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Definitions for Sepsis and Organ Failure and Guidelines for the Use of Innovative Therapies in Sepsis

Objective. —Define the epidemiology of the four recently classified syndromes describing the biologic response to infection: systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, and septic shock. Design. —Prospective cohort study with a follow-up of 28 days or until discharge if earlier. Setting. —Three intensive care units and three general wards in a tertiary health care institution. Methods. —Patients were included if they met at least two of the criteria for SIRS: fever or hypothermia, tachycardia, tachypnea, or abnormal white blood cell count. Main Outcomes Measures. —Development of any stage of the biologic response to infection: sepsis, severe sepsis, septic shock, end-organ dysfunction, and death. Results. —During the study period 3708 patients were admitted to the survey units, and 2527 (68%) met the criteria for SIRS. The incidence density rates for SIRS in the surgical, medical, and cardiovascular intensive care units were 857,804, and 542 episodes per 1000 patient-days, respectively, and 671,495, and 320 per 1000 patient-days for the medical, cardiothoracic, and general surgery wards, respectively. Among patients with SIRS, 649 (26%) developed sepsis, 467 (18%) developed severe sepsis, and 110 (4%) developed septic shock. The median interval from SIRS to sepsis was inversely correlated with the number of SIRS criteria (two, three, or all four) that the patients met. As the population of patients progressed from SIRS to septic shock, increasing proportions had adult respiratory distress syndrome, disseminated intravascular coagulation, acute renal failure, and shock. Positive blood cultures were found in 17% of patients with sepsis, in 25% with severe sepsis, and in 69% with septic shock. There were also stepwise increases in mortality rates in the hierarchy from SIRS, sepsis, severe sepsis, and septic shock: 7%, 16%, 20%, and 46%, respectively. Of interest, we also observed equal numbers of patients who appeared to have sepsis, severe sepsis, and septic shock but who had negative cultures. They had been prescribed empirical antibiotics for a median of 3 days. The cause of the systemic inflammatory response in these culture-negative populations is unknown, but they had similar morbidity and mortality rates as the respective culture-positive populations. Conclusions. —This prospective epidemiologic study of SIRS and related conditions provides, to our knowledge, the first evidence of a clinical progression from SIRS to sepsis to severe sepsis and septic shock. ( JAMA . 1995;273:117-123)

The Natural History of the Systemic Inflammatory Response Syndrome (SIRS): A Prospective Study

Multiple organ failure (MOF) has reached epidemic proportions in most intensive care units and is fast becoming the most common cause of death in the surgical intensive care unit. Furthermore, in spite of the development of successive generations of new and more powerful antibiotics and increasing sophisticated techniques of organ support, our ability to salvage patients once MOF has become established has not appreciably improved over the last two decades. Clearly, new therapeutic strategies aimed at preventing or limiting the development of the physiologic abnormalities that induce organ failure are needed to improve survival in these critically ill patients. Based on our rapidly increasing knowledge of the mechanisms of MOF and the fruits of molecular biology, a number of new therapeutic approaches are in various stages of development. To effectively use these new therapeutic options as they become available, it is necessary to have a clear understanding of the pathophysiology of MOF. Thus, the goals of this review are to integrate the vast amount of new information on the basic biology of MOF and to focus special attention on the potential therapeutic consequences of these recent advances in our understanding of this complex and perplexing syndrome.

Multiple organ failure. Pathophysiology and potential future therapy.

Objective: To determine whether plasma tumor necrosis factor- (TNF-), interleukin-1 (IL-1 ), interleukin-6 (IL-6), and lipopolysaccharide are detectable in patients when they first present with the...

Plasma Cytokine and Endotoxin Levels Correlate with Survival in Patients with the Sepsis Syndrome

Objective. —To examine the incidence, risk factors, and outcome of severe sepsis in intensive care unit (ICU) patients. Design and Setting. —Inception cohort study from a 2-month prospective survey of 11 828 consecutive admissions to 170 adult ICUs of public hospitals in France. Patients. —Patients meeting clinical criteria for severe sepsis were included and classified as having documented infection (ie, documented severe sepsis, n=742), or a clinical diagnosis of infection without microbiological documentation (ie, culture-negative severe sepsis, n=310). Main Outcome Measures. —Hospital and 28-day mortality after severe sepsis. Results. —Clinically suspected sepsis and confirmed severe sepsis occurred in 9.0 (95% confidence interval [CI], 8.5 to 9.5) and 6.3 (95% CI, 5.8 to 6.7) of 100 ICU admissions, respectively. The 28-day mortality was 56% (95% CI, 52% to 60%) in patients with severe sepsis, and 60% (95% CI, 55% to 66%) in those with culture-negative severe sepsis. Major determinants of both early ( P P =.03), whereas secondary deaths were associated with the admission category ( P P P =.01) or cardiovascular ( P =.002) insufficiency, hypothermia ( P =.02), thrombocytopenia ( P =.01), and multiple sources of infection ( P =.02). In patients with documented sepsis, bacteremia was associated with early mortality ( P =.03). Conclusions. —Only three of four patients presenting with clinically suspected severe sepsis have documented infection. However, patients with clinically suspected sepsis but without microbiological documentation and patients with documented infection share common risk factors and are at similarly high risk of death. In addition to the severity of illness score, acute organ failures and the characteristics of underlying diseases should be accounted for in stratification of patients and outcome analyses. ( JAMA . 1995;274:968-974)

Incidence, risk factors, and outcome of severe sepsis and septic shock in adults. A multicenter prospective study in intensive care units. French ICU Group for Severe Sepsis.

Objective. —To assess the efficacy of adjunctive monoclonal antibody antiendotoxin immunotherapy in patients with gram-negative sepsis. Design. —Double-blind, randomized, placebo-controlled trial. Setting. —Thirty-three university-affiliated centers, including Veterans Affairs, community, and municipal hospitals. Patients. —Hospitalized adults with signs of gram-negative infection and a systemic septic response. Intervention. —Patients were assigned to receive either 2 mg/kg of a murine monoclonal antibody directed against gram-negative endotoxin (E5) or placebo. A second infusion was administered 24 hours later. Main Outcome Measures. —Mortality over the 30-day study period, resolution of organ failures, and safety. Results. —Four hundred eighty-six patients were enrolled. Three hundred sixteen had confirmed gram-negative sepsis (54% bacteremic, 46% nonbacteremic). The survival difference was not statistically significant for all patients. Among patients with gram-negative sepsis who were not in shock at study entry (n = 137), E5 treatment resulted in significantly greater survival (relative risk, 2.3; P =.01). Resolution of individual organ failures was more frequent among these patients, occurring in 19 (54%) of 35 patients in the E5 group vs eight (30%) of 27 in the placebo group ( P =.05). Four reversible allergic reactions occurred among 247 patients (1.6%) receiving E5. No other toxicity was identified. Conclusions. —Treatment with E5 antiendotoxin antibody appears safe. It reduces mortality and enhances the resolution of organ failure among patients with gram-negative sepsis who are not in shock when treated. ( JAMA . 1991;266:1097-1102)

M A Martin

Papers

A Controlled Clinical Trial of E5 Murine Monoclonal IgM Antibody to Endotoxin in the Treatment of Gram-Negative Sepsis