• Surgical Infections 12/2011; 12(6):423-5. DOI:10.1089/sur.2011.9909 · 1.72 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Septic shock causing or complicating critical surgical illness results in high mortality. Drotrecogin alfa (activated), known also as recombinant human activated protein C (rhAPC) has become controversial as therapy, owing to persisting questions of efficacy and safety. We hypothesized rhAPC to be effective therapy for critically ill surgical patients with septic shock. Open-label therapy with rhAPC (by predefined criteria) of 108 critically ill surgical patients. Treated patients were matched individually in prospect for age, gender, Acute Physiology and Chronic Health Evaluation (APACHE)-II and -III scores, site of infection, and organism (0-2 points each, maximum 12 points) with 108 patients from our 15,000-patient surgical intensive care unit database who did not receive rhAPC. No match was accepted if <6 points. Multiple organ dysfunction (MOD) scores and data regarding cortisol concentrations, bleeding complications, and transfusion requirements were collected. The primary endpoint was 28-day mortality, with mortality for hospitalization and resolution of organ dysfunction as secondary endpoints. Statistical analyses included ANOVA, c statistic, binary logistic regression, and Kaplan-Meier time-to-event and Cox proportional hazards analyses; α=0.05. The mean match score was 9.2±0.1 points (range, 6-12 points). Patients were well matched by all criteria, including baseline MOD score (9.5±0.7 vs. 9.8±0.3 points, p=0.66). Mean age was 68.1±1.1 years (p=0.49), Mean APACHE-III score was 99.6±1.5 points (p=0.87). Mean time to rhAPC administration was 25±3 h. Survival at 28 days after rhAPC was 71.3% vs. 49.1% (p=0.001); hospital survival was 57.4% vs. 40.7% (p=0.02). By logistic regression, rhAPC therapy resulted in improved 28-day survival (OR 2.57, 95% CI 1.46-4.52, p=0.001) (model χ2 11.244, p=0.001); and hospital survival (OR 1.96, 95% CI 1.14-3.36, p=0.015) (model χ2 6.03, p=0.014). The MOD score decreased significantly (p=0.012) during rhAPC therapy. Therapy with rhAPC appeared to improve survival in surgical ICU patients with life-threatening infection characterized by septic shock and organ dysfunction.
    Surgical Infections 12/2011; 12(6):443-9. DOI:10.1089/sur.2011.133 · 1.72 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Sepsis is a common problem in preterm and term infants. The incidence of neonatal sepsis has declined, but mortality remains high. Recombinant human activated protein C (rhAPC) possess a broad spectrum of activity modulating coagulation and inflammation. In septic adults it may reduce mortality, but no significant benefit has been reported in children with severe sepsis. To determine whether treatment with rhAPC reduces mortality and/or morbidity in neonatal sepsis. For this update searches were carried out in May 2011 of the Cochrane Central Register of Controlled Trials (The Cochrane Library), MEDLINE, EMBASE, CINAHL, and abstracts of annual meetings of the Pediatric Academic Societies. Doctoral dissertations, theses and the Science Citation Index for articles on activated protein C were searched. No language restriction was applied. Randomized or quasi-randomized trials, assessing the efficacy of rhAPC compared to placebo or no intervention as an adjunct to antibiotic therapy of suspected or confirmed severe sepsis in term and preterm infants less than 28 days old. Eligible trials should report at least one of the following outcomes: mortality during initial hospital stay, neurodevelopmental assessment at two years of age or later, length of hospital stay, duration of ventilation, chronic lung disease, periventricular leukomalacia, intraventricular haemorrhage, necrotizing enterocolitis, bleeding, and any other adverse events. Review authors were to independently evaluate the articles for inclusion criteria and quality, and abstract information for the outcomes of interest. Differences were to be resolved by consensus. The statistical methods were to include relative risk, risk difference, number needed to treat to benefit or number needed to treat to harm for dichotomous and weighed mean difference for continuous outcomes reported with 95% confidence intervals. A fixed effect model was to be used for meta-analysis. Heterogeneity tests, including the I(2) statistic, were to be performed to assess the appropriateness of pooling the data. No eligible trials were identified. In October 2011 rhAPC (Xigris®) was withdrawn from the market by Eli Lilly due to a higher mortality in a trial among adults. Xigris® (DrotAA)( rhAPC) should no longer be used in any age category and the product should be returned to the distributor. Despite the scientific rationale for its use, there is insufficient data to use rhAPC for the management of severe sepsis in newborn infants. Due to the results among adults with lack of efficacy, an increase in bleeding and resulting withdrawal of rhAPC from the market, neonates should not be treated with rhAPC and further trials should not be conducted.
    Cochrane database of systematic reviews (Online) 01/2012; 4(4):CD005385. DOI:10.1002/14651858.CD005385.pub3 · 5.94 Impact Factor