The MIND USA Study

描述(由申请人提供)：拟议的Mind-USA(修改ICU诱导的神经功能障碍的影响-美国)研究的长期目标是确定抗精神病药物在治疗脆弱危重患者精神错乱中的作用。我们和其他人已经证明，精神错乱是死亡更多、住院时间更长、费用更高以及通常与中度痴呆相称的长期认知障碍的独立预测因素。快速增长的老年ICU人口特别容易发展为精神错乱，10名内科和外科ICU患者中有7人发展为这种器官功能障碍。抗精神病药物是推荐用于治疗精神错乱的一线药物，在过去的30年里，在对这一适应症的有效性和安全性进行充分测试之前，它们在全球住院患者中得到了广泛使用。氟哌啶醇是最常用的抗精神病药物，超过80%的ICU医生使用氟哌啶醇治疗精神错乱，而非典型抗精神病药物的处方比例为40%。抗精神病药物的安全性问题包括致命性心律失常、锥体外系症状，以及在非ICU老年人群中使用抗精神病药物导致的死亡率增加。最重要的假设是，典型和非典型的抗精神病药物--在本例中为氟哌啶醇和齐拉西酮--用于患有精神错乱的危重患者将改善短期和长期的临床结果。目标1将确定氟哌啶醇或齐拉西酮是否会在14天内与安慰剂相比，以及彼此之间的比较，增加没有急性脑功能障碍的存活天数(称为精神错乱/无昏迷天数或DCFD)。目标2将确定与安慰剂相比，氟哌啶醇或齐拉西酮是否会提高30天、90天和1年的存活率，并相互比较。目标3将确定与安慰剂相比，氟哌啶醇或齐拉西酮是否会减少ICU的住院时间，并进行相互比较。目的4将确定氟哌啶醇或齐拉西酮是否能降低长期神经心理功能障碍的发生率、严重程度和/或持续时间，并与安慰剂相比，在90天和1年的随访中改善生活质量。为了达到这些目标，我们将对876名危重、神志不清的内科/外科ICU患者进行这项多中心、双盲、随机、安慰剂对照的研究，这些患者(A)正在接受机械通气或无创正压呼吸或(B)正在使用血管升压剂休克。在每一组(氟哌啶醇、齐拉西酮和安慰剂)中，292名患者将被登记和治疗，直到精神错乱缓解48小时或14天(以最先发生的为准)，并随访1年。我们将监测许多安全参数，如心律失常和锥体外系症状。这项研究将有足够的能力检测抗精神病药物在4个重要亚组中的效果，包括年龄和65岁、疾病严重程度(APACHE II&>25)、登记时的严重脓毒症、内科和外科ICU患者，并对先前存在的认知障碍患者进行假设生成分析。 与公共卫生相关：每年有数百万重症患者在重症监护病房(ICU)期间出现神志不清(精神错乱)，尽管其中很大一部分患者没有被发现和治疗，但ICU团队最常使用典型和非典型的抗精神病药物来治疗这些患者，尽管没有安慰剂对照试验的支持。Mind-USA试验将是有史以来第一项回答氟哌啶醇或非典型抗精神病药物(齐拉西酮)在治疗内科和外科ICU患者时比安慰剂更好还是更差的问题的研究。这项调查将确定氟哌啶醇或齐拉西酮在1年的随访中是否缩短了精神错乱的持续时间，提高了存活率，影响了住院时间，或改善了长期脑功能和生活质量。

DESCRIPTION (provided by applicant): The long-term objective of the proposed MIND-USA (Modifying the Impact of ICU-Induced Neurological Dysfunction-USA) Study is to define the role of antipsychotics in the management of delirium in vulnerable critically ill patients. We and others have shown that delirium is an independent predictor of more death, longer stay, higher cost, and long-term cognitive impairment often commensurate with moderate dementia. The rapidly expanding aging ICU population is especially vulnerable to develop delirium, with 7 of 10 medical and surgical ICU patients developing this organ dysfunction. Antipsychotics are the first-line pharmacological agents recommended to treat delirium, and over the past 30 years they gained widespread use in hospitalized patients globally prior to adequate testing of efficacy and safety for this indication. Haloperidol, the most commonly chosen antipsychotic, is used by over 80% of ICU doctors for delirium, while atypical antipsychotics are prescribed by 40%. Antipsychotics safety concerns include lethal cardiac arrhythmias, extrapyramidal symptoms, and the highly publicized increased mortality associated with their use in non-ICU geriatric populations. The overarching hypothesis is that administration of typical and atypical antipsychotics-haloperidol and ziprasidone, in this case-to critically ill patients with delirium will improve short- and long-term clinical outcomes. Aim 1 will determine whether haloperidol or ziprasidone will increase days alive without acute brain dysfunction (referred to as delirium/coma-free days or DCFDs) over a 14-day period compared with placebo and compared to one another. Aim 2 will determine whether haloperidol or ziprasidone will improve 30-day, 90-day, and 1-year survival compared with placebo and compared to one another. Aim 3 will determine whether haloperidol or ziprasidone will reduce ICU length of stay compared with placebo and compared to one another. Aim 4 will determine whether haloperidol or ziprasidone will reduce the incidence, severity, and/or duration of long-term neuropsychological dysfunction and improve quality of life at 90-day and 1-year follow-up compared with placebo and compared to one another. To address these Aims, we will conduct this multi-center, double blind, randomized, placebo-controlled investigation in 876 critically ill, delirious medical/surgical ICU patients who are (a) on mechanical ventilation or non-invasive positive pressure ventilation or (b) in shock on vasopressors. In each group (haloperidol, ziprasidone, and placebo), 292 patients will be enrolled and treated until delirium has resolved for 48 hours or to 14 days (whichever occurs first) and followed for 1 year. We will monitor many safety parameters such as cardiac dysrhythmias and extrapyramidal symptoms. This study will have adequate power to detect the effect of antipsychotics in 4 important subgroups including age >65 years, severity of illness (APACHE II > 25), severe sepsis at enrollment, and medical vs. surgical ICU patients, and a hypothesis generating analysis of patients with pre- existing cognitive impairment. PUBLIC HEALTH RELEVANCE: Millions of critically ill patients every year develop confusion (delirium) while in Intensive Care Units (ICUs), and though a large portion of these patients go undetected and untreated, ICU teams most often use typical and atypical antipsychotics to treat such patients despite no support from placebo-controlled trials. The MIND-USA trial will be the first study ever to answer the question of whether haloperidol or an atypical antipsychotic (ziprasidone) is better or worse than a placebo as treatment for delirious medical and surgical ICU patients. This investigation will determine if either haloperidol or ziprasidone shorten delirium duration, improve survival, affect length of stay in the hospital, or improve long-term brain function and quality of life at 1-year follow-up.