Altering Sedation Paradigms to Improve Brain Injury and Survival in Severe Sepsis

描述（由申请人提供）： 继发于脓毒症的机械通气（MV）需求是进入重症监护室的主要原因，通常需要镇静以确保患者的安全和舒适。最近，我们了解到这些镇静药物会导致医源性损伤，如延长呼吸机使用时间和ICU住院时间以及加重急性脑功能障碍。这种急性脑功能障碍，表现为谵妄和昏迷，发生在50%-70%的MV脓毒症患者中，并且不仅是死亡的重要因素，而且也是功能和认知下降的重要因素，其可以在肺和其他器官功能恢复后持续数年，给患者和社会带来重大成本。尽管在急性呼吸衰竭和脓毒症的管理方面取得了进展，但很少有临床试验研究了支持性治疗（如镇静）对这一脆弱人群的短期和长期结局的影响。特别是γ-氨基丁酸（GABA）能的苯二氮卓类药物，已被证明会增加脑功能障碍，促进感染，并延长MV。因此，短效GABA能镇静剂丙泊酚和α 2激动剂右美托咪定正被广泛用于使脓毒症MV患者镇静。然而，只有少数随机试验指导临床医生在这些和其他镇静剂之间进行选择，并且没有探索结果差异的潜在机制，尽管一些数据表明GABA能和α 2激动剂对先天免疫，细胞凋亡，唤醒能力和呼吸驱动有非常不同的影响。在早期的动物和人体研究中，右美托咪定比GABA能药物具有更强的抗炎作用;右美托咪定可提高细菌清除率，而丙泊酚则会降低细菌清除率。此外，用右美托咪定代替苯二氮卓类药物进行镇静可减少20%-30%的谵妄，并改善通气患者的唤醒能力、认知能力和注意力。α 2激动剂在脑干诱导无意识-更类似于自然睡眠-这可能改善自主神经功能和免疫力。所有这些因素共同表明，与GABA能药物相比，α 2激动剂镇静可能改善脓毒症MV患者的结局，包括脑功能、MV和生存率。因此，我们建议MENDS II（最大化镇静效果并降低急性呼吸衰竭脓毒症患者的神经功能障碍和死亡率）研究，在该研究中，我们将检验α 2激动剂对MV严重脓毒症患者的镇静作用（右美托咪定）而非GABA能药物（丙泊酚）将（目的1A）增加无谵妄或昏迷的存活天数，（目的1B）增加无呼吸机天数，（目的2A）改善90天生存率，（目的2B）减少长期认知障碍，和（目的3）减少脓毒症后的促炎细胞因子级联。我们将随机分配530例需要右美托咪定或丙泊酚目标导向镇静的通气、严重脓毒症患者，使研究有90%的把握度检测两组之间1.5个无谵妄/无昏迷天数的差异和10%的死亡率绝对差异。

DESCRIPTION (provided by applicant): The need for mechanical ventilation (MV) secondary to sepsis is the leading cause of admission to the intensive care unit, often necessitating sedation for patient safety and comfort. Recently, we have learned that these sedative medications contribute to iatrogenic injury, such as prolonging ventilator time and ICU length of stay and exacerbating acute brain dysfunction. This acute brain dysfunction, manifested as delirium and coma, occurs in 50%-70% of MV septic patients and is a significant contributor not only to death but also to functional and cognitive decline, which can persist for years after recovery of lung and other organ function, levying significant costs to patients and society. Despite advances in the management of acute respiratory failure and sepsis, few clinical trials have examined the effects that supportive therapies, like sedation, may have on both short- and long-term outcomes in this vulnerable population. The gamma-aminobutyric acid (GABA)-ergic benzodiazepines, in particular, have been shown to increase brain dysfunction, promote infection, and prolong MV. Therefore, the short-acting GABA-ergic sedative propofol and the alpha2 agonist dexmedetomidine are becoming widely used to sedate septic MV patients. There are only a few randomized trials, however, to guide clinicians when selecting between these and other sedatives, and none have explored the mechanisms underlying the differences in outcomes, though some data indicate that GABA-ergic and alpha2 agonist agents have very different effects on innate immunity, apoptosis, arousability, and respiratory drive. In early animal and human studies, dexmedetomidine had more anti-inflammatory effects than the GABA-ergic agents; dexmedetomidine improved bacterial clearance, whereas propofol impaired it. In addition, sedation with dexmedetomidine instead of benzodiazepines reduces delirium by 20%-30% and improves arousability, cognition, and attentiveness in ventilated patients. Alpha2 agonists induce unconsciousness at the brainstem- more akin to natural sleep-which may improve autonomic function and immunity. All these factors converge to suggest that sedation with an alpha2 agonist rather than a GABAergic agent may improve outcomes, including brain function, MV, and survival, for septic MV patients. We therefore propose the MENDS II (Maximizing the Efficacy of Sedation and Reducing Neurological Dysfunction and Mortality in Septic Patients with Acute Respiratory Failure) study, in which we will test the hypotheses that sedation of MV severely septic patients with an alpha2 agonist (dexmedetomidine) rather than a GABAergic agent (propofol) will (Aim 1A) increase days alive without delirium or coma, (Aim 1B) increase ventilator-free days, (Aim 2A) improve 90-day survival, (Aim 2B) decrease long-term cognitive impairment, and (Aim 3) reduce the pro-inflammatory cytokine cascade following sepsis. We will randomize 530 ventilated, severely septic patients requiring goal-directed sedation with dexmedetomidine or propofol, giving the study 90% power to detect a difference of 1.5 delirium/coma-free days and an absolute difference in mortality of 10% between the two groups.