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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: 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.

SUBMITTER: Needham DM

PROVIDER: S-EPMC4792772 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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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.

Needham Dale M DM Colantuoni Elizabeth E Dinglas Victor D VD Hough Catherine L CL Wozniak Amy W AW Jackson James C JC Morris Peter E PE Mendez-Tellez Pedro A PA Ely E Wesley EW Hopkins Ramona O RO

The Lancet. Respiratory medicine 20160129 3

<h4>Background</h4>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.<h4>Methods</h4>We did this ancillary study within ...[more]

PMID: 26832963

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Project description:BackgroundIn 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.MethodsWe 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.ResultsThe 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.ConclusionsRosuvastatin therapy did not improve clinical outcomes in patients with sepsis-associated ARDS and may have contributed to hepatic and renal organ dysfunction. (Funded by the National Heart, Lung, and Blood Institute and the Investigator-Sponsored Study Program of AstraZeneca; ClinicalTrials.gov number, NCT00979121.).

Project description:BackgroundPatients in the intensive care unit (ICU) are known to be at increased risk of developing delirium, but the risk of subsequent neuropsychiatric disorders is unclear. We therefore sought to examine the association between the presence of delirium in the ICU and incident neuropsychiatric disorders (including depressive, anxiety, trauma-and-stressor-related, and neurocognitive disorders) post-ICU stay among adult medical-surgical ICU patients.MethodsRetrospective cohort study utilizing clinical and administrative data from both inpatient and outpatient healthcare visits to identify the ICU cohort and diagnostic information 5 years prior to and 1 year post-ICU stay. Patients ≥ 18 years of age admitted to one of 14 medical-surgical ICUs across Alberta, Canada, January 1, 2014-June 30, 2016, and survived to hospital discharge were included. The main outcome of interest was a new diagnosis of any neuropsychiatric disorder 1 year post-ICU stay. The exposure variable was delirium during the ICU stay identified through any positive delirium screen by the Intensive Care Unit Delirium Screening Checklist (ICDSC) during the ICU stay.ResultsOf 16,005 unique patients with at least one ICU admission, 4033 patients were included in the study of which 1792 (44%) experienced delirium during their ICU stay. The overall cumulative incidence of any neuropsychiatric disorder during the subsequent year was 19.7% for ICU patients. After adjusting for hospital characteristics using log-binomial regression, patients with delirium during the ICU stay had a risk ratio (RR) of 1.14 (95% confidence interval [CI] 0.98-1.33) of developing any neuropsychiatric disorder within 1 year post-ICU compared to those who did not experience delirium. Delirium was significantly associated with neurocognitive disorders (RR 1.59, 95% CI 1.08-2.35), but not depressive disorders (RR 1.16, 95% CI 0.92-1.45), anxiety (RR 1.16, 95% CI 0.92-1.47), and trauma-and-stressor-related (RR 0.82, 95% CI 0.53-1.28) disorders.ConclusionsThe diagnosis of new onset of neurocognitive disorders is associated with ICU-acquired delirium. In this study, significant associations were not observed for depressive, anxiety, and trauma-and-stressor-related disorders.

Project description:BackgroundExperimental evidence has indicated the benefits of statins for the treatment of postoperative delirium. Previously, clinical trials did not reach definite conclusions on the effects of statins on delirium. Some clinical trials have indicated that statins reduce postoperative delirium and improve outcomes, while some studies have reported negative results.AimTo evaluate whether perioperative rosuvastatin treatment reduces the incidence of delirium and improves clinical outcomes.MethodsThis randomized, double-blind, and placebo-controlled trial was conducted in a single center in Jiangsu, China. This study enrolled patients aged greater than 60 years who received general anesthesia during elective operations and provided informed consent. A computer-generated randomization sequence (in a 1:1 ratio) was used to randomly assign patients to receive either rosuvastatin (40 mg/d) or placebo. Participants, care providers, and investigators were all masked to group assignments. The primary endpoint was the incidence of delirium, which was assessed twice daily with the Confusion Assessment Method during the first 7 postoperative days. Analyses were performed on intention-to-treat and safety populations.ResultsBetween January 1, 2017 and January 1, 2020, 3512 patients were assessed. A total of 821 patients were randomly assigned to receive either placebo (n = 411) or rosuvastatin (n = 410). The incidence of postoperative delirium was significantly lower in the rosuvastatin group [23 (5.6%) of 410 patients] than in the placebo group {42 (13.5%) of 411 patients [odds ratios (OR) = 0.522, 95% confidence interval (CI): 0.308-0.885; P < 0.05]}. No significant difference in 30-d all-cause mortality (6.1% vs 8.7%, OR = 0.67, 95%CI: 0.39-1.2, P = 0.147) was observed between the two groups. Rosuvastatin decreased the hospitalization time (13.8 ± 2.5 vs 14.2 ± 2.8, P = 0.03) and hospitalization expenses (9.3 ± 2.5 vs 9.8 ± 2.9, P = 0.007). No significant differences in abnormal liver enzymes (9.0% vs 7.1%, OR = 1.307, 95%CI: 0.787-2.169, P = 0.30) or rhabdomyolysis (0.73% vs 0.24%, OR = 3.020, 95%CI: 0.31-29.2, P = 0.37) were observed between the two groups.ConclusionThe current study suggests that perioperative rosuvastatin treatment reduces the incidence of delirium after an elective operation under general anesthesia. However, the evidence does not reveal that rosuvastatin improves clinical outcomes. The therapy is safe. Further investigation is necessary to fully understand the potential usefulness of rosuvastatin in elderly patients.

Project description:BackgroundDelirium during critical illness results from numerous insults, which might be interconnected and yet individually contribute to long-term cognitive impairment. We sought to describe the prevalence and duration of clinical phenotypes of delirium (ie, phenotypes defined by clinical risk factors) and to understand associations between these clinical phenotypes and severity of subsequent long-term cognitive impairment.MethodsIn this multicentre, prospective cohort study, we included adult (≥18 years) medical or surgical ICU patients with respiratory failure, shock, or both as part of two parallel studies: the Bringing to Light the Risk Factors and Incidence of Neuropsychological Dysfunction in ICU Survivors (BRAIN-ICU) study, and the Delirium and Dementia in Veterans Surviving ICU Care (MIND-ICU) study. We assessed patients at least once a day for delirium using the Confusion Assessment Method-ICU and identified a priori-defined, non-mutually exclusive phenotypes of delirium per the presence of hypoxia, sepsis, sedative exposure, or metabolic (eg, renal or hepatic) dysfunction. We considered delirium in the absence of hypoxia, sepsis, sedation, and metabolic dysfunction to be unclassified. 3 and 12 months after discharge, we assessed cognition with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). We used multiple linear regression to separately analyse associations between the duration of each phenotype of delirium and RBANS global cognition scores at 3-month and 12-month follow-up, adjusting for potential confounders.FindingsBetween March 14, 2007, and May 27, 2010, 1048 participants were enrolled, eight of whom could not be analysed. Of 1040 participants, 708 survived to 3 months of follow-up and 628 to 12 months. Delirium was common, affecting 740 (71%) of 1040 participants at some point during the study and occurring on 4187 (31%) of all 13 434 participant-days. A single delirium phenotype was present on only 1355 (32%) of all 4187 participant-delirium days, whereas two or more phenotypes were present during 2832 (68%) delirium days. Sedative-associated delirium was most common (present during 2634 [63%] delirium days), and a longer duration of sedative-associated delirium predicted a worse RBANS global cognition score 12 months later, after adjusting for covariates (difference in score comparing 3 days vs 0 days: -4·03, 95% CI -7·80 to -0·26). Similarly, longer durations of hypoxic delirium (-3·76, 95% CI -7·16 to -0·37), septic delirium (-3·67, -7·13 to -0·22), and unclassified delirium (-4·70, -7·16 to -2·25) also predicted worse cognitive function at 12 months, whereas duration of metabolic delirium did not (1·14, -0·12 to 3·01).InterpretationOur findings suggest that clinicians should consider sedative-associated, hypoxic, and septic delirium, which often co-occur, as distinct indicators of acute brain injury and seek to identify all potential risk factors that may impact on long-term cognitive impairment, especially those that are iatrogenic and potentially modifiable such as sedation.FundingNational Institutes of Health and the Department of Veterans Affairs.

Project description:IntroductionThe pathophysiology of sepsis-associated delirium is not completely understood and the data on cerebral perfusion in sepsis are conflicting. We tested the hypothesis that cerebral perfusion and selected serum markers of inflammation and delirium differ in septic patients with and without sepsis-associated delirium.MethodsWe investigated 23 adult patients with sepsis, severe sepsis, or septic shock with an extracranial focus of infection and no history of intracranial pathology. Patients were investigated after stabilisation within 48 hours after admission to the intensive care unit. Sepsis-associated delirium was diagnosed using the confusion assessment method for the intensive care unit. Mean arterial pressure (MAP), blood flow velocity (FV) in the middle cerebral artery using transcranial Doppler, and cerebral tissue oxygenation using near-infrared spectroscopy were monitored for 1 hour. An index of cerebrovascular autoregulation was calculated from MAP and FV data. C-reactive protein (CRP), interleukin-6 (IL-6), S-100beta, and cortisol were measured during each data acquisition.ResultsData from 16 patients, of whom 12 had sepsis-associated delirium, were analysed. There were no significant correlations or associations between MAP, cerebral blood FV, or tissue oxygenation and sepsis-associated delirium. However, we found a significant association between sepsis-associated delirium and disturbed autoregulation (P = 0.015). IL-6 did not differ between patients with and without sepsis-associated delirium, but we found a significant association between elevated CRP (P = 0.008), S-100beta (P = 0.029), and cortisol (P = 0.011) and sepsis-associated delirium. Elevated CRP was significantly correlated with disturbed autoregulation (Spearman rho = 0.62, P = 0.010).ConclusionIn this small group of patients, cerebral perfusion assessed with transcranial Doppler and near-infrared spectroscopy did not differ between patients with and without sepsis-associated delirium. However, the state of autoregulation differed between the two groups. This may be due to inflammation impeding cerebrovascular endothelial function. Further investigations defining the role of S-100beta and cortisol in the diagnosis of sepsis-associated delirium are warranted.Trial registrationClinicalTrials.gov NCT00410111.

Project description:Patients in the ICU often sleep poorly for various reasons, which may predispose to delirium. We previously conducted a clinical trial in which we tested the efficacy of ramelteon, a melatonin-receptor agonist used to treat insomnia, versus placebo, in preventing ICU delirium in patients who underwent elective pulmonary thromboendarterectomy (PTE) surgery. Here we examine sleep, activity, and circadian patterns, measured with actigraphy, to understand changes in these metrics with our intervention and in those with and without delirium. Participants wore wrist actigraphy devices while recovering post-operatively in the ICU. For sleep analysis, we extracted total sleep time and sleep fragmentation metrics over the 22:00 to 06:00 period nightly, and daytime nap duration from the daytime period (0:600 to 22:00) for each participant. For activity analyses, we extracted the following metrics: total daytime activity count (AC), maximum daytime AC, total nighttime AC, and maximum nighttime AC. Next, we performed a nonparametric circadian analysis on ACs over each 24-h day and extracted the following: interdaily stability (IS), intra-daily variability (IV), relative amplitude (RA), and low and high periods of activity (L5 and M10) as well as their start times. These metrics were compared between patients who received ramelteon versus placebo, and between patients who became delirious versus those who did not develop delirium. We additionally made comparisons between groups for daytime and nighttime light levels. No differences in sleep, activity, circadian metrics or light levels were found between drug groups. Delirious patients, when compared to those who were never delirious, had a lower IS (0.35 ± 0.16 vs. 0.47 ± 0.23; P = 0.006). Otherewise, no differences in IV, L5, M10, or RA were found between groups. L5 and M10 activity values increased significantly over the post-extubation for the whole cohort. No differences were found for daytime or nighttime light levels between groups. Overall, ramelteon did not impact sleep or circadian metrics in this cohort. Consistent with clinical experience, delirious patients had less inter-daily stability in their rest-activity rhythms. These data suggest that actigraphy might have value for individual assessment of sleep in the ICU, and for determining and detecting the impact of interventions directed at improving sleep and circadian activity rhythms in the ICU.Trial registration: REGISTERED at CLINICALTRIALS.GOV: NCT02691013. Registered on February 24, 2016 by principal investigator, Dr. Robert L. Owens.

Dataset Information

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.

Publications

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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