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.
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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与败血症相关的急性呼吸窘迫综合征患者的重症监护和随后的认知障碍的木伐他汀与安慰剂与安慰剂：一项随机对照试验的辅助研究。
DOI：
10.1016/s2213-2600(16)00005-9
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发表时间：
2016-03
期刊：
影响因子：
--
通讯作者：
Hopkins RO
中科院分区：
文献类型：
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作者：
Needham DM;Colantuoni E;Dinglas VD;Hough CL;Wozniak AW;Jackson JC;Morris PE;Mendez-Tellez PA;Ely EW;Hopkins RO
谵妄常见于机械通气患者，并与出院后持续至少1年的认知障碍相关。临床前和观察性研究表明，在重症监护中使用他汀类药物可能会减少谵妄。我们在一项随机对照试验中评估了他汀类药物的多效性是否可以减少重症监护期间的谵妄和减少随后的认知障碍。我们在SAILS试验中进行了这项辅助研究，这是一项随机对照试验，评估了败血症相关急性呼吸窘迫综合征患者瑞舒伐他汀与安慰剂的死亡率和无呼吸机天数。这项研究是在美国35家医院进行的。患者被随机分配为8个分组，并按医院分层，接受瑞舒伐他汀（40mg负荷剂量，然后每天20mg，直到重症监护出院后第3天，研究第28天或死亡）或安慰剂。患者和调查人员对治疗分配进行了掩饰。重症监护时谵妄用经过验证的混淆评估法进行评估。通过执行功能、语言、口头推理和概念形成、工作记忆、即时记忆和延迟记忆等测试来评估认知功能。我们将认知障碍定义为在其中一个领域中至少有两个标准差低于总体标准，或者至少有两个领域至少有1.5个标准差低于标准。主要终点是意向治疗人群在重症监护期间长达28天的每日谵妄状态，次要终点是6个月和12个月时的认知功能。该试验已在ClinicalTrials.gov注册（NCT00979121和NCT00719446）。在重症监护期间每天对272例患者进行谵妄评估。瑞舒伐他汀组谵妄天数的平均比例为34% (SD 30%)，安慰剂组为31% (29%)；风险比为1.14,95% CI为0.92 - 1.41,p= 0.22。6个月时，瑞舒伐他汀组53例患者中有19例（36%）出现认知障碍，安慰剂组77例患者中有29例（38%）出现认知障碍，两组间差异无统计学意义（治疗效果0.93,95% CI 0.39 - 2.22; p= 0.87）。12个月时，67例患者中有20例（30%）与81例患者中有23例（28%）出现认知障碍，两组间无显著差异（治疗效果1.1,95% CI 0.5 - 2.6; p= 0.82）。大多数患者有谵妄，大约三分之一的幸存者在1年的随访中有认知障碍。尽管临床前和观察性研究令人鼓舞，但该试验在12个月的随访中显示瑞舒伐他汀在减少重症监护患者谵妄或认知障碍方面没有任何益处，尽管该研究并未证明其优越性。因此，仍有必要评估旨在减轻重症监护和重症监护后认知障碍的干预措施，这些干预措施在这一人群中普遍存在。
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.