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Low-dose heparin as treatment for early disseminated intravascular coagulation during sepsis: A prospective clinical study

Authors Liu XL , Wang XZ , Liu XX , Hao D , Jaladat Y , Lu F , Sun T , Lv CJ
Journal Experimental and therapeutic medicine
Year 2014
Links Pubmed DOI PubMed Central

This article is included in 2 Systematic reviews Systematic reviews (2 references)

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The present study aimed to investigate whether low-dose heparin improves the condition of patients suffering from early disseminated intravascular coagulation (pre-DIC) during sepsis. In total, 37 patients were randomly divided into low-dose heparin intervention and control groups. The heparin group received a low-dose of heparin for 5-7 days, while the other group received only saline. The two groups were treated for sepsis. Blood samples were collected at various times and acute physiology and chronic health evaluation (APACHE)-II scores were recorded at day 1 and 7. In addition, the number of days applying mechanical ventilation and in the intensive care unit (ICU) were recorded, as well as the 28-day mortality rate. APACHE-II scores in the two groups decreased following treatment, however, scores in the heparin group decreased more significantly. Prothrombin fragment and thrombin-antithrombin complex levels in the heparin group were significantly decreased. In addition, the number of days applying a ventilator was fewer and the total stay in ICU was significantly shorter compared with the control group. Significantly fewer complications were observed in the heparin group, however, there was no significant difference in the 28-day mortality rate. In conclusion, low-dose heparin improves the hypercoagulable state of sepsis, which subsequently reduces the incidence of DIC or multiple organ dysfunction syndrome, decreasing the number of days of mechanical ventilation and hospitalization.

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Evaluation of recombinant activated protein C for severe sepsis at a tertiary academic medical center.

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Journal Therapeutics and clinical risk management
Year 2013
Links Pubmed DOI PubMed Central

This article is included in 1 Systematic review Systematic reviews (1 reference)

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PURPOSE: Early clinical trials of recombinant human activated protein C (rhAPC) for severe sepsis excluded patients at high risk of bleeding. Recent literature suggests bleeding rates are higher in clinical practice and may be associated with worsened outcomes. Our objective was to evaluate baseline demographics; incidence, and risk factors for major bleeding; and mortality of patients receiving rhAPC for severe sepsis at our institution. METHODS: A retrospective study was performed for all patients receiving rhAPC for treatment of severe sepsis at a tertiary academic medical center from January 2002 to June 2009. Demographic information, clinical variables, intensive care unit, and hospital outcomes were recorded. RESULTS: Of the 156 patients that received rhAPC, 54 (34.6%) did not meet institutional criteria for safe use at baseline due to bleeding precaution or contraindication. Twenty-three (14.7%) patients experienced a major bleeding event. Multivariate analysis demonstrated baseline International Normalized Ratio ≥2.5 (odds ratio [OR] 3.68, 95% confidence interval [CI]: 1.28-10.56; P = 0.03) and platelet count ≤100 × 10(3)/mm(3) (OR 2.86, 95% CI: 1.07-7.67; P = 0.01) as significant predictors of a major bleed. Overall hospital mortality was 57.7%. Multivariate analysis demonstrated the presence of ≥3 organ dysfunctions (OR 2.46, 95% CI: 1.19-5.09; P < 0.05) and medical intensive care unit admission (OR 1.99, 95% CI: 1.00-3.98; P = 0.05) were independent variables associated with hospital mortality. CONCLUSION: Patients receiving rhAPC at our institution had higher APACHE II scores, mortality, and major bleeding events than published postmarketing studies. Risk factors for major bleeding other than package-labeling contraindications and bleeding precautions were identified in our patient population.

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Drotrecogin alfa (activated) in adults with septic shock.

Journal The New England journal of medicine
Year 2012
Links Pubmed DOI

This article is included in 3 Systematic reviews Systematic reviews (3 references) 1 Structured summary of primary studies Structured summaries of primary studies (1 reference)

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<b>BACKGROUND: </b>There have been conflicting reports on the efficacy of recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), for the treatment of patients with septic shock.<b>METHODS: </b>In this randomized, double-blind, placebo-controlled, multicenter trial, we assigned 1697 patients with infection, systemic inflammation, and shock who were receiving fluids and vasopressors above a threshold dose for 4 hours to receive either DrotAA (at a dose of 24 μg per kilogram of body weight per hour) or placebo for 96 hours. The primary outcome was death from any cause 28 days after randomization.<b>RESULTS: </b>At 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% confidence interval [CI], 0.92 to 1.28; P=0.31). At 90 days, 287 of 842 patients (34.1%) in the DrotAA group and 269 of 822 (32.7%) in the placebo group had died (relative risk, 1.04; 95% CI, 0.90 to 1.19; P=0.56). Among patients with severe protein C deficiency at baseline, 98 of 342 (28.7%) in the DrotAA group had died at 28 days, as compared with 102 of 331 (30.8%) in the placebo group (risk ratio, 0.93; 95% CI, 0.74 to 1.17; P=0.54). Similarly, rates of death at 28 and 90 days were not significantly different in other predefined subgroups, including patients at increased risk for death. Serious bleeding during the treatment period occurred in 10 patients in the DrotAA group and 8 in the placebo group (P=0.81).<b>CONCLUSIONS: </b>DrotAA did not significantly reduce mortality at 28 or 90 days, as compared with placebo, in patients with septic shock. (Funded by Eli Lilly; PROWESS-SHOCK ClinicalTrials.gov number, NCT00604214.).

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Severe protein C deficiency is associated with organ dysfunction in patients with severe sepsis

Journal Journal of critical care
Year 2011
Links Pubmed DOI

This article is included in 1 Systematic review Systematic reviews (1 reference)

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Purpose: The aim of this study was to assess the relationship between protein C levels and temporal changes in organ dysfunction. Materials and Methods: Using data from the placebo arm of Recombinant Human Activated PROtein C Worldwide Evaluation in Severe Sepsis trial (N = 775), we compared the development of organ dysfunction over time, in adult severe sepsis patients with and without severe protein C deficiency. Results: At study enrollment (baseline), patients with and without severe protein C deficiency were similar in age and likelihood of comorbidities. Patients with severe protein C deficiency had lower arterial blood pressure (P = .0006), greater serum creatinine concentration (P < .0001), elevated markers of thrombosis and inflammation, and impairment of fibrinolysis (P < .0001). The baseline PaO 2/FiO 2 ratio was not significantly different between the 2 groups. Seven days after study enrollment, cardiovascular and renal function remained significantly worse in patients with severe protein C deficiency (P < .0001), and respiratory dysfunction was greater (P < .0001). Baseline protein C deficiency was seen to be associated with subsequent pulmonary, renal, and hematologic organ failure. Conclusions: Severe protein C deficiency in patients with severe sepsis is associated with both the incidence and severity of organ dysfunction and subsequent worsening of organ function and may be a useful predictor of organ failure in severe sepsis. © 2011 Elsevier Inc.

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Unblinding plan of PROWESS-SHOCK trial.

Journal Intensive care medicine
Year 2011
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This article is included in 1 Systematic review Systematic reviews (1 reference)

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Activated protein C in septic shock: a propensity-matched analysis.

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Journal Critical care (London, England)
Year 2011
Links Pubmed DOI PubMed Central

This article is included in 1 Systematic review Systematic reviews (1 reference)

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INTRODUCTION: The use of human recombinant activated protein C (rhAPC) for the treatment of severe sepsis remains controversial despite multiple reported trials. The efficacy of rhAPC remains a matter of dispute. We hypothesized that patients with septic shock who were treated with rhAPC had an improved in-hospital mortality compared to patients with septic shock with similar acuity who did not receive rhAPC. METHODS: This retrospective cohort study was completed at a large university-affiliated hospital. All patients with septic shock admitted to a 50-bed ICU between July 2003 and February 2009 were included. Patients were treated according to sepsis management guidelines. RESULTS: A total of 563 septic shock patients were included (110 received rhAPC and 453 did not). Treated and untreated groups were matched in patient characteristics, comorbidities, and physiologic variables in a 1:1 propensity-matched analysis (108 received rhAPC, 108 did not). Mean Acute Physiology And Chronic Health Evaluation II (APACHE II) scores were 24.5 for the matched treated and 23.9 for the matched untreated group (P = 0.54). Receipt of rhAPC was associated with reduced in-hospital mortality (35.2% vs. 53.8%, P = 0.005), similar mean days on vasopressors (2 vs. 2, P = 0.90), similar mean days on mechanical ventilation (9 vs. 8.7, P = 0.80), similar mean length of ICU stay in days (11.0 vs. 11.3, P = 0.90), and similar mean length of hospital stay in days (19.5 vs 27, P = 0.11). No patients in either group had intracranial bleeding; differences in gastrointestinal bleeding and transfusion requirements were not statistically significant. CONCLUSIONS: Patients in our institution with septic shock who were treated with rhAPC had a reduced in-hospital mortality compared with patients with septic shock with similar acuity who were not treated with rhAPC. In addition, time on mechanical ventilation, time on vasopressors, lengths of stay and bleeding complications did not differ between the groups.

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Activated protein C and hospital mortality in septic shock: a propensity-matched analysis.

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Journal Critical care medicine
Year 2010
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This article is included in 1 Systematic review Systematic reviews (1 reference)

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OBJECTIVE: Evidence regarding the efficacy and safety of human recombinant activated protein C in severe sepsis is limited, especially outside of clinical trials. We sought to compare the outcomes of patients with septic shock who received early treatment with activated protein C to those who did not. DESIGN, SETTING, AND PATIENTS: A retrospective cohort study at 404 U.S. hospitals. We studied 33,749 patients with sepsis who were admitted to intensive care and administered antibiotics and vasopressors within 2 days of admission. MEASUREMENTS AND MAIN RESULTS: Hospital mortality, intracranial and gastrointestinal hemorrhage, major transfusion. Compared to the entire cohort, the 1576 activated protein C-treated patients included in the matched analysis were younger (mean age, 61 vs. 67), more likely to be white (70% vs. 63%), and had fewer comorbidities. Treated patients were more likely to require mechanical ventilation (77% vs. 48%), to be administered two or more vasopressors (68% vs. 41%), to undergo pulmonary artery catheterization (9% vs. 4%), and to die in the hospital (40.7% vs. 38.1%). In a propensity-matched sample in which all covariates achieved balance, receipt of activated protein C was associated with reduced hospital mortality (40.7% vs. 46.6%; risk ratio, 0.87; 95% confidence interval, 0.80-0.95). This result was insensitive to a hypothetical unmeasured confounder. A similar pattern was observed across groups stratified by age and number of organ-supportive therapies. Four activated protein C-treated patients (0.25%) had hemorrhagic stroke, 107 (6.8%) had gastrointestinal bleeding, and five (0.3%) required major transfusion. CONCLUSIONS: Among patients presenting with septic shock, early treatment with activated protein C may be associated with reduced hospital mortality.

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Statistical analysis plan of PROWESS SHOCK study.

Journal Intensive care medicine
Year 2010
Links Pubmed DOI PubMed Central

This article is included in 1 Systematic review Systematic reviews (1 reference)

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A prospective, observational study of Xigris Use in the United States (XEUS)

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Journal Journal of critical care
Year 2010
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This article is included in 1 Systematic review Systematic reviews (1 reference)

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Background: Use of pharmacologic agents in clinical practice may differ from the manner in which they were studied in rigorous randomized clinical trials. This was a prospective, observational, noninterventional study to determine the profile of patients receiving drotrecogin alfa (activated) in clinical practice, provide additional outcome and safety data, and allow for a comparison to patients studied in the phase 3 Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial. Methods: A total of 548 adult patients with severe sepsis were enrolled from 61 nonteaching or academically affiliated hospitals in the United States. Patients received drotrecogin alfa (activated) as part of physician-directed therapy for severe sepsis. Results: The Xigris Use in the United States (XEUS) patients were younger (58 vs 63 years of age), had more comorbidities, and more sepsis-induced organ dysfunction at baseline compared to high-risk (Acute Physiology and Chronic Health Evaluation II score ≥ 25) PROWESS patients who received drotrecogin alfa (activated), (cardiovascular, 85.0% vs 79.7%; hematologic, 22.3% vs 16.4%; and renal, 57.9% vs 50.7%) (all P < .05). The XEUS patients had a higher mortality rate compared to high-risk PROWESS patients receiving drotrecogin alfa (activated) (36.7% vs 30.9%; P = 062) but a similar safety profile (infusion period serious bleeding, 2.7% vs 2.2%; P = 579; 28-day serious bleeding, 3.1% vs 3.9%; P = 520). The rate of intracranial hemorrhage in XEUS was 0.2%. Conclusions: Patients receiving drotrecogin alfa (activated) in clinical practice were more acutely ill, had a higher mortality rate, but a similar safety profile with respect to serious bleeding events compared to the PROWESS trial. © 2010 Elsevier Inc.

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Biomarkers of thrombosis, fibrinolysis, and inflammation in patients with severe sepsis due to community-acquired pneumonia with and without Streptococcus pneumoniae

Authors Vail GM , Xie YJ , Haney DJ , Barnes CJ
Journal Infection
Year 2009
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This article is included in 1 Systematic review Systematic reviews (1 reference)

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Background: Severe Streptococcus pneumoniae (S. pneum) pneumonia has historically been associated with an acute presentation and increased mortality. Using data from patients with community-acquired pneumonia (CAP) and severe sepsis, we investigated: (1) the baseline patient characteristics and biomarkers of thrombosis, fibrinolysis, and inflammation in patients with CAP due to S. pneum infection (S. pneum CAP) or CAP due to infection with other or unidentified organisms (non-S. pneum CAP); (2) the behavior of these biomarkers over time and during treatment with drotrecogin alfa (activated) (DrotAA, recombinant activated protein C). Patients and Methods: Data from the PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation on Severe Sepsis) trial were retrospectively analyzed by treatment (DrotAA or placebo) in patients with CAP. Results: Patients with S. pneum CAP (n = 157) tended to be younger and had fewer comorbid conditions than patients with non-S. pneum CAP (n = 445). Overall disease severity (median APACHE II scores) was not significantly different between the two groups at baseline. However, there were significant baseline differences in protein C and markers of coagulation, fibrinolysis, and inflammation. Although thrombosis markers were not different at baseline, D-dimer levels significantly increased from baseline to day 4 in placebo-treated patients with S. pneum compared to those with non-S. pneum. DrotAA treatment was associated with statistically significant improvements in protein C and markers of thrombosis in patients with S. pneum. In addition, the proportion of patients with severe protein C deficiency ( ≤ 40% activity) at baseline was significantly greater in patients with S. pneum than those with non-S. pneum. Among patients with S. pneum and severe protein C deficiency at baseline, a significantly greater proportion of patients were no longer severely protein C deficient after 4 days of DrotAA therapy. Conclusion: In this population of patients with severe sepsis, patients with S. pneum CAP had a more severe dysregulation of coagulation, fibrinolysis, and inflammation than patients with non-S. pneum CAP; the former also developed significantly elevated levels of markers of thrombosis. Treatment with DrotAA was associated with significant improvements in protein C levels as well as markers of thrombosis. These characteristics may make patients with S. pneum CAP and severe sepsis particularly suited to derive a benefit from therapy with DrotAA. © 2009 Springer.