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

改变镇静模式以改善严重脓毒症的脑损伤和生存率

• 批准号: 8894072
• 负责人: Pratik Pandharipande
• 金额: $ 47.71万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8894072
• 关键词: Acute; Acute respiratory failure; Admission activity; Agonist; Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Benzodiazepines; Brain; Brain Injuries; Brain Stem; Cessation of life; Clinical; Clinical Trials; Cognition; Coma; Critical Illness; Data; Delirium; Development; Dexmedetomidine; Double-Blind Method; Exposure to; Functional disorder; GABA Agents; GABA Antagonists; GABA Receptor; Goals; Health; High Mobility Group Proteins; Hospitals; Human; Hypothalamic structure; Immunity; Impaired cognition; Incidence; Infection; Inflammatory; Injury; Insulin Resistance; Intensive Care Units; Interleukin-1; Interleukin-6; Interruption; Learning; Length of Stay; Lung; Mechanical ventilation; Multicenter Trials; Natural Immunity; Neurologic Dysfunctions; Organ; Outcome; Patients; Pharmaceutical Preparations; Propofol; Randomized; Randomized Controlled Trials; Recovery; Reducing Agents; Regimen; Research Personnel; Respiratory Failure; Respiratory physiology; Risk; Safety; Secondary to; Sedation procedure; Sepsis; Severities; Sleep; Societies; Subgroup; Supportive care; Survivors; Telephone; Testing; Time; Unconscious State; Ventilator; Vulnerable Populations; Work; abstracting; adverse outcome; confusion assessment method; cost; cytokine; functional decline; gamma-Aminobutyric Acid; hazard; improved; mortality; neuron apoptosis; neuropsychological; novel therapeutics; patient safety; pre-clinical; prospective; randomized trial; respiratory; sedative; septic

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.

描述（由申请人提供）： 败血症继发的机械通气（MV）的需求是重症监护室入院的主要原因，通常需要为患者的安全和舒适而进行镇静。最近，我们了解到这些镇静剂有助于医源性损伤，例如延长呼吸机时间和ICU的住院时间和加剧急性脑功能障碍。这种急性脑功能障碍表现为del妄和昏迷，发生在50％-70％的MV败血症患者中，不仅是死亡的重要贡献者，而且是功能和认知能力下降的重要贡献，这可以在肺部恢复和其他器官功能后数年持续多年，从而使患者和社会付出了重大成本。尽管急性呼吸衰竭和败血症的治疗方面取得了进步，但很少有临床试验检查了支持性疗法（如镇静）对这种脆弱人群中短期和长期结局的影响。尤其是γ-氨基丁酸（GABA） - 含有苯二氮卓类药物，已被证明会增加脑功能障碍，促进感染和延长MV。因此，短作作用的GABA抗镇静剂丙泊酚和α2激动剂右美托咪定被广泛用于镇压化粪池MV患者。但是，在这些镇静剂之间选择时，只有少数随机试验可以指导临床医生，而且没有一个探索结果差异的机制，尽管一些数据表明GABA-ergic和alpha2激动剂对先天性免疫，肥胖，刺激性，唤醒能力和呼吸驱动力的影响非常不同。在早期的动物和人类研究中，右美托咪定具有比GABA-富药物更多的抗炎作用。右美托胺改善了细菌清除率，而丙泊酚则损害了细菌清除率。此外，用右美托咪定而不是苯二氮卓类镇静剂可将del妄降低20％-30％，并改善通风患者的唤醒性，认知和专心。 α2激动剂在脑干上引起无意识 - 更类似于自然睡眠，这可能会改善自主功能和免疫力。所有这些因素都融合以表明使用α2激动剂而非GABA能剂的镇静剂可以改善脓毒症MV患者的预后，包括大脑功能，MV和生存。 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昏迷，（AIM 1B）增加无呼吸机的天数，（AIM 2A）改善90天的存活，（AIM 2B）减少了长期认知障碍，并且（AIM 3）败血后减少促炎性细胞因子级联。我们将随机分配530名通风，严重的败血症患者，需要用右美托胺或丙泊酚进行目标定向的镇静，这项研究的功率为90％，以检测两组之间的差异为1.5 del妄/无昏迷的天数，死亡率的绝对差异为10％。