Septic Shock in Humans

Transcription

1 NIH CONFERENCE Septic Shock in Humans Advances in the Understanding of Pathogenesis, Cardiovascular Dysfunction, and Therapy Moderator: Joseph E. Parrillo, MD; Discussants: Margaret M. Parker, MD; Charles Natanson, MD; Anthony F. Suflfredini, MD; Robert L. Danner, MD; Robert E. Cunnion, MD; and Frederick P. Ognibene, MD Septic shock is the commonest cause of death in intensive care units. Although sepsis usually produces a low systemic vascular resistance and elevated cardiac output, strong evidence (decreased ejection fraction and reduced response to fluid administration) suggests that the ventricular myocardium is depressed and the ventricle dilated. In survivors, these abnormalities are reversible. Failure to develop ventricular dilatation in nonsurvivors suggests that dilatation is a compensatory mechanism needed to maintain adequate cardiac output. With a canine model of septic shock that is very similar to human sepsis, myocardial depression was confirmed using load-independent measures of ventricular performance. Endotoxin administration to humans simulates the qualitative, cardiovascular abnormalities of sepsis. The pathogenesis of septic shock is extraordinarily complex. Diverse microorganisms can generate toxins, stimulating release of potent mediators that act on vasculature and myocardium. A circulating myocardial depressant substance has been closely associated with the myocardial depression of human septic shock. Therapy has emphasized early use of antibiotics, critical care monitoring, aggressive volume resuscitation, and, if shock continues, use of inotropic agents and vasopressors. Pharmacologic or immunologic antagonism of endotoxin or other mediators may prove to enhance survival in this highly lethal syndrome. Annals of Internal Medicine. 1990;113: An edited summary of a Combined Clinical StaflF Conference held 25 January 1989 at the Clinical Center, National Institutes of Health, Bethesda, Maryland. The conference was sponsored by the Clinical Center, National Institutes of Health, U.S. Department of Health and Human Services. Authors who wish to cite a section of the conference and specifically indicate its author can use this example for the form of reference: Parker MM. Cardiac dysfunction in human septic shock, pp In: Parrillo JE, moderator. Septic shock in humans: advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med. 1990;113: Joseph E. Parrillo, MD (James B. Herrick Professor of Medicine; Director, Cardiology Section; Director, Critical Care Medicine Section; Rush-Presbyterian-St Luke's Medical Center, Chicago, Illinois; former Chief, Critical Care Medicine Department, Clinical Center, National Institutes of Health): Shock resulting from a systemic response to serious infection, a syndrome usually termed "septic shock," has been increasing in incidence since the 1930s (1), and all estimates suggest that this rise will continue. Septic shock is presently the commonest cause of death in intensive care units in the United States (2). The reasons underlying this rapid increase and high incidence are many: increased use of cytotoxic and immunosuppressive drug therapies; increasing frequency of invasive devices, such as intravascular catheters, in clinical medicine; increased longevity of patients prone to develop sepsis; and an increase in infections caused by antibiotic-resistant organisms (3-5). Although the precise incidence of septic shock is not known, estimates from 15 years ago have suggested that gram-negative sepsis alone has an incidence of to cases per year (6, 7). Presently, the incidence of and death rates from sepsis and septic shock due to all microorganisms (gram-negative bacteria, gram-positive bacteria, and fungi) are certainly substantially higher than these estimates. A reasonable, current estimate of annual incidence would be cases of sepsis, bouts of septic shock, and deaths from this disease (3, 5). A number of problems have hampered the study of human septic shock (3, 5). First, the serious nature of the disease necessitates immediate therapy, rendering it very difficult for an investigator to separate disease process from therapy. Second, animal models have not been designed to simulate the human disease. In addition, most patients with septic shock have an underlying disease that is difficult to separate from the septic process, and informed consent is difficult to obtain from these patients because they are commonly critically ill. Thus, much of our data on this disease have been obtained from either retrospective descriptions of human sepsis or animal models with little relevance to the human disease. Cardiovascular Pattern during Septic Shock Septic shock is a distributive form of shock, and it differs from other categories of shock. Cardiogenic, extracardiac obstructive, and oligemic shock produce the 1 August 1990 Annals of Internal Medicine Volume 113 Number 3 227

2 Table 1. Classification of Forms of Shock Cardiogenic shock Myopathic shock (reduced systolic function) Acute myocardial infarction Dilated cardiomyopathy Myocardial depression in septic shock Mechanical shock Mitral regurgitation Ventricular septal defect Ventricular aneurysm Left ventricular outflow obstruction shock (aortic stenosis, hypotrophic cardiomyopathy) Arrhythmic shock Extracardiac obstructive shock Pericardial tamponade Constrictive pericarditis Pulmonary embolism (massive) Severe pulmonary hypertension (primary or Eisenmenger) Coarctation of the aorta Oligemic shock Hemorrhage Fluid depletion Distributive shock Septic shock Toxic products (for example, overdose) Anaphylaxis Neurogenic shock Endocrinologic shock acute phase of the shock syndrome by decreasing cardiac output. Septic shock usually results in a severe decrease in systemic vascular resistance and generalized blood flow maldistribution. In more than 90% of patients with septic shock who have been aggressively volume-loaded to assure the absence of hypovolemia, cardiac output is normal or initially elevated (8). Thus, hypotension results from reduced vascular resistance associated with a normal or elevated cardiac output. Septic shock is considered the prototypic example of distributive shock (Table 1). During the past several years, abnormalities of ventricular performance have also been shown during human septic shock. Cardiac performance can be described and measured using- several different methods. Although cardiac output and stroke volume are usually well maintained during the initial stages of human septic shock, the mean arterial pressure is reduced and the stroke work (a measure of both the volume and pressure work of the ventricular muscle) is commonly decreased. However, these cardiac variables are very sensitive to small changes in ventricular preload and afterload, and better measures of intrinsic ventricular performance are needed to evaluate myocardial function in human septic shock. Using radionuclide, gated bloodpool scanning and simultaneous thermodilution hemodynamics, ventricular performance and ventricular volumes are studied serially after onset of human septic shock. The radionuclide-determined left ventricular ejection fraction proved to be a very useful measure of ventricular function during this disease. The ejection fraction is relatively unchanged by acute changes in preload and afterload (9). In an initial (10) and in subsequent (11) follow-up studies, the characteristic pattern of human septic shock included an initial decrease in ejection fraction occurring within 24 hours of septic shock onset (Figure 1). Associated with this disease was an increase in both end-diastolic and end-systolic volume indices. This pattern of decreased ejection fraction and ventricular dilatation was found to be most characteristic of septic shock survivors during the initial few days of the disease (compensated myocardial depression). One of the most interesting characteristics of this pattern was its reversibility. In survivors, the ventricular function and size returned to normal from 7 to 10 days after septic shock onset (Figure 1, bottom). Pathogenesis of Human Septic Shock The pathogenetic mechanisms underlying the cardiovascular dysfunction of septic shock are very complex. Figure 2 provides a schematic diagram of the probable steps leading to the cardiovascular abnormalities, morbidity, and high mortality of this disease (3-5). The sequence begins with a nidus of infection consisting of an abscess, peritonitis, pneumonitis, cellulitis, or another focus. The microorganisms then invade the bloodstream, resulting in positive blood cultures, or the microorganisms may proliferate at an infected site and release large amounts of various mediators into the bloodstream. These mediators may consist of microorganism-elaborated exotoxins, microorganism structural components endotoxin or teichoic acid antigens, or host-manufactured products such as cytokines (tumor necrosis factor, interleukins) or complement activation. Although some of these mediators are undoubtedly more important than others, there are probably 20 or 30 molecular substances that can profoundly affect the peripheral and pulmonary vasculature, and some substances (myocardial depressant substance, detailed below) appear to directly affect the myocardium itself. The vascular and myocardial abnormalities combine to result in generalized cardiovascular insufficiency. Of 100 patients who are admitted to our intensive care unit with septic shock, aggressive therapy reverses the process in approximately 50%, and these patients survive (3-5, 8). Unfortunately, the conditions of the other 50% do not reverse, and these patients die of the mechanisms shown in Figure 2. Nonsurvivors develop either Figure 1. Schematic diagram of the cardiac performance changes during the acute and recovery phases of septic shock in humans (reprinted from references 3 and 10 with permission) August 1990 Annals of Internal Medicine Volume 113 Number 3

3 Figure 2. Sequence of pathogenetic steps leading from a nidus of infection to cardiovascular dysfunction and shock during human sepsis. SVR = systemic vascular resistance; CO = cardiac output; MOSF = multiorgan system failure. unresponsive hypotension or progressive, multiple organ system dysfunction. Unresponsive hypotension is usually due to very low systemic vascular resistance that cannot be corrected by any therapy; only a small proportion (less than 10%) of unresponsive hypotension is due to low cardiac output (decompensated myocardial depression). Multiple organ system dysfunction commonly affects the kidneys, liver, central nervous system, lungs, and heart. Ultimately, this syndrome leads to death from failure of one or several of these organ systems (3-5). Cardiac Dysfunction in Human Septic Shock Margaret M. Parker, MD (Senior Investigator, Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland): The commonest effect of septic shock on the cardiovascular system is a hemodynamic profile characterized by an elevated cardiac index and decreased systemic vascular resistance (8, 12, 13). Early studies (14-16) in humans with septic shock reported a low cardiac index; it is likely that many of these patients had inadequate ventricular preload, as central venous pressure was used at that time to evaluate volume status. It is now recognized that in many patients, central venous pressure does not correlate with pulmonary artery wedge pressure or left atrial pressure, these being more accurate pressure measurements of left ventricular preload. A low cardiac index is, in fact, uncommon even in very late stages of septic shock (8). We did serial studies (8) of hemodynamic variables in an attempt to identify factors of prognostic value. Figure 3 shows that both survivors and nonsurvivors show initially elevated cardiac indices, with no statistically significant difference between them. The major difference between survivors and nonsurvivors is that within 24 hours after onset of hypotension, the mean cardiac index of survivors falls into the normal range where it remains. In contrast, nonsurvivors have persistently elevated cardiac indices at 24 hours and throughout their courses. Figure 3. Serial, mean cardiac index is plotted against time for survivors and nonsurvivors of septic shock. The horizontal dotted line represents the mean for a group of normal controls. The cardiac index returns to normal by 24 hours in survivors (open circles) but remains persistently elevated in nonsurvivors (closed circles) (reprinted from reference 8 with permission). 1 August 1990 Annals of Internal Medicine Volume 113 Number 3 229

4 Table 2. Prognostic Hemodynamic Variables in Human Septic Shock * Time Variable Cutoff Value P Value Initial study At 24 hours Interval between initial and 24-hour studies Heart rate Heart rate Systemic vascular resistance index Heart rate Cardiac index 106 beats/min 95 beats/min 1529 dyn/s cm" 5 m L/min m 2 < < <0.01 < <0.05 * Adapted from reference 8. Early prognostic factors would be useful in predicting outcome and, possibly, in guiding therapy. In a group of 48 prospectively studied patients with septic shock, we evaluated all standard hemodynamic variables for their ability to predict survival or nonsurvival at initial presentation, 24 hours later, and for the interval between the initial and 24-hour studies. The statistically significant predictors of outcome are shown in Table 2 (8). Heart rate is a statistically significant predictor of outcome at all three points. A systemic vascular resistance in the normal range at 24 hours or a cardiac index that has decreased (toward the normal range) over the first 24 hours is predictive of survival. These findings suggest that nonsurvivors have a persistence of the hyperdynamic hemodynamic profile, whereas survivors' he- Figure 4. Serial, mean left ventricular ejection fraction is plotted along the left axis and end-diastolic volume index along the right axis for 33 survivors {open symbols) and 21 nonsurvivors {closed symbols) of septic shock. Survivors (but not nonsurvivors) have an initially depressed ejection fraction and dilated ventricle. Survivors have ejection fractions and end-diastolic volume indices that return toward the normal range with serial studies (reprinted from reference 11 with permission). modynamics begin to return toward normal within 24 hours. Figure 4 shows the serial, mean left ventricular ejection fraction and end-diastolic volume indices for 33 survivors and 21 nonsurvivors of septic shock. The end-diastolic volume index is a more accurate measure of ventricular preload than are pressure measurements. For this study (11), a control group of critically ill, nonseptic patients was used. The survivors have an initially depressed, mean left ventricular ejection fraction of 0.40, compared with the control patients' mean ejection fraction of The depressed ejection fraction is associated with a dilated left ventricle, the enddiastolic volume index being 122 ml/m 2, compared with a control value of 90 ml/m 2. These left ventricular abnormalities persist for the first 2 to 5 days and then return toward normal within 1 to 2 weeks after onset of septic shock. The nonsurvivors, on the other hand, have left ventricular ejection fractions and end-diastolic volume indices that are not significantly different from those of the control patients and that do not change significantly over the course of septic shock. In our patient population, the reversible abnormalities of left ventricular function are usually global; other investigators (17) have reported reversible segmental abnormalities of left ventricular function. We investigated the relation between ejection fraction and end-diastolic volume index. Survivors have a strong negative correlation of these two variables, with r = and P < In nonsurvivors, on the other hand, there is no statistically significant correlation of ejection fraction with end-diastolic volume index (11). Thus, in nonsurvivors, a decrease in ejection fraction is not consistently associated with left ventricular dilatation. The failure of nonsurvivors' left ventricles to dilate may lead to an inability to maintain stroke volume and, hence, cardiac output; this sequence may contribute to the deaths of nonsurvivors. In a different group of patients with septic shock, we compared left and right ventricular function in survivors and nonsurvivors (18). Figure 5 shows the initial and final left and right ventricular ejection fractions and end-diastolic volume indices for the two groups. In the survivors, both right and left ventricular ejection fractions are initially low and return toward normal at recovery, with statistically significant increases in each. Both ventricles are initially dilated but, on recovery, statistically significant decreases in the volume of both ventricles occur. Thus, myocardial depression of human septic shock is a biventricular phenomenon. In the nonsurvivors, both ventricles have normal ejection frac August 1990 Annals of Internal Medicine Volume 113 Number 3

5 tions that do not change significantly from initial to final measurements. The nonsurvivors initially have slightly increased right and left ventricular end-diastolic volume indices that tend to decrease, but these declines fail to achieve statistical significance in the final studies. A Canine Model of Septic Shock Charles Natanson, MD (Senior Investigator, Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland): Previous animal models of septic shock were modified to produce a model that more closely simulates the cardiovascular changes found in human septic shock (19). In the resultant model, we surgically implanted a fibrin clot into the peritoneum of dogs to act as a nidus of infection (20, 21). The dogs were studied while they were awake for 2 to 4 weeks, the period within which cardiovascular changes of human septic shock are known to occur (10). We used serial heart scans and simultaneous thermodilution cardiac outputs to study the dogs both before and after aggressive volume resuscitation. In this model, viable bacteria implanted into an intraperitoneal clot produced a cardiovascular profile similar to that of human septic shock (10, 19). Hypotension occurred between 12 and 24 hours later. The dogs developed substantial decreases in left ventricular ejection fraction 2 to 4 days after sepsis onset; with adequate volume, the dogs manifested left ventricular dilation, high cardiac output, and low systemic vascular resistance. In surviving dogs, these hemodynamic changes returned to normal in 7 to 10 days. This time course and cardiovascular pattern are remarkably similar to those of human septic shock (10). Figure 5. Top left. Serial changes in left and right ventricular ejection fraction and end-diastolic volume index during septic shock in humans. Mean initial and final left ventricular ejection fraction for survivors (closed circles, P < 0.001) and nonsurvivors (open circles, P = 0.03) of septic shock. Top right. Mean initial and final left ventricular end-diastolic volume index for survivors (closed circles, P < 0.02) and nonsurvivors (open circles, P is not significant) of septic shock. Bottom left. Mean initial and final right ventricular ejection fraction for survivors (closed circles, P < 0.001) and nonsurvivors (open circles, P = 0.001) of septic shock. Bottom right. Mean initial and final right ventricular end-diastolic volume index for survivors (closed circles, P < 0.05) and nonsurvivors (open circles, P is not significant) of septic shock. 1 August 1990 Annals of Internal Medicine Volume 113 Number 3 231

6 and lethality (23). Further, compared with nonviable bacteria, viable bacteria produced greater lethality and myocardial depression. However, all bacteria (whether gram-positive or gram-negative, viable or nonviable) produced the same general pattern of cardiovascular changes (23). The fact that structurally and functionally distinct bacteria and bacterial products induce the same pattern of cardiovascular injury strongly supports the presence of a final common pathway of cardiovascular injury associated with septic shock (24, 25). The Mediators of the Common Pathway of Injury Figure 6. Serial left ventricular ejection fraction plotted against time (days) in dogs receiving increasing doses of bacteria (Escherichia coli [E. coli]) and in the control group. Mean left ventricular ejection fraction is represented by diamonds in the control group, hexagons in the 7 x 10 9 survivors, triangles in the 14 x 10 9 survivors, squares in the 30 x 10 9 survivors, and circles in the 30 x 10 9 nonsurvivors. Dosages represent number of colony-forming units of viable E. coli implanted per kilogram body weight. The common origin represents the mean left ventricular ejection fraction for all (control and infected) dogs before surgery. On day 2 and 3, note the progressive corresponding decrease in left ventricular ejection fraction with increasing dosages of bacteria (reprinted from reference 22 with permission). The design of this canine model allowed us to do controlled and detailed studies of the cardiovascular system during septic shock. Three measures of left ventricular function, both load-dependent (ejection fraction and Frank-Starling ventricular function curves) and load-independent (end-systolic volume and pressure plots), all showed similar decreases in left ventricular performance, documenting a sepsis-induced decrease in contractility. Despite this decreased left ventricular function with adequate volume administration, stroke volume and cardiac output increased or remained unchanged. At 30 to 40 hours after clot implantation, left ventricular dilatation occurred without an increase in intraventricular end-diastolic pressure, a change indicative of an increase in ventricular compliance (18, 22). We suggest that this left ventricular dilation helps to maintain stroke volume and cardiac output via the Frank-Starling mechanism and that this cardiovascular change is the appropriate compensatory left ventricular response (dilation) to a sepsis-induced depression of left ventricular systolic performance. The time course and pattern of these sepsis-induced systolic and diastolic changes are remarkably similar in humans and dogs, suggesting that this cardiovascular pattern is the mammalian response to infection (10, 19). In dogs challenged with increasing doses of bacteria, we found corresponding progressive decreases in left ventricular ejection fraction (Figure 6) and progressive downward shifts on both Frank-Starling and end-systolic volume and pressure left ventricular function plots (22). Some types of bacteria (despite equivalent doses) were more potent inducers of cardiovascular changes Endotoxin, a lipopolysaccharide (LPS) in the membrane of gram-negative bacteria, has been proposed to be the initiating mediator of all types of septic shock (23-25). To test this hypothesis, we implanted grampositive bacteria (a microorganism without endotoxin) into dogs and found that it produced all of the same cardiovascular changes as gram-negative bacteria. Blood endotoxin levels were negative, excluding the possibility that these dogs had "leaky" bowel walls that were releasing endotoxin. These studies (23-25) indicated that endotoxin is not the universal mediator of septic shock, although endotoxin was capable of producing the cardiovascular pattern typical of sepsis (26). Thus, endotoxin is sufficient but not necessary to produce septic shock; it is probably one of several important bacterial products that can produce the disease (Figure 3). All the mediators listed in Figure 2 are suspected of producing a common pathway of injury in septic shock (24-25). Recent evidence (27) suggests that tumor necrosis factor, a cytokine released from leukocytes, is a major endogenous toxin in the pathogenesis of septic shock. To study its effects, we infused tumor necrosis factor intravenously in dogs and found that it induced all of the progressive decreases in cardiovascular function produced by viable bacteria within 7 to 10 days (Figure 7) (26). In a similar study (28), we infused dogs with interleukin-1, another cytokine released from leukocytes. In contrast to our tumor necrosis factor findings, high doses of interleukin-1 produced brief hypotension and none of the other sepsis-associated cardiovascular changes. Thus, tumor necrosis factor (unlike interleukin-1) produced the same cardiovascular changes found in human septic shock. Therapy in Canine Septic Shock Using this canine model, we evaluated two conventional therapies: cardiovascular support and antibiotic treatment (29). Cardiovascular support consisted of 3 days of intravascular-monitoring-directed therapy with fluids and dopamine, with the goal of maintaining a normal mean arterial pressure. The intervention closely simulated the conventional intensive care unit fluid and pressor therapy used in human septic shock. Antibiotic therapy consisted of a 5-day course of cefoxitin and gentamicin therapy. Dogs receiving both therapies had a 43% survival rate, and those receiving neither therapy had a 0% survival rate. Dogs receiving cardiovascular August 1990 Annals of Internal Medicine Volume 113 Number 3

7 support alone or antibiotics alone had a 13% survival rate. Thus, antibiotic therapy and cardiovascular support were equally important to survival and were only effective when used together, resulting in a synergistic improvement in outcome. In another study (30), we examined the use of plasmapheresis as a method to treat septic shock. First, dogs were given lethal doses of bacteria and were then treated with fluids and antibiotics. Three groups were studied: a control group that had no further therapy; a second control group that had plasmapheresis at 5 and 24 hours, with the dogs own infected plasma returned; and a group of dogs whose infected plasma was removed and replaced with fresh, frozen plasma at 5 and 24 hours. Unexpectedly, the two control groups had significantly higher survival rates and better blood pressure values than had the true plasma exchange group. Further, the left ventricular ejection fraction values were unchanged in dogs that had infected plasma removed. Thus, these data suggest that removal of all circulating mediators with plasmapheresis has no beneficial effects and may have some harmful consequences when used to treat septic shock. received a volume infusion to simulate the clinical management of sepsis and to evaluate ventricular performance in response to increased preload. The core temperatures of these volunteers rose and peaked within 3 to 4 hours after endotoxin administration. At 3 hours, their cardiac indices and heart rates rose and systemic vascular resistance fell, compared with control values (44). Left ventricular ejection fraction, an index of systolic myocardial performance, fell below baseline and below that of similarly treated controls between 5 and 6 hours after endotoxin administration (Figure 8). Left ventricular end-diastolic and endsystolic volume indices increased. "We also described ventricular performance using the load-independent relation of peak systolic pressure to end-systolic volume Endotoxin Administration to Normal Humans Anthony F. Suffredini, MD (Senior Investigator, Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland): During the past century, bacterial products, including endotoxin, have been administered to humans in clinical or research settings. Various clinical responses, including the pathogenesis and metabolic effects of fever, determination of acute phase reactants, regulation of stress hormone axes, the pathophysiology of hypertension, assessment of bone marrow reserves, leukocyte kinetics, and antitumor effects (31-53), have been evaluated. Dosage sensitivity and end-organ responsiveness to the effects of endotoxin may differ substantially among animal species, providing a strong impetus to define relevant clinical responses to endotoxin in humans (39-41). Endotoxin administration to humans activates several arms of the acute-phase response and can qualitatively reproduce many features of an acute infection, including induction of secondary endogenous mediators (including cytokines, vasoactive amines, and arachidonate metabolites), activation of effector cells (neutrophils and monocyte-macrophages), and metabolic and hemodynamic changes (42). Humans are exquisitely sensitive to the effects of endotoxin. The usual response to intravenous endotoxin is a 45- to 60-minute quiescent period, followed by fever and onset of constitutional symptoms (arthralgias, myalgias, headache, and nausea) that are apparent within 2 or 3 hours and subside within 5 to 8 hours. Limited information (43) is available defining the effect of endotoxin on the human cardiovascular and pulmonary systems, although the relation probably has key clinical importance. We evaluated cardiovascular response to endotoxin administration in normal humans by monitoring it with radial and pulmonary artery catheters and nuclear heart scans (44). After evaluating the initial effects of endotoxin for 3 hours, each volunteer Figure 7. Serial mean ± SE changes in ejection fraction (top), end-diastolic volume index (middle), and end-systolic volume index (bottom) in dogs challenged intravenously with tumor necrosis factor. The solid lines connect mean hemodynamic values in serial dogs, and the dotted arrows indicate the response to volume for each group of dogs (adapted from reference 26 with permission). Circles represent volume infusion before (open circles) and after (closed circles) infusion. 1 August 1990 Annals of Internal Medicine Volume 113 Number 3 233

8 Figure 8. Percentage change (mean ± SE) from baseline in left ventricular ejection fraction (LVEF) (top) and left ventricular end-diastolic volume index (EDVI) (bottom) over a 6-hour period. Volume loading is depicted by horizontal arrows (initiated at 3 hours and completed by 5 hours). Left ventricular ejection fraction rose significantly at 3 hours and fell significantly at 5 hours in the endotoxin group (open circles) compared with the control group (closed circles). Left ventricular end-diastolic volume index rose at 5 hours to a value that was slightly but not significantly higher than that in the control group (reprinted from reference 44 with permission). index, comparing changes from baseline to maximum fluid-loading between subjects who received endotoxin and control groups. The change in this ratio was abnormal in subjects who received endotoxin (Figure 9, Panel D). Left ventricular function was further evaluated by measuring the stroke volume and stroke work indices normalized to the end-diastolic volume (Figure 9, Panels B and C). Systolic function was found to be abnormal during endotoxemia but not because of differences in preload or afterload. Further, the left ventricular pressure to volume ratio was reduced, suggesting that ventricular compliance may have increased after endotoxin administration (Figure 9, Panel A). Follow-up studies using echocardiograms at 24 and 48 hours after endotoxin administration showed no long-term abnormalities. After endotoxin administration, tumor-necrosis-factor functional activity rose and fell (52). These changes preceded alterations in cardiac systolic and diastolic function that occurred from 5 to 6 hours after endotoxin administration, suggesting either a delayed effect of tumor-necrosis-factor activity on cardiac function or generation of other cardiodepressant mediators during endotoxemia (44) August 1990 Annals of Internal Medicine Volume 113 Number 3 Thus, the cardiovascular changes following endotoxin administration to normal humans were qualitatively similar to those seen in clinical shock: a hyperdynamic cardiovascular state with a depressed and dilated left ventricle and reversible abnormalities of ventricular performance and volume. These data (44) suggest that endotoxin can serve as a major mediator of the cardiovascular dysfunction that develops during human septic shock. Gas exchange variables showed a rise in the mixed venous oxygen tension and a narrowing of the arterialvenous oxygen content. Administration of intravenous saline to increase pulmonary wedge pressure to a high normal range led to a widening of the alveolar-arterial oxygen gradient and to a small but significant drop in the partial pressure of arterial oxygen (45). To evaluate whether alveolar neutrophil influx might be related to these gas exchange changes (46), bronchoalveolar lavage was done; however, no increase in the total number of cells or in the differential cell counts was seen (45). Ventilation scans of the lung using technetium 99m-labeled diethylenetriamine pentacetate showed a significant increase in the clearance rate, suggesting that endotoxin may induce an increase in alveolar epithelial permeability. Thus, intravenous endotoxin administration and volume infusion in normal volunteers caused alterations in pulmonary function and gas exchange. These abnormalities may occur either by a non-neutrophil-dependent mechanism or may represent an effect of circulating, nonpulmonary neutrophils on the lung (45). Histologically, human septic shock is characterized by cell damage and vascular disruption, withfibrindeposition and microthrombi commonly detected in several organs. The regulation of the fibrinolytic enzyme pathway in sepsis and shock plays a pivotal role in the subsequent development of fibrin deposition, microthrombi, and disseminated intravascular coagulation. The endothelial cell is a major participant in the fibrinolytic pathway, producing both tissue plasminogen activator (tpa) and its inhibitor, plasminogen activator inhibitor-1. We took sequential measurements of tpa and plasminogen activator inhibitor-1 in normal human subjects after intravenous endotoxin administration (53). An early rise in functional tpa activity was found at 1 hour, peaked at 2 hours, and was undetectable 3 hours after endotoxin administration. Further evidence of plasminogen activation was documented as early as 2 hours by a sevenfold increase in plasmin inhibitorplasmin complexes. Plasminogen activator inhibitor-1 activity rose sixfold at 3 hours and was associated with an abrupt decline and absence of tpa activity. Endotoxin administration thus activates the fibrinolytic system by an early release of tpa. However, within 3 hours after endotoxin administration, a procoagulant state characterized by an increase in plasminogen activator inhibitor and undetectable tpa activity occurs (53). In summary, administration of small doses of endotoxin to normal humans produces myocardial depression, ventricular dilatation, decreased arterial oxygenation, increased alveolar permeability, and activation of the fibrinolytic system. These abnormalities are qualita-

9 Figure 9. Change from baseline to the point of maximal volume load in ratios reflecting ventricular performance. Panel A. PCW/EDVI denotes the ratio of pulmonary capillary wedge pressure to left ventricular end-diastolic volume index. Panel B. SVI/EDVI is the ratio of stroke volume index to left ventricular end-diastolic volume index. Panel C. LVSWI/EDVI is the ratio of left ventricular strokework index to left ventricular enddiastolic volume index. Panel D. PSP/ESVI is the ratio of peak systolic pressure to left ventricular end-systolic volume index. Three subjects who participated in both the control and endotoxin parts of the study at 3-month intervals are depicted by symbols surrounding the data points (reprinted from reference 44 with permission). tively similar to those of spontaneous human septic shock, suggesting that endotoxin can serve as a major mediator of the early cardiovascular, pulmonary, and hematologic alterations that occur during sepsis in hu- Mediators and Endotoxin Inhibitors Robert L. Danner, MD (Senior Investigator, Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland): Antibiotics appear to have little immediate effect on the course and outcome of septic shock, although they often rapidly inhibit or lyse the causative bacteria (or do both) and sterilize the bloodstream. This severe, acute toxicity that is unresponsive to antibiotic therapy is presumably due to systemic or circulating toxins and mediators (54). In fact, it has been hypothesized that the endotoxins of gram-negative bacteria may be released by the action of antibiotics, resulting in clinical deterioration (55). This concern and continued, high mortality from septic shock, despite use of potent antibiotics, have fueled 1 August 1990 Annals of Internal Medicine Volume 113 Number 3 235

10 interest in developing therapeutic strategies that neutralize or inhibit the key toxins and mediators of septicemia. The toxins and mediators of septic shock can be divided into exogenous (those produced by the microorganism) and endogenous (those produced by the host) substances (Figure 2). Of the exogenous mediators, the endotoxins of gram-negative bacteria have been the most extensively studied and will be discussed in detail below. Endotoxins, however, are not the only bacterial products involved in the development of septic shock. Other cell-membrane or cell-wall components, such as peptidoglycans, muramyl dipeptide, and lipotechoic acid, have biologic effects that implicate them in the development of septic shock (54). Further, some bacterial exotoxins, including staphylococcal enterotoxin B, toxic shock syndrome toxin-1, and pseudomonas exotoxin A (54), can cause shock and lethality in animals and have been associated with shock in humans. Of the endogenous mediators, cytokines have recently been recognized as playing central roles in host response to septicemia (56). Antibodies against one of the cytokines, tumor necrosis factor, have been found to protect animals from endotoxin and bacterial challenge (27, 56, 57). Interestingly, endotoxin, muramyl dipeptide (a cellwall component), and several exotoxins (staphylococcal enterotoxin, toxic shock syndrome toxin-1) can induce tumor-necrosis-factor release in vivo and probably produce many of their toxic effects via this endogenous mediator (56, 58, 59). Platelet-activating factor, in turn, is released by tumor necrosis factor and may mediate many of its effects (60, 61). Many additional mediators and mediator systems are involved in the pathophysiology of septic shock. Endotoxin Endotoxins are lipopoiysaccharides found in the outer membrane of gram-negative bacteria. Functionally, the Figure 10. Chemical structures of endotoxin, lipid A, and lipid X. molecule can be divided into three parts (Figure 10). The highly variable O-polysaccharide side chain conveys serotypic specificity to bacteria and can activate the alternate pathway of complement. The R-core region containing 2-keto-3-deoxy-octonate is less variable between different gram-negative bacteria. It is hypothesized that antibodies to this region may be cross-protective in infections caused by widely varying gramnegative bacteria (62). The lipid-a component of the molecule has been identified to be responsible for most of the toxicity of endotoxin. Lipid A stimulates tumornecrosis-factor release and can directly activate the classical pathway of complement in the absence of antibody (54). The evidence implicating endotoxin in septic shock is mostly circumstantial. Endotoxin has biologic effects analogous to those seen during septic shock. Endotoxin has been shown to cause fever, interleukin-1 and tumornecrosis-factor release, complement activation, disseminated intravascular coagulation, and shock in animals (54). Further, it induces in humans cardiovascular changes that are qualitatively similar to spontaneous septic shock (see above). Naturally occurring antibodies to endotoxin are associated with increased survival in gram-negative septic shock in humans (63). More recently, Ziegler and colleagues (64) showed that immune plasma from volunteers vaccinated with the Escherichia coli (E. coli) J5 mutant prevented death in patients with gram-negative septicemia. Although these compelling arguments favor a major role for endotoxin in septic shock, several findings bring this hypothesis into doubt. Mice differing in their sensitivity to endotoxin by as much as 5000-fold have been found to have the same lethal response to challenge with identical doses of live, gram-negative bacteria (65). In human studies (66), volunteers made tolerant to endotoxin were not protected from the clinical manifestations of experimental typhoid fever or tularemia. Finally, direct measurement of circulating endotoxin has not consistently correlated with the clinical manifestations and outcome of gram-negative septicemia (67). In an effort to clarify the incidence and significance of endotoxemia in humans, we did serial endotoxin determinations every 4 hours for 24 hours in 100 consecutive patients admitted to an intensive care unit with septic shock (68). Endotoxin was measured with a sensitive, chromogenic, limulus-amebocyte lysate assay. Detectable endotoxemia was found in 43 patients. The level of endotoxemia in many of these patients would not have been detectable by the older limulus gelation assay. In addition, endotoxemia often occurred intermittently, underscoring the need for frequent, serial sample collection. Only 20 of the 43 patients with endotoxemia had a positive limulus assay on initial determination. We found that the presence of endotoxemia was associated with blood culture positivity (54% compared with 25%, P < 0.01), lactic acidemia (5.5 ± 0.8 compared with 3.0 ± 0.3 mmol/l, P < 0.005), low systemic vascular resistance (456 ± 30 compared with 582 ± 33 dyn/ sec cm, P < 0.05), and depressed radionuclide-determined left ventricular ejection fraction (34 ± 2% compared with 45 ± 2%, P < 0.001). In the subgroup of patients with septic shock documented by positive August 1990 Annals of Internal Medicine Volume 113 Number 3

11 Figure 11. Increasing concentrations of lipid X (x-axis) produce a concentration-dependent decrease in the ability of endotoxin to prime neutrophils for enhanced superoxide release (see text) (reprinted from reference 74 with permission). blood culture (n = 37), endotoxemia was associated with a higher mortality (39% compared with 7%, P < 0.05). Interestingly, only 26% of the endotoxin-positive patients had documented gram-negative bacteremia, suggesting that endotoxemia may play a pathogenic role in many cases of septic shock even when gram-negative organisms are not isolated from the blood. These results support the hypothesis that endotoxin is an important bacterial toxin in the pathogenesis of human septic shock and suggests that neutralization or inhibition of this toxin may be useful in therapy. Previously described anti-endotoxin approaches to treatment of septic shock have involved use of drugs or antibodies that protect by binding to endotoxin. Polymyxin B has been found to block many in-vitro and in-vivo actions of endotoxin, including lethality in animals (69, 70), by binding tightly to the lipid-a portion of the lipopolysaccharide molecule. Its clinical use, however, as an antibiotic or an anti-endotoxin therapy has been limited by its toxicity. Antibodies to endotoxin can also protect animals from endotoxin and bacterial challenge, presumably by either neutralizing endotoxin directly or enhancing the clearance of both endotoxin and bacteria from the circulation. O-polysaccharide-sidechain-specific antibodies appear to be the most protective, but it is unfeasible to produce a polyvalent antisera against all of the potential pathogens in human septic shock (62). This problem led to development of anticore endotoxin antibodies directed against the less variable core region of the lipopolysaccharide molecule (64). Although immune plasma from volunteers vaccinated with E. coli J5 mutant was shown to prevent death in patients with gram-negative septicemia (64), the identity of the actual protective factor in this plasma has been debated (62, 71). Investigations currently under way with monoclonal antibodies against the R-core region of endotoxin should resolve this controversy. Recently, a new approach to anti-endotoxin therapy has been investigated. Lipid X, a monosaccharide precursor of lipid A, was shown to protect mice and sheep from lethal endotoxin challenge (72, 73). The structural similarity (Figure 10) between lipid X and lipid A (the toxic moiety of endotoxin) suggested the possibility of direct antagonism. To investigate the anti-endotoxin activity of lipid X, we used endotoxin's ability to prime and activate neutrophils for an enhanced respiratory burst (74). Because activated neutrophils may play a pathogenetic role in the multiple organ system failure of septic shock (74), neutrophil priming may have mechanistic and pathogenetic relevance in the sepsis syndrome. Lipid X was found to block lipopoly saccharideinduced priming of human neutrophils in a dose-dependent manner (Figure 11). Lipid-X-exposed neutrophils that were subsequently washed to remove free lipid X could not be primed on exposure to lipopoly saccharides (74), suggesting that lipid X (74) affected the neutrophil directly, decreasing its sensitivity to lipopoly saccharides, rather than neutralizing them by binding to them. Further, we found that increasing concentrations of lipid X shifted serial lipopolysaccharide dose-response curves rightward (Figure 12). This pattern of inhibition is consistent with competitive inhibition and suggests that lipid X may indeed be directly antagonizing the action of lipopoly saccharides (74). In summary, endotoxemia in humans is associated with the severe manifestations of sepsis, such as organ dysfunction and cardiac depression, and may play a role in the pathophysiology of many patients with septic shock. Lipid X is representative of a new group of compounds with unique anti-endotoxin properties. Antitoxin and antimediator therapy may prove useful in management of septic shock. Myocardial Depressant Substance Robert E. Cunnion, MD (Senior Investigator, Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland): Two mechanisms have been postulated to cause myocardial depression in septic shock (75). The first postulated mech- Figure 12. Increasing concentrations of lipid X shift serial endotoxin (LPS) curvesrightward,consistent with competitive inhibition of LPS by lipid X (see text) (reprinted from reference 74 with permission). 1 August 1990 Annals of Internal Medicine Volume 113 Number 3 237

12 Figure 13. The effect of serum from control and patient groups on the extent of shortening of spontaneously beating, rat heart cells in vitro. Open circles indicate survivors; closed circles, nonsurvivors; and horizontal lines, the means for the patient groups (reprinted from reference 83 with permission). anism is that coronary hypoperfusion leads to ischemic myocardial dysfunction. Arguments for this mechanism have been based on animal studies of endotoxic or hemorrhagic shock (76, 77), models hemodynamically very different from human sepsis. Until recently, coronary circulation in human septic shock had not been studied directly. The second postulated mechanism is the presence in the bloodstream of one or more active, circulating myocardial depressant substances (78). As with earlier studies of coronary perfusion, investigations of circulating myocardial depressant activity historically have used sera from animal models of endotoxic or hemorrhagic shock (79, 80). Not only are these investigations of doubtful relevance to human septic shock, but most used isolated, papillary muscle preparations to assay for myocardial depressant activity, so the assays were difficult to establish and reproduce. To study coronary circulation in humans, we placed coronary sinus thermodilution catheters in patients with septic shock to measure coronary sinus blood flow and to sample coronary sinus venous blood (81). The patients with septic shock had coronary blood flows equal to or greater than those of controls. There was no difference in myocardial lactate extraction between patients with septic shock with myocardial depression and patients with septic shock without myocardial depression. Together, the preservation of myocardial blood flow and this net myocardial lactate extraction exclude global ischemia as the cause of myocardial depression in septic shock. Studies of coronary oxygen transport (81) showed a pattern of abnormalities, suggesting that sepsis results in a deranged autoregulation of coronary flow, a derangement analogous to the pattern of arteriovenous shunting in other organs in human septic shock. These findings have since been corroborated by other workers (82). Accordingly, our focus has returned to circulating myocardial depressant activity. The search for myocardial depressant substances in human sepsis had been hampered by a need for a less cumbersome, in-vitro myocardial contractility assay that could be correlated with in-vivo measurements of cardiac function. Our bioassay for myocardial depressant activity in human serum, reported in 1985 (83), uses newborn-rat myocytes in primary tissue culture. These cells adhere to the bottom of a Petri dish and, after 3 to 4 days of growth, they exhibit spontaneous contractions at rates of 30 to 100 beats/min. The movement of the cell can be analyzed using an edge detection system; videodensitometry permits quantitative recording of the extent and velocity of shortening during a single myocyte's* contraction. This system permits very small amounts of serum to be assayed for effects on myocardial cell contractility. When newborn-rat myocytes were exposed in vitro to sera taken from patients during the acute phase of human septic shock, their extent and velocity of shortening were depressed significantly (Figure 13) (83). The quantity of depression in vitro correlated with the amount of decrease in the in-vivo left ventricular ejection fraction. This in-vitro depression did not occur with sera from normal volunteers, critically ill nonseptic patients, or patients with reduced ejection fractions due to structural heart disease, nor was depression seen with sera taken from patients in the recovery phase after septic shock. These findings were the first strong evidence that a circulating myocardial depressant substance or substances played a pathophysiologic role in the myocardial dysfunction of human septic shock. Subsequently, the assay system has been refined by placing microscopic latex beads onto the cultured myocytes, thus allowing the use of a video, closed-loop tracking system to quantitate myocyte contractions with greater ease and accuracy than does videodensitometry (84). Movement of the latex bead is tracked electronically and converted to an analogue signal. Recent experiments using the modified assay system have furthered our understanding of circulating myocardial depressant activity in septic shock. Sera from 34 patients with septic shock were assayed for myocardial depressant activity, and results were correlated with the patients' clinical characteristics (85). A patient was considered positive for myocardial depressant substance if his or her serum consistently depressed the myocytes by 20% or more; almost half (43%) of patients with septic shock in this consecutive series were positive for myocardial depressant substance. As in our 1985 study, in-vitro depression of myocardial cell contractility again correlated with in-vivo depression of ejection fraction. Patients with circulating myocardial depressant substance activity (myocardial-depressant-substance-positive patients) had higher pulmonary artery wedge pressures and larger end-diastolic volume indices than those without such circulating activity (Table 3) (85). Further, these myocardial-depressant-substance-positive patients had higher mean peak lactic acid levels, suggesting either greater inadequacy of cardiac output in relation to the body's metabolic needs or perhaps a direct peripheral vascular effect of a myocardial depressant substance or substances. Hence, high levels of myocardial depressant activity can be found in sera from a large proportion of patients with septic shock, particularly those with the most severe cardiovascular derangements. Myocardial depressant activity was associated August 1990 Annals of Internal Medicine Volume 113 Number 3

13 with a trend toward increased mortality (36% mortality in myocardial-depressant-substance-positive compared with 10% in myocardial-depressant-substance-negative patients) in this study. The structural and chemical nature of this myocardial depressant activity represents an area of active investigation. Previous experiments (83) have shown myocardial depressant substance to have several specific characteristics. As the concentration of depressant serum placed on the myocytes is increased from 0% to 5%, 10%, and 20%, there is a concentration-dependent, stepwise decrease in both the extent and velocity of myocardial-cell shortening. Depressant activity is water soluble and will not diffuse through a dialysis membrane. Recent molecular filtration experiments (85) with Amicon filters (Amicon Corporation, Danvers, Massachusetts) suggest that myocardial depressant substance is a moderately sized molecule, weighing at least daltons. In recent experiments (86), we have used the myocyte assay to study the activity of several putative mediators of septic shock. Highly purified preparations of interleukin-1, interleukin-2, and endotoxin produced no depression of myocyte contraction, even in concentrations substantially higher than those measured during septic shock. However, tumor necrosis factor, in a dose of 250 U/mL, produced significant depression of myocyte shortening, with a mean decrease of 24%. These findings suggest that tumor necrosis factor may be one of several molecules that have key roles in directly producing the myocardial depression of human septic shock. Management of Septic Shock Frederick P. Ognibene, MD (Senior Investigator, Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland): Optimal treatment for patients with septic shock involves prompt and aggressive monitoring and management in an intensive care unit. Several retrospective studies have examined the utility of intensive care units in improving outcome from septic shock. One community hospital study (87) showed a decrease in mortality in patients with septic shock, from 92% to 61%, when on-site physicians were used in the intensive care unit, and a recent university hospital study (88) showed a similar decrease in septic shock mortality, from 74% to 57%, when intensive care units with trained, critical care physicians were used. In intensive care units, physicians can use invasive techniques, such as indwelling arterial catheters, to monitor both blood pressure and arterial blood gases, and can thus follow hemodynamic, respiratory, and acid-base changes. Pulmonary artery catheters provide assessment of intravascular volume and help differentiate sepsis from other forms of shock. The critical care environment also allows rapid, therapeutic intervention with appropriate fluids and vasopressors as well as other cardiac, pulmonary, and metabolic support. Intensive care units provide an environment for aggressive oxygen supplementation, mechanical ventilation when hypoxemia is unresponsive to conventional pressure measures, and institution of positive end-expiratory pressure to provide adequate oxygenation until lung injury heals (89, 90). Prompt institution of an empiric antibiotic regimen that includes appropriate therapy against the subsequently isolated and identified microorganism or microorganisms has been associated with improved survival and decreased frequency of shock (91, 92). It is essential that broad-spectrum antibiotic coverage be initiated pending culture results. Volume, Vasoactive Agents, and Cardiovascular Resuscitation Volume resuscitation with hemodynamic monitoring should be one of the first therapeutic steps in management of patients with septic shock. In a recent study (93), we evaluated left ventricular performance in three groups of patients: critically ill, nonseptic control patients; patients with sepsis without hypotension; and patients with septic shock. All patient groups received statistically similar amounts of fluid and had similar increments in pulmonary artery wedge pressure. In the control patients, volume infusion led to increases in both end-diastolic volume index (a volume measure of preload) and left ventricular stroke work index (a measure of ventricular performance using both volume and pressure). These changes were normal responses. Patients with septic shock had dilated ventricles before volume challenge, and they had markedly diminished cardiac response to volume administration. Volume infusion resulted in only minor increments of both enddiastolic volume and left ventricular stroke work indices. Patients with sepsis without hypotension showed a response that was intermediate to those of the control and septic shock groups. Thus, patients with septic shock showed altered myocardial function in response Table 3. Characteristics of Patients with and without Myocardial Depressant Substance (MDS)* Characteristics MDS-Positive, n = 14 Patient Groupst MDS-Negative, n = 20 Plasma lactate, mmolll 6.9 ± ± 0.4 Pulmonary artery wedge pressure, mm Hg 17 ± 2 12 ± 1 End-diastolic volume index, ml/m ± ± 10 Ejection fraction, %% 28 ± 3 39 ± 3 * Adapted from reference 85. t Values are expressed as mean ± SE. X Determined 2 to 4 days after onset of septic shock. 1 August 1990 Annals of Internal Medicine Volume 113 Number 3 239

14 to volume, manifested by an inability to either dilate or increase contractility of the ventricle in response to volume. This decreased ventricular performance probably represents one of the important pathogenetic mechanisms resulting in the serious hemodynamic consequences of septic shock. The typical resuscitation of a patient with septic shock involves aggressive volume resuscitation and, if hypotension persists, vasopressor agents. If a patient with septic shock remains hypotensive after volume has raised pulmonary artery wedge pressure to 15 to 18 mm Hg, then dopamine is administered to raise the mean blood pressure to at least 60 mm Hg. If the dopamine dose exceeds 20 /tg/kg min, another vasopressor, typically norepinephrine, is administered, and the dose is titrated to maintain a mean blood pressure of 60 mm Hg. Data from a canine model (94) have been used to assess the effects of norepinephrine with and without dopamine on renal blood flow. The addition of dopamine to pressor doses of norepinephrine resulted in significantly higher renal blood flow and lower renal vascular resistance than norepinephrine infusions alone. Extrapolating this data to clinical management of septic shock, patients requiring therapy with norepinephrine to support blood pressure may benefit from simultaneous administration of low-dose dopamine (approximately 1 to 4 jug/kg min) to increase renal blood flow. Use of norepinephrine in patients with septic shock who fail to respond to dopamine has been controversial. Norepinephrine is known to be a powerful vasoconstrictor, and some investigators were concerned that further vasoconstriction might worsen the shock syndrome in some patients. However, recent data (95, 96) show that norepinephrine can reverse septic shock in patients who are unresponsive to volume and dopamine therapy. In our clinical experience, more than 200 patients with septic shock have been treated with norepinephrine when volume and dopamine therapy have failed to increase blood pressure. In many of these patients, shock was reversed, and patient survival achieved without irreversible, end-organ damage. Once blood pressure is normalized with norepinephrine, the lowest dosage that maintains blood pressure should be administered to minimize any potential vasoconstrictor effects on organ blood flow. Overall survival in norepinephrine-treated patients is approximately 40%, a substantial survival rate for such a critically ill patient group. Other Therapies Other therapies have been advocated for treatment of septic shock. High-dose corticosteroid therapy was found to be effective in some animal models of septic shock. Recently, however, three large clinical trials (97-99) have shown no differences in mortality between corticosteroid-treated patients and control patients. In addition, these data showed corticosteroids to be unable to prevent or reverse shock. These studies have also documented the occurrence of superinfections in corticosteroid-treated patients. Based on these data, corticosteroid therapy in patients with septic shock should be reserved only for those with suspected or documented adrenal insufficiency. Antihistamines have not proved to be effective, and recent studies (100, 101) have failed to document elevated histamine levels during human septic shock. Although arachidonic acid metabolites may account for some of the vascular effects of sepsis, inhibition of eicosanoids has not been shown to be therapeutically useful. Some animal models of shock are very dependent on endorphins; however, clinical data on use of naloxone to inhibit endorphin receptors have not shown clinical efficacy. Inhibition of endotoxin using an antisera (64) has been associated with improved survival for patients with gram-negative bacteremia. Clinical trials are presently evaluating this important lead. We need a more comprehensive understanding of the septic shock pathogenetic cascade (outlined in Figure 2) to develop effective therapies that interrupt key steps in the sequence and reduce the very high mortality from this disease. Acknowledgments: The authors thank the nursing staff of the 10-D intensive care unit and the technical staff of the Critical Care Medicine Department, for doing many of the studies cited; and Shelia Robinson, Sandy Montgomery, Geri Byrd, and Nancy Connor for preparation of the manuscript. Requests for Reprints: Joseph E. Parrillo, MD, Rush-Presbyterian-St. Luke's Medical Center, 1653 West Congress Parkway, Chicago, IL Current Author Addresses: Dr. Parrillo: Rush-Presbyterian-St. Luke's Medical Center, 1653 West Congress Parkway, Chicago, IL Drs. Parker, Natanson, Suflfredini, Danner, Cunnion, and Ognibene: National Institutes of Health, Building 10, Room 10-D-48, Bethesda, MD References 1. 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