Sepsis, severe sepsis or sepsis syndrome: need for clarification.
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Humans↗
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Gram-negative sepsis, the sepsis syndrome, and the role of antiendotoxin monoclonal antibodies.
The incidence and mortality, pathogenesis, clinical manifestations, and management of sepsis and the sepsis syndrome are reviewed, and the use of antiendotoxin monoclonal antibodies to treat patients with sepsis is discussed. The sepsis syndrome and septic shock are induced by the presence of endotoxin, a lipopolysaccharide found in the outer membrane of gram-negative bacteria. Proper management of gram-negative sepsis includes appropriate antimicrobial therapy, fluids and electrolytes, nutritional support, administration of vasopressors, and mechanical ventilation if necessary. To date, two antiendotoxin monoclonal antibodies have been produced and subjected to extensive clinical testing. HA-1A, a human cell line-derived monoclonal immunoglobulin M (IgM) antibody that contains only a small fragment of murine protein, was tested in one trial. HA-1A significantly reduced mortality in patients with sepsis and gram-negative bacteremia and produced better resolution of major morbidities than placebo in those patients. E5, an IgM antibody produced entirely via murine monoclonal antibody technology, was evaluated in two trials. Results from the first trial showed that E5 significantly reduced mortality in patients with gram-negative infection who were not in refractory shock. In contrast, results from the second trial did not show any significant reduction in mortality among patients with gram-negative infection who received E5. However, resolution of major morbidities occurred more frequently among E5 recipients in both trials. HA-1A and E5 were both well tolerated in the trials. The cost of therapy is expected to be $3000-$4000 per treatment course. The antiendotoxin monoclonal antibodies represent the next step along the path toward important reductions in morbidity and mortality from gram-negative infection. However, the financial implications of the use of HA-1A and E5 are enormous, and stringent patient selection criteria for administration of these products will have to be developed.
Antibodies, Monoclonal↗
American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis.
OBJECTIVE: To define the terms "sepsis" and "organ failure" in a precise manner. DATA SOURCES: Review of the medical literature and the use of expert testimony at a consensus conference. SETTING: American College of Chest Physicians (ACCP) headquarters in Northbrook, IL. PARTICIPANTS: Leadership members of ACCP/Society of Critical Care Medicine (SCCM). RESULTS: An ACCP/SCCM Consensus Conference was held in August of 1991 with the goal of agreeing on a set of definitions that could be applied to patients with sepsis and its sequelae. New definitions were offered for some terms, while others were discarded. Broad definitions of sepsis and the systemic inflammatory response syndrome were proposed, along with detailed physiologic variables by which a patient could be categorized. Definitions for severe sepsis, septic shock, hypotension, and multiple organ dysfunction syndrome were also offered. The use of severity scoring methods were recommended when dealing with septic patients as an adjunctive tool to assess mortality. Appropriate methods and applications for the use and testing of new therapies were recommended. CONCLUSION: The use of these terms and techniques should assist clinicians and researchers who deal with sepsis and its sequelae.
Critical Care↗
Hypothermia in the sepsis syndrome and clinical outcome. The Methylprednisolone Severe Sepsis Study Group.
OBJECTIVE: To evaluate the consequences of clinical hypothermia associated with sepsis syndrome and septic shock. DESIGN: Analysis of data from a multi-institutional, randomized, placebo-controlled, prospective study with predetermined end-point analysis of development of shock, recovery from shock, hospital length of stay, and death. SETTING: Multi-institutional medical and surgical ICUs. PATIENTS: Patients meeting predetermined criteria for severe sepsis syndrome. INTERVENTIONS: Appropriate sepsis and shock care with 50% of patients receiving methylprednisolone and 50% receiving placebo. MEASUREMENTS AND MAIN RESULTS: The occurrence rate of hypothermia (< 35.5 degrees C) is 9% in this population. When compared with febrile patients, hypothermic patients had a higher frequency of central nervous system dysfunction (88% vs. 60%), increased serum bilirubin concentration (35% vs. 15%), prolonged prothrombin times (50% vs. 23%), shock (94% vs. 61%), failure to recover from shock (66% vs. 26%), and death (62% vs. 26%). The hypothermic patients were also more likely to be classified as having a rapidly or ultimately fatal disease upon study admission. CONCLUSIONS: This prospective study confirms that hypothermia associated with sepsis syndrome has a significant relationship to outcome manifest by increased frequency of shock and death from shock. This finding is in sharp contrast to the protective effects of induced hypothermia in septic animals and perhaps man.
Adolescent↗
Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine.
An American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference was held in Northbrook in August 1991 with the goal of agreeing on a set of definitions that could be applied to patients with sepsis and its sequelae. New definitions were offered for some terms, while others were discarded. Broad definitions of sepsis and the systemic inflammatory response syndrome were proposed, along with detailed physiologic parameters by which a patient may be categorized. Definitions for severe sepsis, septic shock, hypotension, and multiple organ dysfunction syndrome were also offered. The use of severity scoring methods when dealing with septic patients was recommended as an adjunctive tool to assess mortality. Appropriate methods and applications for the use and testing of new therapies were recommended. The use of these terms and techniques should assist clinicians and researchers who deal with sepsis and its sequelae.
Critical Care↗
A controlled clinical trial of E5 murine monoclonal IgM antibody to endotoxin in the treatment of gram-negative sepsis. The XOMA Sepsis Study Group.
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.
Aged↗
Interaction of sepsis and sepsis plus sympathomimetics on myocardial oxygen availability.
The ability to regulate myocardial blood flows (Q) in accord with changing myocardial O2 needs may be depressed in sepsis. This could be an important concern when sympathomimetics are used to augment systemic oxygen delivery (QO2) in this syndrome as increased myocardial O2 needs may accompany an infusion of this class of drugs. Therefore after measuring the effect of sepsis on myocardial O2 metabolism, we then infused various sympathomimetics to evaluate the sepsis+sympathomimetic interaction on myocardial QO2. We measured Q to the left (LV) and right (RV) ventricles by the radioactive microsphere technique in 36 unanesthetized mature sheep, before and during the infusion of dopamine, dobutamine, dopexamine, norepinephrine, salbutamol, or placebo. Randomly selected for infusion, these drugs were titrated to augment the thermodilution-derived cardiac index (CI) by greater than 20%. This study was repeated 24-48 h after cecal ligation and perforation had resulted in a hyperdynamic septic state [change (delta) in CI = sepsis - baseline = +54%; P less than 0.01]. During the septic study, both Q-LV (delta = +80%; P less than 0.01) and Q-RV (delta = +84%; P less than 0.01) were increased above baseline values; the augmented Q to both LV and RV was directly correlated with the arterial perfusion pressure (PA) x CI product and the mean pulmonary artery pressure (PPA) x CI product, respectively. Only 23% of study animals demonstrated net transmyocardial lactate production during the septic study. When the infusion of sympathomimetics was accompanied by an increase in the PPA x CI and PA x CI products, a further increase in both Q-RV and Q-LV, respectively, occurred. Also, neither the ventricular endocardial-to-epicardial flow ratios nor transmyocardial lactate extraction were modified by the sympathomimetics infusion. We conclude that the septic response to infection in this animal model was not accompanied by significant abnormalities in the metabolic regulation of myocardial QO2 (R. E. Cunnion, G. L. Scher, and M. M. Parker, Circulation 73: 637-644, 1986).
Animals↗
The Baltimore Sepsis Scale: measurement of sepsis in patients with burns using a new scoring system.
A new sepsis scale has been developed, and it consists of 13 parameters, each of which is measured daily on a variable point scale. In 41 patients with major burns the Baltimore Sepsis scale correlated well with death or survival, with occurrence of septicemia, and with the level of serum interleukin-6. It did not correlate well with the level of plasma endotoxin or with the type of organism that was grown in blood cultures (gram-positive or gram-negative). We propose that the Baltimore Sepsis Scale would be an accurate and easy scale to use for the measurement of interventions that are aimed at improving the septic state.
Burns↗
A comparison of ceftazidime and aminoglycoside based regimens as empirical treatment in 1316 cases of suspected sepsis in the newborn. European Society for Paediatric Infectious Diseases--Neonatal Sepsis Study Group.
We report a prospective, non-blind, randomised, multicentre, parallel group, multinational investigation to compare ceftazidime to aminoglycoside based regimens as empirical treatment in 1316 cases of suspected sepsis in the newborn. In each of the 15 study centres either ceftazidime alone (CAZ) or ceftazidime + ampicillin (CAZ + AMP) was compared to an amino-glycoside/ampicillin combination (AG + AMP). In all cases treatment was based on "an intention to treat". Bacteria considered to be pathogenic were isolated from 176/1316 (13.4%) patients. The incidence of proven infection varied from 39% in a Yugoslav centre to 6% in a British centre; a further 489/1316 (37.1%) patients fulfilled the criteria for clinically suspected sepsis. A total of 210 bacterial isolates from 197 infection sites in 176 patients were considered to be clinically significant. The cure rate for evaluable patients with proven infection who were treated with CAZ + AMP (97%, 30/31) was significantly higher than that for the corresponding patients treated with AG + AMP (66%, 26/39), (P < 0.002). The difference in cure rate between CAZ monotherapy (79%, 34/43) and AG + AMP (86%, 32/37) was not significant. Treatment failed in 28/150 (18.7%) evaluable patients. There were significantly fewer failures (P < 0.001) with CAZ + AMP than with AG + AMP therapy. There were 55 staphylococcal infections. Treatment was successful in 16/19 evaluable patients treated with CAZ or CAZ + AMP and in 16/29 evaluable patients treated with AG + AMP. None of the study centres encountered problems with ceftazidime resistant bacteria. The cure rate for patients with only clinical and radiological evidence of sepsis was greater than 94% in all treatment groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Aminoglycosides↗
Predictors of bacteremia and gram-negative bacteremia in patients with sepsis. The Veterans Affairs Systemic Sepsis Cooperative Study Group.
BACKGROUND: We analyzed data from the Department of Veterans Affairs trial of steroid therapy for systemic sepsis to identify predictors of bacteremia and gram-negative bacteremia. METHODS: Of the 2568 patients screened for entry in the trial, 465 met the following criteria: presence of four of seven clinical signs of sepsis; blood cultures at the time of screening; and complete data on nine clinical parameters. The multivariate logistic regression model was used to identify predictors of bacteremia and gram-negative bacteremia. Predicted probabilities of having these types of infections were calculated using the identified predictors. Patients were then classified into groups with and without bacteremia (and gram-negative bacteremia) based on the predicted probability. Misclassification error rates were calculated for each method of categorization by comparing the true with the predicted grouping of patients. RESULTS: Three factors were independently predictive of bacteremia and gram-negative bacteremia: elevated temperature, low systolic blood pressure, and low platelet count. Using these three factors, classification methods were identified that predicted blood infection better than chance, but misclassification was also high. For predicting bacteremia, the maximum predicted positive rate was 83%, with a specificity of nearly 100% and a sensitivity of only 5%. For predicting gram-negative bacteremia, the maximum predicted positive accuracy was 100%, with a specificity also of 100% and a sensitivity of almost 0%. CONCLUSIONS: Using simple clinical parameters, we could not predict either bacteremia or gram-negative bacteremia with sufficient accuracy to be clinically meaningful; however, our approach represents a step in the direction of forecasting the bacterial organism responsible for sepsis in advance of culture results.
Adrenal Cortex Hormones↗
Plasma elastase alpha 1-antitrypsin and lactoferrin in sepsis: evidence for neutrophils as mediators in fatal sepsis.
Increased vasopermeability and vasodilation, presumably the result of endothelial perturbation, are considered among the basic pathogenetic mechanisms in septic shock. Neutrophils have been implicated as a source for mediators in endothelial injury. We measured elastase-alpha 1-antitrypsin (alpha 1AT) complexes and lactoferrin as markers for release of neutrophil granule contents in plasma from patients with sepsis on admission to the Intensive Care Unit, and we delineated the relationship of neutrophil activation to other inflammatory parameters and to hemodynamic and biochemical parameters. Levels of elastase-alpha 1AT and lactoferrin significantly correlated with each other (r = 0.58; p less than 0.008), and were increased (greater than 3.33 and 5 nmol/L, respectively) in 96% and 71% of the patients, respectively. Lactoferrin, but not elastase-alpha 1AT, correlated with the number of white blood cells (r = 0.38; p = 0.008). Elastase-alpha 1 AT levels were significantly higher (p = 0.008), whereas white blood cell counts were lower (p = 0.015) in patients with shock when compared with patients without abnormal blood pressure. Both elastase-alpha 1AT and lactoferrin levels correlated with lactate levels (r = 0.33; p = 0.024 and r = 0.30; p = 0.04), suggesting a role for neutrophil activation in the pathogenesis of hypoxygenation. In addition, elastase-alpha 1AT correlated with the concentrations of interleukin 6 (IL-6) (r = 0.46; p = 0.001) and C3a (r = 0.38; p = 0.009), suggesting that cytokines and complement may contribute to the degranulation of neutrophils in sepsis. Elastase-alpha 1AT complexes were inversely related to C1-inhibitor (r = -0.33; p = 0.028) and to platelet numbers (r = -0.42; p = 0.003). Levels of elastase-alpha 1AT complexes in plasma appeared to be of prognostic significance; levels were higher in 27 patients who died than in 21 patients who survived (p = 0.01). The mortality in 27 patients with concentrations below 10 nM was 37%, whereas it was 81% in 21 patients with higher levels. The overall mortality in this study was 56%. These results provide further evidence that activation and degranulation of neutrophils, induced by multiple agonists, are involved in the development of fatal complications in patients with sepsis.
Bacterial Infections↗
The bacteriology of primary wound sepsis in potentially contaminated abdominal operations: the effect of irrigation, povidone-iodine and cephaloridine on the sepsis rate assessed in a clinical trial.
Two hundred and nine potentially contaminated abdominal operations were randomly allocated to prophylaxis with a single dose of 1 g cephaloridine intraincisionally, irrigation of the wound at the end of the operation with saline or spraying of the wound with povidone-iodine. In high risk operations (ileocolorectal or those in obese patients) the rate of major wound sepsis in those protected by cephaloridine was 3.8% compared with 13.2% in the irrigation and 16.7% in the povidone-iodine groups. In low risk operations no significant differences in sepsis rates were found. Bacteriological studies of incised organs, subcutaneous fat and pus showed that the majority of wound infections arose from endogenous sources. The outstanding problem remains that of prevention of contamination of the abdominal wall during surgery.
Abdomen↗
Hyperdynamic sepsis in baboons: II. Relation of organ damage to severity of sepsis evaluated by a newly developed morphological scoring system.
The purpose of our study was to set up a baboon hyperdynamic sepsis model with live bacteria administration, which produces within 8 hr an organ failure comparable to human pathological conditions. Twelve adult male baboons were instrumented and studied for 8 hr under pentobarbital (2-3 mg/kg BW/hr) anesthesia breathing spontaneously. The animals were divided into two groups: 1) Live Escherichia coli were infused intravenously at a dose of 1.0-2.0 x 10(10) CFU/kg BW over 8 hr; 2) Live E. coli were infused i.v. at a dose of 5 x 10(8) CFU/kg BW over 2 hr. Organ damage was monitored by a newly developed scoring system. Organ damage was clearly dependent on the concentration of the bacterial challenge. Bacterial challenge at a dosage of 5.0 x 10(8) produces insignificant hemodynamic effects, while the 1.0-2.0 x 10(10) animals demonstrated massive hemodynamic alterations and needed much higher fluid support. The higher E. coli dosage was associated with an overwhelming organ damage seen, e.g., from the lung weight (12 g/kg BW vs. 9.6 g/kg BW with the lower dosage) or from the organ failure score, which is based on macroscopic pathology, histological data and organ weight. The percentage of animals with one, two, or three organ failures (organ failure score > or = 2) was higher in baboons with the higher dosage/kg BW. Therefore, we believe that the less severe organ damage in the acute phase after 8 hr with live bacteria 5 x 10(8) CFU/kg BW infusion over 2 hr is better to monitor the efficacy of newly developed therapeutic regimens, since in another set of experiments this model still produces lethal organ damage (80%) in a subchronic setting over 72 hr.
Adrenal Glands↗
Sepsis-the Wayne State University Symposium--Part II. The increasing incidence of sepsis and antibiotic resistance.
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Bacteria↗
[Problems of surgical infection in the studies of sepsis (review of the reports of the All-Union conference "Actual problems of the studies of sepsis", Tbilisi, May 29-31, 1990)].
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Antisepsis↗
[Staphylococcus aureus sepsis in patients with hematological malignancies: increase in MRSA sepsis].
From January 1978 to August 1990, Staphylococcus aureus bacteremia (SAB) were identified in 31 patients with hematological malignancies at Jichi Medical School hospital. Mortality due to SAB was 48.4% (15/31). Of the variables analyzed, four factors were significantly associated with a poor prognosis; elderly age (p = 0.015), high granulocyte count (more than 500/microliters) (p = 0.015), presence of DIC (p = 0.011) and presence of pneumonia (p = 0.023). The incidence of methicillin-resistant SAB was 32.3% (10/31) and the first patient developed in 1985. Although not statistically significant, there was a trend of higher mortality for methicillin-resistant SAB (70%) than for methicillin-sensitive SAB (38.1%). Most strains of methicillin-resistant Staphylococcus aureus were sensitive to minocycline, chloramphenicol and vancomycin.
Adult↗
[Combination of exchange transfusion and directed antibiotic therapy in the treatment of severe sepsis. A case of multi-resistant Serratia marcescens sepsis].
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Anti-Bacterial Agents↗
Sepsis--the Wayne State University Symposium--part III. Bacteremia and endotoxemia: a discussion of their roles in the pathophysiology of gram-negative sepsis.
Bacteremia, or the presence of live bacteria in the bloodstream, does not seem a prerequisite for septic shock. Indeed, only a small portion of all patients who sustain gram-negative bacteremia ever develop the shock syndrome. Endotoxin in the laboratory model is capable of producing a number of pathophysiological alterations which can partly explain the varied picture of septic shock seen in man. Endotoxin is released from gram-negative bacteria upon their death, and it probably acts as an antigen which reacts with antibody and subsequently activates the complement cascade. The resultant production of vasoactive polypeptides and release of histamine from mast cells might account for the increased vascular permeability and early hyperdynamic cardiovascular function seen in septic shock. These changes may also contribute to ultimate stagnation and pooling in the peripheral microcirculation. Endotoxin is a potent stimulus to the sympathoadrenal system which causes varying effects on the periphery. Continued catecholamine stimulation at the periphery may ultimately contribute to stagnant anoxia by an effect on pre- and postcapillary sphincters. Endotoxin, by itself, will not directly impair cardiac contractility, but evidence for depressed function implies an interaction of endotoxin with other biochemical systems, such as vasoactive polypeptides, to indirectly produce the observed effects. Expression of a hemodynamic model closely approximating human septic shock requires, in addition to a source of endotoxin, a focus of inflammation. Such a focus, in all probability, supplies some as yet unidentified factor(s) which help produce the observed increase in cardiac output. The Limulus test has confirmed the presence of endotoxemia in gram-negative shock and has raised questions about the contribution of gut flora to the propagation of the syndrome. An enterogenous source of endotoxin may also be important in patients in whom a source of inflammation is not readily observable. Gram-negative shock remains an important and grave clinical problem. Knowledge about the relative roles of endotoxin various foci of inflammation, and generation of vasoactive peptides is accumulating slowly. Hopefully, by creating a clearer understanding of the pathophysiology, such knowledge will ultimately result in further improvement in our efforts to prevent and treat this syndrome.
Animals↗