Jay Steingrub

Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: Effect on survival in patients with septic shock

ObjectiveTo assess the safety and efficacy of the nitric oxide synthase inhibitor 546C88 in patients with septic shock. The predefined primary efficacy objective was survival at day 28. DesignMultiple-center, randomized, two-stage, double-blind, placebo-controlled, safety and efficacy study. SettingA total of 124 intensive care units in Europe, North America, South America, South Africa, and Australasia. PatientsA total of 797 patients with septic shock diagnosed for <24 hrs. InterventionsPatients with septic shock were allocated to receive 546C88 or placebo (5% dextrose) for up to 7 days (stage 1) or 14 days (stage 2) in addition to conventional therapy. Study drug was initiated at 0.05 mL·kg−1·hr−1 (2.5 mg·kg−1·hr−1 546C88) and titrated up to a maximum rate of 0.4 mL·kg−1·hr−1 to maintain mean arterial pressure between 70 and 90 mm Hg while attempting to withdraw concurrent vasopressors. Measurements and Main ResultsHemodynamic variables, organ function data, microbiological data, concomitant therapy, and adverse event data were recorded at baseline, throughout treatment, and at follow-up. The primary end point was day-28 survival. The trial was stopped early after review by the independent data safety monitoring board. Day-28 mortality was 59% (259/439) in the 546C88 group and 49% (174/358) in the placebo group (p < .001). The overall incidence of adverse events was similar in both groups, although a higher proportion of the events was considered possibly attributable to study drug in the 546C88 group. Most of the events accounting for the disparity between the groups were associated with the cardiovascular system (e.g., decreased cardiac output, pulmonary hypertension, systemic arterial hypertension, heart failure). The causes of death in the study were consistent with those expected in patients with septic shock, although there was a higher proportion of cardiovascular deaths and a lower incidence of deaths caused by multiple organ failure in the 546C88 group. ConclusionsIn this study, the nonselective nitric oxide synthase inhibitor 546C88 increased mortality in patients with septic shock.

Hospitalizations, costs, and outcomes of severe sepsis in the United States 2003 to 2007.

Objectives:To assess trends in number of hospitalizations, outcomes, and costs of severe sepsis in the United States. Design:Temporal trends study using the Nationwide Inpatient Sample. Patients:Adult patients with severe sepsis (defined as a diagnosis of sepsis and organ dysfunction) diagnosed between 2003 and 2007. Measurements and Main Results:We determined the weighted frequency of patients hospitalized with severe sepsis. We calculated age- and sex-adjusted population-based mortality rates for severe sepsis per 100,000 population and also used logistic regression to adjust in-hospital mortality rates for patient characteristics. We calculated inflation-adjusted costs using hospital-specific cost-to-charge ratios. We identified a rapid steady increase in the number of cases of severe sepsis, from 415,280 in 2003 to 711,736 in 2007 (a 71% increase). The total hospital costs for all patients with severe sepsis increased from

Enteral omega-3 fatty acid, gamma-linolenic acid, and antioxidant supplementation in acute lung injury

15.4 billion in 2003 to

Rosuvastatin for Sepsis-Associated Acute Respiratory Distress Syndrome

24.3 billion in 2007 (57% increase). The proportion of patients with severe sepsis and only a single organ dysfunction decreased from 51% in 2003 to 45% in 2007 (p < .001), whereas the proportion of patients with three or four or more organ dysfunctions increased 1.19-fold and 1.51-fold, respectively (p < .001). During the same time period, we observed 2% decrease per year in hospital mortality for patients with severe sepsis (p < .001), as well as a slight decrease in the length of stay (9.9 days to 9.2 days; p < .001) and a significant decrease in the geometric mean cost per case of severe sepsis (

Acute Kidney Injury in Patients with Acute Lung Injury: Impact of Fluid Accumulation on Classification of Acute Kidney Injury and Associated Outcomes

20,210 per case in 2003 and

Randomized Clinical Trial of Activated Protein C for the Treatment of Acute Lung Injury

19,330 in 2007; p = .025). Conclusions:The increase in the number of hospitalizations for severe sepsis coupled with declining in-hospital mortality and declining geometric mean cost per case may reflect improvements in care or increases in discharges to skilled nursing facilities; however, these findings more likely represent changes in documentation and hospital coding practices that could bias efforts to conduct national surveillance.

Liposomal prostaglandin E1 (TLC C-53) in acute respiratory distress syndrome: a controlled, randomized, double-blind, multicenter clinical trial. TLC C-53 ARDS Study Group

CONTEXT The omega-3 (n-3) fatty acids docosahexaenoic acid and eicosapentaenoic acid, along with γ-linolenic acid and antioxidants, may modulate systemic inflammatory response and improve oxygenation and outcomes in patients with acute lung injury. OBJECTIVE To determine if dietary supplementation of these substances to patients with acute lung injury would increase ventilator-free days to study day 28. DESIGN, SETTING, AND PARTICIPANTS The OMEGA study, a randomized, double-blind, placebo-controlled, multicenter trial conducted from January 2, 2008, through February 21, 2009. Participants were 272 adults within 48 hours of developing acute lung injury requiring mechanical ventilation whose physicians intended to start enteral nutrition at 44 hospitals in the National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. All participants had complete follow-up. INTERVENTIONS Twice-daily enteral supplementation of n-3 fatty acids, γ-linolenic acid, and antioxidants compared with an isocaloric control. Enteral nutrition, directed by a protocol, was delivered separately from the study supplement. MAIN OUTCOME MEASURE Ventilator-free days to study day 28. RESULTS The study was stopped early for futility after 143 and 129 patients were enrolled in the n-3 and control groups. Despite an 8-fold increase in plasma eicosapentaenoic acid levels, patients receiving the n-3 supplement had fewer ventilator-free days (14.0 vs 17.2; P = .02) (difference, -3.2 [95% CI, -5.8 to -0.7]) and intensive care unit-free days (14.0 vs 16.7; P = .04). Patients in the n-3 group also had fewer nonpulmonary organ failure-free days (12.3 vs 15.5; P = .02). Sixty-day hospital mortality was 26.6% in the n-3 group vs 16.3% in the control group (P = .054), and adjusted 60-day mortality was 25.1% and 17.6% in the n-3 and control groups, respectively (P = .11). Use of the n-3 supplement resulted in more days with diarrhea (29% vs 21%; P = .001). CONCLUSIONS Twice-daily enteral supplementation of n-3 fatty acids, γ-linolenic acid, and antioxidants did not improve the primary end point of ventilator-free days or other clinical outcomes in patients with acute lung injury and may be harmful. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00609180.

A replicable method for blood glucose control in critically Ill patients.

BACKGROUND In the acute respiratory distress syndrome (ARDS), inflammation in the lungs and other organs can cause life-threatening organ failure. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) can modulate inflammatory responses. Previous observational studies suggested that statins improved clinical outcomes in patients with sepsis. We hypothesized that rosuvastatin therapy would improve clinical outcomes in critically ill patients with sepsis-associated ARDS. METHODS We conducted a multicenter trial in which patients with sepsis-associated ARDS were randomly assigned to receive either enteral rosuvastatin or placebo in a double-blind manner. The primary outcome was mortality before hospital discharge home or until study day 60 if the patient was still in a health care facility. Secondary outcomes included the number of ventilator-free days (days that patients were alive and breathing spontaneously) to day 28 and organ-failure-free days to day 14. RESULTS The study was stopped because of futility after 745 of an estimated 1000 patients had been enrolled. There was no significant difference between study groups in 60-day in-hospital mortality (28.5% with rosuvastatin and 24.9% with placebo, P=0.21) or in mean (±SD) ventilator-free days (15.1±10.8 with rosuvastatin and 15.1±11.0 with placebo, P=0.96). The groups were well matched with respect to demographic and key physiological variables. Rosuvastatin therapy, as compared with placebo, was associated with fewer days free of renal failure to day 14 (10.1±5.3 vs. 11.0±4.7, P=0.01) and fewer days free of hepatic failure to day 14 (10.8±5.0 vs. 11.8±4.3, P=0.003). Rosuvastatin was not associated with an increased incidence of serum creatine kinase levels that were more than 10 times the upper limit of the normal range. CONCLUSIONS Rosuvastatin therapy did not improve clinical outcomes in patients with sepsis-associated ARDS and may have contributed to hepatic and renal organ dysfunction. (Funded by the National Heart, Lung, and Blood Institute and the Investigator-Sponsored Study Program of AstraZeneca; ClinicalTrials.gov number, NCT00979121.).

Small bowel necrosis associated with early postoperative jejunal tube feeding in a trauma patient.

Objective:It has been suggested that fluid accumulation may delay recognition of acute kidney injury. We sought to determine the impact of fluid balance on the incidence of nondialysis requiring acute kidney injury in patients with acute lung injury and to describe associated outcomes, including mortality. Design:Analysis of the Fluid and Catheter Treatment Trial, a factorial randomized clinical trial of conservative vs. liberal fluid management and of management guided by a central venous vs. pulmonary artery catheter. Setting:Acute Respiratory Distress Syndrome Network hospitals. Patients:One thousand patients. Interventions:None. Measurements and Main Results:The incidence of acute kidney injury, defined as an absolute rise in creatinine of ≥0.3 mg/dL or a relative change of >50% over 48 hrs, was examined before and after adjustment of serum creatinine for fluid balance. The incidence of acute kidney injury before adjustment for fluid balance was greater in those managed with the conservative fluid protocol (57% vs. 51%, p = .04). After adjustment for fluid balance, the incidence of acute kidney injury was greater in those managed with the liberal fluid protocol (66% vs. 58%, p = .007). Patients who met acute kidney injury criteria after adjustment of creatinine for fluid balance (but not before) had a mortality rate that was significantly greater than those who did not meet acute kidney injury criteria both before and after adjustment for fluid balance (31% vs. 12%, p < .001) and those who had acute kidney injury before but not after adjustment for fluid balance (31% vs. 11%, p = .005). The mortality of those patients meeting acute kidney injury criteria after but not before adjustment for fluid balance was similar to patients with acute kidney injury both before and after adjustment for fluid balance (31% vs. 38%, p = .18). Conclusions:Fluid management influences serum creatinine and therefore the diagnosis of acute kidney injury using creatinine-based definitions. Patients with “unrecognized” acute kidney injury that is identified after adjusting for positive fluid balance have higher mortality rates, and patients who have acute kidney injury before but not after adjusting for fluid balance have lower mortality rates. Future studies of acute kidney injury should consider potential differences in serum creatinine caused by changes in fluid balance and the impact of these differences on diagnosis and prognosis.

Pathogenetic and predictive value of biomarkers in patients with ALI and lower severity of illness: results from two clinical trials

RATIONALE Microvascular injury, inflammation, and coagulation play critical roles in the pathogenesis of acute lung injury (ALI). Plasma protein C levels are decreased in patients with acute lung injury and are associated with higher mortality and fewer ventilator-free days. OBJECTIVES To test the efficacy of activated protein C (APC) as a therapy for patients with ALI. METHODS Eligible subjects were critically ill patients who met the American/European consensus criteria for ALI. Patients with severe sepsis and an APACHE II score of 25 or more were excluded. Participants were randomized to receive APC (24 microg/kg/h for 96 h) or placebo in a double-blind fashion within 72 hours of the onset of ALI. The primary endpoint was ventilator-free days. MEASUREMENTS AND MAIN RESULTS APC increased plasma protein C levels (P = 0.002) and decreased pulmonary dead space fraction (P = 0.02). However, there was no statistically significant difference between patients receiving placebo (n = 38) or APC (n = 37) in the number of ventilator-free days (median [25-75% interquartile range]: 19 [0-24] vs. 19 [14-22], respectively; P = 0.78) or in 60-day mortality (5/38 vs. 5/37 patients, respectively; P = 1.0). There were no differences in the number of bleeding events between the two groups. CONCLUSIONS APC did not improve outcomes from ALI. The results of this trial do not support a large clinical trial of APC for ALI in the absence of severe sepsis and high disease severity.