title: Rosuvastatin versus placebo for delirium in intensive care and subsequent cognitive impairment in patients with sepsis-associated acute respiratory distress syndrome: an ancillary study to a randomised controlled trial.
abstract: BACKGROUND
  Delirium is common in mechanically ventilated patients and is associated with cognitive impairment lasting at least 1 year after hospital discharge. Preclinical and observational studies suggest that the use of statins might reduce delirium in intensive care. We assessed whether the pleiotropic effects of statins can reduce delirium in intensive care and decrease subsequent cognitive impairment in a randomised controlled trial.
  
  
  METHODS
  We did this ancillary study within the SAILS trial, a randomised controlled trial assessing mortality and ventilator-free days for rosuvastatin versus placebo for patients with sepsis-associated acute respiratory distress syndrome. This study was done at 35 hospitals in the USA. Patients were randomly assigned in permuted blocks of eight and stratified by hospital to receive either rosuvastatin (40 mg loading dose and then 20 mg daily until the earliest of 3 days after discharge from intensive care, study day 28, or death) or placebo. Patients and investigators were masked to treatment assignment. Delirium was assessed with the validated Confusion Assessment Method for intensive care. Cognitive function was assessed with tests for executive function, language, verbal reasoning and concept formation, and working, immediate, and delayed memory. We defined cognitive impairment as having one of these domains at least two SDs below population norms or at least two domains at least 1·5 SDs below norms. The primary endpoint was daily delirium status in intensive care up to 28 days in the intention-to-treat population and secondary endpoints were cognitive function at 6 months and 12 months. This trial is registered with ClinicalTrials.gov (NCT00979121 and NCT00719446).
  
  
  RESULTS
  272 patients were assessed for delirium daily in intensive care. The mean proportion of days with delirium was 34% (SD 30%) in the rosuvastatin group versus 31% (29%) in the placebo group; hazard ratio 1·14, 95% CI 0·92-1·41, p=0·22. At 6 months, 19 (36%) of 53 patients in the rosuvastatin group versus 29 (38%) of 77 in the placebo group had cognitive impairment, with no significant difference between groups (treatment effect 0·93, 95% CI 0·39-2·22; p=0·87). At 12 months, 20 (30%) of 67 patients versus 23 (28%) of 81 patients had cognitive impairment, with no significant difference between groups (treatment effect 1·1, 95% CI 0·5-2·6; p=0·82).
  
  
  CONCLUSIONS
  Most patients had delirium, with around a third of survivors having cognitive impairment over 1 year of follow-up. Despite encouraging preclinical and observational studies, this trial shows no benefit of rosuvastatin in reducing delirium in intensive care or cognitive impairment during 12 months of follow-up although the study was not powered for superiority. Thus, there is continued need to evaluate interventions aimed at attenuating intensive care and post-intensive-care cognitive impairments commonly observed in this population.
  
  
  BACKGROUND
  National Heart, Lung and Blood Institute; Johns Hopkins Institute for Clinical and Translational Research; the SAILS trial was also supported by AstraZeneca.
authors.affiliation: Outcomes After Critical Illness and Surgery Group, Johns Hopkins University, Baltimore, MD, USA; Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Physical Medicine and Rehabilitation, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: dale.needham@jhmi.edu.
authors.forename: Dale M
authors.initials: DM
authors.lastname: Needham
authors.affiliation: Outcomes After Critical Illness and Surgery Group, Johns Hopkins University, Baltimore, MD, USA; Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Colantuoni
authors.affiliation: Outcomes After Critical Illness and Surgery Group, Johns Hopkins University, Baltimore, MD, USA; Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Victor D
authors.initials: VD
authors.lastname: Dinglas
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Harborview Medical Center, University of Washington, Seattle, WA, USA.
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Hough
authors.affiliation: Outcomes After Critical Illness and Surgery Group, Johns Hopkins University, Baltimore, MD, USA; Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Amy W
authors.initials: AW
authors.lastname: Wozniak
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Jackson
authors.affiliation: Division of Pulmonary, Critical Care & Sleep Medicine, University of Kentucky, Lexington, KY, USA.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Morris
authors.affiliation: Outcomes After Critical Illness and Surgery Group, Johns Hopkins University, Baltimore, MD, USA; Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Mendez-Tellez
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA; Geriatric Research, Education and Clinical Center Service, Department of Veterans Affairs Medical Center, Tennessee Valley Healthcare System, Nashville, TN, USA.
authors.forename: E Wesley
authors.initials: EW
authors.lastname: Ely
authors.affiliation: Department of Medicine, Pulmonary and Critical Care Division, Intermountain Medical Center, Murray, UT, USA; Psychology Department and Neuroscience Center, Brigham Young University, Provo, UT, USA; Center for Humanizing Critical Care, Intermountain Health Care, Murray, UT, USA.
authors.forename: Ramona O
authors.initials: RO
authors.lastname: Hopkins
mesh_terms: D000328:Adult; D000368:Aged; D060825:Cognitive Dysfunction / Q000209:etiology / Q000517:prevention & control*; D003210:Concept Formation; D003693:Delirium / Q000209:etiology / Q000517:prevention & control*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007806:Language Disorders / Q000209:etiology; D008297:Male; D008568:Memory; D008875:Middle Aged; D012121:Respiration, Artificial / Q000009:adverse effects; D012128:Respiratory Distress Syndrome / Q000209:etiology / Q000628:therapy; D000068718:Rosuvastatin Calcium / Q000627:therapeutic use*; D018805:Sepsis / Q000150:complications; D013997:Time Factors
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000068718:Rosuvastatin Calcium
references.citation: J Chem Neuroanat. 2005 Oct;30(2-3):144-57
references.pmid: 16122904
references.citation: J Crit Care. 2006 Jun;21(2):125-32
references.pmid: 16769455
references.citation: N Engl J Med. 2006 Jun 15;354(24):2564-75
references.pmid: 16714767
references.citation: Lancet Infect Dis. 2007 May;7(5):358-68
references.pmid: 17448939
references.citation: Exp Neurol. 2007 Jul;206(1):59-69
references.pmid: 17521631
references.citation: J Clin Epidemiol. 2007 Aug;60(8):757-65
references.pmid: 17606170
references.citation: Biostatistics. 2007 Oct;8(4):708-21
references.pmid: 17267392
references.citation: Am J Cardiol. 2007 Nov 15;100(10):1548-51
references.pmid: 17996517
references.citation: Intensive Care Med. 2007 Dec;33(12):2051-7
references.pmid: 17701161
references.citation: Anesthesiology. 2009 Jan;110(1):67-73
references.pmid: 19104172
references.citation: Am J Respir Crit Care Med. 2009 Jun 15;179(12):1107-14
references.pmid: 19324974
references.citation: Arch Intern Med. 2009 Oct 12;169(18):1658-67
references.pmid: 19822822
references.citation: Can J Anaesth. 2009 Nov;56(11):793-801
references.pmid: 19711147
references.citation: Br J Anaesth. 2010 Feb;104(2):183-90
references.pmid: 20086063
references.citation: Acta Neuropathol. 2010 Jun;119(6):737-54
references.pmid: 20309566
references.citation: Age Ageing. 2010 Jul;39(4):470-5
references.pmid: 20554540
references.citation: J Crit Care. 2010 Dec;25(4):656.e7-22
references.pmid: 20413251
references.citation: Chest. 2011 Sep;140(3):580-5
references.pmid: 21896517
references.citation: J Am Geriatr Soc. 2011 Nov;59 Suppl 2:S249-55
references.pmid: 22091569
references.citation: JAMA. 2012 Feb 22;307(8):795-803
references.pmid: 22307571
references.citation: Ann Clin Microbiol Antimicrob. 2012;11:13
references.pmid: 22564676
references.citation: Trials. 2012;13:132
references.pmid: 22867278
references.citation: Intensive Care Med. 2012 Dec;38(12):1965-73
references.pmid: 22903241
references.citation: Crit Care Med. 2013 Jan;41(1):263-306
references.pmid: 23269131
references.citation: PLoS One. 2013;8(1):e52929
references.pmid: 23349694
references.citation: Am J Respir Crit Care Med. 2013 Sep 1;188(5):567-76
references.pmid: 23805899
references.citation: N Engl J Med. 2013 Oct 3;369(14):1306-16
references.pmid: 24088092
references.citation: Am J Respir Crit Care Med. 2014 Mar 15;189(6):666-73
references.pmid: 24417431
references.citation: Lancet Respir Med. 2014 Mar;2(3):180
references.pmid: 24745050
references.citation: N Engl J Med. 2014 Jun 5;370(23):2191-200
references.pmid: 24835849
references.citation: Crit Care Med. 2014 Aug;42(8):1899-909
references.pmid: 24810528
references.citation: N Engl J Med. 2014 Oct 30;371(18):1695-703
references.pmid: 25268516
references.citation: Curr Atheroscler Rep. 2015 Jan;17(1):470
references.pmid: 25398644
references.citation: Crit Care Med. 2015 Jan;43(1):40-7
references.pmid: 25251759
references.citation: Trials. 2015;16:218
references.pmid: 25982544
references.citation: BMJ. 2015;350:h2538
references.pmid: 26041151
references.citation: Intensive Care Med. 2015 Jun;41(6):1048-56
references.pmid: 25894620
references.citation: J Clin Epidemiol. 2015 Dec;68(12):1481-7
references.pmid: 26186981
references.citation: Arterioscler Thromb Vasc Biol. 2003 Jan 1;23(1):58-63
references.pmid: 12524225
references.citation: JAMA. 2001 Dec 5;286(21):2703-10
references.pmid: 11730446
references.citation: N Engl J Med. 2000 May 4;342(18):1301-8
references.pmid: 10793162
references.citation: Crit Care Med. 2005 Jun;33(6):1199-205
references.pmid: 15942331
references.citation: Clin Sci (Lond). 1999 May;96(5):461-6
references.pmid: 10209077
references.citation: Am J Respir Crit Care Med. 2005 Feb 15;171(4):340-7
references.pmid: 15542793
references.citation: Ann Behav Med. 2005 Apr;29 Suppl:55-65
references.pmid: 15921490
references.citation: Epidemiol Rev. 1998;20(1):57-70
references.pmid: 9762509
references.citation: Cardiology. 2004;102(3):166-70
references.pmid: 15334028
references.citation: Crit Care Med. 2004 Apr;32(4):955-62
references.pmid: 15071384
references.citation: Mol Cell Biochem. 2003 Apr;246(1-2):45-50
references.pmid: 12841342
references.citation: JAMA. 2003 Jun 11;289(22):2983-91
references.pmid: 12799407
references.citation: Crit Care Med. 2003 Apr;31(4):1226-34
references.pmid: 12682497