Maximizing Efficacy of Goal-Directed Sedation to Reduce Neurological Dysfunction in Mechanically Ventilated Infants and Children Study (mini-MENDS)

在机械通气婴儿和儿童研究中最大限度地提高目标导向镇静效果以减少神经功能障碍 (mini-MENDS)

基本信息

批准号：
10685311
负责人：
Pratik Pandharipande
金额：
$ 84.41万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-15 至 2025-07-31
项目状态：
未结题

项目摘要

The need for mechanical ventilation (MV) following acute respiratory and myocardial failure is the leading cause of admission to the pediatric intensive care unit (PICU). Over 90% of MV pediatric patients receive continuous sedation, most commonly with gamma-aminobutyric acid (GABA) agonist benzodiazepines. Recently, we demonstrated that exposure to the benzodiazepine midazolam contributed to iatrogenic harm in pediatric patients—prolonging PICU length of stay and increasing the prevalence and duration of delirium. Delirium, itself a manifestation of acute brain dysfunction, is prevalent in the PICU with rates of up to 30% in older children, over 50% in infants and toddlers, and over 60% in pediatric patients requiring MV. Delirium in children is a significant contributor to longer duration on MV, prolonged PICU length of stay, and death, with significant consequential costs. Adult studies have shown that an alternative sedation paradigm using dexmedetomidine, an alpha-2 agonist, decreases the duration of delirium and coma, length of MV, ICU length of stay, cost, and infection rates compared to benzodiazepine-based sedation. Dexmedetomidine has unique anti-inflammatory and anti-oxidant characteristics, making it an appealing sedative agent as inflammation, endothelial and blood-brain barrier (BBB) injury are mechanistically associated with prolonged delirium and worse cognitive impairment in adults. Though sedation may be unavoidable in PICUs, a dexmedetomidine- based regimen may complement goal-directed sedation, as over-sedation (30%) rather than under-sedation (10%) is common in the PICU setting, and thus far, sedation protocolization alone have not demonstrated significant impact on improving outcomes in pediatric patients. The FDA recently published warnings regarding the possible role of anesthetics, including benzodiazepines, on cognitive development in children. We therefore propose mini-MENDS (Maximizing the Efficacy of Goal-Directed Sedation to Reduce Neurological Dysfunction in Mechanically Ventilated Infants and Children Study), in which we will test the hypotheses that sedation of MV pediatric patients with an alpha-2 agonist (dexmedetomidine) versus a GABA- ergic agent (midazolam) will (Aim 1A) decrease daily delirium prevalence, (Aim 1B) decrease length of MV, (Aim 2A) improve functional and behavioral recovery, (Aim 2B) be associated with fewer symptoms of post- traumatic stress, (Aim 2C) decrease the incidence of cognitive impairment, and (Aim 3) reduce levels of pro- inflammatory cytokines and biomarkers of endothelial and blood brain barrier injury. We will randomize 372 pediatric patients on MV, aged 6 months to 11 years, to receive goal-directed continuous sedation with either dexmedetomidine or midazolam for up to 10 days. The study will have 80% power to detect at least a 10% absolute reduction in daily delirium prevalence between groups, this a clinically meaningful outcome; extrapolation of current pediatric data would estimate a 10% decrease in delirium prevalence to be associated with a 1.2-day (20%) decrease in PICU LOS and 15% lower odds of dying.

急性呼吸和心肌衰竭后需要机械通气（MV）是领先的儿科重症监护室（PICU）入院的原因。超过90％的MV儿科患者接受连续镇静，最常见于γ-氨基丁酸（GABA）激动剂苯并二氮卓类药物。最近，我们证明了暴露于苯二氮卓类咪达唑仑造成了医源性伤害小儿患者 - 延长PICU的住院时间，并增加了del妄的患病率和持续时间。 del妄本身是急性脑功能障碍的表现，在PICU中普遍存在，速率高达30％年龄较大的儿童，婴儿和幼儿的50％以上，需要MV的儿科患者超过60％。 del妄儿童是MV持续时间更长的重要贡献者巨大的后果成本。成人研究表明，使用的替代镇静范式使用右美托咪定（一种α-2激动剂）降低了del妄和昏迷的持续时间，MV的长度，ICU长度与基于苯二氮卓的镇静相比，住院，成本和感染率的速度。右美托胺具有独特性抗炎和抗氧化剂特征，使其成为炎症的吸引人镇静剂，内皮和血脑屏障（BBB）损伤在机械上与长时间的ir妄和成人认知障碍较差。尽管在Picus中可能不可避免地镇静，但右美托咪定 - 基于的方案可以完成目标定向的镇静，因为过度隔离（30％）而不是隔离不足（10％）在PICU设置中很常见，到目前为止，仅镇静协议尚未证明对改善小儿患者的结局的重大影响。 FDA最近发布了有关麻醉药（包括苯二氮卓类药物）在儿童认知发展中的可能作用。我们因此，提案小型措施（最大化目标定向镇静的功效以减少机械通气婴儿和儿童研究中的神经功能障碍），我们将测试假设MV儿科患者患有α-2激动剂（右美托胺）与GABA- ERGIC剂（咪达唑仑）将（AIM 1A）减少每日ir妄患病率，（AIM 1B）降低MV的长度，（AIM 2A）改善功能和行为恢复，（AIM 2B）与后的症状更少有关创伤性压力（AIM 2C）减少了认知障碍的事件，（AIM 3）内皮和血脑屏障损伤的炎症细胞因子和生物标志物。我们将随机化372 MV的儿科患者，年龄在6个月至11岁之间，接受目标定向的连续镇静右美托咪定或咪达唑仑长达10天。该研究将具有80％的能力来检测至少10％群体之间的每日ir妄患病率的绝对降低，这是临床上有意义的结果；当前儿科数据的外推将估计ir妄患病率降低10％与PICU LOS减少1.2天（20％）相关，垂死的几率降低了15％。