Pharmacological Management of Delirium

描述（由申请人提供）：大约有270万65岁及以上的美国人在重症监护室（ICU）至少呆了一天，医疗费用总计275亿美元。高达80%的老年ICU患者在住院期间发生谵妄，这对他们的医院相关健康结局产生了负面和独立的影响。患有谵妄的老年人接受潜在有害的药物治疗，如抗胆碱能药物和苯二氮卓类药物，并且比没有谵妄的老年人更容易发生福尔斯、受伤、压疮和束缚。这些并发症导致ICU和住院时间延长、死亡率升高、功能状态较差、康复受限、机构化增加和医疗保健费用增加。目前，没有FDA批准的药物化合物来降低与谵妄相关的死亡率和发病率。几种神经递质的紊乱，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），已被认为参与了谵妄的病理生理学。这些神经递质被提出作为发展谵妄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分散的随机临床试验表明，老年人谵妄的药物治疗是复杂的，可能需要减少苯二氮卓类药物和抗胆碱能药物的使用，沿着使用低剂量精神抑制剂，如氟哌啶醇。然而，还没有随机对照试验评价这种药物治疗对减少谵妄严重程度、持续时间及其相关并发症的疗效。该提案正在寻求资金，以进行一项随机对照试验，该试验将评价谵妄药理学方案的疗效，包括1）减少抗胆碱能药物的暴露; 2）减少苯二氮卓类药物的暴露; 3）每日使用低剂量氟哌啶醇。该研究的主要结局是谵妄严重程度（通过谵妄评定量表（DRS-R-98）测量）和谵妄持续时间（通过ICU混乱评估方法（CAM-ICU）测量）。 公共卫生相关性：患有谵妄的住院老年人是我们患者人群中的一个脆弱且快速增长的部分，特别是那些入住重症监护室的患者。在住院和ICU期间，这些患者容易发生各种医院获得性并发症，如福尔斯、损伤、压疮和束缚。随后，这些并发症导致死亡率、功能状态较差、康复受限、住院时间延长、住院人数增加和医疗保健费用增加。 有证据表明，一个特定的神经递质功能障碍参与谵妄的病理生理学，并修改这些神经递质的水平可能会降低谵妄的严重程度和持续时间，从而改善谵妄患者的死亡率和发病率。 本提案的主要目标是进行一项随机对照临床试验，评价多组分药物干预在降低谵妄严重程度和持续时间以及随后缩短ICU和住院时间方面的疗效。提出的个性化干预的一个主要优点是减少暴露于潜在的有害药物，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.