Myocardial dysfunction in septic shock: Part I. Clinical manifestation of cardiovascular dysfunction.

SEPSIS AND SEPTIC SHOCK are the most common causes of intensive care unit (ICU) mortality.1,2 The National Hospital Discharge Survey from the Center for Disease Control’s National Center for Health Statistics found septicemia to be the 13th leading cause of death in the United States while recording 2.5 million septicemia-related hospital discharges in the United States from 1979 to 1987.3 In 1997, the most recent year for which data are available, approximately 350,000 patients were admitted to U.S. acute care hospitals with a primary diagnosis of septicemia (approximately 1.5% of total admissions).4 Septicemia was listed as a discharge diagnosis in 680,000 hospital admissions (approximately 2.5% of the total admissions).4 In 4 decades, the age-adjusted mortality of sepsis climbed from 0.5 to 7 per 100,000 episodes.5 Estimates of the annual incidence of gram-negative bacteremia in American ICUs in the 1980s varied between 300,000 and 500,000 cases per year.2,6,7 With a case-fatality rate of 33% to 40% for gramnegative bacteremia and 90% for gram-negative shock,1,2 associated annual mortality was estimated to be 18,000 to 100,000 per year.2,7 Although some of these latter patients eventually succumbed to multisystem organ failure, most died of the refractory hypotension and cardiovascular collapse of septic shock. From 1979 to 1987, the cost for caring for such patients accounted for $5 to $10 billion in health care expenditures annually.3 There is little reason to believe that the incidence and annual mortality are significantly different in any other developed nation. Similarly, the associated health care expenditures would be quite substantial. Given the documented increase in incidence of gram-negative bacteremia since the 1950s and the fact that the above-mentioned estimates do not include substantial and increasing numbers of episodes of septicemia associated with gram-positive organisms and fungi, the true current incidence, associated mortality, and health care costs of sepsis and septic shock are probably considerably higher. Sepsis is the systemic response to infection and is initiated through the effects of one or more components of the invading microorganism. These components may include structural elements (eg, endotoxin from gram-negative bacteria) or secreted exotoxins (eg, toxic shock toxins from toxigenic Staphylococcus aureus serotypes or pyrogenic streptococcal exotoxin A from invasive streptococcus A serotypes). These substances are thought to trigger the local and systemic release of endogenous inflammatory mediators, notably cytokines such as tumor necrosis factorand interleukin-1 . Further amplification of the inflammatory response occurs through the stimulation of polymorphonuclear leukocytes, tissue macrophages/monocytes, and endothelial cells that release a cascade of other biologically active mediators, including platelet-activating factor and nitric oxide. This activation and amplification cascade elaborates counterregulatory anti-inflammatory cytokines, such as transforming growth factor , as well as soluble cytokine inhibitors, such as interleukin-1 receptor antagonist. The net effect of these proinflammatory and anti-inflammatory stimuli is the organ pathophysiology associated with the systemic inflammatory response syndrome and sepsis as defined in a Society of Critical Care Medicine/American College of Chest Physicians consensus conference (Table 1).8 Eventually, as a consequence of failure of homeostatic mechanisms, multiple organ dysfunction syndrome may ensue. If the inflammatory stimulus is particularly intense, effects on the cardiovascular system as manifested by septic shock may dominate the clinical presentation. Sepsis-associated myocardial depression is one manifestation of cardiovascular dysfunction in septic shock. This article reviews the clinical manifestations of cardiac dysfunction in sepsis by exploring historic concepts in reference to current theories. Specific abnormalities of left and right ventricular dysfunction in clinical sepsis are reviewed. Prognostication in sepsis and septic shock based on cardiovascular abnormalities is examined. Finally, potential pathophysiologic mechanisms of septic myocardial depression ranging from whole-organ physiology to molecular biology are examined. In particular, the roles of cytokines and nitric oxide in septic myocardial dysfunction are reviewed.