A randomized clinical trial of hydroxymethylglutaryl- coenzyme a reductase inhibition for acute lung injury (The HARP Study).
BACKGROUND
There is no effective pharmacological treatment for acute lung injury (ALI). Statins are a potential new therapy because they modify many of the underlying processes important in ALI.


OBJECTIVE
To test whether simvastatin improves physiological and biological outcomes in ALI.


METHODS
We conducted a randomized, double-blinded, placebo-controlled trial in patients with ALI. Patients received 80 mg simvastatin or placebo until cessation of mechanical ventilation or up to 14 days. Extravascular lung water was measured using thermodilution. Measures of pulmonary and nonpulmonary organ function were assessed daily. Pulmonary and systemic inflammation was assessed by bronchoalveolar lavage fluid and plasma cytokines. Systemic inflammation was also measured by plasma C-reactive protein.


RESULTS
Sixty patients were recruited. Baseline characteristics, including demographics and severity of illness scores, were similar in both groups. At Day 7, there was no difference in extravascular lung water. By Day 14, the simvastatin-treated group had improvements in nonpulmonary organ dysfunction. Oxygenation and respiratory mechanics improved, although these parameters failed to reach statistical significance. Intensive care unit mortality was 30% in both groups. Simvastatin was well tolerated, with no increase in adverse events. Simvastatin decreased bronchoalveolar lavage IL-8 by 2.5-fold (P = 0.04). Plasma C-reactive protein decreased in both groups but failed to achieve significance in the placebo-treated group.


CONCLUSIONS
Treatment with simvastatin appears to be safe and may be associated with an improvement in organ dysfunction in ALI. These clinical effects may be mediated by a reduction in pulmonary and systemic inflammation. Clinical trial registered with www.controlled-trials.com (ISRCTN70127774).
Craig
Thelma R
TR
Regional Intensive Care Unit, Royal Victoria Hospital, Belfast, UK.
Duffy
Martin J
MJ
Shyamsundar
Murali
M
McDowell
Cliona
C
O'Kane
Cecilia M
CM
Elborn
J Stuart
JS
McAuley
Daniel F
DF
D055371:Acute Lung Injury / Q000150:complications / Q000188:drug therapy*; D001992:Bronchoalveolar Lavage Fluid; D002097:C-Reactive Protein / Q000187:drug effects; D016207:Cytokines / Q000187:drug effects; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007249:Inflammation / Q000188:drug therapy / Q000209:etiology; D008297:Male; D008875:Middle Aged; D009102:Multiple Organ Failure / Q000517:prevention & control; D019821:Simvastatin / Q000627:therapeutic use*; D016896:Treatment Outcome
D016207:Cytokines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D002097:C-Reactive Protein; D019821:Simvastatin