.

CAUSES WITH FOCAL SIGNS

•

No meningism — stroke, space occupying lesions (e.g. tumor, hemorrhage, abscess), injury, inflammation

•

Meningism — meningoencephalitis, subarachnoid hemorrhage (SAH)

CAUSES WITHOUT FOCAL SIGNS

• Toxins •

Organ failures

•

Metabolic - (CO2, O2, ammonia, temperature, pH, electrolytes, glucose, serum osmolality)

• Endocrine • Seizures

General examination is very important •

•

•

Dirty restroom – Uremia

Consider the neurological findings in light of the vital signs, evidence of trauma, acute or chronic illness, and/or drug ingestion

•

Fruity sweat- Ketoacidosis

•

Musty or fishy - Acute hepatic failure

Are there signs of trauma, such as a battle sign (bruising of the mastoid bone) or raccoon eyes (periorbital ecchymosis), which may each suggest

•

Garlic - Organophosphates, insecticides, thallium

•

Onion – Paraldehyde

Skin •

•

Diaphoresis - Thyroid storm, hypoglycemia, malignant catatonia, acute sympathetic hyperactivity, drug exposure (organophosphates, sympathomimetics, cholinergics) Dry skin - Hypothyroidism, drug exposure (barbiturates, anticholinergics, cyclic antidepressants) Acne - Long-term antiepileptic use

•

Bullae - Drug exposures (barbiturates, sedativehypnotics)

•

Butterfly rash - Systemic lupus erythematosus

•

•

Also look for deep rapid Kussmaul breathing, secondary to a metabolic acidosis, as in diabetes ketoacidosis

PUPILLARY RESPONSES

Assess the pupils for size, asymmetry and reactivity to light. Different sized pupils correspond to different types of lesions •

Pinpoint pupils (<2mm) occur in pontine lesions and certain overdoses (e.g. Opioid, Organophosphorus, clonidine)

Dark pigmentation - Addison disease

•

Fixed mid-sized pupils occur in midbrain lesions

•

Edema - Acute renal failure

•

•

Purpura - Meningococcal meningitis, thrombotic thrombocytopenic purpura, vasculitis, disseminated intravascular coagulation, aspirin intoxication

•

Rash - Meningitis, viral encephalitis, rickettsia infection, drug ingestion (alcohol, amphetamines, cocaine, ethylene glycol, arsenic, cyclic antidepressants, phencyclidine, phenothiazine)

One dilated pupil suggests CN3 compression – e.g. ICH, PCOM aneurysm or raised ICP (parasympathetic nerves are in the superficial parts of the nerve, so tend to be more vulnerable to compressive lesions – ptosis and ‘down and out’ eye positioning tends not to occur due to sparing of the more central motor fibers)

•

Dilated pupils found with anticholinergic syndrome and with amphetamines, cocaine and other sympathomimetic drugs.The absence of large pupils does not exclude any of these drugs as pupil size can be influenced by other co-ingested drugs.

•

Cold, malar flush, yellow tinge, puffy face Myxedema coma

LEVEL OF CONSCIOUSNESS

•

Glasgow Coma Scale (GCS) is most commonly used

•

Other scores such as the FOUR score are used to assess patients with low GCS as it also accounts brainstem reflexes, intubation, use of sedatives or paralytic drugs.

OCULAR DEVIATION AND DYSCONJUGATE GAZE

Dysconjugate gaze - Most individuals have a degree of exophoria when drowsy for any reason and any underlying strabismus tends to worsen.

Tonic deviation •

PATTERN OF BREATHING

Breathing pattern is often forgotten in intubated patients, but is important as the pattern of breathing correlates with the level of the lesion, and may suggest other causes •

Cheyne-Stokes respiration (not specific) Crescendo-decrescendo breathing pattern followed by apnea or hypopnea; persists in sleep. Seen in Bihemispheric (unilateral or bilateral) or brainstem lesions.

• Central hyperventilation Sustained hyperventilation, respiratory rates exceeding 40 per minute, seen in Bihemispheric, pons, midbrain lesions •

Irregular ataxic breathing - Irregular respiratory rate, rhythm; amplitudes interrupted by apnea, indicates various brainstem lesion

•

Cluster - Irregular clusters of breaths followed by apneic periods of variable duration, Bihemispheric or pons lesions

•

Apneustic - Prolonged inspiration with a 2- to 3-s

Eyes deviate in the same direction of lesions as in frontal lobe lesions, commonly a stroke. This can also be a result of a Todd’s paralysis following a seizure (whereas during the seizure the eyes deviate in the opposite direction — away from the origin of the ‘irritative’ focus).

• A pontine lesion deviates eyes on the opposite side. ‘Wrong way eyes’ may also be seen in thalamic hemorrhage.

•

Lateral gaze deviation from a pontine lesion cannot be overcome by stimulating oculocephalic or oculovestibular reflexes (see below), whereas supranuclear (e.g. frontal lesions) can. Hence they can be distinguished clinically.

Skew deviation •

Vertical separation of the ocular axes is called skew deviation

•

This is suggestive of a pontine or vestibulocerebellar lesion on the side of the inferior eye, or a medial longitudinal fasciculus lesion on the side of the superior eye

Abnormal eye position can also result from cranial nerve

CHAPTER 239

•

pause, then expiration, seen in lesions of lateral 1095 tegmentum of lower pons

not necessary

1096 palsies (CN6 is particularly at risk due to it’s long course)

and orbital entrapment in trauma

•

Periodic alternating gaze - lateral deviation every few minutes, left and right - Bihemispheric, midbrain, vermis

Introduce iced water into the external ear canal through a small cather until one of the following occurs:

—

nystagmus (in the intact brainstem the slow phase is towards the irrigated ear)

•

Ping-pong - lateral deviation every few seconds, left and right - Bihemispheric, vermis

—

ocular deviation

•

Convergence nystagmus - bilateral abduction, slow with rapid jerk back –Mesencephalon

—

200mL of iced water has been instilled

•

•

Bobbing - rapid down, slow up – Pontine lesion

Allow 5 minutes between testing ears to allow reequilibration of the oculovestibular system

•

Dipping -slow down, rapid up – Bihemispheric lesion

•

As consciousness is lost, the fast component (towards the non-irrigated ear) is lost and the slow component tonically deviates the eye in the direction of the irrigated ear

SPONTANEOUS EYE MOVEMENTS

BEYOND MEDICINE

•

FUNDOSCOPY

Important findings include: •

Papilloedema —optic disc swelling due to raised intracranial pressure. However, the absence of papilloedema does not rule out intracranial hypertension.

•

Evidence of Terson syndrome — vitreous, subhyaloid, or retinal bleeding in association with subarachnoid hemorrhage

OCULOVESTIBULAR REFLEXES

Vertical oculo-vestibular eye responses can be assessed by irrigated both ears simultaneously •

If the brainstem is intact, cold water causes the eyes to deviate downwards and warm water causes the eyes to deviate upwards

Caveats •

Brainstem encephalitis, deep metabolic coma and certain drugs may mimic brainstem death

•

Drugs include recently administered antiepileptics such as phenytoin and barbiturates. Like phenytoin, tricyclic overdose may cause bilateral vestibular failure, as might aminoglycoside vestibulotoxicity.

Baclofen overdose can also mimic brain death Another caveat pertains to the trauma patient — ocular movements may be impaired if a blowout fracture has trapped the extraocular muscles

Oculocephalic reflex (‘doll’s eye’ reflex) •

Ensure the C-spine is cleared

•

The patient’s eyes are held open

•

The head is briskly turned from side to side with the head held briefly at the end of each turn

•

•

A positive response occurs when the eyes rotate to the opposite side to the direction of head rotation, thus indicating that the brainstem (CN3,6,8) is intact

Typical findings for various lesions are shown in this figure:

•

•

•

A similar result is seen when the head is flexed and extended — a positive result is downward deviation of the eyes during extension, and upward deviation during flexion (the eyelids, if closed, may also open as part of the ‘doll’s head phenomenon’).

These vertical responses indicate that the brainstem (CN3,4,8) is intact The eyes should gradually return to the midposition in a smooth, conjugate movement if the brainstem is intact Patients with metabolic coma (e.g. hepatic failure) may have exaggerated, brisk oculocephalic reflexes

Oculovestibular reflex (caloric stimulation) •

•

The head is elevated to 30 degrees above horizontal so that the lateral semicircular canal is vertical, and so that stimulation with generate a maximal response Check that the tympanum is intact and that the external ear canal is clear — C-spine clearance is

Caloric responses

Oculocephalic responses

Cool water

Turn right

Turn left

Tilt back

Tilt forward

A Brainstem intact (metabolic encephalopathy)

B Right lateral pontine lesion (gaze paralysis)

C MLF lesion (bilateral internuclear ophthalmoplegia)

D Right paramedian pontine lesion (1 1/2 syndrome)

E Midbrain lesion (bilateral)

CORNEAL REFLEX

Corneal reflex is of limited use

Right side

Left side

Bilateral

Warm water Bilateral

• •

Patients that chronically wear contact lenses may have diminished corneal reflexes Loss of the corneal reflex is usually a late sign in coma

Assessment

MOTOR RESPONSES

Posturing can occur spontaneously or in response to a stimulus • Abnormal flexion is decorticate posturing — adduction of arm, internal rotation of shoulder, pronation of forearm, flexion of wrist (lower limbs are extended); indicates a lesion above the brainstem

Traditional method is to stroke the cornea with cotton wool

•

Corneal stimulation can also be performed by dropping a few drops of sterile saline onto the cornea from a height of 10 cm (less traumatic)

•

Reflex is present and intact if the patient blinks and eyes roll upwards

•

Afferent: CN5

•

Efferent: CN7 (blink) and CN3 (eye movement)

• tone

•

Indicates that the pons and midbrain are intact (the reflex pathway involves the trigeminal nerve, the spinal CN5 nucleus, the lateral brainstem tegmentum, and the CN3 and CN7 nuclei)

• clonus

• •

•

Extension is decerebrate posturing — abduction of arm, external rotation of shoulder, supination of forearm, extension of wrist (lower limbs are extended); indicates a lesion extending to the midbrain or below

Assess for:

•

deep tendon reflexes

•

plantar reflexes

If the eye turns upwards but the eyelid does not close there is a CN7 lesion (Bell’s phenomenon)

•

involuntary movements (such as subtle signs of seizures and myoclonus)

If the eye does not turn upwards and the eyelid does not close there is a CN5 lesion

Look for asymmetry

Gag reflex •

Sensory = CN9, motor = CN10

Being the first one to find a patient with an acute alteration in consciousness can be a frightening experience. Your immediate actions and skilled assessments may literally save his life.

•

May be absent in normal people and those accustomed to an endotracheal tube

•

•

Best assessed using a laryngoscope or a tongue depressor, look for bilateral palatal elevation

Wijdicks EF, et al. FOUR score and Glasgow Coma Scale in predicting outcome of comatose patients: a pooled analysis. Neurology 2011; 77:84–85

•

Walker MC, O’Brien MD. Neurological examination of the unconscious patient. JR Soc Med 1999; 92:353-5.

Cough reflex

JOURNAL ARTICLES

TEXTBOOKS

•

mediated by CN10

•

•

can be stimulated by a suction catheter down and endotracheal tube

Brazis, Paul W et al . Localization in clinical neurology (5th edition). Lippincott Williams and Wilkins, 2007

•

Bersten AD, Soni N. Oh’s Intensive Care Manual (6th edition). Butterworth-Heinemann, 2008.

•

Poser JB, et al. Plum and Posner’s Diagnosis of Stupor and Coma (4th edition), Oxford university Press, 2007.

CHAPTER 239

•

GAG AND COUGH REFLEXES

1097

Salt Sensitivity in Hypertension

C H A P T E R

240

Shashank R Joshi

The human body has evolved to balance salt intake with need through means such as the renin-angiotensin system.

The well-known effect of sodium on blood pressure can be explained by comparing blood to a solution with its salinity changed by ingested salt. Artery walls are analogous to a selectively permeable membrane, and they allow solutes, including sodium and chloride, to pass through (or not), depending on osmosis. When salt is ingested, it is dissolved in the blood as two separate ions :- Na+ and Cl−. The water potential in blood will decrease due to the increase solutes, and blood osmotic pressure will increase. While the kidney reacts to excrete excess sodium and chloride in the body, water retention causes blood pressure to increase.

and salting is an important method of food preservation.

Salt has been used in foods throughout and before history for more than 8000 years. It has had politically and economically important place in human history. Salt was scarce in most areas until recently and important as a traded commodity also used as currency, in fact the world “salary” comes from salt. The word “salary” comes from the Latin word for salt because the Roman Legions were sometimes paid in salt, which was quite literally worth its weight in gold. In Britain, the suffix “-wich” in a place name means it was once a source of salt, as in Sandwich and Norwich. The Natron Valley was a key region that supported the Egyptian Empireto its north, because it supplied it with a kind of salt that came to be called by its name, natron. There is more salt in animal tissues such as meat, blood and milk, than there is in plant tissues. Nomads who subsist on their flocks and herds do not eat salt with their food, but agriculturalists, feeding mainly on cereals and vegetable matter, need to supplement their diet with salt. With the spread of civilization, salt became one of the world’s main trading commodities. Some of the earliest evidence of salt processing dates to around 8,000 years ago, when people living in an area in what is now known as the country of Romania were boiling spring water to extract the salts; a salt-works in China dates to approximately the same period. Salt was prized by the ancient Hebrews, the Greeks, the Romans, the Byzantines, the Hittites and the Egyptians. Salt became an important article of trade and was transported by boat across the Mediterranean Sea, along specially built salt roads, and across the Sahara in camel caravans. The scarcity and universal need for salt has led nations to go to war over salt and use it to raise tax revenues. Salt is also used in religious ceremonies and has other cultural significance.

HISTORY OF SALT

Salt and Sodium

INTRODUCTION

Salt and Sodium has been intensely studied for its role in human physiology and impact on human health.

In particular, excessive dietary salt consumption over an extended period of time has been associated with Hypertension apart from other adverse health effects.

Salt chemically is defined as any combination of an acid and base resulting in formation of an ionic compound (examples KCl, KBr, NaSO4, etc.). Common edible salt is composed of sodium chloride NaCl (table salt) is the ionic combination of the cation (Na+) and anion (Cl-). Salt is found naturally in seawater (around 3%), in mineral deposits (halite) and in natural bodies of water (lakes, streams). Salt can be mined from underground deposits, either by rock salt mining or vacuum evaporation. It can be evaporated from seawater (sea salt, fleur de sel) or other bodies of water. Sodium is necessary for life for osmo-regulation, maintaining “water balance” and nerve transduction and other biological functions. Human body contains about 250 grams of salt (3 or 4 full salt shakers).

Salt is essential for human life, and saltiness is one of the basic human tastes. The tissues of animals contain larger quantities of salt than do plant tissues. Salt is one of the oldest and most ubiquitous food seasonings,

Table 1: Comparable amounts of sodium (in mg and mmol) and salt (in g)

*

Sodium (mg)

Sodium (mmol)

Salt* (g)

400

17

1

2000

87

5

4000

174

10

a teaspoon of salt contains approximately 6 g salt

The terms salt and sodium are often used synonymously, although on a weight basis salt comprises 40% sodium and 60% chloride. Table 1 indicates an overview of different units.8 Sodium is the principal cation in extracellular fluid in the body. In healthy individuals, almost 100% of ingested sodium is absorbed during digestion. Sodium and chloride are the chemical components of common table salt; however, sodium can be found in other forms.

Sodium is found naturally in a variety of foods, such as milk, meat and shellfish etc. It is often found in high

1099

Table 2: Selected scientific reviews/reports on salt and health Year

Main recommendation

Scientific Advisory Committee on Nutrition, UK

2003

Reduce the mean population salt intake to 6 g/day

Diet, Nutrition and the Prevention of Chronic Diseases: report of a Joint WHO/FAO Expert Consultation

2003

Salt consumption of <5 g/day while ensuring that the salt is iodized

Institute of Medicine (IOM). Dietary Reference Intakes: Water, Potassium, Sodium Chloride, and Sulfate

2004

Set 3.75 g/day as an adequate intake, and 5.8 g/ day as the upper tolerable intake level for most adults

World Health Organization (WHO) Forum on Reducing Salt Intake in Populations

2006

Salt consumption of <5 g/day

Institute of Medicine (IOM). A Population‐ Based Policy and Systems Change Approach to Prevent and Control Hypertension

2010

Salt consumption of 5.75 g/day or less

American Heart Association (AHA) Presidential Advisory

2011, 2012 Salt consumption of 3.75 g/day or less

amounts in processed foods such as breads, crackers, processed meats, snack foods, condiments Data from around the world suggest that the population average sodium consumption is well above the minimal physiological needs, and in many countries is above the value recommended by the 2002 Joint World Health Organization/Food and Agriculture Organization of the United Nations (WHO/ FAO) Expert Consultation of 2 g sodium/day (equivalent to 5 g salt/day). Increased sodium consumption is associated with increased blood pressure, whereas lower sodium consumption appears to decrease blood pressure in adults.

SALT AND HUMAN HEALTH

The relationship between dietary salt intake and the development of hypertension has been the subject of continuing debate for decades. Despite abundant epidemiological, experimental, and interventional observations demonstrating an association between salt intake and blood pressure, skepticism still remains regarding how a high salt intake can be mechanistically linked to an increase in blood pressure. This skepticism is partly due to the heterogeneity in the blood pressure responses to increases in salt intake in humans. Our inability to explain why salt raises blood pressure in some individuals described as ‘salt sensitive’, but not in others, termed as ‘salt resistant’, has hampered the development of a comprehensive theory as to how a high salt intake causes high blood pressure in salt sensitive subjects.

Extensive studies have been conducted to identify the pathophysiological mechanisms responsible for the heterogeneity of responses to increased.

The DASH-Sodium study was a sequel to the original DASH (Dietary Approaches to Stop Hypertension) study. Both studies were designed and conducted by the National Heart, Lung, and Blood Institute in the United States, each involving a large, randomized sample.

While the original study was designed to test the effects of several varying nutrients on blood pressure, DASH-

Sodium varies only in salt content in the diet. Participants were pre-hypertensive or at stage 1 hypertension, and either ate a DASH-Diet or a diet reflecting an “average American Diet”. During the intervention phase, participants ate their assigned diets containing three distinct levels of sodium in random order. Their blood pressure is monitored during the control period, and at all three intervention phases. The study concluded that the effect of a reduced dietary sodium intake alone on blood pressure is substantial, and that the largest decrease in blood pressure occurred in those eating the DASH eating plan at the lowest sodium level (1,500 milligrams per day). However, this study is especially significant because participants in both the control and DASH diet group showed lowered blood pressure with decreased sodium alone. In agreement with studies regarding salt sensitivity, participants of African descent showed high reductions in blood pressure.

Excess Dietary Salt Intake and Health: The Evidence.

Numerous authoritative scientific reviews that have critically examined this association have confirmed the harmful health impact of excess salt consumption, particularly on cardiovascular health, and unequivocally recommended salt reduction (Table 2).

A number of randomized controlled trials (RCTs) have concluded that decreased sodium intake relative to usual or higher intake results in lowered blood pressure in adults with or without hypertension. A review concerning advice to reduce sodium consumption concluded that intensive behaviour-change interventions targeting decreasing sodium WHO| Guideline 6 Sodium intake for adults and children. There is little disagreement that decreased sodium intake decreases blood pressure, but there is some concern that it might also lead to adverse effects in health. Decreased sodium intake results in reduced blood volume and thus activates the renin– angiotensin– aldosterone and sympathetic nervous systems (indicated by increased adrenaline and noradrenaline), which

CHAPTER 240

Review / reports

BEYOND MEDICINE

1100

Fig. 1: Causes and consequences of salt sensitivity of blood pressure and their relation to ABPM. ANP- atrial natriuretic peptide; ADMA- asymmetrical dimethylarginine; SNSsympathetic nervous system; RAAS- renin-angiotensinaldosterone system; LVH- left ventricular hypertrophy help to control blood volume. Likewise, a reduction in blood volume without a concurrent reduction in blood lipids can lead to an increased concentration of lipids in the blood. A systematic review reported an increase in renin, aldosterone, adrenaline and noradrenaline, total cholesterol and triglyceride with reduced sodium.

However, the changes in blood lipids and catecholamine levels were transient and no longer present after 4 weeks of reduced sodium intake. Although the changes in renin and aldosterone levels persisted with longer term reduced sodium intake, the importance of these changes is uncertain. An increased risk of cardiovascular morbidity and mortality with increased renin or aldosterone level has been reported , but the evidence is not conclusive.

Unlike blood pressure, a change in these hormones is not currently recognized as a reliable biomarker for future risk. intake successfully reduced blood pressure in adults with or without hypertension. However, the reductions in sodium intake and in blood pressure were modest, and the authors concluded that environmental changes (e.g. reduction of sodium in processed foods) would facilitate a greater reduction in sodium consumption and, therefore, have a greater impact on blood pressure.

SALT SENSITIVITY

The simplest definition of salt sensitivity of blood pressure (SSBP) states that it is a physiological trait present in rodents and other mammals, including humans, by which the blood pressure (BP) of some members of the population exhibits changes parallel to changes in salt intake. In animals, the trait has been inbred such that the salt-sensitive (SS) ones will sustain increases in BP with salt loading and decreases with salt depletion, whereas the salt resistant (SR) ones will not. In humans, the trait is normally distributed; therefore, the distinction between

SS and SR members of the population has been made by choosing an arbitrary magnitude of the salt-induced change in BP to define the groups. Regardless of possible causation by abnormalities of sodium handling, the SS phenotype is not usually characterized by alterations in salt balance (eg, impaired natriuresis or expanded plasma volume) but rather by a hypertensive response to maintain it. In an unselected population, SSBP is a continuous, normally distributed quantitative trait. As with any other trait with these characteristics, there is the issue of whether population members with the largest and smallest quantities of the trait represent the randomness of its distribution or are qualitatively different from the population at large. The Gaussian distribution of population BP is probably the result of a random mixture of pro-hypertensive and antihypertensive genes and genetic variants in a heterogeneous population interacting with environmental factors (eg, diet), physiological characteristics (eg, aging), and clinical features (eg, renal function). Research on SSBP in humans is more complex than that in animal rodent strains. The reason is that methodological issues such as random error in BP measurements and physiological issues such as the multiple sources for BP variability may confound the assessment of the BP responses to salt loading or salt depletion. Therefore, defining an individual as SS or SR depends on the selection of arbitrarily chosen cut offs for the magnitude of the BP changes. Environmental factors substantially affect whatever the genetic component may be for SSBP in humans. Additionally, despite the unquestionable influence of environmental factors in the determination of SSBP in humans, estimates of its heritability have been as high as 74% in blacks and 50% in Chinese subjects, both higher than those for hypertension.

However we do not have evidence base whether the Asian Indian subjects have heritability like the Chinese or African American populations and is now an area we are investigating. An important issue is the clinical significance of the SSBP phenotype. There was increasing understanding that it represents an abnormality. The reasons were that it contradicts the basic physiological tenet that salt balance can be maintained by natriuretic and anti-natriuretic systems independently of BP, it occurs less frequently than salt resistance in normal subjects, and is associated with several forms of human and experimental hypertension.

Mechanisms of salt sensitivity are complex

They may include low birth weight with reduced nephron number, subtle renal injury and inflammation, nonmodulation of the renin-angiotensin-aldosterone axis and ouabain-like activity (Na /K -ATPase inhibition), changes in potassium intake, and expression of ion channels and supporting cellular skeleton, activation of macrophages by hypertonic interstitial environment, changes in nitric oxide signaling and presence of endogenous inhibitors, diminished atrial and other natriuretic peptides, aberrant renal prostanoid production, central activation of the sympathetic nervous system, among other candidates by the hyperinsulinemia

frequently present in lean hypertensive subjects. However, in numerous studies, salt sensitivity with high-salt diet were linked to higher nocturnal blood pressure (or lesser nighttime blood pressure decrease), recognizable only by ambulatory blood pressure monitoring (ABPM) and independently predicting adverse outcome in hypertensive patients.6 Thus, knowledge of a given patientâ&#x20AC;&#x2122;s salt sensitivity is important for diagnostic, prognostic, and therapeutic reasons.

Research into the possible physiological mechanisms determining SSBP has been driven mostly by a conceptual framework derived from the work of Guyton and coworkers. The major tenet of such framework is that one or many mechanisms that normally regulate the adaptation of the cardiovascular system to a salt load must be impaired in SSBP. This somehow leads to the need for the whole animal to raise BP to excrete the salt load via pressure natriuresis. The result is that an SS animal or human being will be able to maintain a normal salt balance at the expense of developing hypertension, the main feature of SSBP. Obviously, the putative defect can involve a variety of mechanisms. Activation of a natriuretic system required to excrete a salt load (eg, natriuretic peptides, renal eicosanoids) may be impaired, or conversely, lack of physiological suppression of an

CHAPTER 240

Studies of salt sensitivity in rats were pioneered by Dahl, inspired by ecological and epidemiological studies of the association of salt intake with human hypertension. Dahl et al selected Sprague-Dawley rats with the highest BP response to a high-salt diet (facilitated by triiodothyronine administration) and mated them with equally responsive siblings. After few generations, an SS strain with a consistent hypertensive response to a high-salt diet was created. Contrary to common belief, this was not a pure inbred strain because its descendants were also outbred with other SS Sprague-Dawley rats as a result of breeding problems and small litters. Additionally, Sprague-Dawley rats without a hypertensive response to a high-salt diet were inbred to produce the SR strain. From the creation of these strains and the demonstration that a donor SS kidney transplanted into an SR rat conferred SSBP to the recipient (and vice versa), a major role for a renal abnormality was hypothesized as the factor determining the phenotype. Later, Rapp and Dene developed the fully inbred DS/Jr and DR/Jr strains that have subsequently been used by most researchers. The original SS and subsequent DS/Jr rats developed fulminant hypertension when exposed to a high salt (8%) diet and died by the age of 8 weeks. They had a plethora of vascular lesions, renal fibrosis, and cardiac hypertrophy. Several investigators reported a variety of physiological abnormalities contributing to hypertension in DS/Jr rats, among them differences in cellular ion transport and concentration, enhanced sympathetic activity and blunted baroreflexes, reduced renal medullary blood flow, disturbed balance between vasoconstrictors and vasodilators with a special role for nitric oxide (NO), enhanced oxidative stress, and activated Rac1 GTPase mineralocorticoid receptor interaction.

anti-natriuretic system in response to a salt load (eg, 1101 ineralocorticoid or renal transport activity) might be the culprit. Evidence for a genetic basis of salt sensitivity has come from heritability estimates in family studies. Miller et al examined the change in BP between random-sodium and low sodium diets among white US families and found a higher correlation in monozygotic pairs compared with sibling pairs: 0.72 for systolic BP (SBP), 0.62 for diastolic BP (DBP), and 0.68 for MAP in monozygotic twins compared with 0.50, 0.33, and 0.36, respectively, for siblings. Svetkey et al used an established inpatient protocol253 to examine the change in BP between intravenous sodium loading and furosemide induced volume depletion in black US families and found evidence of heritability, although effects of variable family sizes contributed to variation in estimates. Additional evidence was provided by the description of an association of salt sensitivity with haptoglobin phenotypes. The BP response to a change in salt (sodium chloride) intake is not uniform. Different types of study designs have been used to identify subgroups of the population whose BP response to salt is greater (or lesser) than other subgroup responses. Studies include small, brief challenge studies, feeding trials, and meta-analyses of trials. Factors that might influence the BP response to salt include sex, age, adiposity, raceethnicity, and clinical conditions (hypertension, diabetes mellitus, and chronic kidney disease). For several factors, evidence is insufficient to make strong conclusions because individual studies were not designed to test the effects of salt reduction simultaneously in a comparator group. For example, a few trials have tested the effects of salt reduction in patients with diabetes mellitus, but none tested the effects concurrently in patients without diabetes mellitus. Additionally, most meta-analyses that aggregate published data across studies rather than analyzing individual-level data are poorly suited to identify subgroups that are SS because of potential residual confounding. In contrast, in some studies, the effects of salt were examined in both sexes, in blacks (versus whites), across the age span in adults, and over a broad range of BPs. In summary, a strong and consistent body of evidence has documented that on average blacks compared with whites have a greater BP response to a change in salt intake and that this finding is independent of baseline BP level. Likewise, individuals with hypertension have a greater BP response to a change in salt than individuals without hypertension, and older individuals have a greater BP response than younger adults. The effects of salt reduction depend on concurrent diet. The effects of salt on BP are greater in the setting of a low-potassium intake and in the setting of poor-quality diet compared with the DASH diet. A less consistent body of evidence suggests that women might be more SS than men and that overweight individuals are more SS than normal-weight individuals. The effects of salt reduction in Asians and in individuals with diabetes mellitus or chronic kidney disease have been tested in few studies, in which salt reduction lowered BP. However, the absence of comparator

BEYOND MEDICINE

1102 groups precludes strong statements about whether these

groups are more SS than corresponding groups without the factor. Current methods for determining SSBP are labor intensive and therefore costly; thus, they are rarely if ever undertaken outside the clinical research arena.

Two areas of research seeking easily obtainable surrogate markers for SSBP have developed recently, one based on analysis of BPs and heart rates from ambulatory monitors and the other based on excretion of proximal tubular cells or renal exosomes. A group of Italian researchers hypothesized that characteristics in a 24-hour ABPM would reflect SSBP in individuals on habitual salt intake.

Other investigators had measured beat-by-beat BP and pulse rate variability in 34 essential hypertensive subjects studied during 1 week of low- and high salt diets and determined by sophisticated spectral analysis methods that SSBP was associated with lesser baroreflex sensitivity and higher pulse interval power. In other words, pulse rate and SSBP increased in parallel in their SS patients but were unaffected by salt intake in SR individuals.

Continued research on hemodynamic characteristics that are surrogates of SSBP such as those conducted with ABPM techniques may conceivably provide a biomarker, particularly with incorporation of predictive variables into multivariate models that achieve high sensitivity and specificity compared with direct measurement of SSBP with currently accepted techniques. Additionally, an easily obtained biomarker from urine samples might be developed from continued research on properties of urine renal tubular cells or exosomes. Emerging novel knowledge about the storage of sodium in tissue compartments and the study of possible differences in such storage between SS and SR animals or humans, coupled with the ability to use magnetic resonance imaging techniques to measure such storage, may also lead to the development of a radiological marker for the SSBP phenotype.

Almost five decades ago, Guyton and Coleman proposed that whenever arterial pressure is elevated, pressure natriuresis enhances the excretion of sodium and water until blood volume is reduced sufficiently to return arterial pressure to control values. According to this hypothesis, hypertension can develop only when something impairs the excretory ability of sodium in the kidney. However, recent studies suggest that nonosmotic salt accumulation in the skin interstitium and the endothelial dysfunction which might be caused by the deterioration of vascular endothelial glycocalyx layer (EGL) and the epithelial sodium channel on the endothelial luminal surface (EnNaC) also play an important role in nonosmotic storage of salt. These new concepts emphasize that sodium homeostasis and salt sensitivity seem to be related not only to the kidney malfunction but also to the endothelial dysfunction. Further investigations will be needed to assess the extent to which changes in the sodium buffering capacity of the skin interstitium and develop the treatment strategy for modulating the endothelial dysfunction.

Thus “Salt sensitivity” is estimated to be present in

51% of the hypertensive and 26% of the normotensive populations. The individual blood pressure response to salt is heterogeneous and possibly related to inherited susceptibility. Although the mechanisms underlying salt sensitivity are complex and not well understood, genetics can help to determine the blood response to salt intake.

Salt Recommendation

Salt reduction is a WHO goal globally now. A modest reduction in salt intake for 4 or more weeks causes significant and, from a population viewpoint, important falls in BP in both hypertensive and normotensive individuals, irrespective of sex and ethnic group.

With salt reduction, there is a small physiological increase in plasma renin activity, aldosterone and noradrenaline.

This will likely lower population BP and, thereby, reduce cardiovascular disease. WHO recommends a reduction in sodium intake to reduce blood pressure and risk of cardiovascular disease, stroke and coronary heart disease in adults. WHO recommends a reduction to < 2 g/day sodium (5 g/day salt) in adults. WHO recommends a reduction in sodium intake to control blood pressure in children. These recommendations apply to all individuals, with or without hypertension (including pregnant or lactating women), except for individuals with illnesses or taking drug therapy that may lead to hyponatraemia or acute build-up of body water, or require physiciansupervised diets (e.g. patients with heart failure and those with type I diabetes).

Available information indicates that most salt in India is added during cooking and/or at the table in contrast to the developed world where processed foods contribute most substantially to overall population salt intake. However, with rapidly increasing urbanization, proliferation of multinational food outlets/fast food centres, increasing availability of prepared foods, and increasing frequency of eating out, processed foods are anticipated to become a major source of salt intake.

Salt Rich Foods in India to be avoided •

Preserved foods like: Pappads, pickles, dried fish etc

-

Namkeen bhujiya, dalmoth, mathri, sev, farsan chaat-pakori, french fries

-

Convenience foods are high in sodium : instant foods, TV Dinners

-

Salted nuts, potato chips, popcorn, salted crackers, biscuits and Crisps.

•

Salted butter, and processed cheese

•

Frozen foods

-

Sea fish, cured meats, sausages, ham, and bacon

-

Instant cooked cereals and commercial salad dressings

•

Pastries, cakes, and ice creams

TIPS TO REDUCE SALT IN DIET

•

•

For seasoning of foods, herbs, spices, lemon, lime, vinegar or salt-free seasoning blends make a better choice than table salt.

In rice and other cereal preparations like roti, poori, do not mix salt. Avoid the use of salted rice, salted porridge, and other salted cereal mixes.

Avoid packaged mixes, canned soups, or broths— they generally have a high sodium content.

•

Use fresh vegetables. Avoid the use of canned veg­ etables as they contain salt preservatives.

•

Substitute fruits, salad, and fresh vegetables for salted snack foods.

•

Limit the use of foods packed in brine such as pickles, pickled vegetables, and olives.

•

Use little or no sauces: avoid tomato ketchup, soy sauce, MSG, mustard sauce, and chutney.

•

Use fresh poultry, fish and lean meat, rather than the canned, smoked or processed types.

REFERENCES

1.

https://en.wikipedia.org/wiki/Salt

2.

Ando K, Fujita T. Pathophysiology of salt sensitivity hypertension. Ann Med 2012; 44(Suppl 1):S119–26.

Frisoli TM, Schmieder RE, Grodzicki T, Messerli FH. Salt 1103 and hypertension: is salt dietary reduction worth the effort? Am J Med 2012; 125:433–9.

4.

Armando I, Villar VA, Jose PA Genomics and Pharmacogenomics of Salt-sensitive Hypertension. Curr Hypertens Rev 2015; 11:49-56.

5.

Elijovich F, Weinberger MH, Anderson CA, et al.Salt Sensitivity of Blood Pressure: A Scientific Statement From the American Heart Association.American Heart Association Professional and Public Education Committee of the Council on Hypertension; Council on Functional Genomics and Translational Biology; and Stroke Council.

Hypertension 2016; 68:e7-e46.

6.

Joshi SR, Saboo B, Vadivale M, Dani SI,et al.Prevalence of diagnosed and undiagnosed diabetes and hypertension in India--results from the Screening India’s Twin Epidemic (SITE) study. Diabetes Technol Ther 2012; 14:8-15.

7.

Bhansali A, Dhandania VK, Deepa M, et al.Prevalence of and risk factors for hypertension in urban and rural India: the ICMR-INDIAB study. J Hum Hypertens 2015; 29:204-9.

8. Mohan S, Prabhakaran D. Review of Salt and Health: Situation in South‐East Asia Region. Technical Paper.

Technical Working Group Meeting on Regional Action Plan and Targets for prevention and control of non commumnicable. Bangkok, Thailand.2013.

9. Ben-Dov IZ, Bursztyn. Can Salt Sensitivity of Blood Pressure Be Assessed Without Changing Salt Diet?

Hypertension 2011; 57:156-157.

CHAPTER 240

•

3.

C H A P T E R

241

The ICMR INDIAB Study – A Compendium of Type 2 Diabetes in India: Lessons Learnt for the Nation Viswanathan Mohan, Ranjit Mohan Anjana, Rajendra Pradeepa, Ranjit Unnikrishnan, Tanvir Kaur, Ashok Kumar Das

ABSTRACT

Diabetes and associated metabolic non communicable diseases (NCDs) including hypertension, obesity etc are no longer a disease of affluent developed nations, the prevalence rates of diabetes and metabolic NCDs is steadily increasing in developing countries like India.

The epidemiological transition occurring in the India, as a result of rapid urbanization and economic development, has perhaps made it one of the epicentres of the diabetes epidemic. Currently, in India, there are large data deficits on diabetes and associated metabolic NCDs with regards to their prevalence and disease outcomes. The national Indian Council of Medical Research–India Diabetes (ICMR–INDIAB) study was designed to provide accurate and comprehensive state- and national-level data on the prevalence of diabetes and other metabolic NCDs in India. Phase I results of the ICMR-INDIAB study was conducted in four regions (Tamil Nadu, Maharashtra, Jharkhand and Chandigarh) between 2008 and 2010. The results of the ICMR-INDIAB study shows that of the four regions studied, the prevalence of diabetes was highest in Chandigarh followed by Tamilnadu, Maharashtra and Jharkhand. The glycemic control among self-reported diabetic subjects is poor in India, with less than a third of subjects exhibiting good glycemic control. In addition, India has a huge burden of hypertension, obesity and dyslipidemia and poor levels of physical activity, which may predispose to even larger increases in NCDs in the future. Thus, the results from ICMR-INDIAB study helps not only in earlier detection of diabetes/prediabetes through screening, it also lays the foundation for effective NCD prevention and control in India.

BURDEN OF DIABETES IN INDIA

The alarming increase in the prevalence of diabetes globally , has made it a major public health and economic problem.

Diabetes and associated metabolic non communicable diseases (NCDs) including hypertension, obesity etc are no longer a disease of affluent, developed nations, as the prevalence of diabetes is increasing disproportionately in developing countries1 and India is not exempted from it. Indeed, nearly two thirds of the world’s population with diabetes currently lives in low- and middle-income regions.2 Type 2 diabetes can be considered the prototype of chronic NCDs. While type 1 diabetes and other types account for 5% to 10% of all cases of diabetes, type 2

diabetes remains by far, the most common form of diabetes and has attained epidemic proportions worldwide..

The second highest number of people with diabetes in the world currently is in India (69.2 million) and these numbers are expected to increase to 123.5 million by 2040.3 The majority of NCDs including diabetes occur due to the combined effects of behavioral risk factors including physical inactivity, unhealthy diets, tobacco consumption and the harmful use of alcohol. The greatest effects of these risk factors are unfortunately observed in developing countries, and in poorer people within all countries, mirroring the underlying socioeconomic determinants (poverty, illiteracy, social inequality and poor health infrastructure). Given that there is a growing epidemic of diabetes and associated metabolic NCDs in India, reliable and informative epidemiological data is vital to quantify impacts and predictors of disease and to facilitate formulation of prevention/ control strategies.

Currently, in India, there are large data deficits on diabetes and associated metabolic NCDs with regards to the distribution, trends, determinants and disease outcomes.

Even where data is available, there is considerable heterogeneity within regions and the variable quality of the data limits their value. In the last two decades several epidemiological studies have been done in India to estimate the magnitude of diabetes, hypertension, obesity and other NCDs. However, the earlier studies conducted in India suffer from several limitations; they are mostly regional, have small sample sizes, low response rates, use of varied diagnostic criteria, problems with sample design, lack of standardization, measurement errors and incomplete reporting of results.4 This results in a lot of available information either not being used or being presented in an incomplete way, thereby providing inaccurate projections for policy makers. Thus there was a need for a large representative population-based study that will provide state-wise and rural–urban estimates of diabetes and other related NCDs including obesity, hypertension and dyslipidemia. The Indian Council of Medical Research–India Diabetes (ICMR–INDIAB) study directly addresses this need and provides accurate and comprehensive state- and national-level data on the prevalence of diabetes and other metabolic NCDs in India.

Figure 1: Phases of the ICMR-INDIAB Study and completed regions

Arunachal Pradesh

Punjab Chandigarh

Bihar

Meghalaya Assam Manipur

Gujarat

Tripura Jharkhand

Maharashtra

Mizoram

PHASE I – Completed [Chandigarh, Jharkhand, Maharashtra & Tamil Nadu]

Andhra Pradesh

PHASE II- Ongoing

NE COMPONENT- Ongoing Tamilnadu

Six regions completed [ Arunachal Pradesh, Assam, Manipur, Meghalaya, Mizoram, Tripura]

Fig. 1: Phases of the ICMR-INDIAB Study and completed regions

MULTICENTRE EARLIER STUDIES

There have been very few multicentre studies on the prevalence of diabetes in India. In early 1970’s, the Indian Council of Medical Research (ICMR), conducted a systematic collaborative study on diabetes in 34,194 individuals aged > 15 years in 6 different parts of the country using uniform methodology and sampling techniques.5 Capillary blood glucose was used for diagnosis of diabetes. This study reported an overall prevalence of 2.1 % in urban areas and 1.5% in rural areas, while in those above 40 years of age, the prevalence was 5% in urban and 2.8% in rural areas. The National Urban Diabetes Survey6 showed an overall age-standardized prevalence of 12.1% for diabetes and 14% for impaired glucose tolerance (IGT) in six large metropolitan cities.

The Prevalence of Diabetes in India Study conducted in 49 urban and 59 rural areas7 reported diabetes prevalence of 5.9% and 2.7% in small towns and rural areas respectively. The Five City Study Group8 reported that 33.5% of the urban dwellers had BMI ≥ 25 -29.9 kg/ m2. The WHO-ICMR NCD Risk Factor Surveillance Study conducted in urban and rural areas of six different states (44,523 individuals aged 15-64 years) between 2003-2005, reported an overall prevalence of self-reported diabetes of 4.5%.9 In another cross-sectional survey conducted among the employees and their family members of 11 medium-to-large industries from 5 urban sites including Delhi, Hyderabad, Bangalore, Chennai and Trivandrum, reported an overall diabetes prevalence of 10.1%.10 After nearly 30 years, the Indian Council of Medical Research (ICMR), New Delhi and the Department of Health Research (DHR), Government of India took up the large multicentre “ICMR- India Diabetes [INDIAB] Study, which is nationally coordinated by the Madras Diabetes Research Foundation, Chennai, while the Northeast component is coordinated by the Regional Medical Research Centre, Dibrugarh.

THE ICMR-INDIAB STUDY

The ICMR-INDIAB Study, is an ongoing nationwide crosssectional, door-to-door survey conducted in adults of either gender, aged ≥20 years and above from all 28 states

CHAPTER 241

Five regions completed [Andhra Pradesh (undivided), Bihar, Gujarat, Karnataka, Punjab]

Karnataka

(now 29 States), National Capital territory (NCT) of New 1105 Delhi and 2 union territories (UTs) namely Chandigarh and Puducherry in the mainland of India in a phased manner.11 Each state, the National Capital Territory and the Union Territories will have an urban component (towns including metros, wherever applicable) and a rural component (villages). A stratified multi-stage sampling design has been adopted and from each state, 4,000 individuals [2,800 individuals in rural areas and 1,200 individuals in urban areas] are being studied.

Thus the total sample size for the study is estimated to be 1,24,000 individuals. The primary objectives of the study are to determine the prevalence of diabetes mellitus and prediabetes in India by estimating the state-wise prevalence of the same and to compare the prevalence rates in urban and rural areas across the country. The additional objectives of the study are to determine the prevalence of metabolic NCDs including hypertension, dyslipidemia, obesity and coronary artery disease (CAD) among subjects with and without diabetes and to assess the level of glycemic control among individuals with selfreported diabetes.

In view of the complexity of the study and the logistics involved, the study has been planned in phases. The different phases of the study are presented in Figure 1.

The first phase of the study which has been completed in 4 regions of India, which includes three states randomly selected to represent the south (Tamil Nadu), west (Maharashtra) and east (Jharkhand) of India and one UT representing northern India (Chandigarh) has already provided authentic epidemiological data on diabetes, hypertension, dyslipidemia and obesity in the country till date. Currently the North East component, which includes 8 north eastern states namely Sikkim, Assam, Meghalaya, Tripura, Mizoram, Manipur, Nagaland and Arunachal Pradesh is underway. Phase II, which includes 17 states, the National Capital territory of New Delhi and 1 union territory is also in progress. Currently, fifteen states/UT have been surveyed and the lessons learnt from Phase I (involving four regions), conducted from November 2008 to April 2010, are presented here.

LESSONS LEARNT FROM PHASE I OF THE ICMR-INDIAB STUDY

Diabetes and prediabetes

In Phase I, of the 16,607 individuals (5112 urban and 11,495 rural) selected for the study, 14,277 (4186 urban and 10,091 rural) participated, of whom 13,055 gave blood samples. In all study subjects, an interviewer-administered questionnaire was used to obtain demographic, behavioral, medical information and knowledge of diabetes. Weight, height, and waist circumference were measured and body mass index (BMI) was calculated. Blood pressure was recorded using an electronic instrument as the mean of two readings taken five minutes apart. Fasting and 2 hour post glucose capillary blood glucose (CBG) was used for diagnosis of diabetes, as CBG has been shown to be a feasible alternative for screening of diabetes and IGT in epidemiological studies in developing countries where

Figure 2: Prevalence# of diabetes in urban and rural population

1106

16 14

Urban 13.7

Percentage (%)

12 10

Overall 13.5

10.4

10.9

8.4

14.2 *

13.6

8.3

6.5

6

5.3

4

BEYOND MEDICINE

*

*

7.8

8

Rural

*

3.0

2 0 #

Tamil Nadu

Weighted prevalence

Maharashtra

* p<0.05 compared with rural population

Jharkhand

Chandigarh

REGIONS

Fig. 2: Prevalence# of diabetes (self-reported, newly diagnosed and overall diabetes) in urban and rural population obtaining venous samples is difficult or even impossible in some situations.12 In addition, in every fifth subject (n= 2,042), a fasting venous sample was collected and lipids (total cholesterol, triglycerides and HDL cholesterol) were measured. Glycemic control among subjects with self-reported diabetes was assessed by measurement of glycated hemoglobin (HbA1c).

Diabetes was defined as individuals diagnosed by a physician and on glucose-lowering medications (selfreported) and/or those who had a fasting CBG ≥126 mg/ dl and/or a 2 h post glucose CBG value ≥220 mg/dl.13 The overall weighted prevalence of diabetes was 10·4% (Tamil Nadu: Urban-13.7: Rural- 7.8%), 8·4% (Maharashtra: Urban-10.9%: Rural- 6.5%), 5·3% (Jharkhand: Urban-13.5%: Rural- 3.0%) and 13·6% (Chandigarh: Urban-14.2%: Rural8.3%) [Figure 2]. The prevalence of self reported diabetes among urban residents of Tamil Nadu, Maharashtra, Jharkhand and Chandigarh were 8·5%, 3·7%, 8·4% and 6·6% while that among rural residents was 4·1%, 1·7%, 0·7% and 3·1% respectively. The prevalence of newly diagnosed diabetes among urban residents of Tamil Nadu, Maharashtra, Jharkhand and Chandigarh were 5·2%, 7·2%, 5·1% and 7·6% and that among rural residents, 3·8%, 4·9%, 2·3% and 5·2% respectively. This translated to 4.8 million individuals with diabetes in Tamil Nadu.

In Maharashtra, an estimated 6.0 million had diabetes , Jharkhand ,0.96 million and in Chandigarh 0.12 million had diabetes in 2011. The ICMR-INDIAB study estimated the number of individuals with diabetes in India in 2011 to be 62.4 million.14 The figure for diabetes from the ICMRINDIAB study was accepted by the International Diabetes federation (IDF) for India in 2011, which reported a figure of 61.3 million people with diabetes in India in the age group of 20-79 years.15 One of the points of concern is that the take-off point in prevalence of diabetes was at 25–34 years with a decline after age 65. At every age interval, the prevalence of diabetes in urban areas was higher compared with rural areas. Age, male gender, family history of diabetes, urban residence, abdominal obesity, generalized obesity,

Table 1: Distribution of glycated hemoglobin (HbA1c) among individuals with self reported diabetes HbA1c levels (%)

Area wise

Gender wise

Overall

Urban

Rural

Male

Female

<7

31.3

30.8

30.9

31.3

31.0

7.0-7.9

17.4

15.7

16.6

16.6

16.6

8.0-8.9

17.9

15.7

19.8

12.9

16.8

9.0-9.9

9.7

10.8

10.6

9.8

10.3

>10

23.6

27

22.1

29.4

25.3

hypertension and income status were significant risk factors associated with diabetes.14 The overall weighted prevalence of ‘prediabetes’ defined as individuals with impaired fasting glucose [IFG] or impaired glucose tolerance [IGT] or both in Tamil Nadu, Maharashtra, Jharkhand and Chandigarh were 8.3%, 12.8%, 8.1% and 14.6% respectively. Among urban residents it was 9·8% (Tamil Nadu), 15·2% (Maharashtra), 10·7% (Jharkhand) and 14·5% (Chandigarh). Among rural residents the corresponding prevalence of prediabetes was 7·1%, 11·1%, 7·4% and 14·7% respectively. This study reported that in 2011, Maharashtra have 9·2 million individuals with prediabetes, Tamil Nadu, 3·9 million, Jharkhand, 1·5 million and Chandigarh 0.13 million individuals, with prediabetes. Extrapolated to the whole country, these estimates translated to 77.2 million with prediabetes in India. The risk factors associated with prediabetes were age, family history of diabetes, abdominal obesity, hypertension and income status.14 In Phase I of the ICMR-INDIAB study, self-reported diabetes was reported in 480 subjects. The mean HbA1c levels among them were highest in Chandigarh (9.1%), followed by Tamil Nadu (8.2%), Jharkhand (8.2%), and Maharashtra (8.0%).16 The study reported that there was no significant difference in the mean HbA1c among urban and rural dwellers in any of the regions studied. Overall, good glycemic control (HbA1c <7%) was observed only in 31.0% and 25.3% had an HbA1c level of >10.0%. There was significant difference in the glycemic control among urban and rural as well as male and female population in the regions studied (Table 1). This study showed that levels of glycemic control in India remain unacceptably poor. Nearly 70% of subjects fail to meet the recommended HbA1c goal of <7%. More than 60% of the individuals in both urban and rural areas reported that they had not checked their HbA1c in the past year. The various risk factors associated with poor glycemic control were younger age, duration of diabetes, insulin use, and high triglyceride levels.16 There is evidence to show that increasing knowledge regarding diabetes and its complications has significant benefits including increase in compliance to treatment, thereby decreasing the complications associated with diabetes.17 Although there have been small regional studies on the subject of diabetes awareness in India, the

1107

Table 2: Gender and areawise knowledge regarding diabetes in the 4 regions studied Have you heard of a condition called diabetes? - YES Tamil Nadu

Maharashtra

Jharkhand

Chandigarh

Overall

Male

64.2*

54.4*

32.7*

33.5*

46.7*

Female

57.2

43.3

20.5

34.3

39.6

Urban

72.3#

56.5#

52.3#

50.8#

58.4#

Rural

55.8

45.2

16.5

27.6

36.8

Gender

Area

Table 3: Prevalence of overweight and obesity in the four regions studied-ICMR-INDIAB study (Phase I) Regions

Overweight a Urban

Generalized Obesity (%)b

Abdominal obesity (%)c

Combined obesity (%)d

Rural Overall Urban

Rural Overall Urban

Rural Overall Urban

Rural Overall

16.5

14.6*

15.2

35.7

20.0*

37.4

22.1*

15.3*

19.3

Maharashtra

13.6

10.3*

11.3

26.1

12.2*

16.6

26.7

15.0*

18.7

20.2

9.7*

13.0

Jharkhand

13.1

5.7*

7.8

30.4

4.3*

11.8

37.2

8.7*

16.9

26.3

3.1*

9.8

18.9

14.8*

15.9

40.3

27.9*

31.3

46.6

32.1*

36.1

34.0

24.0*

26.6

Tamil Nadu

Chandigarh

24.6

26.6

28.8

BMI ≥23 kg/m but <25 kg/m for both genders ; BMI ≥ 25 kg/m for both genders; Waist circumference ≥ 90 cm for men and ≥ 80 cm for women; d Individuals with both generalized and abdominal obesity. a

2

2

b

2

c

*p<0.001 compared to urban areas

ICMR-INDIAB study provides data at a national level or indeed even in a whole state of India on the awareness about diabetes. Awareness and knowledge about diabetes were also assessed in the general population, as well as in individuals with diabetes in Phase I.18 Overall, only 43.2% of the study population had heard about a condition called diabetes. Awareness of diabetes was higher among urban residents compared to their rural counterparts (58.4% vs.

36.8%) [Table 2] . Urban residents had better awareness rates than rural residents in all four regions, with highest rates in Tamil Nadu followed by Maharashtra, Jharkhand and Chandigarh . Overall 46.7% of males and 39.6% of females reported that they knew about a condition called diabetes. This study reported that males had better awareness rates about diabetes than females in all regions, except Chandigarh as shown in Table 2.

Of the general population, 41.5% knew about a condition called diabetes and among them, over 80.0% knew that the prevalence of diabetes was increasing. Among the self-reported diabetic population, 93.0% knew that the prevalence of diabetes was increasing. Among the general and diabetic population, 56.3% and 63.4%, were aware that diabetes could be prevented and 51.5% and 72.7% respectively knew that diabetes could affect other organs.

Among the general population who answered in the affirmative for the question “Do you think diabetes can affect other organs?”, the most common organs reported were the feet (54.0%), eyes (52.3%), kidneys (36.3%), heart (33.6%) and nerves (18.7%). While, among individuals with diabetes, the knowledge of diabetic complications was comparatively better (eyes – 73.5%, feet – 61.3%,

kidneys – 47.9%, heart – 45.1% and nerve problems – 26.8%). It is disturbing that even among subjects with diabetes; this basic knowledge was still so poor.18

PREVALENCE OF OTHER METABOLIC NCDS IN INDIAB STUDY

Obesity

India, being the second most populous country in the world is currently experiencing rapid epidemiological transition. Industrialization and urbanization also contribute to increased prevalence of obesity. Studies from different parts of India have provided evidence on the rising prevalence of obesity.19,20 The prevalence of generalized obesity (GO) defined as BMI ≥ 25 kg/m2 for both genders21 abdominal obesity (AO) defined as a waist circumference ≥ 90 cm for men and ≥ 80 cm for women22 and combined obesity (CO) defined as individuals with both GO and AO were assessed in the ICMR-INDIAB study in both urban and rural areas (Table 3).23 The prevalence of overweight was highest in Chandigarh (15.9%) followed by Tamil Nadu (15.2%), Maharashtra (11.3%) and Jharkhand (7.8%). The prevalence of GO was 24.6, 16.6, 11.8 and 31.3 per cent among residents of Tamil Nadu, Maharashtra, Jharkhand and Chandigarh. The prevalence of AO and CO also followed the same trend as that of overweight. The prevalence of GO, AO and CO were significantly higher among urban residents compared to rural residents in all the four regions studied. The various risk factors associated with GO, AO and CO were female gender, hypertension, diabetes, higher socio-economic status, physical inactivity and urban residence. In all the

CHAPTER 241

* p<0.001 compared to females; p<0.001 compared to rural area #

Figure 5: Physical inactivity levels in urban and rural population of India

Figure 3: Age standardized prevalence of hypertension in four regions of India 50

Prevalence of hypertension (%)

Prevalence of hypertension (%)

Urban

40

20

Rural

Overall

80

Overall

31.5

30

31.5

30

Rural

26.2 26.2

27.6

24.0

28.1 24.0

20

30.7

28.9

28.1

27.6

25.0 28.9

25.0 21.7

23.8

71.2 *

80 70

40

21.7

30.7 23.8

25.8 25.8

19.8

19.8

70 60 60 50

58.7 58.7

59.6

* *

65.0

Rural

# 50 50

40.3

40 30 30 20

0

0

Tamil Nadu

Tamil Nadu

Maharashtra

Maharashtra

Jharkhand

Jharkhand

Chandigarh Chandigarh

Note: No significant difference among urban and rural areas in all the four regions studied

Figure 4: Prevalence of different components of dyslipidemia

Fig. 3: Age standardized prevalence of hypertension in four Figure 4: Prevalence of different components of dyslipidemia regions of India Hypertriglyceridemia Hypercholesterolemia

Note: No significant difference among urban and rural areas in all the four regions studied

LowHypercholesterolemia HDL Cholesterol

100

59.6

65.0

Rural

#Urban

40.3

50 40

10 0

10

0

71.2 *

Urban

20 10

10

90100 80 90

Percentage (%) Percentage (%)

BEYOND MEDICINE

Urban

50

Percentage Percentage (%) (%)

1108

Dyslipidemia Hypertriglyceridemia

Low HDL Cholesterol(n=2042)

(n=2042) 72.3 72.3

70 80

Dyslipidemia

79.0 79.0

60 70 50 60 29.5

40 50 30 40 20 30 10 20

13.9

29.5

13.9

0 10 0 Hypercholesterolemia- Cholesterol ≥200 mg/dl; Hypertriglyceridemia-Triglycerides ≥150 mg/dl ; Low HDL cholesterol -HDL-C <40 (m); <50 mg/dl (f); Dyslipidemia -any one lipid abnormality Hypercholesterolemia- Cholesterol ≥200 mg/dl; Hypertriglyceridemia-Triglycerides ≥150 mg/dl ; Low HDL cholesterol -HDL-C <40 (m); <50 mg/dl (f); Dyslipidemia -any one lipid abnormality

Fig. 4: Prevalence of different components of dyslipidemia (n=2042)

four regions studied age was significantly associated with AO and CO, but not with GO.

Hypertension

High blood pressure is ranked as the third most important risk factor for attributable burden of disease in south Asia.24 The prevalence of hypertension is also rising in India. In the ICMR-INDIAB study, the overall, age standardized prevalence of hypertension defined using Joint National Committee 7 Criteria25 in the four regions studied was 26.3% (self-reported: 5.5%; newly detected: 20.8%).26 The age-standardized prevalence of hypertension (Figure 3) was highest in Tamilnadu: 27.6% followed by Chandigarh: 25.8%, Maharashtra: 25.0% and Jharkhand: 23.8%. The prevalence of hypertension was higher in urban areas compared to rural areas and newly diagnosed HTN was higher than self-reported HTN across all three states and the UT. In the four regions studied, the ratio of newly diagnosed to self-reported hypertension was 3.8:1. The prevalence of hypertension increased with increasing age, even in the age group of 20–24 years, the prevalence of hypertension ranged from 5.4–13.9% in urban and from 9–10% in rural areas. Salt intake ≥6.5 g per day, conferred 1.4 times higher risk for hypertension even after adjusting for confounding variables.

Male

Female

Total

Male

Female

Total

* p<0.001 compared to male subjects p<0.001 compared to rural subjects * p<0.001 compared to male subjects

#

#

Fig. 5: Physical inactivity levels in the urban and rural population of India

p<0.001 compared to rural subjects

Dyslipdemia

Asian Indians are known to have a unique pattern of dyslipidemia with lower HDL cholesterol, increased triglyceride levels and higher proportion of small dense LDL cholesterol.27 In the ICMR-INDIAB study, in every 5th subject (n= 2042), lipids were measured to assess the pattern and prevalence of dyslipidemia in India.28 Overall, prevalence of dyslipidemia, defined using National Cholesterol Education Programme (NCEP) guidelines (atleast one lipid abnormality),29 was 79% in the 4 regions studied, with highest rates found in Chandigarh (82.9%), followed by Jharkhand (80%), Maharashtra (77%) and Tamilnadu (76.9%). Hypercholesterolemia (serum cholesterol levels ≥200 mg/dl) was observed in 13.9% and hypertriglyceridemia (serum triglycerides levels ≥150 mg/dl) in 29.5%. Low HDL-C (HDL cholesterol levels <40 mg/dl for men and <50 mg/dl for women) was the most common lipid abnormality (72.3%) in all the four regions studied [Figure 4]; in 44.9% of subjects, it was present as an isolated abnormality. High LDL-C levels were observed in 11.8%. There were no urban rural differences observed in any of the four regions studied. In the population studied, 7.7% had all three lipid abnormalities (hypercholesterolemia + hypertriglyceridemia + low HDL-C) and 4.8% of the population had all four lipid abnormalities (hypercholesterolemia + hypertriglyceridemia + low HDL-C + high LDL-C). Of the studied population, only 21.1% had no lipid abnormality.

The significant risk factors for dyslipidemia included obesity, diabetes, and dysglycemia.28

PHYSICAL INACTIVITY AS A RISK FACTOR FOR NCDS

The majority of NCDs occur due to the synergistic effects of behavioral risk factors such as physical inactivity, unhealthy diets, tobacco consumption and the harmful use of alcohol. The rising prevalence of NCDs can be attributed, at least in part, to two of the most important modifiable risk factors including increasing levels of physical inactivity and unhealthy diets.30 ICMR-INDIAB study assessed the reports on the levels of physical activity and inactivity in India using Global Physical Activity Questionnaire (GPAQ).31 Overall, 54.4% of the population were inactive (males: 41.7%), while 31.9% (males: 58.3%)

SUMMARY

In summary, the Phase I results of the ICMR-INDIAB study shows that of the four regions studied, the prevalence of diabetes was highest in Chandigarh followed by Tamilnadu, Maharashtra and Jharkhand. Again, the prevalence of prediabetes was highest in Chandigarh followed by Maharashtra, Tamilnadu and Jharkhand. The glycemic control among self-reported diabetic subjects is poor in India, with less than a third of subjects exhibiting good glycemic control. Knowledge and awareness about diabetes in India, particularly in rural areas, is abysmally low. In addition, the prevalence of other metabolic NCDs including obesity, hypertension and dyslipidemia are higher in both urban and rural areas of India compared with earlier studies. With greater urbanization and longevity, we can expect huge increases in the numbers of people with diabetes and other metabolic NCDS in India in the future. This phase of the study also reports that nearly half of the population in the four regions studied was inactive, with fewer than 10% engaging in recreational physical activity. Hence it is recommended to improve overall physical activity, at least 150 minutes of moderate-intensity aerobic PA or at least 75 minutes of vigorous-intensity aerobic activities throughout the week to reduce the risk of various NCDs. Thus, the results from ICMR-INDIAB study helps not only in earlier detection of diabetes/prediabetes through screening, it also lays the foundation for effective NCD prevention and control in India.

ACKNOWLEDGEMENT

The authors acknowledge the Indian Council of Medical Research, New Delhi, for the financial support for the study. This is the tenth paper from the ICMR-INDIAB Study (ICMR –INDIAB -10).

REFERENCES

1.

Terzic A, Waldman S: Chronic diseases: the emerging pandemic. Clinical and translational science 2011; 4:225–226.

2.

Frank B. Hu. Globalization of Diabetes. Diabetes Care 2011; 34:1249-1257

3.

International Diabetes Federation. IDF Diabetes Atlas, 7 ed.

Brussels, Belgium: International Diabetes Federation, 2015.

4.

Anjana RM, Ali MK, Pradeepa R, Deepa M, Datta M, 1109 Unnikrishnan R, et al. The need for obtaining accurate nationwide estimates of diabetes prevalence in India rationale for a national study on diabetes. Indian J Med Res. 2011; 133:369-380.

5.

Ahuja MMS. Epidemiological studies on diabetes mellitus in India. In: Ahuja MMS (ed) Epidemiology of diabetes in developing countries. Interprint, New Delhi 1979: 29-38.

6.

Ramachandran A, Snehalatha C, Kapur A, Vijay V, Mohan V, Das AK, et al; Diabetes Epidemiology Study Group in India (DESI). High prevalence of diabetes and impaired glucose tolerance in India: National Urban Diabetes Survey. Diabetologia 2001; 44:1094–1101.

7.

Sadikot SM, Nigam A, Das S, Bajaj S, Zargar AH, Prasannakumar KM et al, DiabetesIndia. The burden of diabetes and impaired glucose tolerance in India using the WHO 1999 criteria: Prevalence of Diabetes in India Study (PODIS). Diabetes Res Clin Pract 2004; 66:301–307.

8.

Singh RB, Pella D, Mechirova V, Kartikey K, Demeester F, Tomar RS, et al ; Five City Study Group. Prevalence of obesity, physical inactivity and under nutrition, a triple burden of diseases during transition in a developing economy. The Five City Study Group. Acta Cardiol 2007; 62:119-127.

9.

Mohan V, Mathur P, Deepa R, Deepa M, Shukla DK, Menon GR, Anand K, Desai NG, Joshi PP, Mahanta J, Thankappan KR, Shah B. Urban rural differences in prevalence of selfreported diabetes in India--the WHO-ICMR Indian NCD risk factor surveillance. Diabetes research and clinical practice 2008; 80:159-168.

10. Ajay V.S, D. Prabhakaran D, Jeemon P, Thankappan K.R, Mohan V, Ramakrishnan L, Joshi P, Ahmed F.U, Mohan B.V.M, Chaturvedi V, Mukherjee R and K. S. Reddy.

Prevalence and determinants of diabetes mellitus in the Indian industrial population Diabetes Med 2008; 25:11871194.

11. Anjana RM, Pradeepa R, Deepa M, Datta M, Sudha V, Unnikrishnan R, et al. The Indian Council of Medical Research-India Diabetes (ICMR-INDIAB) study: methodological details. J Diabetes Sci Technol 2011; 5:906914.

12. Priya M, Mohan Anjana R, Pradeepa R, Jayashri R, Deepa M, Bhansali A, et al. Comparison of capillary whole blood versus venous plasma glucose estimations in screening for diabetes mellitus in epidemiological studies in developing countries. Diabetes Technol Ther 2011; 13:586-91.

13. World Health Organization.Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia: Report of a WHO/IDF Consultation, Geneva, World Health Organization,p 39, 2006 14. Anjana RM, Pradeepa R, Deepa M, Datta M, Sudha V, Unnikrishnan R, et al; ICMR–INDIAB Collaborative Study Group. Prevalence of diabetes and prediabetes (impaired fasting glucose and/or impaired glucose tolerance) in urban and rural India: phase I results of the Indian Council of Medical Research-INdia DIABetes (ICMR-INDIAB) study. Diabetologia 2011; 54:3022-3027 15. International Diabetes Federation, Diabetes Atlas. Unwin N, Whiting D, Guariguata L, Ghyoot G, Gan D (eds).

Fifth Edition, International Diabetes Federation, Brussels, Belgium, 2011, pp 11–74.

CHAPTER 241

were active and 13.7% (males: 61.3%) were highly active.32 Figure 5 presents the physical inactivity levels in the urban and rural areas studied in Phase I of the ICMR-INDIAB study. Subjects were more inactive in urban, compared to rural, areas (65.0% vs. 50.0%) and female subjects were significantly more inactive than their male counterparts.

Physical inactivity was highest in Chandigarh (66.8%) followed by Tamilnadu (60.0%), Maharashtra (55.2%) and Jharkhand (34.9%). Absence of recreational activity was reported by 88.4%, 94.8%, 91.3% and 93.1% of the subjects in Chandigarh, Jharkhand, Maharashtra and Tamilnadu respectively. Most of the time spent in moderate to vigorous intensity activity was at the workplace. Even among those who reported recreational physical activity (8.1%), the time spent in moderate to vigorous intensity activity was overall <20 mins/day.

1110 16. Unnikrishnan R, Anjana RM, Deepa M, Pradeepa R, Joshi SR, Bhansali A, et al; ICMR–INDIAB Collaborative Study Group. Glycemic control among individuals with selfreported diabetes in India--the ICMR-INDIAB Study.

Diabetes Technol Ther 2014; 16:596-603.

BEYOND MEDICINE

17. Visser A, Snoek F. Perspectives on education and counseling for diabetes patients. Patient Educ Couns 2004; 53:251-5.

18. Deepa M, Bhansali A, Anjana RM, Pradeepa R, Joshi SR, Joshi PP, et al. Knowledge and awareness of diabetes in urban and rural India: The Indian Council of Medical Research India Diabetes Study (Phase I): Indian Council of Medical Research India Diabetes. Indian J Endocrinol Metab 2014; 18:379-385 19. Bhardwaj S, Misra A, Misra R, Goel K, Bhatt SP, Rastogi KV, et al. High prevalence of abdominal, intra-abdominal and subcutaneous adiposity and clustering of risk factors among urban Asian Indians in North India. PLoS One 2011; 6:e24362.

20. Deepa M, Farooq S, Deepa R, Manjula D, Mohan V. Prevalence and significance of generalized and central body obesity in an urban Asian Indian population in Chennai, India (CURES: 47). Eur J Clin Nutr 2009; 63:259-67.

21. World Health Organization (WHO) Expert Consultation.

Appropriate body mass index for Asian populations and its implications for policy and intervention strategies.

Lancet 2004; 363:157–163.

22. World Health Organization (WHO).. The Asia Pacific Perspective. Redefining Obesity and Its Treatment.

International Association for the Study of Obesity and International Obesity Task Force. International Diabetes Institute: Melbourne, 2000.

23. Pradeepa R, Anjana RM, Joshi SR, Bhansali A, Deepa M, Joshi PP, et al, for the ICMR– INDIAB Collaborative Study Group. Prevalence of generalized and abdominal obesity in urban and rural India- the ICMR-INDIAB Study (Phase-I) [ICMR-INDIAB-3]. Indian J Med Res. 2015; 142:139-50.

24. Lim SS, Vos T, Flaxman AD, Danaei G, Shibuya K, Adair-Rohani H, et al. A comparative risk assessment

of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380:2224–2260.

25. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo Jr JL et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC-7). JAMA 2003; 289:2560–2572.

26. Bhansali A, Dhandania VK, Deepa M, Anjana RM, Joshi SR, Joshi PP, et al for the ICMR– INDIAB Collaborative Study Group. Prevalence of and risk factors for hypertension in urban and rural India: the ICMR-INDIAB Study. J Hum Hypertens 2015; 29:204-209.

27. Misra A, Luthra K, Vikram NK. Dyslipidemia in Asian Indians: determinants and significance. J Assoc Physicians India 2004; 52:137-142.

28. 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;9:e96808.

29. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001; 285:2486–2497.

30. World Health Organization: Global strategy on diet, physical activity and health- Diet and physical activity: a public health priority. 2015. http://www.who.int/ dietphysicalactivity/en/ accessed on 17.08.2015 31. Bull FC, Maslin TS, Armstrong T Global physical activity questionnaire (GPAQ): nine country reliability and validity study. J Phys Act Health 2009; 6: 790–804.

32. Anjana RM, Pradeepa R, Das AK, Deepa M, Bhansali A, Joshi SR, et al; ICMR– INDIAB Collaborative Study Group. Physical activity and inactivity patterns in India - results from the ICMR-INDIAB study (Phase-1) [ICMRINDIAB-5]. Int J Behav Nutr Phys Act 2014; 26;11:26.