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Abstract
BackgroundAcute lung injury (ALI) is a common devastating clinical syndrome characterized by life-threatening respiratory failure requiring mechanical ventilation and multiple organ failure. There are in vitro, animal studies and pre-clinical data suggesting that statins may be beneficial in ALI. The Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction (HARP-2) trial is a multicenter, prospective, randomized, allocation concealed, double-blind, placebo-controlled clinical trial which aims to test the hypothesis that treatment with simvastatin will improve clinical outcomes in patients with ALI.Methods/DesignPatients fulfilling the American-European Consensus Conference Definition of ALI will be randomized in a 1:1 ratio to receive enteral simvastatin 80 mg or placebo once daily for a maximum of 28 days. Allocation to randomized groups will be stratified with respect to hospital of recruitment and vasopressor requirement. Data will be recorded by participating ICUs until hospital discharge, and surviving patients will be followed up by post at 3, 6 and 12 months post randomization. The primary outcome is number of ventilator-free days to day 28. Secondary outcomes are: change in oxygenation index and sequential organ failure assessment score up to day 28, number of non pulmonary organ failure free days to day 28, critical care unit mortality; hospital mortality; 28 day post randomization mortality and 12 month post randomization mortality; health related quality of life at discharge, 3, 6 and 12 months post randomization; length of critical care unit and hospital stay; health service use up to 12 months post-randomization; and safety. A total of 540 patients will be recruited from approximately 35 ICUs in the UK and Ireland. An economic evaluation will be conducted alongside the trial. Plasma and urine samples will be taken up to day 28 to investigate potential mechanisms by which simvastatin might act to improve clinical outcomes.Trial registrationCurrent Controlled Trials ISRCTN88244364.
Highlights
Acute lung injury (ALI) is a common devastating clinical syndrome characterized by life-threatening respiratory failure requiring mechanical ventilation and multiple organ failure
Pre-treatment with simvastatin for four days results in attenuation of both pulmonary and systemic inflammatory responses in a model of ALI induced by lipopolysaccharide (LPS) inhalation [10]
This study provided proof of concept data of a beneficial effect with significant improvements in nonpulmonary organ dysfunction, as measured by the Sequential Organ Failure Assessment (SOFA) score as well as a trend to improvements in pulmonary dysfunction, as measured by the oxygenation index (OI), respiratory system compliance and lung injury score in the simvastatin-treated group
Summary
Acute lung injury (ALI) is a common devastating clinical syndrome characterized by life-threatening respiratory failure requiring mechanical ventilation and multiple organ failure. Patients receiving pressure support via non-invasive ventilation for any other reason will be defined as receiving assisted ventilation Patients transferred to another hospital or other health care facility will be followed to day 28 to assess this endpoint. The secondary clinical outcomes are change in OI from baseline to day 3, 7, 14 and 28; change in SOFA score from baseline to day 3, 7, 14 and 28; non pulmonary organ failure free days (defined as the number of days in the first 28 days after randomization that the patient received no cardiovascular, renal, liver or neurological support as defined by the Critical Care Minimum Dataset [14]); all cause mortality 28 days post randomization; mortality at (first) discharge from critical care; mortality at (first) discharge from hospital and mortality at 12 months post randomization.
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