Rationale: Severe community-acquired pneumonia (sCAP) is a leading cause of death worldwide. Adjunctive therapies for sCAP are needed to further improve outcome. A systemic inhibitor of coagulation, tifacogin (recombinant human tissue factor pathway inhibitor) seemed to provide mortality benefit in the sCAP subgroup of a previous sepsis trial.Objectives: Evaluate the impact of adjunctive tifacogin on mortality in patients with sCAP.Methods: A multicenter, randomized, placebo-controlled, double-blind, three-arm study was conducted from July 2005 to June 2008 at 188 centers in North and South America, Europe, South Africa, Asia, Australia, and New Zealand. Adults with sCAP were randomized to receive a continuous intravenous infusion of tifacogin 0.025 mg/kg/h, tifacogin 0.075 mg/kg/h, or matching placebo over 96 hours.Measurements and Main Results: Severity-adjusted 28-day all-cause mortality. Of 2,138 randomized patients, 946, 238, and 918 received tifacogin 0.025 mg/kg/h, tifacogin 0.075 mg/kg/h, and placebo, respectively. Tifacogin 0.075 mg/kg/h was discontinued after the first interim analysis according to prespecified futility criterion. The 28-day all-cause mortality rates were similar between the 0.025 mg/kg/h (18%) and placebo groups (17.9%) (P = 0.56). Greater reduction in prothrombin fragment 1+2 and thrombin antithrombin complexes levels relative to baseline throughout the first 96 hours was found with tifacogin 0.025 mg/kg/h than with placebo. The incidence of adverse events and serious adverse events were comparable between the tifacogin 0.025 mg/kg/h and placebo groups.Conclusions: Tifacogin showed no mortality benefit in patients with sCAP despite evidence of biologic activity.
To evaluate whether administration of afelimomab, an anti-tumor necrosis factor F(ab')2 monoclonal antibody fragment, would reduce 28-day all-cause mortality in patients with severe sepsis and elevated serum levels of IL-6.Prospective, randomized, double-blind, placebo-controlled, multiple-center, phase III clinical trial.One hundred fifty-seven intensive care units in the United States and Canada.Subjects were 2,634 patients with severe sepsis secondary to documented infection, of whom 998 had elevated interleukin-6 levels.Patients were stratified into two groups by means of a rapid qualitative interleukin-6 test kit designed to identify patients with serum interleukin-6 levels above (test positive) or below (test negative) approximately 1000 pg/mL. Of the 2,634 patients, 998 were stratified into the test-positive group, 1,636 into the test-negative group. They were then randomly assigned 1:1 to receive afelimomab 1 mg/kg or placebo for 3 days and were followed for 28 days. The a priori population for efficacy analysis was the group of patients with elevated baseline interleukin-6 levels as defined by a positive rapid interleukin-6 test result.In the group of patients with elevated interleukin-6 levels, the mortality rate was 243 of 510 (47.6%) in the placebo group and 213 of 488 (43.6%) in the afelimomab group. Using a logistic regression analysis, treatment with afelimomab was associated with an adjusted reduction in the risk of death of 5.8% (p = .041) and a corresponding reduction of relative risk of death of 11.9%. Mortality rates for the placebo and afelimomab groups in the interleukin-6 test negative population were 234 of 819 (28.6%) and 208 of 817 (25.5%), respectively. In the overall population of interleukin-6 test positive and negative patients, the placebo and afelimomab mortality rates were 477 of 1,329 (35.9%)and 421 of 1,305 (32.2%), respectively. Afelimomab resulted in a significant reduction in tumor necrosis factor and interleukin-6 levels and a more rapid improvement in organ failure scores compared with placebo. The safety profile of afelimomab was similar to that of placebo.Afelimomab is safe, biologically active, and well tolerated in patients with severe sepsis, reduces 28-day all-cause mortality, and attenuates the severity of organ dysfunction in patients with elevated interleukin-6 levels.
Rationale: Delirium is common in the ICU and portends worse ICU and hospital outcomes. The effect of delirium in the ICU on post-hospital discharge mortality and health resource use is less well known. Objectives: To estimate mortality and health resource use 2.5 years after hospital discharge in critically ill patients admitted to the ICU. Methods: This was a population-based, propensity score-matched, retrospective cohort study of adult patients admitted to 1 of 14 medical-surgical ICUs from January 1, 2014, to June 30, 2016. Delirium was measured by using the 8-point Intensive Care Delirium Screening Checklist. The primary outcome was mortality. The secondary outcome was a composite measure of subsequent emergency department visits, hospital readmission, or mortality. Measurements and Main Results: There were 5,936 propensity score-matched patients with and without a history of incident delirium who survived to hospital discharge. Delirium was associated with increased mortality 0-30 days after hospital discharge (hazard ratio, 1.44 [95% confidence interval, 1.08-1.92]). There was no significant difference in mortality more than 30 days after hospital discharge (delirium: 3.9%, no delirium: 2.6%). There was a persistent increased risk of emergency department visits, hospital readmissions, or mortality after hospital discharge (hazard ratio, 1.12 [95% confidence interval, 1.07-1.17]) throughout the study period. Conclusions: ICU delirium is associated with increased mortality 0-30 days after hospital discharge.
Although mandatory laparotomy has been standard of care for patients with abdominal gunshot wounds (GSWs) for decades, this approach is associated with non-therapeutic operations, morbidity, and long hospital stays. This systematic review and meta-analysis sought to summarize outcomes of selective nonoperative management (SNOM) of civilian abdominal GSWs. We searched electronic databases (March 1966–April 1, 2017) and reference lists of articles included in the systematic review for studies reporting outcomes of SNOM of civilian abdominal GSWs. We meta-analyzed the associated risks of SNOM-related failure (defined as laparotomy during hospital admission), mortality, and morbidity across included studies using DerSimonian and Laird random-effects models. Between-study heterogeneity was assessed by calculating I2 statistics and conducting tests of homogeneity. Of 7155 citations identified, we included 41 studies [n = 22,847 patients with abdominal GSWs, of whom 6777 (29.7%) underwent SNOM]. The pooled risk of failure of SNOM in hemodynamically stable patients without a reduced level of consciousness or signs of peritonitis was 7.0% [95% confidence interval (CI) = 3.9–10.1%; I2 = 92.6%, homogeneity p < 0.001] while the pooled mortality associated with use of SNOM in this patient population was 0.4% (95% CI = 0.2–0.6%; I2 = 0%, homogeneity p > 0.99). In patients who failed SNOM, the pooled estimate of the risk of therapeutic laparotomy was 68.0% (95% CI = 58.3–77.7%; I2 = 91.5%; homogeneity p < 0.001). Risks of failure of SNOM were lowest in studies that evaluated patients with right thoracoabdomen (3.4%; 95% CI = 0–7.0%; I2 = 0%; homogeneity p = 0.45), flank (7.0%; 95% CI = 3.9–10.1%), and back (3.1%; 95% CI = 0–6.5%) GSWs and highest in those that evaluated patients with anterior abdomen (13.2%; 95% CI = 6.3–20.1%) GSWs. In patients who underwent mandatory abdominopelvic computed tomography (CT), the pooled risk of failure was 4.1% versus 8.3% in those who underwent selective CT (p = 0.08). The overall sample-size-weighted mean hospital length of stay among patients who underwent SNOM was 6 days versus 10 days if they failed SNOM or developed an in-hospital complication. SNOM of abdominal GSWs is safe when conducted in hemodynamically stable patients without a reduced level of consciousness or signs of peritonitis. Failure of SNOM may be lower in patients with GSWs to the back, flank, or right thoracoabdomen and be decreased by mandatory use of abdominopelvic CT scans.
Several hospitals have been developing programmes for organ donation after cardiac death. Such programmes offer options for organ donation to patients who do not meet brain-death criteria but wish to donate their organs after withdrawal of life-support. These programmes also increase the available organ pool at a time when demand exceeds supply. Given that potential donors are managed in intensive care units, intensivists will be key components of these programmes. Donation after cardiac death clearly carries a number of important ethical issues with it. In the present issue of Critical Care two established groups debate the ethical acceptability of using medications/interventions in potential organ donors for the sole purpose of making the organs more viable. Such debates will be an increasingly common component of intensivists' future practice.
1 Department of Critical Care Medicine, University of Calgary and Alberta Health Services, ICU Administration - Ground Floor - McCaig Tower, Foothills Medical Center, Calgary, AB, Canada. 2 O'Brien Institute for Public Health, University of Calgary, Calgary, AB, Canada. 3 Libin Cardiovascular Institute, University of Calgary, Calgary, AB, Canada. 4 Department of Community Health Sciences, University of Calgary, Calgary, AB, Canada. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: [email protected]
The long-term impact of critical illness on survivors' physical and mental health remains unknown. Our aim was to create a follow-up clinic for survivors of critical illness in order to quantitatively examine muscle weakness, physical functioning and mental health and relate these findings to health-related quality of life (HRQL) and ICU risk factors.
