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)是住进重症监护病房的首要原因，为了患者的安全和舒适，通常需要镇静。最近，我们了解到这些镇静药物导致医源性损伤，如延长呼吸机时间和ICU住院时间，加剧急性脑功能障碍。这种急性脑功能障碍，表现为精神错乱和昏迷，发生在50%-70%的MV脓毒症患者中，不仅是死亡的重要原因，而且是功能和认知能力下降的重要因素，在肺和其他器官功能恢复后可持续数年，给患者和社会带来巨大代价。尽管在急性呼吸衰竭和脓毒症的治疗方面取得了进展，但很少有临床试验研究镇静等支持性疗法对这一脆弱人群的短期和长期结果的影响。尤其是γ-氨基丁酸(GABA)能的苯二氮卓类药物，已经被证明增加了大脑功能障碍，促进了感染，并延长了MV。因此，短效GABA能镇静剂异丙酚和α2激动剂右美托咪定正被广泛用于感染性MV患者的镇静。然而，只有少数几个随机试验来指导临床医生在这些镇静剂和其他镇静剂之间进行选择，还没有人探索导致结果差异的机制，尽管一些数据表明，GABA受体激动剂和Alpha2激动剂在先天性免疫、细胞凋亡、唤醒和呼吸驱动方面的作用截然不同。在早期的动物和人类研究中，右美托咪定比GABA能药有更多的抗炎作用；右美托咪定促进细菌清除，而异丙酚则削弱它。此外，使用右旋美托咪定替代苯二氮卓类药物镇静可减少20%-30%的神志不清，并改善呼吸机患者的觉醒能力、认知能力和注意力。Alpha2激动剂在脑干诱导无意识--更类似于自然睡眠--这可能会改善自主神经功能和免疫力。所有这些因素都表明，使用α2激动剂而不是GABA能药物的镇静可能会改善感染性MV患者的预后，包括脑功能、MV和生存率。因此，我们提出了MODES II(最大化镇静效果，减少脓毒症合并急性呼吸衰竭患者的神经功能障碍和死亡率)研究，其中我们将检验以下假设：使用α2激动剂(右美托咪定)而不是GABA能药(异丙酚)的MV严重脓毒症患者镇静将(目标1A)增加无精神障碍或昏迷的存活天数，(目标1B)增加无呼吸机天数，(目标2A)改善90天存活，(目标2B)减少长期认知损害，以及(目的3)减少脓毒症后促炎细胞因子的级联反应。我们将随机选择530名需要目标导向镇静剂右旋美托咪定或异丙酚的呼吸机严重败血症患者，使研究有90%的力量来检测两组之间1.5天的精神错乱/无昏迷天数的差异和10%的绝对死亡率差异。

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.