Cognitive Outcomes in the Pragmatic Investigation of Optimal Oxygen Targets (CO-PILOT) Trial

项目摘要 根据我们之前的工作，四分之一的重症监护室（ICU）幸存者将获得认知能力 在12个月时出现类似于阿尔茨海默病和相关痴呆（ADRD）的损伤。这导致减少 失业，生活质量下降，失去独立性。这个日益严重的公共卫生问题 尤其是每年影响到200万到300万机械通气的ICU患者。目前， 危重成人的机械通气普遍涉及吸入氧气分数（FiO 2）的滴定 维持动脉血氧饱和度（SpO 2）。然而，最佳SpO 2目标仍然未知;目前 建议范围从耐受SpO 2值低至88%（急性呼吸窘迫综合征 网络）追求高达98%的SpO 2值（英国胸科学会）。因为缺氧是一种 与ADRD发病机制有关，我们假设在机械通气期间以较低SpO 2为目标， 与更高的SpO 2目标相比，与更差的长期整体认知显著相关。解决 基于这一假设，我们建议对NIH资助的最佳氧的实用研究进行辅助研究 目标（试点）试验。PILOT母体试验是一项分组随机、分组交叉试验， (88%至92%）、中等（93%至96%）和高（>96%）SpO 2目标，以及 将在三年内从医学ICU招募2,250名患者。PILOT的结局是无呼吸机 天和死亡率，但没有评估长期的全球认知。因此，我们建议进行这项辅助研究， 标题为认知结果的试点（共同试点），其中有以下具体目标：（1）确定是否 较低的SpO 2目标（88 - 92%）与6个月整体认知能力较差显著相关， 机械通气ICU患者的SpO 2目标较高（>92%）;以及（2）确定SpO 2目标有多低 （88-92%）影响个别认知领域，特别是即时和延迟记忆，在6个月 相比之下，机械通气ICU患者的SpO 2目标更高（>92%）。CO-PILOT将入组 在18个月期间参加PILOT的189名幸存者的子集。R21将提供 获得6个月认知和次要结果测量所需的资金和资源。半年 整体认知及其个体认知领域（中间和延迟记忆、注意力、视觉空间 结构和语言）将通过面对面的神经心理学测试来确定， 神经心理状态评估可重复成套测验（RBANS）。飞行员有可能 母试验可能报告较低的SpO 2目标可改善生存率，但CO-PILOT辅助试验可能揭示 这将以牺牲长期认知为代价。因为病人和他们的家人 不同的偏好，他们认为理想的结果是什么，这两项研究是必要的，以提供一个 对SpO 2目标进行广泛结局的综合评价。

PROJECT SUMMARY Based upon our previous work, one out of four intensive care unit (ICU) survivors will acquire cognitive impairment similar to Alzheimer’s disease and related dementias (ADRD) at 12-months. This leads to reduced employment, decreased quality of life, and loss of independence. This growing public health problem especially affects the 2 to 3 million ICU patients who are mechanically ventilated each year. Currently, mechanical ventilation of critically ill adults universally involves titration of the fraction of inspired oxygen (FiO2) to maintain arterial oxygen saturation (SpO2). The optimal SpO2 target, however, remains unknown; current recommendations range from tolerating SpO2 values as low as 88% (Acute Respiratory Distress Syndrome Network) to pursuing SpO2 values as high as 98% (British Thoracic Society). Because hypoxia is strongly implicated in ADRD pathogenesis, we hypothesize that targeting lower SpO2 during mechanical ventilation is significantly associated with worse long-term global cognition compared with higher SpO2 targets. To address this hypothesis, we propose this ancillary study to the NIH-funded Pragmatic Investigation of optimaL Oxygen Targets (PILOT) trial. The PILOT parent trial is a cluster-randomized, cluster-crossover trial comparing low (88% to 92%), intermediate (93% to 96%), and high (>96%) SpO2 targets during mechanical ventilation and will enroll 2,250 patients from the medical ICU over a three-year period. PILOT’s outcomes are ventilator-free days and mortality but is not assessing long-term global cognition. Therefore, we propose this ancillary study titled Cognitive Outcomes in PILOT (CO-PILOT) which has the following specific aims: (1) determine if the lower SpO2 target (88 to 92%) is significantly associated with worse 6-month global cognition compared with higher (>92%) SpO2 targets in mechanically ventilated ICU patients; and (2) determine how low SpO2 targets (88-92%) affects individual cognitive domains, particularly immediate and delayed memory, at 6-months compared with higher (>92%) SpO2 targets among mechanically ventilated ICU patients. CO-PILOT will enroll a subset of 189 survivors who are enrolled in PILOT over an 18-month period. This R21 will provide the funding and resources needed to obtain 6-month cognitive and secondary outcome measurements. Six-month global cognition and its individual cognitive domains (intermediate and delayed memory, attention, visuospatial construction, and language) will be determined by face-to-face neuropsychological testing using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). It is possible that the PILOT parent trial may report that a lower SpO2 target improves survival, but the CO-PILOT ancillary trial may reveal that this will come at the expense of long-term cognition. Because patients and their families likely have different preferences for what they consider the ideal outcome is, both studies are necessary to provide a comprehensive evaluation of SpO2 targets on a wide range of outcomes.