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PubMed2005

Pediatric cancer patients in clinical trials of sepsis: factors that predispose to sepsis and stratify outcome.

OBJECTIVE: To delineate the factors that predispose pediatric oncology and hematopoietic stem cell transplant (HSCT) patients to sepsis and to identify factors that stratify their outcome. DATA SOURCE: Peer-reviewed literature available via MEDLINE search. STUDY SELECTION: All types of study. CONCLUSIONS: Pediatric oncology patients account for a relatively high proportion of severe sepsis in children. Available data suggest that outcomes among the non-HSCT oncology population are not substantially different from that of the general population. Data suggest that children with cancer (non-HSCT) who survive their septic episode will have a high probability of 6-month survival. In light of these findings, pediatric oncology patients are an important source of potential candidates for clinical trials of sepsis. In addition, HSCT patients seem to have significantly worse outcomes from sepsis than the non-HSCT oncology population, and thus, their participation in clinical trials is needed. However, in view of these worse outcomes, it is important to stratify the randomization for this population and to ensure that studies are adequately powered to assess outcomes in this subgroup.

Adolescent↗
PubMed2006

Intravenous polyclonal IgM-enriched immunoglobulin therapy in sepsis: a review of clinical efficacy in relation to microbiological aetiology and severity of sepsis.

The efficacy of intravenous polyclonal immunoglobulin (IVIG) as adjunct therapy in sepsis has long been debated. Clinical trials have yielded contradicting results, in part due to the varying study design and varying microbiological aetiologies. In most trials, the study drug has been IVIG containing polyclonal IgG. However, in recent reports, the efficacy of IgM-enriched IVIG as adjunct therapy in sepsis has been highlighted. Here we review studies on IgM-enriched IVIG therapy in sepsis and we discuss the clinical efficacy in relation to microbiological aetiology and severity of sepsis. The results suggest that patients most likely to benefit from IgM-enriched IVIG therapy are those with Gram-negative septic shock.

Adjuvants, Immunologic↗
PubMedDate not supplied

TPN catheter sepsis: lack of effect of subcutaneous tunnelling of PVC catheters on sepsis rate.

In an effort to diminish the incidence of catheter related sepsis in total parenteral nutrition, the effect of a 10-cm long subcutaneous tunnel was studied in a prospective randomized manner. This tunnel created a longer anatomical distance between puncture site of the catheter and the subclavian vein. In the control group, a direct puncture technique was employed. Eighty-one catheters (group A) were inserted according to the direct technique, 69 (group B) were tunnelled. Catheter sepsis was defined as an episode of clinical sepsis for which no other cause can be identified and which resolves upon removal of the catheter. No significant differences were noted between the two groups, suggesting that tunnelling of subclavian PVC catheters does not diminish the incidence of catheter related sepsis.

Catheters, Indwelling↗
PubMed2006

The disconnect between animal models of sepsis and human sepsis.

Frequently used experimental models of sepsis include cecal ligation and puncture, ascending colon stent peritonitis, and the i.p. or i.v. injection of bacteria or bacterial products (such as LPS). Many of these models mimic the pathophysiology of human sepsis. However, identification of mediators in animals, the blockade of which has been protective, has not translated into clinical efficacy in septic humans. We describe the shortcomings of the animal models and reasons why effective therapy for human sepsis cannot be derived readily from promising findings in animal sepsis.

Animals↗
PubMed1992

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↗
PubMed1991

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↗
PubMed1985

Catheter-related sepsis in patients on intravenous nutrition: a prospective study of quantitative catheter cultures and guidewire changes for suspected sepsis.

One hundred and ninety-five central venous catheters used for intravenous nutrition in 113 patients were studied prospectively. Catheter-related sepsis (CRS), defined by recovery of the same organism from the catheter tip and peripheral blood cultures, occurred with only 3.3 per cent of catheters or 2.3 per 1000 days of therapy. In contrast, CRS was suspected with 30 per cent of catheters and catheter contamination occurred in 37 per cent. Contamination was defined by a positive catheter tip culture without recovery of the same organism from the blood. CRS was present in 4 of 12 cases (33 per cent) with greater than 1000 colony forming units on the catheter tip but in only 2 of 54 (4 per cent) with fewer organisms. Thirty-eight cases suspected of having CRS were randomized to have catheter removal and later replacement, or replacement over a guidewire. There were no significant differences in the catheter contamination rate but there were significantly fewer problems of insertion in the guidewire group. However, transfer of Klebsiella sp., during the guidewire procedure, resulted in subsequent sepsis in one case. It is concluded that replacement of catheters over a guidewire is a safe and convenient way of establishing whether sepsis is catheter-related. Because organisms may be transferred, the procedure is not an appropriate treatment for catheter-related sepsis.

Adolescent↗
PubMed1995

Oxidative metabolism in sepsis and sepsis syndrome.

The high mortality associated with sepsis syndrome and multiple organ dysfunction syndrome has persisted despite extraordinary research efforts in the laboratory and the intensive care unit. These syndromes produce systemic tissue damage that is likely to result from widespread inflammation and subsequent endothelial injury. This article reviews the oxidative metabolic effects and responses to sepsis syndrome at several levels: the oxygen transport system, the cell, and the mitochondrion. Specifically, aerobic metabolism of carbon substrates and oxygen is altered in sepsis. As a result of systemic inflammation and nonmetabolic oxygen use, oxidative stress may occur both outside and inside the cell. The consequences of these oxidative processes during sepsis may be ongoing cell damage mediated by reactive oxygen and nitrogen oxide species that culminates in multisystem organ failure.

Energy Metabolism↗
PubMed2000

Recombinant bactericidal/permeability-increasing protein (rBPI21) as adjunctive treatment for children with severe meningococcal sepsis: a randomised trial. rBPI21 Meningococcal Sepsis Study Group.

BACKGROUND: Endotoxin is a primary trigger of the inflammatory processes that lead to shock, multiorgan failure, and purpura fulminans in meningococcal sepsis. Bactericidal/permeability-increasing protein (BPI) is a natural protein, stored within the neutrophil granules, that binds to and neutralises the effects of endotoxin in vitro, in laboratory animals, and in humans. To establish whether a recombinant 21-kDa modified fragment of human BPI (rBPI21), containing the active antimicrobial and endotoxin-neutralising moiety, would decrease death and long-term disability from meningococcal sepsis, we did a randomised, double-blind, placebo-controlled trial of rBPI21 in children with severe meningococcal sepsis. METHODS: We enrolled children (2 weeks to 18 years of age) presenting to 22 centres in the UK and the USA with a clinical picture suggestive of meningococcal sepsis, and with evidence of severe disease. Children were randomly assigned rBPI21 (2 mg/kg over 30 min followed by 2 mg/kg over 24 h) or placebo (0.2 mg/mL human albumin solution) in addition to conventional medical therapy. Primary outcome variables were mortality, amputations, and change in paediatric overall performance category (POPC) from before illness to day 60. Analysis was by intention to treat. FINDINGS: Of 1287 patients screened, 892 were excluded, including 57 patients who died or who met criteria for imminent death before receiving the study drug. 190 patients received rBPI21, and 203 placebo. 34 (8.7%) of 393 patients died during the study: 14 (7.4%) in the rBPI21 group and 20 (9.9%) in the placebo group (odds ratio 1.31 [95% CI 0.62-2.74], p=0.48). Compared with patients randomised to placebo, fewer patients treated with rBPI21 had multiple severe amputations (six of 190 [3.2%] vs 15 of 203 [7.4%], odds ratio 2.47 [0.94-6.51], p=0.067), and more had a functional outcome similar to that before illness (as measured by the POPC scale) at day 60 (136 of 176 [77.3%] vs 126 of 190 [66.3%], p=0.019). INTERPRETATION: Because most deaths occurred in the interval between identification of patients and study drug administration, the mortality rate in the placebo group was substantially lower than predicted. The trial was therefore underpowered to detect significant differences in mortality. However, patients receiving rBPI21 had a trend towards improved outcome in all primary outcome variables. Given the excellent severity match between placebo and rBPI21 groups at study entry, the results overall indicate that rBPI21 is beneficial in decreasing complications of meningococcal disease.

Adolescent↗
PubMed1996

Use of predicted risk of mortality to evaluate the efficacy of anticytokine therapy in sepsis. The rhIL-1ra Phase III Sepsis Syndrome Study Group.

OBJECTIVES: To investigate a novel anticytokine therapy in patients with sepsis syndrome, and the relationship between a patient's baseline mortality risk and survival benefit. DESIGN: Data from a recent phase III, double-blind, placebo-controlled, multicenter clinical trial with patients randomized to three treatment arms: an intravenous loading dose of recombinant human interleukin-1-receptor antagonist (rhIL-1ra) or placebo, followed by a continuous infusion of rhIL-1ra (1.0 mg/kg/hr, or 2.0 mg/kg/hr), or placebo for 72 hrs. SETTING: Sixty-three investigative centers in eight countries. PATIENTS: The study population consisted of 893 patients: 302 placebo patients; 298 patients treated with 1.0 mg/kg/hr of rhIL-1ra; and 293 patients treated with 2.0 mg/kg/hr of rhIL-1ra. MEASUREMENTS AND MAIN RESULTS: An independent, sepsis-specific, log-normal regression model that predicts the risk of mortality over 28 days was applied to all patients enrolled into the rhIL-1ra sepsis study. The ability of the Predicted Risk of Mortality model to predict 28-day mortality in the placebo patients was determined and the relationship between mortality risk and efficacy of rhIL-1ra was investigated. The trial data were also analyzed using two other risk-assessment models for comparison with Predicted Risk of Mortality. A significant increase in survival time was demonstrated for all patients treated with rhIL-1ra (n = 893, p < .02 Predicted Risk of Mortality log-normal), but patients with a Predicted Risk of Mortality of < 24% derived little benefit. Retrospective examination of time-to-death data demonstrated that rhIL-1ra reduced risk of death in the first 2 days for patients with > or = 24% Predicted Risk of Mortality (n = 580, p < .005 Predicted Risk of Mortality log-normal). This same effect was not present in patients with a Predicted Risk of Mortality of < 24% on entry into the study. The Predicted Risk of Mortality model predicted a 28-day mortality rate of 35% for placebo patients compared with 34% observed and accurately stratified patients along the full range of risks. There was a wide distribution of individual patient risks for 28-day mortality for all patients, as well as within categorical subgroups, such as shock and organ system dysfunction. Two alternate risk models were assessed and the Acute Physiology Score of Acute Physiology and Chronic Health Evaluation III also demonstrated a statistically significant survival benefit for rhIL-1ra (p = .04 Predicted Risk of Mortality log-normal) for all patients treated. CONCLUSIONS: Using an appropriate analytic model, a statistically significant increase in survival time from rhIL-1ra was measured. A direct relationship was found between a patient's Predicted Risk of Mortality at study entry to efficacy of rhIL-1ra. Individual risk or severity assessment may be a useful tool for evaluating the clinical benefit of new therapeutic approaches to sepsis and for monitoring outcomes at the bedside.

APACHE↗
PubMed1996

INTERSEPT: an international, multicenter, placebo-controlled trial of monoclonal antibody to human tumor necrosis factor-alpha in patients with sepsis. International Sepsis Trial Study Group.

OBJECTIVE: To determine the safety and efficacy of BAY x 1351, a murine monoclonal antibody to recombinant human tumor necrosis factor (TNF)-alpha, in patients with sepsis. DESIGN: An international, multicenter, prospective, placebo-controlled trial in patients with sepsis, stratified into shock/nonshock groups. SETTING: Forty acute clinical care facilities in 14 countries. PATIENTS: Of the 564 patients enrolled in the study, 553 patients received study drug or placebo. INTERVENTIONS: Patients received 15 mg/kg or 3 mg/kg of BAY x 1351, or placebo, as a single intravenous infusion. MEASUREMENTS AND MAIN RESULTS: The patients were well matched for severity of illness and for risk factors known to influence the outcome of sepsis. There was no difference in 28-day mortality rates between groups (placebo group 66 [39.5%] of 167;3 mg/kg group 57 [31.5%] of 181; 15 mg/kg group 87 [42.4%] of 205). Approximately 9 months after this study had begun, an interim safety examination of NORASEPT, a North American Sepsis Trial using the same monoclonal antibody, indicated that there was no benefit to patients in the nonshock group and further enrollment of these nonshock septic patients into INTERSEPT was stopped. The analysis therefore focused on the 420 patients in shock. The primary efficacy variable was the 28-day, all-cause mortality rate: placebo group 57 (42.9%) of 133; 3-mg/kg group 51 (36.7%) of 139; and 15-mg/kg group 66 (44.6%) of 148 (not significant). Two secondary efficacy variables were identified prospectively: shock reversal and frequency of organ failures. Life-table analysis showed that in patients who survived 28 days, there was a more rapid reversal of shock in both treatment groups compared with placebo (15-mg/kg group vs. placebo group log-rank statistic p = .007, 3-mg/kg group vs. placebo group p = .01). Similarly, in patients surviving 28 days, there was a significant delay in the time to the onset of first organ failure (log rank 15 mg/kg vs. placebo p = .03, 3 mg/kg vs. placebo p = .07), and more patients in the placebo group developed at least one organ failure: 15-mg/kg group 33 (40.2%) of 82; 3-mg/kg group 39 (44.3%) of 88; and placebo group 45 (59.2%) of 76 (15 mg/kg vs. placebo p = .03, 3 mg/kg vs. placebo p = .06). No significant adverse events were associated with the monoclonal antibody treatment. CONCLUSIONS: INTERSEPT provides additional clinical data implicating TNF-alpha as an integral mediator of septic shock. The study suggested a possible role for anti-TNF antibody as adjunctive therapy, but this possibility requires confirmation by another clinical trial.

APACHE↗
PubMed1992

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↗
PubMedDate not supplied

Frequency and timing of symptoms in infants screened for sepsis: effectiveness of a sepsis-screening pathway.

To determine the frequency and timing of symptoms and to evaluate the effectiveness of a sepsis-screening pathway in term and near-term infants, data were collected prospectively for a period of 1 year from December 1, 2000, to November 30, 2001. Results confirmed that a sepsis-screening pathway using a combination of at least 2 serial complete blood cell count and C-reactive protein measurements in both symptomatic and asymptomatic infants is a safe, simple strategy that prevents unnecessary treatment of infants with risk factors with antibiotics. However, most infants with presumed or suspected early-onset sepsis are symptomatic. Routine treatment of asymptomatic infants with risk factors or prior treatment with intrapartum antibiotics is unnecessary. A combined approach of screening in the presence of risk factors and /or symptoms of sepsis and adequate follow-up for infants discharged at less than 72 hours of age may help reduce unnecessary treatment of infants with antibiotics.

Bacteremia↗
PubMed2006

Advances in the management of sepsis: the randomised controlled trials behind the Surviving Sepsis Campaign recommendations.

The Surviving Sepsis Campaign is the first international, multiorganisation, multidisciplinary attempt to reduce the appalling morbidity and mortality related to sepsis. Under the auspices of the campaign, guidelines have been published that cover more than 50 aspects of care of the septic patient. Campaign guidelines on antimicrobial therapy cover very general aspects of antibiotic policy and are mostly supported by expert opinion rather than randomised controlled trials. However, these 'common sense' recommendations on antibiotic therapy have been included in this review. The core areas of the Surviving Sepsis Campaign guidelines have been crystallised into resuscitation and management 'bundles'. This review focuses on the most important clinical trials that form the basis of these core guidelines.

Anti-Bacterial Agents↗
PubMed1996

Aerosolized surfactant in adults with sepsis-induced acute respiratory distress syndrome. Exosurf Acute Respiratory Distress Syndrome Sepsis Study Group.

BACKGROUND: Patients with acute respiratory distress syndrome (ARDS) have a deficiency of surfactant. Surfactant replacement improves physiologic function in such patients, and preliminary data suggest that it may improve survival. METHODS: We conducted a prospective, multicenter, double-blind, randomized, placebo-controlled trial involving 725 patients with sepsis-induced ARDS. Patients were stratified according to the risk of death at base line (indicated by their score on the Acute Physiological and Chronic Health Evaluation [APACHE III] index) and randomly assigned to receive either continuously administered synthetic surfactant (13.5 mg of dipalmitoylphosphatidylcholine per milliliter, 364 patients) or placebo (o.45 percent saline; 361 patients) in aerosolized form for up to five days. RESULTS: The demographic and physiologic characteristics of the two treatment groups were similar at base line. The mean (+/- SD) age was 50 +/- 17 years in the surfactant group and 53 +/- 18 years in the placebo group, and the mean APACHE III scores at randomization were 70.4 +/- 25 and 70.5 +/- 25, respectively. Hemodynamic measures, measures of oxygenation, duration of mechanical ventilation, and length of stay in intensive care unit did not differ significantly in the two groups. Survival at 30 days was 60 percent for both groups. Survival was similar in the groups when analyzed according to APACHE III score, cause of death, time of onset and severity of ARDS, presence or absence of documented sepsis, underlying disease, whether or not there was a do-not-resuscitate order, and medical center. Increased secretions were significantly more frequent in the surfactant group; the rates of other complications were similar in the two groups. CONCLUSIONS: The continuous administration of aerosolized synthetic surfactant to patients with sepsis-induced ARDS had no significant effect on 30-day survival, length of stay in the intensive care unit, duration of mechanical ventilation, or physiologic function.

Administration, Inhalation↗
PubMed2005

The Surviving Sepsis Campaign sepsis change bundles and clinical practice.

The Surviving Sepsis Campaign (SSC) is an international effort to reduce mortality in severe sepsis and septic shock. The campaign included the creation of evidence-based guidelines sponsored and endorsed by 11 international organizations. From these guidelines, sepsis change bundles for initial resuscitation (6 hours) and management (24 hours) were created as a performance improvement tool. In this issue of Critical Care, Gao et al. have evaluated performance at their institution by using a close adaptation of the two SSC bundle sets and demonstrated an association between 100% compliance with the bundle elements and clinical outcome. The next step will be to demonstrate that the use of education and feedback for performance improvement will increase compliance and decrease mortality in the patient population in general.

Clinical Protocols↗
PubMed2005

[Biochemical disturbances in patients with Systemic Inflammatory Response Syndrome (SIRS) and sepsis. Part I. Biochemical disturbances in patients with sepsis].

Analysis of biochemical transformations occurring in the course of SIRS and sepsis inclines a critical attitude towards, obligatory nowadays, criteria of these states. They are non-specific and, in an unsatisfying way, they define the state of a current immunological response of the organism from the laboratory as well as clinical point of view. The purpose of the project of a new approach to sepsis--PIRO is to create a more objective, measurable system of evaluation of clinical state of a patient suspected of sepsis.

Humans↗
PubMedDate not supplied

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↗