Pharmacological Management of Delirium

描述(由申请人提供)：大约270万65岁及以上的美国人在重症监护病房(ICU)至少呆了一天，联邦医疗保险总共花费了275亿美元。在这些老年ICU患者中，高达80%的患者在住院期间出现了精神错乱，这对他们与医院相关的健康结局产生了负面和独立的影响。患有精神错乱的老年人接受潜在有害的药物治疗，如抗胆碱药和苯二氮卓类药物，并且比没有精神错乱的老年人更容易摔倒、受伤、压疮和束缚。这些并发症导致ICU和住院时间延长，死亡率更高，功能状态更差，康复有限，制度化程度增加，医疗费用更高。目前，还没有FDA批准的药物化合物来降低与精神错乱相关的死亡率和发病率。多种神经递质，如乙酰胆碱、多巴胺、谷氨酸、5-羟色胺、去甲肾上腺素和γ-氨基丁酸(GABA)的紊乱，被认为参与了痴呆症的病理生理过程。这些神经递质被认为是治疗妄想的药物治疗的潜在靶点。然而，最有力的数据支持乙酰胆碱增强、GABA减少和多巴胺减少的关键治疗作用。药物流行病学研究和零星的随机临床试验表明，老年人精神错乱的药理学管理是复杂的，可能需要包括减少苯二氮类药物和抗胆碱类药物的使用，以及使用小剂量的神经抗精神病药，如氟哌啶醇。然而，目前还没有一项随机对照试验来评估这种药物治疗在减少神志不清的严重程度、持续时间和相关并发症方面的效果。这项提案正在寻求资金，以进行一项随机对照试验，以评估治疗精神错乱的药理学方案的有效性，该方案包括1)减少接触抗胆碱能药物；2)减少苯二氮类药物的接触；3)每天使用低剂量的氟哌啶醇。这项研究的主要结果是用妄想评定量表(DRS-R-98)衡量的妄想严重程度；以及用ICU中的混乱评估方法(CAM-ICU)衡量的妄想持续时间。 与公共卫生相关：患有妄想症的住院老年人在我们的患者群体中是一个脆弱且迅速增长的部分，特别是那些住进重症监护病房的人。在住院和ICU期间，这些患者容易出现各种医院获得性并发症，如跌倒、受伤、压疮和束缚。随后，这些并发症会导致死亡率、功能状态变差、有限的康复、住院时间延长、更多的住院费用和更高的医疗费用。有证据表明，一种特定的神经递质功能紊乱参与了妄想的病理生理过程，改变这些神经递质的水平可能会降低妄想的严重程度和持续时间，从而提高妄想患者的死亡率和发病率。这项建议的主要目标是进行一项随机对照临床试验，评估多组分药物干预在减少妄想的严重程度和持续时间方面的有效性，并随后减少ICU和住院时间。拟议的个体化干预的一个主要优势是减少潜在有害药物的暴露，并在ICU护理的关键早期使用低剂量的氟哌啶醇。

DESCRIPTION (provided by applicant): Approximately 2.7 million Americans aged 65 and older spent at least one day in the intensive care unit (ICU) costing MEDICARE a total of $27.5 billion. Up to 80% of these older ICU patients had delirium during their hospital stay that affects negatively and independently their hospital related health outcomes. Older adults with delirium receive potentially harmful medications such as anticholinergics and benzodiazepines and are more prone to falls, injuries, pressure ulcers and restraints than their counterparts with no delirium. These complications contribute to prolonged ICU and hospital length of stay, higher mortality rates, poorer functional status, limited rehabilitation, increased institutionalization, and higher health care costs. Currently, there is no FDA-approved pharmacological compound to reduce mortality and morbidity related to delirium. Disturbances in several neurotransmitters, such as acetylcholine, dopamine, glutamate, serotonin, norepinephrine, and gamma-aminobutyric acid (GABA), have been suggested to be involved in the pathophysiology of delirium. These neurotransmitters are put forward as potential targets for the development of pharmacological therapeutics for delirium. However, the strongest data supports a critical therapeutic role for acetylcholine enhancement, GABA reduction, and dopamine reduction. Pharmaco-epidemiological studies and scattered randomized clinical trials have demonstrated that the pharmacological management of delirium among older adults is complicated and may need to include a combination of a reduction in the use of benzodiazepines and anticholinergics, along with the use of low dose neuroleptics such as haloperidol. However, there have been no randomized controlled trials evaluating the efficacy of such a pharmacological management on reducing delirium severity, duration, and its related complications. This proposal is seeking funding to conduct a randomized controlled trial that would evaluate the efficacy of a pharmacological protocol for delirium that includes 1) a reduction of exposure to anticholinergic medications; 2) a reduction of exposure to benzodiazepines; and 3) daily use of a low dose of haloperidol. The primary outcomes of the study are delirium severity, as measured by the Delirium Rating Scale (DRS-R-98); and delirium duration as measured by the Confusion Assessment Method in the ICU (CAM-ICU). PUBLIC HEALTH RELEVANCE: Hospitalized older adults suffering from Delirium are a vulnerable and rapidly growing segment of our patient population, especially those admitted to the Intensive Care Units. During their hospital and ICU stay, these patients are prone to develop various hospital acquired complications such as falls, injuries, pressure ulcers, and restraints. Subsequently, these complications contribute to mortality, poorer functional status, limited rehabilitation, prolonged length of stay, increased institutionalization, and higher health care costs. Evidence suggests that a specific disturbance in the neurotransmitter function is involved in the pathophysiology of delirium and that modifying the levels of these neurotransmitters may decrease the severity and duration of delirium and thus improving mortality and morbidity of patients with delirium. The primary goal of this proposal is to conduct a randomized controlled clinical trial that will evaluate the efficacy of a multi-component pharmacological intervention in reducing delirium severity and duration and subsequently decrease ICU and hospital length of stay. A major advantage of the proposed individualized intervention is reducing exposure to potentially harmful medications and using low dose of haloperidol during the critical early days of ICU care.