Variables Affecting Outcome in Critically Ill Patients

Variables Affecting Outcome in Critically Ill Patients* Bart Chernow, MD, FCCP

Critical care medicine has evolved as a field of science and clinical care. Despite important contributions to our understanding of the molecular basis of critical illness, we still remain troubled by our lack of insight into why some patients have favorable outcomes from critical illness and others do not. This article explores the hypothesis that at least five important variables may alter the outcome of patients suffering from a variety of critical illnesses. These variables include the premorbid immune or genetic status of the patient, the patient’s gender, the circulating cholesterol concentration, the patient’s age, and various iatrogenic and nosocomial events. Insights into the importance of these five variables may provide opportunities for physicians and scientists to improve outcome in patients suffering from critical illness. Clearly, altering iatrogenic and nosocomial events is already within the realm of opportunity. (CHEST 1999; 115:71S–76S)

the Editor-in-Chief of CHEST created a R ecently, new category for articles published in this jour-

nal.1 That category includes articles describing opinions and hypotheses. The present article represents opinions and hypotheses that I have generated as a physician-scientist in the area of critical care medicine. Many critical care practitioners face the issue of trying to understand why some patients die with a given condition, while other patients with the same condition and equal severity of illness survive. The purpose of this article is to describe five major categories that I believe may help explain the still baffling circumstance of why certain patients survive a critical medical insult, while others do not. Background/History

Modern critical care may date its origins to the landmark article published by Drinker and McKhann,2 describing the iron lung for the treatment of the neuromuscular weakness-induced respiratory failure of poliomyelitis. Others might date the modern era of critical care to the early 1960s, with the description of closed-chest cardiac massage3 and the use of a synchronized capacitor discharge for defibrillation in the treatment of cardiac arrhythmias.4 Regardless of when the modern advent of critical care began, it has been quite clear that the scientific database of this new discipline has increased exponentially over the last 2 decades. Per*From the Johns Hopkins University School of Medicine, Baltimore, MD. Correspondence to: Bart Chernow, MD, FCCP, Johns Hopkins University School of Medicine, 720 Rutland Ave, Suite 124, Baltimore, MD 21205-2196; e-mail: [email protected]

haps the scientific underpinnings of our specialty have been most notable in the basic science and clinical research contributions regarding sepsis and septic shock. Despite several generations of new antimicrobial agents, the mortality rate of this syndrome due to infectious diseases remains unacceptably high. The mechanisms for the physiologic, pathologic, and characteristic hemodynamic changes continue to be elucidated. In the late 1980s, we learned that cytokines such as tumor necrosis factor (TNF) are released in response to endotoxin, and the hemodynamic responses to endotoxin were clearly delineated.5,6 It became evident7 that the circulating TNF concentration in patients could correlate with the level of infection and even the mortality rate. As a consequence of recognizing the central role of cytokines, a series of large studies were performed but were unsuccessful in their attempt to demonstrate the efficacy of anticytokine therapy in the treatment of septic shock.8 –11 These failed therapies and other similarly unsuccessful therapies have left the clinical community frustrated with an apparent disconnection between what is found at the research bench and what seems to work in humans with serious infection. To add further concern to this issue, it has become clear that sepsis provides patients with a marked disadvantage in terms of longterm survival,12 even if the patient survives an acute episode. Quartin et al12 studied a large population of patients with sepsis. They followed the survivors of sepsis for 5 years and compared their outcomes with a control group of similarly ill, nonseptic subjects. They found that sepsis increases the risk of death for up to 5 years after the initial septic event. Clearly, the approach to dealing with this major CHEST / 115 / 5 / MAY, 1999 SUPPLEMENT

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clinical problem needs to be modulated. Researchers from the American College of Chest Physicians, in collaboration with the National Institutes of Health, have helped to define a strategy for bridging the gap between the research bench and the bedside.13 Anticytokine therapy has worked in at least two other conditions,14,15 and thus, there is something unique about the septic episode that may preclude the traditional anticytokine approach to therapy. In the meantime, new experimental therapies continue to be described.16,17 The pivotal roles of nuclear factor kappa B18 –20 and the various families of chemokines21,22 have been discovered. Perhaps modulating these variables may be helpful. With this background, let me now turn to what I consider the five major variables that may create discrepancies in predicted outcome in critically ill patients by either clinical assessment or scoring systems: (1) preinfectious or preoperative immune or genetic status; (2) gender; (3) circulating cholesterol concentration; (4) age; and (5) iatrogenic/nosocomial events.

Preinfectious/Preoperative Immune or Genetic Status It is impossible in this short essay to define the enormous variability that clearly exists within the genetic and immune makeup of people. Several recent discoveries underscore the importance of these genetic and immune differences between human beings. An example of the genetic basis for a particular disease ailment is seen in a recent article by Chen et al23 These investigators recently discovered the genetic basis and molecular mechanism for what is known as idiopathic ventricular fibrillation. Between 5% and 10% of patients who suffer a cardiac arrest due to ventricular fibrillation have no definable cardiac cause for the ventricular fibrillation event. Therefore, this entity is known as idiopathic ventricular fibrillation. Since there are . 300,000 sudden deaths due to ventricular fibrillation in the United States each year, this genetically based entity is not trivial, but may clearly explain why some patients have an unexpected cardiac arrest due to ventricular fibrillation. There is a strong genetic influence on how patients will respond to critical illness or injury. As an example, in patients who suffer a fatal meningococcal infection, the genetic influence on cytokine production may be extremely important.24 If TNF production (an example of proinflammatory cytokine release) is low, and interleukin-10 production (antiinflammatory cytokine release) is high, the risk for death is markedly increased. Van Dissel et al25 recently confirmed this work in febrile patients and 72S

demonstrated that if patients have an increased ratio of interleukin-10 to TNF-a concentrations, a fatal outcome is more likely. Stu¨ber et al26 demonstrated that there is a genomic polymorphism within the TNF locus that influences the amount of TNF released into the circulation. Patients with an exaggerated TNF response were found to have a higher mortality rate due to this polymorphism. Similarly, there is a polymorphism at the b2-adrenergic receptor that may make some patients more prone to desensitization to bronchodilators.27 Another example of the genetic basis for disease is the finding that plasma homocysteine levels may be important predictors of mortality in patients with coronary artery disease.28 Preoperative antiendotoxin antibody concentrations are inversely related to outcome following open heart surgery. If the preoperative antiendotoxin antibody concentrations are increased, the postoperative complication rate is decreased. Low levels are associated with a high morbidity rate.29 The finding that some patients have high endotoxin core antibody concentrations and also circulating levels of cytokine antagonists may explain why some of the anticytokine and antiendotoxin therapies have failed.30 A growing body of evidence regarding what Dr. Roger Bone31 called “immunologic dissonance” supports the concept of an association between ratios of inflammatory and anti-inflammatory cytokine concentrations and outcome.32,33

Gender Women seem to do better than men in terms of outcome from serious infections. Immune function is clearly augmented in female subjects due to increased circulating concentrations of immunoglobulins and higher plasma concentrations of prolactin.34 Prolactin has important effects on the immune system,35 and in fact, it is my bias that the increased plasma concentrations of prolactin in women may be particularly important in the survival advantage that they exhibit with serious infection. Women respond to injury and trauma with increased serum insulinlike growth factor-1 concentrations in comparison to men, in whom insulin-like growth factor-1 concentrations decrease.36 Men seem to demonstrate immunosuppression perhaps as a consequence of higher testosterone concentrations.37 Testosterone blocking agents or estradiol administration may be useful in augmenting immune status in male trauma patients.37 Women may have different stress hormone responses than men.38 The survival advantage in sepsis that women have over men is not seen in other conditions. For example, coronary artery disPerioperative Cardiopulmonary Evaluation and Management

ease and its consequences affect women with equal severity to men, and in some cases, women have worse outcomes.39,40

Cholesterol Concentrations We have been trained to think of hypercholesterolemia as being bad, and hypocholesterolemia as being good. However, a growing body of evidence supports the concept that marked hypocholesterolemia may actually increase the risk of death in critically ill patients. Indeed, it has been demonstrated that circulating cholesterol concentrations , 120 mg/dL are associated with an increased risk of death in critically ill patients.41 Furthermore, it has been shown that in the extreme elderly (. 85 years of age), increased circulating cholesterol concentrations are associated with long life due to diminished death rates from serious infection and cancer.42 Some of the reasons for this discrepancy between traditional teaching and observations that we have made at the clinical bedside have now been made clear. We now understand that lipoproteins (highdensity lipoprotein, [HDL], low-density lipoprotein [LDL], etc) may serve as “mops” within the circulation to sop up endotoxin and other foreign substances. In fact, a series of experiments demonstrated that low lipid concentrations exist in various forms of critical illness,43 and administration of high-density lipoprotein may offer a protective effect for the prevention and treatment of endotoxemia.43,44 High circulating LDL concentrations due to LDL receptor deficiency protect subjects against lethal doses of endotoxin and Gram-negative bacteria.45 Clinicians should always consider that a patient who has a total cholesterol concentration , 120 mg/dL in the ICU may have a serious microbial infection. In addition, it does not appear that lowering a patient’s cholesterol concentration from high levels into the normal range adversely affects immune function. This latter theory has been tested and found to be correct.46

Age Age is clearly a relevant factor in outcome from serious illness. Older men and women have an augmented inflammatory response. A manifestation of this response is evidenced in age-related increases in circulating adhesion molecule concentrations. We know that concentrations of these adhesion molecules are increased in septic shock, and the higher the concentration, the more likely it is that the

patient may die.47 Older men and women have higher concentrations than similarly ill younger men and women,48 and as an example, older people have a higher probability of death from severe burn injury than younger people.49 The effect of age on survival from specific cardiac events has been reviewed extensively in several recent articles.50 –52

Iatrogenic/Nosocomial Events Adverse drug reactions in hospitalized patients account not only for a great deal of morbidity, but also for a large number of deaths.53–55 Infection acquired in the ICU is common, and time in the unit, especially with indwelling catheters, may contribute to the frequency with which nosocomial infection occurs.56 Bloodstream infections due to central venous catheters are important. A number of strategies have been developed to try to limit such infections. Clinicians must be vigilant regarding this all-toofrequent problem.57–59 In addition to adverse drug reactions as a cause of adverse outcome, the underuse of drugs may also alter outcome. Let us focus on adrenergic receptor blockers as an example. A review on adrenergic receptors has been written by Insel,60 and it is clear that there is a specific adrenergic nervous system within the human heart.61 One of the most important articles in recent years, in my opinion, has been the work of Gauthier et al.62 These investigators identified b3-adrenergic receptors within the human heart. These receptors mediate negative inotropic effects and may contribute to a worsening of heart failure. The important observation herein leads to an explanation for why b-adrenergic receptor blockade may be helpful in patients with congestive heart failure. Our intuition as clinicians should be to give badrenergic receptor agonists for hearts that are not pumping effectively; however, b-blockers clearly improve outcome, and b-agonists may worsen outcome!63 Prophylactic atenolol has been demonstrated to reduce myocardial ischemia following surgery,64 and several other recent publications support b-blocker-induced reduction of death as a consequence of cardiac and noncardiac causes.65,66 Underuse of b-adrenergic receptor antagonists in elderly patients who survive acute myocardial infarction leads to worse outcome.67 Recent articles continue to emphasize the importance of b-blockade following myocardial infarction68 and in congestive heart failure.69 It is my opinion that we can work hard to prevent adverse drug effects in our ICU patients, supporting the work of Cullen et al,70 and that drug classes such as b-blockers are important to use when indicated to CHEST / 115 / 5 / MAY, 1999 SUPPLEMENT

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try to limit worse outcome in certain groups of patients, especially those patients with heart failure. Conclusions Writing an article about variables that might contribute to alterations in outcome in critically ill patients is difficult, and I admit to the limitations inherent in such an essay. It is clear that many other important variables may alter outcome, such as whether a patient has used alcohol, is a cigarette smoker, has certain comorbidities, and the state of the patient’s preexisting health prior to a septic episode or other critical event. The aggressiveness with which therapy is instituted and the length of time that the patient has suffered critical illness may affect outcome. I do not wish to suggest that the five groupings of variables I discussed should replace severity of illness scoring systems or even have the same level of importance. Rather, the purpose of this essay is to share information stemming from my close following of the critical care literature, and to perhaps provide insights to clinicians that may be helpful in explaining to patients and their families why some patients do well and others do not. 1. It is clear that there is interpatient variability based on genetic makeup and premorbid immune status. As the human genomic project advances, it is increasingly clear that single nucleotide polymorphisms and other genetic differences help to define why we as individuals respond differently to different types of critical events. We should use this growing body of knowledge to explain to patients and their families why we cannot account for a particular outcome by our other methods of prediction. 2. Women seem to do better than men, and girls do better than boys with infection. However, other forms of critical illness such as cardiac injury do not provide the same level of survival advantage to female subjects. 3. Lipoproteins may be important “mops” within the circulation for dealing with endotoxemia. Clinicians should be aware that when severe hypocholesterolemia is evident on the hospital admission biochemical profile, serious microbial infection should be suspected. 4. Elderly men and women (. 75 years of age) may have an augmented anti-inflammatory response that may lead to a higher mortality rate. As we design cytokine-modulating therapies, age should be a consideration. 5. All of us should try to limit iatrogenic sources of infection, and in particular, it is my opinion that an increased emphasis on reducing adverse drug reactions and catheter-related infections is requisite. Critical care medicine has come a long way in the 74S

last 20 years. I believe that the quality of care provided in ICUs worldwide has improved, and we are providing compassionate care with augmented monitoring capabilities. However, we still have a “ways to go” regarding the prevention and treatment of serious infections that lead to sepsis and septic shock. References 1 Block AJ. Opinions/hypotheses: a new department in CHEST. Chest 1998; 113:855 2 Drinker P, McKhann CF. The use of a new apparatus for the prolonged administration of artificial respiration. JAMA 1929; 92:1658 –1660 3 Kouwenhoven WB, Jude JR. Closed-chest cardiac massage. JAMA 1960; 173:1064 –1067 4 Lown B, Amarasingham R, Neuman J. New method for terminating cardiac arrhythmias: use of synchronized capacitor discharge. JAMA 1962; 182:548 –555 5 Michie HR, Manogue KR, Spriggs DR, et al. Detection of circulating tumor necrosis factor after endotoxin administration. N Engl J Med 1988; 318:1481–1486 6 Suffredini AF, Fromm RW, Parker MM, et al. The cardiovascular response of normal humans to the administration of endotoxin. N Engl J Med 1989; 321:280 –287 7 Marano MA, Fong Y, Moldawer LL, et al. Serum cachectin/ tumor necrosis factor in critically ill patients with burns correlates with infection and mortality. Surg Gynecol Obstet 1990; 170:32–38 8 Fisher Jr CJ, Agosti JM, Opal SM, et al. Treatment of septic shock with the tumor necrosis factor receptor: Fc fusion protein. N Engl J Med 1996; 334:1697–1702 9 Bernard GR, Wheeler AP, Russell JA, et al. The effects of ibuprofen on the physiology and survival of patients with sepsis. N Engl J Med 1997; 336:912–918 10 Abraham E, Glauser MP, Butler T, et al. p55 tumor necrosis factor receptor fusion protein in the treatment of severe sepsis and septic shock. JAMA 1997; 277:1531–1538 11 Opal SM, Fisher CJ Jr, Dhainaut J-FA, et al. Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. Crit Care Med 1997; 25:1115–1124 12 Quartin AA, Schein RMH, Kett DH, et al. Magnitude and duration of the effect of sepsis on survival. JAMA 1997; 277:1058 –1063 13 Executive Summary of an American College of Chest Physicians, National Institute of Allergy and Infectious Disease, and National Heart, Lung, and Blood Institute Workshop. From bench to bedside: the future of sepsis research. Chest 1997; 111:744 –753 14 Fekade D, Knox K, Husssein K, et al. Prevention of JarischHerxheimer reactions by treatment with antibodies against tumor necrosis factor a N Engl J Med 1996; 335:311–315 15 Moreland LW, Baumgartner SW, Schiff MH, et al. Treatment of rheumatoid arthritis with a recombinant tumor necrosis factor receptor (p75)-Fc fusion protein. N Engl J Med 1997; 337:141–147 16 Zisman DA, Kunkel SL, Strieter RM, et al. MCP-1 protects mice in lethal endotoxemia. J Clin Invest 1997; 99:2832–2836 17 Sevransky JE, Shaked G, Novgrodsky A, et al. Tyrphostin AG 556 improves survival and reduces multiorgan failure in canine Escherichia coli peritonitis. J Clin Invest 1997; 99: 1966 –1973 18 Bo¨hrer H, Qiu F, Zimmermann T, et al. Role of NFkB in the mortality of sepsis. J Clin Invest 1997; 100:972–985 Perioperative Cardiopulmonary Evaluation and Management

19 Beg AA, Baltimore D. An essential role for NF-kB in preventing TNF-a-induced cell death. Science 1996; 274: 782–784 20 Barnes PJ, Karin M. Nuclear factor-kB—a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 1997; 336:1066 –1071 21 Adams DH, Lloyd AR. Chemokines: leucocyte recruitment and activation cytokines. Lancet 1997; 349:490 – 495 22 Luster AD. Chemokines— chemotactic cytokines that mediate inflammation. N Engl J Med 1998; 338:436 – 445 23 Chen Q, Kirsch GE, Zhang D, et al. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature 1998; 392:293–296 24 Westendorp RGJ, Langermans JAM, Huizinga TWJ, et al. Genetic influence on cytokine production and fatal meningococcal disease. Lancet 1997; 349:170 –173 25 van Dissel JT, van Langevelde P, Westendorp RGJ, et al. Anti-inflammatory cytokine profile and mortality in febrile patients. Lancet 1998; 351:950 –953 26 Stu¨ber F, Petersen M, Bokelmann F, et al. A genomic polymorphism within the tumor necrosis factor locus influences plasma tumor necrosis factor-a concentrations and outcome of patients with severe sepsis. Crit Care Med 1996; 24:381–384 27 Tan S, Hall IP, Dewar J, et al. Association between b2adrenoceptor polymorphism and susceptibility to bronchodilator desensitisation in moderately severe stable asthmatics. Lancet 1997; 350:995–999 28 Nygård O, Nordrehaug JE, Refsum H, et al. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 1997; 337:230 –236 29 Bennett-Guerrero E, Ayuso L, Hamilton-Davies C, et al. Relationship of preoperative antiendotoxin core antibodies and adverse outcomes following cardiac surgery. JAMA 1997; 277:646 – 650 30 Goldie AS, Fearon KCH, Ross JA, et al. Natural cytokine antagonists and endogenous antiendotoxin core antibodies in sepsis syndrome. JAMA 1995; 274:172–177 31 Bone RC. Immunologic dissonance: a continuing evolution in our understanding of the systemic inflammatory response syndrome (SIDS) and the multiple organ dysfunction syndrome (MODS). Ann Intern Med 1996; 125:680 – 687 32 Pellegrini JD, Puyana JC, Lapchak PH, et al. A membrane TNF-a/TNFR ratio correlates to MODS score and mortality. Shock 1996; 6:389 –396 33 Donnelly SC, Strieter RM, Reid PT, et al. The association between mortality rates and decreased concentrations of interleukin-10 and interleukin-1 receptor antagonist in the lung fluids of patients with the adult respiratory distress syndrome. Ann Intern Med 1996; 125:191–196 34 Zelllweger R, Wichmann MW, Ayala A, et al. Females in proestrus state maintain splenic immune functions and tolerate sepsis better than males. Crit Care Med 1997; 25:106 –110 35 Ben-Jonathan N, Mershon JL, Allen DL, et al. Extrapituitary prolactin: distribution, regulation, functions, and clinical aspects. Endocr Rev 1997; 17:639 – 669 36 Houston-Bolze MS, Downing MT, Sayed AM, et al. Gender differences in the responses of serum insulin-like growth factor-1 and transthyretin (prealbumin) to trauma. Crit Care Med 1996; 24:1982–1987 37 Angele MK, Ayala A, Monflils BA, et al. Testosterone and/or low estradiol: normally required but harmful immunologically for males after trauma-hemorrhage. J Trauma 1998; 44: 78 – 84 38 Van Cauter E, Leproult R, Kupfer DJ. Effects of gender and age on the levels and circadian rhythmicity of plasma cortisol. J Clin Endocrinol Metab 1996; 81:2468 –2473

39 Malacrida R, Genoni M, Maggioni AP, et al. A comparison of the early outcome of acute myocardial infarction in women and men. N Engl J Med 1998; 338:8 –14 40 Fitzpatrick LA. Coronary artery disease in women—an equal opportunity killer [editorial]. J Clin Endocrinol Metab 1998; 83:719 –720 41 Gui D, Spada PL, De Gaetano A, et al. Hypocholesterolemia and risk of death in the critically ill surgical patient. Intensive Care Med 1996; 22:790 –794 42 Weverling-Rijnsburger AWE, Blauw GJ, Lagaay AM, et al. Total cholesterol and risk of mortality in the oldest old. Lancet 1997; 350:1119 –1123 43 Gordon BR, Parker TS, Levine DM, et al. Low lipid concentrations in critical illness: implications for preventing and treating endotoxemia. Crit Care Med 1996; 24:584 –589 44 DiPiro JT, Cue JI, Richards CS, et al. Pharmacokinetics of reconstituted human high-density lipoprotein in pigs after hemorrhagic shock with resuscitation. Crit Care Med 1996; 24:440 – 444 45 Netea MG, Demacker PNM, Kullberg BJ, et al. Low-density lipoprotein receptor-deficient mice are protected against lethal endotoxemia and severe Gram-negative infections. J Clin Invest 1996; 97:1366 –1372 46 Muldoon MF, Flory JD, Marsland A, et al. Effects of lovastatin on the immune system. Am J Cardiol 1997; 80: 1391–1394 47 Sessler CN, Windsor AC, Schwartz M, et al. Circulating ICAM-1 is increased in septic shock. Am J Respir Crit Care Med 1995; 151:1420 –1427 48 Boldt J, Muller M, Heesen M, et al. Does age influence circulating adhesion molecules in the critically ill? Crit Care Med 1997; 25:95–100 49 Ryan CM, Schoenfeld DA, Thorpe WP, et al. Objective estimates of the probability of death from burn injuries. N Engl J Med 1998; 338:363–366 50 Kober L, Torp-Pedersen C, Ottesen M, et al. Influence of age on the prognostic importance of left ventricular dysfunction and congestive heart failure on long-term survival after acute myocardial infarction. Am J Cardiol 1996; 78:156 –162 51 Shapira OM, Kelleher RM, Zelingher J, et al. Prognosis and quality of life after valve surgery in patients older than 75 years. Chest 1997; 112:885– 894 52 Battistella FD, Din AM, Perez L. Trauma patients 75 years and older: long-term follow-up results justify aggressive management. J Trauma 1998; 44:618 – 624 53 Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 1998; 279:1200 –1205 54 Bates DW, Spell N, Cullen DJ, et al. The costs of adverse drug events in hospitalized patients. JAMA 1997; 277:307– 311 55 Classen DC, Pestotnik SL, Evans RS, et al. Adverse drug events in hospitalized patients: excess length of stay, extra costs, and attributable mortality. JAMA 1997; 277:301–306 56 Vincent J-L, Bihari DJ, Suter PM, et al. The prevalence of nosocomial infection in intensive care units in Europe: results of the European Prevalence of Infection in Intensive Care (EPIC) Study. JAMA 1995; 274:639 – 644 57 Maki DG, Stolz SM, Wheeler S, et al. Prevention of central venous catheter-related bloodstream infection by use of an antiseptic-impregnated catheter: a randomized, controlled trial. Ann Intern Med 1997; 127:257–266 58 Mimoz O, Pieroni L, Lawrence C, et al. Prospective, randomized trial of two antiseptic solutions for prevention of central venous or arterial catheter colonization and infection in intensive care unit patients. Crit Care Med 1996; 24:1818–1823 59 Cook D, Randolph A, Kernerman P, et al. Central venous CHEST / 115 / 5 / MAY, 1999 SUPPLEMENT

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catheter replacement strategies: a systematic review of the literature. Crit Care Med 1997; 25:1417–1424 Insel PA. Adrenergic receptors— evolving concepts and clinical implications. N Engl J Med 1996; 334:580 –585 Huang M-H, Griend DS, Sunday ME, et al. An intrinsic adrenergic system in mammalian heart. J Clin Invest 1996; 98:1298 –1303 Gauthier C, Tavernier G, Charpentier F, et al. Functional b3-adrenoceptor in the human heart. J Clin Invest 1996; 98:556 –562 Niebauer J, Coats AJS. Treating chronic heart failure: time to take stock. Lancet 1997; 349:966 –967 Wallace A, Layug B, Tateo I, et al. Prophylactic atenolol reduces postoperative myocardial ischemia. Anesthesiology 1998; 88:7–17 Australia/New Zealand Heart Failure Research Collaborative Group. Randomised, placebo controlled trial of carvedilol in

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patients with congestive heart failure due to ischaemic heart disease. Lancet 1997; 349:375–380 Mangano DT, Layug EL, et al. Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery. N Engl J Med 1996; 335:1713–1720 Soumerai SB, McLaughlin TJ, Spiegelman D, et al. Adverse outcomes of underuse of b-blockers in elderly survivors of acute myocardial infarction. JAMA 1997; 277:115–121 Barron HV, Viskin S, Lundstrom RJ, et al. of b-Blocker dosages and mortality after myocardial infarction. Arch Intern Med 1998; 158:449 – 453 Constant J. A review of why and how we may use b-blockers in congestive heart failure. Chest 1998; 113:800 – 808 Cullen DJ, Sweitzer BJ, Bates DW, et al. Preventable adverse drug events in hospitalized patients: a comparative study of intensive care and general care units. Crit Care Med 1997; 25:1289 –1297

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