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
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 effe...
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Published in | The lancet respiratory medicine Vol. 4; no. 3; p. 203 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
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01.03.2016
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Abstract | 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.
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).
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).
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.
National Heart, Lung and Blood Institute; Johns Hopkins Institute for Clinical and Translational Research; the SAILS trial was also supported by AstraZeneca. |
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AbstractList | 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.
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).
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).
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.
National Heart, Lung and Blood Institute; Johns Hopkins Institute for Clinical and Translational Research; the SAILS trial was also supported by AstraZeneca. |
Author | Hough, Catherine L Hopkins, Ramona O Mendez-Tellez, Pedro A Wozniak, Amy W Jackson, James C Ely, E Wesley Needham, Dale M Colantuoni, Elizabeth Morris, Peter E Dinglas, Victor D |
Author_xml | – sequence: 1 givenname: Dale M surname: Needham fullname: Needham, Dale M email: dale.needham@jhmi.edu organization: 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 – sequence: 2 givenname: Elizabeth surname: Colantuoni fullname: Colantuoni, Elizabeth organization: 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 – sequence: 3 givenname: Victor D surname: Dinglas fullname: Dinglas, Victor D organization: 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 – sequence: 4 givenname: Catherine L surname: Hough fullname: Hough, Catherine L organization: Division of Pulmonary and Critical Care Medicine, Harborview Medical Center, University of Washington, Seattle, WA, USA – sequence: 5 givenname: Amy W surname: Wozniak fullname: Wozniak, Amy W organization: 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 – sequence: 6 givenname: James C surname: Jackson fullname: Jackson, James C organization: Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA – sequence: 7 givenname: Peter E surname: Morris fullname: Morris, Peter E organization: Division of Pulmonary, Critical Care & Sleep Medicine, University of Kentucky, Lexington, KY, USA – sequence: 8 givenname: Pedro A surname: Mendez-Tellez fullname: Mendez-Tellez, Pedro A organization: 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 – sequence: 9 givenname: E Wesley surname: Ely fullname: Ely, E Wesley organization: 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 – sequence: 10 givenname: Ramona O surname: Hopkins fullname: Hopkins, Ramona O organization: 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 |
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SubjectTerms | Adult Aged Cognitive Dysfunction - etiology Cognitive Dysfunction - prevention & control Concept Formation Delirium - etiology Delirium - prevention & control Double-Blind Method Female Humans Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use Language Disorders - etiology Male Memory Middle Aged Respiration, Artificial - adverse effects Respiratory Distress Syndrome, Adult - etiology Respiratory Distress Syndrome, Adult - therapy Rosuvastatin Calcium - therapeutic use Sepsis - complications Time Factors |
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 |
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