Rosuvastatin for Sepsis-Associated Acute Respiratory Distress Syndrome

Abstract

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.

Simvastatin to reduce pulmonary dysfunction in patients with acute respiratory distress syndrome: the HARP-2 RCT

“…At randomisation, the tidal volume was 8.1 ml/kg of predicted body weight and it is possible that this level of tidal volume may have confounded the potential effects of simvastatin. However, this is unlikely given the similar absence of benefit for rosuvastatin in the SAILS study, 12 in which the mean tidal volume was 6.6-6.8 ml/kg of predicted body weight. Our data for tidal volume and plateau pressure are consistent with those seen in other clinical trials in critical care in which ventilation is not strictly protocolised.…”

“…This was approximately 10 : 1 in this study, which is similar to other ARDS trials. 12 This represents a considerable workload and should be considered when setting up such trials. Surprisingly, the appropriate clinical outcome or set of clinical outcomes to use in a trial recruiting patients with ARDS requiring mechanical ventilation in ICU to date has not been defined.…”

“…1 patients with sepsis-induced respiratory failure in the USA. 12 Our trial examined simvastatin and investigated ALI due to all aetiologies, as well as studying the potential mechanism of action by which statins act. In addition, unlike the US trial, an economic evaluation was undertaken in this study.…”

Roles of the Mevalonate Pathway and Cholesterol Trafficking in Pulmonary Host Defense

“…One randomized, double-blinded, placebo-controlled trial found that simvastatin was associated with improvements in non-pulmonary organ dysfunction in acute lung injury patients [142]. This said, enthusiasm for statins as potential acute lung injury therapeutics was recently reduced by the reporting of a large multicenter ARDS Clinical Trials Network study which found that rosuvastatin did not improve mortality or ventilator-free days and was instead associated with fewer days free of renal and hepatic failure [143]. …”

Reporting data on long-term follow-up of critical care trials

“…10 The SAILS trial randomised patients within 48 h of enrolment to receive either rosuvastatin or placebo for a maximum of 28 days (or until the third day after discharge from the intensive care unit (ICU), hospital discharge or death). The primary outcome of the original study was 60-day in-hospital mortality.…”