18 Death: Diagnosis and management Death is Nature \200\231s master stroke, albeit a cruel one , because it allows geno- types space and opportunity to try on new phenotypes. Our bodies and minds are these perishable phenotypes \200\224the froth, on the wave of our genes. Thes e genes are not really our genes. It is we who belong to them for a few decades. As our neu rofibrils begin to tangle, and a neonate walks to a wis- dom that eludes us, we are forced to give Nature credit for her daring idea. 18 \200\234Some say that the world is a vale of tears. I say it is a place of soul making \200\235 \200\224John Keats \200\224the first medical student to formulate these ideas abou t pain. They did not do him much good, because he died shortly after expressing them. But h is ideas can do us good \200\224perhaps if, each day, we try at least once for authentic in teractions with a patient, unencumbered by professional detachment, research interests, def ensive medicine, a wish to show off to our peers, or to get though the day with the minimum of fuss. Of course, Nature, in her haphazard way, can get it wrong: People often die in the wrong or der (one of our chief roles is to prevent this misordering of deaths, not the phenomenon of death itself). Death is not our enemy. A life well lived is the goal of every man, and our goal should be to help our patients achieve this as much as possible. As Osler said of the healing professions, \200\234And, finally, remember what we are \200\224 useful supernume raries in the battle, simply stage accessories in the drama, playing minor, but essential, parts at the exits and entrances, or picking up, here and there, a strutter, who may have t ripped upon the stage. \200\235 19 Causes of death Homicide, suicide, accident, or natural causes. Diagnosing death The pronouncement of death is an important respon- sibility of the physician. The physical exam done to diagnose death is a key symbolic ritual that brings c losure to the patient \200\231s life and closure for the physician, members of the healthca re team, and, most especially, the patient \200\231s family. Death is determined by the abs ence of pulse and respira- tions, no auscultated heart sounds, and fixed pupils. If a patie nt is on a ventilator, brain death may be diagnosed even if the heart is still beating, via brain death criteria that entail the irreversible absence of brain function, particularly in the brainstem. Death of the brainstem is recognized by establishing the absence of crani al nerve and respiratory reflexes. The Uniform Determination of Death Act recognizes that d eath can be diagnosed by neurologic criteria. In addition to evidence of a catastrophic bra in injury, the following prerequisite criteria must be met: \212 Deep coma with absent res pirations (hence on a ventilator). \212 The absence of drug intoxication and hypothermia ( <32 C). \212 The absence of hypoglycemia, acidosis, hepatic failure, and electrolyte e n i c i d e m t u o b a g n k n h T i i 19 imbalance. Tests: For determination of brain death, the following tests should be per- formed by quali fied personnel. Repeat the tests after a suitable interval \200\224at least 6 hrs, although sometimes 12 \200\22324 hrs is required to confirm irrevers- ibility of the coma. It is of ten recommended that a neurologist perform the confirmatory tests. \212 Tests to establish that brainstem reflexes are absent: \212 Unreactive pupils. Absent corneal response. \212 No oculocephalic reflex (Doll \200 \231s eye test). \212 No vestibulo-ocular reflexes (i.e., no eye movement occurs after or during slow injection of 60 mL of ice-cold water into each ear canal in turn). Visualize th e tympanic membrane first to eliminate false negative tests (e.g., due to wax). \212 No motor response within the cranial nerve distribution should be elicited by adequat e stimulation (e.g., absent facial grimacing when pressing on supraorbital ridge). \212 No gag reflex or response to bronchial stimulation with a catheter to the level of the carina. \212 Additional tests: \212 No spontaneous or reflex motor responses to noxious stimuli. There should also be no autonomic response to noxious stimuli or vagal stimulation. Spinal reflexes are not relevan t to the diagnosis of brain death. \212 Positive apnea test: No respiratory effort in response to hypercarbia. A tube is inse rted through the endotracheal tube to the level of the carina 19 Osler W. Doctor and Nurse, in Aequanimitas , 2nd ed. Philadelphia: P. Blakiston \200\231 s Son & Co.; 1925. in order to deliver continuous oxygen at a rate of 2 \200\2234 L/min. The ven- tilator is d isconnected, allowing P a CO 2 to rise to \211 60 mm Hg or more (for patients with COPD, a rise of 20 mm Hg above their baseline). P a CO 2 typically rises at a rate of 3 mm Hg per minute. Patients should be monitored for any hemo-dynamic instability during the test, and the test should be stopped if SBP falls by \211 20%, cardiac arrhythmias emerge, or the patient becomes hypoxic. Other considerations: Ancillary studies may be needed when the prerequisite criteria cannot be met (e.g., the patient is receiving sedative or anesthetic infusions). An electroenceph alogram (EEG) recording is not a standard requirement, unless brain death is to be diagnose d within 6 h of apparent cessation of brain activity. Cerebral blood flow studies (e.g., wi th isotope angiography) are helpful when the patient is receiving treatments that sup- pres s cerebral metabolic activity. Organ donation: The point of diagnosing brain death is partl y that this allows organs (kidney, liver, cornea, heart, or lungs) to be donated and remove d with as little damage from hypoxia as possible. Do not avoid the topic with loved ones. M any are glad to give consent and to think that some good can come after the death of their relative, that some part of the relative will go on living, giving a new life to another pe rson. After death Inform the patient \200\231s attending and consultants. Meet with the pat ient \200\231s next of kin and offer emotional support. Ask if they want an autopsy. Autops y permission may be granted (in order of priority) by spouse, adult child, parent, sibling. Sign death certificates promptly. If DOA or within 24 h of admission, or the cause is viol ence, trauma, accident, neglect, surgery, anesthesia, therapeutic mishap, drug/alcohol over dose, sui- cide, poisoning, or is unknown or suspicious, inform the Coroner/Medical Examine r. 20 Facing death \200\234People imagine that they are not afraid of death when they think of i t while they are in good health \200\235 (Marcel Proust). So, to get into the mood, as a th ought experiment, place a finger in your left supraclavicular fossa, and feel there the cra ggy node of Virchow, telling of some distant gastric malig- nancy, as if it were your death warrant. Perhaps you have just 4 months left. Live with this \200\234knowledge \200\235 f or the rest of the day, or rest of the week, and see how it changes your attitude to family and friends, on the one hand, and the million irrelevances that clutter our minds, on the other. As the week unfolds, you may experience thoughts and feelings that are new to you, b ut all too familiar to your patients. And as the months and years roll by, and you find you rself sitting opposite certain patients, put that finger once more on that metaphorical nod e and turn it over in your mind, and it will turn you, so you are sitting not opposite your patient but beside him. There is only so much comfort you can bring in this way, as, in th e end, you cannot tame death. Whenever you find yourself thinking it is better for them not to know, suspect that you mean: It is easier for me not to tell . We find it hard to tell for many reasons: It distresses patients; it may hold up a ward round; we do not like ackno wledging our impotence to alter the course of diseases; telling reminds us of our own morta lity and may unlock our previous griefs. We use many tricks to minimize the pain: rationali za- tion ( \200\234They would not want to know \200\235); intellectualization ( \200\234Res earch shows that 37% of people at stage 3 survive 2 yrs \200 \200\235); brusque honesty ( \200\234You are unlikely to survive 1 month \200\235 and, so saying, the doctor rushes off to more vital things); inappropriate delegation ( \200\234The nurse will explain it all to you when you are calmer \200\235). Why it may help the patient to be told \212 The patient already half knows but everyone sh ies away so he cannot e n i c i d e m discuss his fears (of pain, or that his family will not cope). \212 There may be many affa irs for the patient to put in order. \212 To enable him to judge if unpleasant therapy is worthwhile and to set realistic goals. t u o b a g n k n h T Most patients are told less than they would like to know . Breaking bad news Being able to deliver bad news compassionately and effectively is one of the most important skills of the physician. Although each discussion must be individualized to the particular patient, some gen- eral principles have been recommended. These have been encapsulated in the mnemonic S PIKES 20 : \212 S etting the stage: Sit down. Arrange for privacy. Avoid interruptions. \212 P atient \200\231s perceptions: What does the patient know about the situation? \212 I nvitation for information: How does the patient want to be given infor- i i mation? Patients may either desire or shun information. \212 K nowledge: Fire a warning shot before providing information, \200\234I \200\231m so rry to tell you that \200 \200\235 Use language that the patient can understand. \212 E motions: Acknowledge emotions and offer empathetic statements, \200\234I 21 can see that this is upsetting to you. \200\235 Be authentic in your empathy. \212 S ummary and strategy: Review discussion and set agenda based on goals of care. Addre ss any lingering misunderstanding, uncertainty, or fears. What are the patient \200\231s wo rries likely to be? Put yourself in the patient \200\231s place. \212 Give some informatio n, and then the opportunity to ask for more. \212 Be sensitive to hints that they may be r eady to learn more. \200\234I \200\231m worried about my son. \200\235 \200\234What is wo rrying you most? \200\235 \200\234Well, it will be a difficult time for him (pause) starti ng school next year. \200\235 Silence, broken by the doctor \200\234I get the impression t here are other things worrying you. \200\235 The patient now has the opportunity to proceed further, or to stop. Ensure that the patient \200\231s personal physician and the nurses k now what you have and have not said. Also make sure that this is written in the notes. Living wills/advance directives If a patient has the capacity to make her own decisions, th en she should be asked directly what her treatment preferences are. If a patient lacks capa city and her views are known, comply with them. Some patients spell out their views in a wr itten document. But these views change, are ambiguous, or are hard to interpret, even if a living will exists. Living wills only take effect when the patient is terminally ill. In ma ny cases, there can be uncertainty or disagreement about whether to invoke the living will because it is not clear that the patient is \200\234absolutely, hopelessly ill. \200\235 I f a patient desires to complete an advance directive, it is often more prefer- able to have the patient designate a durable power of attorney for health- care or a healthcare agent \200\224a person who will speak for the patient if the patient is too ill to speak for hims elf. Designation of a healthcare agent can also be fraught with difficulties, especially if the named surrogate has not had a prior discussion with the patient about his wishes. Perh aps the best strategy is to focus less on completion of the advance directive form and more on the discussion involved in advance care plan- ning. This will be an ongoing process wit h the patient, reviewing the goals of care in light of the changing clinical situation and the patient \200\231s hopes, fears, prognosis, quality of life, loved ones \200\231 wishes, and underlying values. 20 Baile WF, Buckman R, Lenzi R. Oncologist. 2000; 5: 302 \200\223311. Stages of acceptance Accepting death takes time, and may involve pass- ing through \200 \234stages \200\235 on a path. It helps to know where your patient is on this path (but pro gress is rarely orderly and need not always be forward: The same ground often needs to be c overed many times). At first, there may be shock and numbness , then denial (which reduces anxiety), then anger (which may lead you to dislike your patient, but anger can have positi ve attributes (e.g., in energizing people \200\224and it can trump fear and pain; it is dif ferent from hostility), then grief , and then, perhaps, acceptance . Finally there may be i ntense longing for death as the patient moves beyond the reach of worldly cares. 21 The phy sician can be a guide on the patient \200\231s journey. The physician is there to bid patie nts, in the words of T. S. Eliot, with the call, \200\234Not fare well, but fare forward, voyagers. \200\235 22 Palliative care When the patient \200\231s journey finds him or her on the path of a life-l imiting illness, it is time to start thinking about palliative care. The palliative care ph ilosophy can be introduced at any point in a serious, debilitating illness and becomes more of the focus as the patient enters the terminal phases of his or her illness. The National Consensus Project for Quality Palliative Care states: \200\234The goal of palliative care is to prevent and relieve suffering and to support the best possible quality of life for p atients and their families, regardless of the stage of the disease or the need for other th erapies. Palliative care is both a philosophy of care and an organized, highly structured s ystem for delivering care. Palliative care expands traditional disease-model medi- cal trea tments to include the goals of enhancing quality of life for patient and family, optimizing function, helping with decision making, and providing opportunities for personal growth. A s such, it can be delivered concurrently with life-prolonging care or as the main focus of care. \200\235 23 For conditions such as congestive heart failure, optimal symptom manage- ment and improved functional status are often achieved by prescribing the best evidence-bas ed cardiac regimen. Elements of palliative care (1) Patient population, anyone with a life- threatening illness, condition, or injury; (2) patient- and family-centered care, respectin g the uniqueness of the patient and family as the unit of care; (3) timing , beginning at t he diagnosis of the condition through cure, until death, or into the period of family berea vement; (4) comprehensive care, multidimensional care to identify and relieve suffering and distress; (5) interdisciplinary team, to utilize the skills of each discipline; (6) attent ion to relief of suffering, do not just think about pain, but other symptoms like dyspnea, anorexia, nausea, change in bowel habits, fatigue, insomnia, delir- ium, anxiety, depressio n (many of which can be assessed on a 0 \200\22310 scale to monitor treatment effect, as wi th pain); (7) communication skills, sharing information, listening, setting goals of care; (8) skill in care of the dying and the bereaved, with particular attention to prognosticati on (think especially of functional status, as with the Palliative Performance Scale, 24 whi ch can be used across different diseases), preparation, and anticipatory guidance; 22 21 Bach JS. Ich habe genug , Cantata No. 82, composed for the Feast of the Purification, 17 27. 22 Eliot TS. The dry salvages. In: The Four Quartets. New York: Mariner Books; 1968. 23 National Consensus Project for Quality Palliative Care. Clinical Practice Guidelines for Q uality Palliative Care, 2nd ed. 2009. http://www.nationalconsensusproject.org. Accessed Sep tember 10, 2012. 24 Anderson F, Downing GM, Hill J. et al. Palliative performance scale (PP S): a new tool. J Palliat Care. 1996;12(1):5 \200\22311. (9) continuity of care across settings , whether in hospital, home, long-term care facility , or inpatient hospice \200 or while transitioning from one to another; (10) equitable acc ess, across all patient populations and settings; (11) quality assessment and performance i mprovement, consistent with the IOM aims for quality healthcare delivery. In the words of D ame Cicely Saunders, the founder of the modern hospice movement: \200\234You matter becaus e you are you, and you matter to the end of your life. We will do all we can not only to he lp you die peacefully, but also to live until you die. \200\235 25 e n i c i d e m t u o b a g n k n h T Surviving residency If some fool or visionary were to say that our aim should be to pro- du ce the greatest health and happiness for the greatest number of our patients, we would not expect to hear cheering from the tattered ranks of midnight house staff: Rather, our ears a re detecting a decimated groan \200\224 because these men and women know that there is some thing at stake in a house staff training program far more elemental than health or happines s: Namely, survival. Here, we are talking about our own survival, not that of our patients. It is hard to think of a greater peacetime challenge than the first few months on the ward s. Within the first weeks, however brightly shone the intern \200\231s armor, it will now b e smeared and splattered, if not with blood, then with the fallout from very many decisions that were taken with- out sufficient care and attention. It was not because the intern was lazy. All of us are stunned to realize at some point in our training that the forces of Na ture (e.g., our need for sleep) and the exigencies of ward life teach us to be second-rate: For to insist on being first-rate in all areas at all times is to sign a kind of death war rant for many of our patients, and, more pertinently for this page, for ourselves. Perfecti onism cannot survive in our clinical world. The perfect is the enemy of the good. To cope w ith this fact, or, to put it less depressingly, to flour- ish in this new world, don \200 \231t keep repolishing your armor (what are the 10 causes of atrial fibrillation \200\224or are there 11?), rather furnish your mind \200\224and nourish your body (regular food and d rink make those midnight groans of yours less intrusive). Do not voluntarily deny yourself the restorative power of sleep. The move to an 80 hr work week is a recognition that our bo dies (and minds) need time to rejuvenate. We cannot prepare you for the adversity that you may encounter or the tests to your character that may ensue. Neither would we dream of impo s- ing on you a set of standard regimens on how to survive. Finding out what can lead you t hrough adversity is the art of living. Plan your free time and recreation in advance. What will you choose: physical fitness, martial arts, yoga, music, poetry, writing, culinary del ights, the sermon on the mount, juggling, meditation, a love affair \200\224or will you mak e an art form out of the ironic observation of your contemporaries? Work \200\223life balan ce does not necessarily mean that the time devoted to our professional and personal lives i s evenly weighted. Our profession puts cer- tain demands on our time and energy that we can not escape. Work \200\223life bal- ance is about \200\234figuring out what \200\231s reall y important and fulfilling to you, right now, and living intentionally, as best you can. \200\235 26 It \200\231s about remembering that patient care \200\234ultimately depends on the soul of the doctor. \200\235 27 i i 23 25 Saunders C. Nursing Times. 1976; 72(26): 1003 \200\2231005. 26 Harrison R. Evolving tren ds in balancing work and family for future academic physicians: A role for personal stories . Med Teacher. 2008;30:316 \200\223318. 27 Gaufberg E. Time to care. Health Affairs. 2008;2 7(3):845 \200\223849. Some physicians nourish their inner person through a religious belief and attend mosque, ch urch, synagogue, or temple. Some find spirituality and meaning through other means. A multi cultural society provides diversity and room for all branches of expression. Bear in mind n ot to compare yourself with your contemporaries. Those who make the most noise are often no t waving but drowning . Find time to reflect on your experiences. Residency can encompass t remendous up-and-down swings in energy, motivation, and mood, which can be precipitated by small incidents. If you are depressed for more than a day, speak to a sympathetic friend, p artner, or counselor to help you put it in perspective. Seek help for your own problems. Fi nd professional help if needed. You are not the best person to plan your assessment, treatm ent, and referral. When in doubt, communicate. Think about your future career, and seek out an advisor and mentor in the specialty that you think you will pursue after your training. Such inquiries supply energy to get you through the long, though now limited, hours of res idency, and may motivate you if the going gets tough. Not that this is any guarantee that t he plans will work, but if your yoga, your sermons, and your fitness regimens turn to ashes in your mouth, then at least you will know the direction in which to spit. Residency is no t just a phase to get through and to enjoy where possible (there are frequently many such p ossibilities); it is also the anvil on which we are beaten into a new and perhaps rather un comfortable shape. Luckily, not all of us are made of iron and steel, so there is a fair ch ance that, in due course, we will spring back into something resembling our normal shape, a nd, in so doing, we may come to realize that it was our weaknesses, not our strengths, whic h served us best. And, in the end, we will be better doctors (and our future patients will be better cared for) for our having endured the hardships. 24 On being busy: Corrigan \200\231s secret door Unstoppable demands, increased expectations a s to what medical care should bring, the rising number of elderly patients, coupled with th e intro- duction of new and complex treatments all conspire, it might be thought, to make d octors ever busier. In fact, doctors have always been busy. In Great Britain, Sir Dominic C orrigan was so busy 150 yrs ago that he had to have a secret door made in his consulting ro om so that he could escape from the ever-growing waiting room of eager patients. We are all familiar with the phenomenon of being hopelessly over- stretched \200 and of needing Corr igan \200\231s secret door. Competing, urgent, and simultanous demands make carrying out an y task all but impossible: The resident is trying to put up an IV infusion on a hypotensive patient when his pager goes off. On his way to the phone, a patient is falling out of bed, being held in, apparently, only by his visibly lengthening catheter (which had taken the h ouse officer an hour to insert). He knows he should stop to help but, instead, as he picks up the phone, he starts to tell the nurse about \200\234this man dangling from his Foley \200\235 (knowing in his heart that the worst will have already happened). But he is interr upted by a thud coming from the bed of the lady who has just had her occluded left anterior descending artery attended to: However, it is not her, but her visiting husband who has co l- lapsed and is now having a seizure. At this moment a Code Blue is called, summoning him to some other patient. In despair, he turns to the nurse and groans: \200\234There must be some way out of here! \200\235 At times like this, we all need Corrigan to take us by the shadow of our hand and walk with us through his metaphorical secret door, into a calm inner world. To enable this to happen, make things as easy as possible for yourself. First, however lonely you feel, you are not alone. Do not pride yourself on not asking for help. If a decision is a hard one, share it with a colleague. Second, take any chance you g et to sit down and rest. Have a cup of coffee with other members of the staff, or with a fr iendly patient (patients are sources of renewal, not just devourers of your energies). Thir d, do not miss meals. If there is no time to go to the cafeteria, know where you can find f ood on the wards or ensure that food is put aside for you to eat when you can: Hard work an d sleeplessness are twice as bad when you are hungry. Fourth, avoid making work for yoursel f. It is too easy for physicians in train- ing, trapped in their image of excessive work an d blackmailed by misplaced guilt, to remain on the wards following up on patients, rewritin g notes, or rechecking lab results at an hour when the priority should be caring for themse lves. Fifth, when a bad part of the rotation is looming, plan a good time for when you are off duty, to look forward to during the long nights. Finally, remember that however busy th e call day (and night), your period of duty will end. For you, as for Macbeth: e n i c i d e m t u o b a g n k n h T i i Come what come may, Time and the hour runs through the roughest day. 25 Epidemiology Gregory P. Prokopowicz , M.D., M.P.H. y g o o m e d p E l Contents Why epidemiology is relevant to the practicing physician 26 Evidence-based medicine 27 Asso ciations and causality 28 Risk of disease and its outcomes 29 Evaluation of diagnostic test s 31 The effectiveness of therapy 32 Screening 34 i i 2 Why epidemiology is relevant to the practicing physician Epidemiology is the study of the d istribution of clinical phenomena in human populations. Clinical epidemiology is the applic ation of epidemio- logic methods to the care of the patient. The fruits of clinical epidemi ology include identification of the causes of disease, prediction of the develop- ment of d isease and its clinical outcomes, rational use of clinical tests, assessment of the risks a nd benefits of therapies, and evaluation of screen- ing technologies. Identification of cau ses of disease Epidemiologic methods enable one to determine the risk factors responsible f or disease. The association of smoking with lung cancer, dyslipidemia with coronary artery disease, and hypertension with stroke are examples of the valuable findings of epide- miolo gy with relevance for the practitioner. Novel risk factors, such as C-reactive protein for coronary artery disease, continue to be identified. The up-to-date physician should have an awareness of how such associa- tions are derived and whether they are likely to be importa nt for clinical care. Prediction of disease and its clinical outcomes By identifying risk f actors, the physician can predict which of his or her patients is most likely to develop di sease. Risk scores, such as the Framingham score for coronary artery disease or the CHADS2 score for thromboembolism in atrial fibrilla- tion, can be used to estimate the risk of cli nical outcomes in a given patient and thereby guide the choice of therapy. Rational use of clinical tests Laboratory and radiographic tests are a daily part of clinical practice, but few tests provide totally unambiguous results. Quantification of test performance, using s ensitivity, specificity, posi- tive and negative predictive values, and likelihood ratios, facilitate appropri- ate selection and interpretation of tests. Assessment of risks and ben efits of therapy Quantitative measures of effect, such as the number needed to treat , enab le the clinician to accurately weigh the benefits of therapy against any harms, and to comp are the cost effectiveness of competing therapies. Evaluation of screening technologies An increasing number of investi- gations may be performed on the healthy patient with the inte nt of detect- ing early disease. Emerging technologies, such as multislice spiral computed tomography and genetic testing with single nucleotide polymorphisms, will reveal new abnorm alities of uncertain significance. Appropriate counseling of the patient with respect to su ch screening tests requires an understand- ing of the issues involved. 26 Evidence-based medicine Evidence-based medicine (EBM) as been defined as the conscientious and judicious use of current best evidence from clinical research in the manage- ment of in dividual patients. The problem Traditionally, the teaching and practice of medicine has rel ied largely on three sources of knowledge: Pathophysiology, expert opin- ion, and personal clinical experience. Important limitations have become apparent in these sources of informa tion. Predictions from pathophysiology may not hold in clinical practice; for example, supp ression of ventricular ectopy following myocardial infarction with encainide or flecainide led to a surprising increase in mortality. Expert opinion may be out of date or biased due to conflict of interest. And personal experience is likely to be unduly influenced by strik ing clinical outcomes, such as a rare but devastat- ing side effect in a generally safe dru g. The solution EBM directs the physician to be aware of the quality of the information on which his or her practice is based, and to conscientiously choose the most reliable sources . This presupposes a hierarchy of evidence (i.e., a ranking of types of information accordi ng to susceptibility to bias and chance effects). Such hierarchies generally place randomiz ed controlled trials (RCTs) at the highest tier, followed by observational studies, then un systematic clinical observations, pathophysiologic reasoning, and expert opinion. Meta-anal yzes and systematic reviews are often given even greater credence than RCTs, although this depends on the quality of the review. The four steps of EBM Formulate the clinical question : The first step is to focus our sometimes vague uncertainty into a question that can be an swered. The acronym PICO may be of help: What sort of Patient are we considering; what is t he Intervention we are contemplating; to what alternative can we Compare the intervention; and what Outcomes are important for our patient? Search the literature: The practice of EBM optimally requires access to com- puterized literature sources such as PubMed. Time spent learning appropri- ate search techniques (e.g., by using the tutorials) will pay off with b etter results. Appraise the literature that you have found: Here, we are interested in the validity of the study, the results of the study, and the applicability to our patient. Appl y the findings to the individual patient: In applying the findings to our particular patien t, we must consider our patient \200\231s unique clinical charac- teristics and values. Cri ticisms of EBM Searching the primary literature and assessing its validity in the context o f a busy clinical practice is difficult. In response, proponents of EBM have suggested the use of pre-appraised literature sources , such as ACP PIER, Clinical Evidence, Up-To-Date, and the jour- nals Evidence-Based Medicine and ACP Journal Club. These resources provide cl inically relevant summaries of the primary literature and obviate the labo- rious critical appraisal of individual papers by the clinician. In addition, tools for winnowing out the c linically useful articles from the morass of medical literature have been developed; these including literature filters and selective e-mail notification services. The suggestion has been made that EBM is primarily a means of controlling costs by denying what would otherwi se be considered appropriate care. While certain techniques of EBM may be used to this end, the principles of EBM do not require that the least expensive alternative be chosen, and e vi- dence-based practice guidelines have not invariably resulted in lower costs. y g o o m e d p E l i i 27 Perhaps the most significant criticism of EBM is that it has never itself been subject to t he sort of rigorous evaluation that it espouses for other thera- pies. Specifically, we do not know if physicians who adhere closely to the principles of EBM have better patient outc omes than those who do not. Proponents of EBM point to studies showing that expert opinions voiced in traditional review articles may lag behind evidence from the latest stud- ies, a nd that patients receiving therapies for which there is good evidence do better than those who do not. But these are indirect measures of the effectiveness of EBM; direct comparisons of EBM practitioners with non- EBM practitioners, either in the form of RCTs or observatio nal studies, are lacking. Associations and causality Association Epidemiological research is concerned with comparing rates of disease in populations with different exposures (e.g., rates of lung cancer in a population of men who smoke, compared with men who do not). A difference in rates suggests an association between the disease and the expo- sure (in this case, smoking). The search f or meaningful associations may be complicated by the presence of confounders , or factors t hat are related to both the exposure and the disease. For example, an apparent association between alcohol use and lung cancer may simply reflect the fact that both are related to to bacco use. Associations may also be due simply to chance. The strength of an association is expressed as the risk ratio \200\224 the risk of developing the disease among those with t he exposure, divided by the risk of developing the disease among those without the exposure , or the odds ratio, a similar but not identical measure. Prevalence and incidence To compa re rates of disease between groups, standard measures of disease occurrence are used. Preva lence is the number of cases of disease present in a defined population divided by the tota l num- ber of people in that population. Since it is not usually practical to count an enti re population at once, the period prevalence is often given, indicating that the measuremen t took place over a period of time. For example, the prevalence of obesity (body mass index [BMI] >30) in the United States during the 2009 \200\22310 National Health and Nutrition E xamination Survey (NHANES) survey period was 35.7%. Lifetime prevalence is the proportion o f a population that has ever experienced the condition of interest, and point prevalence is the proportion with the condition at a given point in time. For example, the lifetime prev alence of headache in women has been reported at 99%, and the point prevalence at 22%. Inci dence is the number of new cases occurring in a defined population that is initially free o f the disease, over a specified time period (e.g., the incidence of breast cancer among U.S . women from 2008 was 127 per 100,000 [Surveillance Epidemiology and End Results (SEER) can cer statistics review]). Observational studies Associations are often discovered using obse rva- tional studies . Such studies are distinguished from experimental studies or clinical trials in that the investigator does not control the exposure; she or he merely observes th e subjects who are exposed and those who are not and records the outcomes occurring in each group. Observational studies usually take one of three forms: 1 Cohort studies: The group, or cohort, consisting of subjects exposed to the suspected causal factor (e.g., smoking) i s followed alongside a control group consisting of subjects not exposed. The incidence of t he disease is compared between the groups over the duration of the study. Because the expos ure information is recorded as it occurs, prospective cohort studies do not 28 have recall bias. However, they can be very expensive and time-consuming, particularly for diseases with low incidence rates. y g o o m e d p E 2 Case \200\223control studies: The study group consists of those with the disease (e.g., l ung cancer); the control group consists of those without the dis- ease. The previous occurr ence of the exposure (e.g., smoking) is com- pared between each group. Case \200\223control studies are particularly useful for the investigation of rare diseases, but they suffer fr om recall bias: inaccuracy in the subjects \200\231 reporting of the exposure (e.g., smokin g). 3 Cross-sectional studies: The population of interest is surveyed for the pres- ence of both the exposure and the disease at the same time. This design is usually quick and inexp ensive, and provides prevalence data, but it may not enable the investigator to determine w hether the exposure preceded development of the disease, since both are measured at the sam e time. Establishing causality The finding of an association between an expo- sure and a di sease does not prove that the exposure causes the disease. Reports abound in the media of s upposed links between various foods and worsened or improved health; which will turn out to be valid? Sir Austin Bradford Hill, a British epidemiologist, recognized this problem in t he context of evaluating occupational hazards, and proposed nine criteria for establishing causality: 1 Strength of the association: Does the disease occur much more frequently among the exposed than among the unexposed, such as with lung cancer, or is it only slightly mor e common? l i i 29 2 Consistency: Does the relation hold across different studies in different populations? 3 Specificity: Is the exposure the only potential cause of the disease, or vise versa? This is not required for causality, but when present it strengthens the argument. 4 Temporality: Does the cause precede the effect? 5 Dose response: Does a greater exposure lead to a greater risk of disease? 6 Plausibility: Is there a plausible biologic mechanism to explain the causality? 7 Coherence: Does the cause-and-effect relation fit with histopathology and other information about the disease? 8 Experiment: Does alteration of the exposure, if possible, result in a change in frequency of outcome? 9 Analogy: Is there a similar disease known to be caused by a similar exposure? Risk of disease and its outcomes As physicians, we are frequently called on to prognosticat e. Our patients want to know: Should I be worried about this cough? Is my cholesterol low e nough? How long am I going to be in the hospital? Application of epide- miologic principles can help answer these questions. Which is more likely: An uncommon manifestation of a comm on disease or a common manifestation of an uncommon disease? When we consider the significa nce of a new symptom reported by a patient, we are engaging in a process of risk stratifica tion. Is the sudden, stabbing mid-back pain reported by this 65-yr-old diabetic with hypert ension likely to be from muscle strain? Myocardial infarction? Aortic dissection? In for- m ulating a diagnosis, we estimate the likelihood of various diseases in our patient and also consider how commonly each disease would present with the symptoms we see in front of us. Proper use of epidemiology can guide our application of this information to the patient. Co nsider the develop- ment of angioedema in a person taking an angiotensin-converting enzyme (ACE) inhibitor. Angioedema is a rare symptom with ACE inhibitor use