Charles Natanson

Intensive Insulin Therapy and Pentastarch Resuscitation in Severe Sepsis

BACKGROUND The role of intensive insulin therapy in patients with severe sepsis is uncertain. Fluid resuscitation improves survival among patients with septic shock, but evidence is lacking to support the choice of either crystalloids or colloids. METHODS In a multicenter, two-by-two factorial trial, we randomly assigned patients with severe sepsis to receive either intensive insulin therapy to maintain euglycemia or conventional insulin therapy and either 10% pentastarch, a low-molecular-weight hydroxyethyl starch (HES 200/0.5), or modified Ringers lactate for fluid resuscitation. The rate of death at 28 days and the mean score for organ failure were coprimary end points. RESULTS The trial was stopped early for safety reasons. Among 537 patients who could be evaluated, the mean morning blood glucose level was lower in the intensive-therapy group (112 mg per deciliter [6.2 mmol per liter]) than in the conventional-therapy group (151 mg per deciliter [8.4 mmol per liter], P<0.001). However, at 28 days, there was no significant difference between the two groups in the rate of death or the mean score for organ failure. The rate of severe hypoglycemia (glucose level, < or = 40 mg per deciliter [2.2 mmol per liter]) was higher in the intensive-therapy group than in the conventional-therapy group (17.0% vs. 4.1%, P<0.001), as was the rate of serious adverse events (10.9% vs. 5.2%, P=0.01). HES therapy was associated with higher rates of acute renal failure and renal-replacement therapy than was Ringers lactate. CONCLUSIONS The use of intensive insulin therapy placed critically ill patients with sepsis at increased risk for serious adverse events related to hypoglycemia. As used in this study, HES was harmful, and its toxicity increased with accumulating doses. (ClinicalTrials.gov number, NCT00135473.)

Septic Shock in Humans: Advances in the Understanding of Pathogenesis, Cardiovascular Dysfunction, and Therapy

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.

Pneumocystis carinii Pneumonia: A Comparison Between Patients with the Acquired Immunodeficiency Syndrome and Patients with Other Immunodeficiencies

Clinical features of 49 episodes of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome were compared with those of 39 episodes in patients with other immunosuppressive diseases. At presentation patients with the syndrome were found to have a longer median duration of symptoms (28 days versus 5 days, p = 0.0001), lower mean respiratory rate (23.4 versus 30, p = 0.005), and higher median room air arterial oxygen tension (69 mm Hg versus 52 mm Hg, p = 0.0002). The survival rate from 1979 to 1983 was similar for the two groups (57% and 50% respectively). Patients with the syndrome had a higher incidence of adverse reactions to trimethoprim-sulfamethoxazole (22 of 34 versus 2 of 17, p = 0.0007). Survivors with the syndrome at initial presentation had a significantly lower respiratory rate, and higher room air arterial oxygen tension, lymphocyte count, and serum albumin level compared to nonsurvivors. Pneumocystis carinii pneumonia presents as a more insidious disease process in patients with the syndrome, and drug therapy in these patients is complicated by frequent adverse reactions.

A circulating myocardial depressant substance in humans with septic shock. Septic shock patients with a reduced ejection fraction have a circulating factor that depresses in vitro myocardial cell performance.

We have previously described a subpopulation of patients with septic shock who had a reversible depression of radionuclide-determined left ventricular ejection fraction (EF). To investigate the mechanism of this myocardial depression, an in vitro model of mammalian myocardial cell performance was established employing primary spontaneously beating rat myocardial cells. The contraction of a single cardiac cell was quantitated by recording the changes in area occupied by the cell during contraction and relaxation. In 20 septic shock patients during the acute phase, the mean left ventricular EF was decreased (mean = 0.33, normal mean = 0.50), and serum obtained during this acute phase induced a mean (+/- standard error of the mean) 33 +/- 4% decrease in extent and 25 +/- 4% decrease in velocity of myocardial cell shortening during contraction (P less than 0.001). In contrast, serum obtained from 11 of these same patients before shock (n = 2) or after recovery (n = 9) of the left ventricular EF (mean = 0.50) showed a return toward normal in extent and velocity of shortening (P less than 0.001). Sera from 17 critically ill nonseptic patients, from 10 patients with structural heart disease as a cause for a depressed EF, and from 12 healthy laboratory personnel, induced no significant changes in in vitro myocardial cell performance. In 20 patients during the acute phase of septic shock, the decreased EF in vivo demonstrated a significant correlation (r = +0.52, P less than 0.01) with a decrease in the extent of myocardial cell shortening in vitro. The quantitative and temporal correlation between the decreased left ventricular EF and this serum myocardial depressant substance argues for a pathophysiologic role for this depressant substance in producing the reversible cardiomyopathy seen during septic shock in humans.

Selected Treatment Strategies for Septic Shock Based on Proposed Mechanisms of Pathogenesis

Dr. Charles Natanson (Critical Care Medicine Department, Clinical Center, National Institutes of Health [NIH], Bethesda, Maryland): Sepsis and septic shock are heterogeneous clinical syndromes that can be triggered by many microorganisms, including gram-negative bacteria, gram-positive bacteria, and fungi [1-3]. Participants in a recent consensus conference tried to define sepsis and septic shock. Sepsis was characterized as a systemic response to infection manifested by tachycardia, tachypnea, change in temperature, and leukopenia or leukocytosis. Septic shock was defined as severe sepsis accompanied by hypotension [4]. However, patients with sepsis may have one or several signs and symptoms, and no single physiologic or laboratory parameter can universally identify this syndrome. Advances in molecular biology and immunology during the past decade have increased our understanding of the pathogenesis of septic shock (Figure 1). In particular, we now believe that the hosts inflammatory response to infection contributes substantially to the development of septic shock [5-7]. Infections begin when microorganisms circumvent or penetrate host barriers such as skin and mucosa. Depending on the infecting agents virulence and the patients immunocompetence, local host defenses may be overwhelmed, resulting in microbial invasion of the bloodstream. Toxic bacterial products present in the circulation activate systemic host defenses, including plasma factors (complement and clotting cascades) and cellular components (neutrophils, monocytes, macrophages, and endothelial cells). In turn, activated cells produce potentially toxic host mediators (cytokines such as tumor necrosis factor [TNF] and interleukin-1 [IL-1], kinins, eicosinoids, platelet-activating factor, and nitric oxide) that augment the inflammatory response. This escalating immune response, in concert with microbial toxins, can lead to shock, multiple organ failure, and death. Figure 1. The pathogenesis and treatment of septic shock. Standard sepsis treatment strategies include use of antibiotics to kill invading bacteria, surgical procedures to eradicate the nidus of infection, and intensive life-support procedures such as dialysis, mechanical ventilation, and use of vasoactive drugs. Despite these approaches, the mortality rate from septic shock is high, ranging from 25% to 75% [1, 8-12]. In addition, the reported incidence of sepsis syndrome in U.S. hospitals increased 139%, from 73.6 to 175.9 per 100 000 persons discharged between 1979 and 1987 [13]. This increase may be caused by several medical trends: improved life-support technology that keeps patients who have a high risk for infection alive at the extremes of age; increased use of invasive medical procedures; advances in cancer chemotherapy and immunotherapy; and the prevalence of acquired immunodeficiency syndrome. The increasing incidence of sepsis and its high mortality rate have mobilized a search for new therapies. Development of new drugs to treat sepsis has been based in part on the premise that neutralizing bacterial toxins and potentially harmful host mediators could stop or slow this syndrome. The discussants in this conference review several of these new therapies that are directed at different elements of the inflammatory cascade, including a bacterial toxin (endotoxin), host proteins that mediate the inflammatory response (TNF and IL-1), an inflammatory cell (the neutrophil), and a low-molecular-weight messenger (nitric oxide) that causes hypotension. Other targets (eicosinoids, platelet-activating factor, bradykinin, and so on) are being evaluated to treat this syndrome. Each target selected for discussion was studied in our laboratories or evaluated in human clinical trials. Each discussant offers unique insight into the pathogenesis of septic shock and into the difficulties inherent in inhibiting a potentially toxic inflammatory mediator that may also play a role in host defense. Antiendotoxin Therapies in Septic Shock Dr. William D. Hoffman (Critical Care Medicine Department, Clinical Center, NIH, Bethesda, Maryland): The outer membrane of gram-negative bacteria contains lipopolysaccharides called endotoxin [14]. Endotoxin induces an inflammatory response that may protect the host from infection but may also cause multiple-organ failure and death when present in excess amounts. Specific immunochemical properties have been associated with different components of the endotoxin molecule. The O-polysaccharide chain (O-side chain) of endotoxin is exposed on the outside surface of gram-negative bacteria. The O-side chain is not toxic when injected into animals and has a molecular structure that varies among gram-negative bacteria. The core sugar and lipid A regions of endotoxin are embedded deeply in the outer bacterial membrane, and their molecular structures are similar for all gram-negative bacteria. In contrast to the O-side chain, lipid A is toxic when given to animals [14]. Effects of Endotoxin Challenge-Endotoxemia in Sepsis Experimental observations have supported and challenged the concept that endotoxin-directed therapies can benefit patients with septic shock. Reversible organ dysfunction and hemodynamic changes that are qualitatively similar to those seen in patients with septic shock develop in animals injected with endotoxin [15] and healthy human volunteers injected with safe doses of endotoxin [16]. In addition, development of endotoxemia in patients with septic shock has been associated with severe organ damage [9]. However, neither induced tolerance to endotoxin in humans [17] nor genetic resistance to endotoxin in mice [18] is protective during gram-negative infections. In addition, increased sensitivity to endotoxin does not alter the course of gram-negative infection in animals [19]. Finally, endotoxin and endotoxemia are not necessary to produce the septic shock syndrome, and endotoxin may be only one of many bacterial products that can trigger the septic response [3, 15]. Approaches to Antiendotoxin Therapy Although no antiendotoxin therapy is in clinical use, several are being investigated (Table 1). Antibodies to the O-side chain produce serotype-specific [20], complement-dependent bactericidal activity [21]. However, serotype specificity limits the clinical utility of O-side chain therapies because treating patients empirically with an effective dose of antibody for every probable infecting bacterial strain would be difficult. This problem led to investigation of antibodies directed at core and lipid A structures of endotoxin, because these antibodies might cross-protect against diverse gram-negative bacteria [22]. Although core or lipid A antibodies were thought to mediate antiendotoxin [23] or endotoxin-clearing effects [24], the function of these antibodies is unknown and controversial [25-28]. Nevertheless, core-directed antibodies are the only antiendotoxin therapies studied in clinical trials. Other antiendotoxin agents listed in Table 1 may reduce the host inflammatory response by directly neutralizing endotoxin, increasing its clearance, antagonizing its effects on host cells, or inducing tolerance. Controlled therapeutic trials of agents that reduce the bioactivity of endotoxin and have no antibacterial effect may determine whether circulating endotoxin is a useful therapeutic target in septic shock. Table 1. Approaches to Antiendotoxin Therapies for Septic Shock* Polyclonal Antibodies Directed at Core Epitopes and Lipid A The first clinical trial of core-directed antibodies studied patients with gram-negative bacteremia treated with control (n = 100) or J5 antiserum (n = 91) [8]. In that study, 21 of 39 patients with localized gram-negative infection but no bacteremia were included in the gram-negative bacteremia group because they had been given appropriate antibiotics before blood cultures were obtained [8]. The sepsis-related mortality rate for patients with gram-negative bacteremia given J5 antiserum was 22% (compared with 39% with control serum). In a subgroup of patients who required vasopressor drugs for more than 6 hours, the mortality rate was 44% (compared with 77% with control serum). The effect of J5 antiserum on mortality from all causes or in patients with gram-negative infection was not reported [8]. Five subsequent clinical trials (Table 2) using polyclonal core-reactive antiserum or immunoglobulin to prevent or treat gram-negative sepsis showed essentially no survival benefit [29-34]. Table 2. Summary of 10 Clinical Trials with Lipopolysaccharide Core-Directed Antibodies* Monoclonal Antibodies Directed at Core Epitopes and Lipid A: E5 and HA-1A Monoclonal antibodies were developed to produce a more specific antiendotoxin therapy with less risk for transmission of infection. E5, a murine IgM, protected mice injected with bacteria [35], and HA-1A, a human IgM, protected mice and rabbits injected with bacteria [36]. However, E5 did not protect sheep given endotoxin [37], and other researchers subsequently could not reproduce the beneficial effects of HA-1A in mice and rabbits [38]. E5 Clinical Trials E5 was tested in two multicenter, randomized, placebo-controlled clinical trials (Table 2). In the first trial of 468 patients, E5 provided no significant benefit to patients with gram-negative infection. The antibody improved survival in a retrospectively identified subgroup of 137 patients with gram-negative infection without refractory shock (30% compared with 43%; P = 0.01) [39]. A second trial of 847 patients was conducted to confirm this favorable effect (Table 2). However, in the second study, E5 did not significantly improve survival in the 530 patients who had gram-negative infection without refractory shock (E5, 30% mortality compared with control, 26%; P = 0.21) [40]. Using a meta-analysis and combining data from the two trials, researchers found that E5 substantially decreased the time to recovery from organ dysfunction and improv

Cell-free hemoglobin-based blood substitutes and risk of myocardial infarction and death: A meta-analysis

CONTEXT Hemoglobin-based blood substitutes (HBBSs) are infusible oxygen-carrying liquids that have long shelf lives, have no need for refrigeration or cross-matching, and are ideal for treating hemorrhagic shock in remote settings. Some trials of HBBSs during the last decade have reported increased risks without clinical benefit. OBJECTIVE To assess the safety of HBBSs in surgical, stroke, and trauma patients. DATA SOURCES PubMed, EMBASE, and Cochrane Library searches for articles using hemoglobin and blood substitutes from 1980 through March 25, 2008; reviews of Food and Drug Administration (FDA) advisory committee meeting materials; and Internet searches for company press releases. STUDY SELECTION Randomized controlled trials including patients aged 19 years and older receiving HBBSs therapeutically. The database searches yielded 70 trials of which 13 met these criteria; in addition, data from 2 other trials were reported in 2 press releases, and additional data were included in 1 relevant FDA review. DATA EXTRACTION Data on death and myocardial infarction (MI) as outcome variables. RESULTS Sixteen trials involving 5 different products and 3711 patients in varied patient populations were identified. A test for heterogeneity of the results of these trials was not significant for either mortality or MI (for both, I2 = 0%, P > or = .60), and data were combined using a fixed-effects model. Overall, there was a statistically significant increase in the risk of death (164 deaths in the HBBS-treated groups and 123 deaths in the control groups; relative risk [RR], 1.30; 95% confidence interval [CI], 1.05-1.61) and risk of MI (59 MIs in the HBBS-treated groups and 16 MIs in the control groups; RR, 2.71; 95% CI, 1.67-4.40) with these HBBSs. Subgroup analysis of these trials indicated the increased risk was not restricted to a particular HBBS or clinical indication. CONCLUSION Based on the available data, use of HBBSs is associated with a significantly increased risk of death and MI.

Serial cardiovascular variables in survivors and nonsurvivors of human septic shock: Heart rate as an early predictor of prognosis

Forty-eight septic shock patients with positive blood cultures had conventional serial hemodynamic evaluations until recovery or death to identify early cardiovascular variables that predicted outcome. There were 19 (40%) survivors and 29 nonsurvivors. At the initial evaluation, both survivors and nonsurvivors demonstrated an elevated cardiac index (CI), low systemic vascular resistance index (SVRI), and normal stroke volume index. However, only an initial heart rate (HR) less than 106 beat/min significantly predicted survival. Twenty-four hours after the onset of shock, both an HR less than 95 beat/min and an SVRI greater than 1529 dyne.sec/cm5.m2 predicted survival. Comparing the hemodynamic profiles from the initial to the 24 h time point, a decrease in HR greater than 18 beat/min or a decrease in CI greater than 0.5 L/min.m2 predicted survival. Twenty-two deaths occurred in the first week of study, of which 18 (82%) were due primarily to low SVRI and four (18%) to low CI. Seven deaths occurred after 1 wk, all of which were due to multiple organ failure.

The coronary circulation in human septic shock.

Reversible myocardial depression, manifested by ventricular dilatation and decreased ejection fraction, is common in human septic shock. A proposed mechanism, based on animal studies, is myocardial ischemia resulting from inadequate coronary blood flow. Coronary flow observations have not been reported for human septic shock. To determine whether myocardial depression in human septic shock is associated with reduced coronary flow, thermodilution coronary sinus catheters were placed in seven patients with septic shock for measurements of coronary flow and myocardial metabolism. Four of the seven patients developed myocardial depression. These patients had coronary flow similar to or higher than that of control subjects and similar to that of the other three patients, who did not develop myocardial depression. None of the patients had net myocardial lactate production. In general, compared with values in control subjects, the oxygen content difference (arterial minus coronary sinus) was narrowed, and the fractional extraction of arterial oxygen was diminished. This pattern of disordered coronary autoregulation is analogous to the pattern of arteriovenous shunting in other organs in patients with septic shock. The preservation of coronary flow, the net myocardial lactate extraction, and the increased availability of oxygen to the myocardium argue against global ischemia as the cause of myocardial depression in human septic shock.

Meta-Analysis: The Effect of Steroids on Survival and Shock during Sepsis Depends on the Dose

Despite effective antibiotics, septic shock remains the most common cause of death in the intensive care unit, incurring a mortality rate of 30% to 50% (1, 2). Several therapies targeting the upregulated inflammatory pathways of sepsis have been studied to improve survival. However, few therapies have proven beneficial (3-10). In the 1960s, preclinical studies reported that high doses of glucocorticoids in models of Escherichia coli and endotoxic shock improved survival. These studies prompted the initiation of human sepsis trials (11-13). Subsequently, more than 50 human trials have examined the role of high-dose steroid therapy in sepsis. These trials administered doses of methylprednisolone as high as 30 to 120 mg/kg of body weight over 24 hours. Because the reported results of these trials were inconsistent, there was little consensus on the appropriate use of steroids in patients with septic shock. To clarify the treatment effects of high-dose steroids, 3 meta-analyses performed in the 1990s examined the more rigorously conducted randomized, controlled clinical trials of sepsis (7, 14, 15). The meta-analysis by Lefering and colleagues (14) incorporated 10 trials and found no overall beneficial effect of glucocorticoid therapy on mortality in septic patients (absolute difference in mortality rates between treatment and control groups, 0.2 percentage point [95% CI, 9.2 percentage points to 8.8 percentage points]). A second meta-analysis by Cronin and colleagues (15) examined 9 trials with variable effects (P= 0.02) and reported no evidence of a beneficial effect of high-dose steroids on mortality from sepsis (relative risk for death with treatment, 1.13 [CI, 0.99 to 1.29]). A third meta-analysis, performed by our group (7), examined the trials included in the previous meta-analyses. Nine trials, which were the same as those investigated by Cronin and colleagues (15), met inclusion criteria for that analysis (7). In this group of trials, we identified 1 study (16) as a statistical outlier that accounted for the variability reported by Cronin and colleagues. After exclusion of this outlier, our analysis revealed a homogenous group of 8 studies (P> 0.2) that demonstrated an overall increase in mortality associated with the use of high-dose steroids in septic patients (odds ratio of survival with treatment, 0.70 [CI, 0.55 to 0.91]; P= 0.008) (7). The increased mortality in these studies may have been due to the immunosuppressive effects of steroids, which led to more severe secondary infections (17-19). In response to these overall discouraging results, the use of high-dose glucocorticoids in septic patients decreased in the late 1980s and 1990s. Recently, interest in examining the role of the adrenal axis in sepsis has been renewed. Briegel and colleagues (20) reported that septic patients have an attenuated response to corticotropin stimulation testing during their acute illness. Furthermore, Annane and colleagues (21) demonstrated that a high cortisol level and an attenuated response to corticotropin stimulation indicate relative adrenal insufficiency during sepsis that may increase mortality. On the basis of these findings, several clinical trials have been performed to determine whether administering glucocorticoids in dosages similar to the amount produced physiologically during a stressful state (that is, 300 mg of cortisol per day) affects outcome in septic patients. We performed the current study to update our previous meta-analysis and compare recent clinical trials with previous clinical trials of steroid use in patients with sepsis (22). Methods Literature Search We searched MEDLINE for medical literature published from 1988 to December 2003 by using the following keywords: steroids and sepsis, steroids and septic shock, glucocorticoids and sepsis, glucocorticoids and septic shock, corticosteroids and sepsis, and corticosteroids and septic shock. Studies were included if they met all of the following criteria: randomized, controlled trial design; enrollment of adult patients who met criteria for sepsis or septic shock; and a primary end point, including either the discontinuation of vasopressor therapy or a change in survival comparing glucocorticoid treatment with a control group with or without placebo. Included studies must have administered similar treatments to both the control and steroid groups, with the exception of the administration of a predetermined glucocorticoid regimen. Criteria for sepsis or septic shock needed to be clearly defined in each study and be consistent with the American College of Chest Physicians and Society of Critical Care Medicine Consensus Conference (23) definition for sepsis (including documented site or strong suspicion of infection, temperature > 38 C or < 36 C, heart rate > 90 beats/min, respiratory rate > 20 breaths/min, and leukocyte count > 12 109 cells/L), severe sepsis (sepsis plus organ dysfunction; hypotension or hypoperfusion, including oliguria, altered mental status, or lactate acidosis), and septic shock (hypotension despite fluid resuscitation plus hypoperfusion abnormalities) (23). Data Collection Two investigators trained in critical care medicine independently reviewed the included studies by using a standardized protocol and data collection form. A third author trained in critical care medicine evaluated and resolved discrepancies. We collected data on patient characteristics, study characteristics, treatment interventions, and treatment outcomes. Abstracted data included the presence of sepsis, severe sepsis, or septic shock; type, dose, and duration of glucocorticoid administered; incidence and severity of secondary infections; response to corticotropin stimulation testing; the number of patients with shock reversal; and the number of patient deaths. We evaluated the quality of the included trials by assessing the method and adequacy of randomization, blinding protocols, completeness of follow-up, adherence to treatment protocols, and co-interventions or treatments to each group in the studies. Our primary goal was to compare the effect of glucocorticoid administration on survival in the recent studies with the effects reported in the previously analyzed trials (22). Since the glucocorticoid regimen differed among the trials, we converted all dosages to hydrocortisone equivalents (24). Statistical Analysis Survival data were analyzed by using a Cochran-Mantel-Haenszel test to estimate the pooled effect of steroids (25). The similarity of the effect across studies was assessed by using a Breslow-Day test and reported with an I2 value (26, 27). When statistically significant heterogeneity of treatment effects was observed, studies were partitioned (for example, early vs. late studies) to decrease the heterogeneity of studies in a particular partition and increase the differences among the partitions, which can be seen when the I2 value is substantially lower in each partition as compared with the overall I2 value (28). One study increased the I2 value substantially in the set of early studies and was removed from all subsequent analyses. Partitioning variables were determined by regressing study characteristics (for example, steroid dose in first 24 hours) on mortality, specifically the log relative survival benefit (29). Regression was performed by using an inverse-variance-weighted restricted maximum likelihood random-effects method. When the regression was performed by using log steroid dose in the first 24 hours as the independent variable, 1 study was observed to be both a statistical outlier and influential. An indicator variable for this study was included in the regression analysis. Similar estimates of the slope associated with the effect of log steroid dose in the first 24 hours were observed when the influential study was removed and for early and late studies separately. A regression analysis that included control group mortality rate as an additional independent variable did not change the relationship between steroid dose in the first 24 hours and relative survival benefit. All pooled relative survival benefits are reported with associated 95% CIs by using a fixed-effects model. Random-effects estimates of survival were also calculated and reported. Statistically significant differences in characteristics between early and late studies were assessed by using analysis of variance (ANOVA) (when a weighted analysis was needed) or a 2-sample Wilcoxon test (when an unweighted analysis was performed). To analyze the different types of severity of illness scores used in the studies, we computed an effect size for each. This effect size was calculated by determining the difference between the mean steroid severity score and the mean control severity score, divided by the control standard deviation in each study. Role of the Funding Sources The Warren G. Magnuson Clinical Center at the National Institutes of Health, Bethesda, Maryland, provided intramural funds for this study. The funding source played no role in the design, conduct, or reporting of the study or decision to submit the manuscript for publication. Data Synthesis Comparison of Study Methods Since 1988, more than 1300 articles on steroids and sepsis have been published. Five randomized, controlled trials, all published after 1997, met inclusion criteria and were included in our analysis (30-34) (Figure 1). Four of these studies were published manuscripts, and 1 study was reported in abstract form (33). Figure 1. Flow diagram of the published articles evaluated for inclusion in this meta-analysis. The 5 studies published after 1997 were randomized, double-blind, placebo-controlled trials (Table 1). Each study listed specific inclusion and exclusion criteria that were consistent with American College of Chest Physicians and Society of Critical Care Medicine Consensus Conference definitions of sepsis and septic shock (23). Each study used a severity of illness score (Simplified Ac

Depressed Left Ventricular Performance: Response to Volume Infusion in Patients with Sepsis and Septic Shock

Volume infusion, to increase preload and to enhance ventricular performance, is accepted as initial management of septic shock. Recent evidence has demonstrated depressed myocardial function in human septic shock. We analyzed left ventricular performance during volume infusion using serial data from simultaneously obtained pulmonary artery catheter hemodynamic measurements and radionuclide cineangiography. Critically ill control subjects (n = 14), patients with sepsis but without shock (n = 21), and patients with septic shock (n = 21) had prevolume infusion hemodynamic measurements determined and received statistically similar volumes of fluid resulting in similar increases in pulmonary capillary wedge pressure. There was a strong trend (p = 0.004) toward less of a change in left ventricular stroke work index (LVSWI) after volume infusion in patients with sepsis and septic shock compared with control subjects. The LVSWI response after volume infusion was significantly less in patients with septic shock when compared with critically ill control subjects (p less than 0.05). These data demonstrate significantly altered ventricular performance, as measured by LVSWI, in response to volume infusion in patients with septic shock.