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）呆了至少一天，花费了医疗保险总计275亿美元。高达80%的老年ICU患者在住院期间患有谵妄，这对他们的医院相关健康结果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，如抗胆碱能药和苯二氮卓类药物，与没有谵妄的老年人相比，他们更容易跌倒、受伤、压疮和束缚。这些并发症导致ICU和住院时间延长、死亡率增加、功能状况恶化、康复受限、机构化增加和医疗费用增加。目前，还没有fda批准的药物化合物可以降低与谵妄相关的死亡率和发病率。一些神经递质的紊乱，如乙酰胆碱、多巴胺、谷氨酸、血清素、去甲肾上腺素和γ -氨基丁酸（GABA），已被认为与谵妄的病理生理有关。这些神经递质被认为是开发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，老年人谵妄的药物管理是复杂的，可能需要包括减少苯二氮卓类药物和抗胆碱能药物的使用，以及使用低剂量的神经抑制剂，如氟哌啶醇。然而，目前还没有随机对照试验评估这种药物管理在减少谵妄严重程度、持续时间及其相关并发症方面的疗效。该提案正在寻求资金来进行一项随机对照试验，以评估谵妄的药理学方案的有效性，该方案包括：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)每日使用小剂量氟哌啶醇。研究的主要结果是谵妄严重程度，用谵妄评定量表（DRS-R-98）测量；神志不清评估法（CAM-ICU）测量谵妄持续时间。

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.