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)

• 批准号: 10274781
• 负责人: Pratik Pandharipande
• 金额: $ 84.76万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10274781
• 关键词: Acute; Admission activity; Adult; Age; Anesthetics; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Behavioral; Benzodiazepines; Biological Markers; Blood - brain barrier anatomy; Brain; Cessation of life; Characteristics; Child; Childhood; Clinical; Cognition; Cognitive; Coma; Communication; Complement; Conscious; Consequentialism; Critical Care; Critical Illness; Data; Delirium; Developmental Delay Disorders; Dexmedetomidine; E-Selectin; Endothelium; Enrollment; Exposure to; Failure; Functional disorder; GABA Agents; GABA Agonists; Goals; Guidelines; Hospital Costs; Iatrogenesis; Impaired cognition; Incidence; Infant; Inflammation; Inflammatory; Infusion procedures; Injury; Interleukin-1 beta; Interleukin-10; Interleukin-6; Length; Length of Stay; Link; Mechanical ventilation; Mediating; Mediation; Medicine; Memory; Mental Health; Midazolam; Modeling; Morbidity - disease rate; Myocardial; Natural Immunity; Neurocognitive; Neurologic Dysfunctions; Nursery Schools; Organ; Outcome; Oxidants; Patient-Focused Outcomes; Patients; Pediatric Intensive Care Units; Persons; Pharmaceutical Preparations; Phase; Plasminogen Activator Inhibitor 1; Post-Traumatic Stress Disorders; Predictive Value; Prevalence; Problem Solving; Procedures; Propofol; Protocols documentation; Psychiatrist; Publishing; Randomized; Recovery; Regimen; Reporting; Risk; Role; Screening procedure; Sedation procedure; Severity of illness; Societies; Specificity; Survivors; Syndrome; TNF gene; Testing; Toddler; Validation; aged; alpha 2 agonist; base; brain dysfunction; cognitive development; cognitive recovery; confusion assessment method; cost; cytokine; endothelial dysfunction; epidemiology study; functional status; improved; improved outcome; infection rate; mortality; neuropsychiatry; pediatric patients; post-traumatic symptoms; reduce symptoms; respiratory; sedative; tool; ventilation

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.

在急性呼吸衰竭和心肌衰竭后， 进入儿科重症监护室（PICU）的原因。超过90%的MV儿科患者接受 持续镇静，最常见的是γ-氨基丁酸（GABA）激动剂苯二氮卓类。 最近，我们证明接触苯二氮卓类咪达唑仑会导致医源性伤害， 儿科患者-延长PICU住院时间，增加谵妄的患病率和持续时间。 谵妄本身是急性脑功能障碍的一种表现，在PICU中很普遍，在儿童中的发病率高达30%。 年龄较大的儿童，超过50%的婴儿和幼儿，超过60%的需要MV的儿科患者。谵妄 儿童是MV持续时间延长、PICU住院时间延长和死亡的重要因素， 重大的间接成本。成人研究表明，一种替代的镇静模式， 右美托咪定，一种α-2激动剂，减少谵妄和昏迷的持续时间，MV的长度，ICU的长度 与苯二氮卓类镇静剂相比，右美托咪定具有独特的 抗炎和抗氧化特性，使其成为一种有吸引力的抗炎镇静剂， 内皮和血脑屏障（BBB）损伤与长时间的谵妄有关， 更严重的认知障碍。虽然镇静可能是不可避免的PICU，右美托咪定- 基础方案可以补充目标导向镇静，因为过度镇静（30%）而不是镇静不足 (10%）在PICU环境中很常见，到目前为止，单独的镇静协议尚未证明 对改善儿科患者的结局有显著影响。FDA最近发布了警告， 包括苯二氮卓类在内的麻醉剂对儿童认知发育的可能作用。我们 因此，提出了mini-MENDS（最大限度地提高目标导向镇静的功效， 机械通气婴儿和儿童的神经功能障碍研究），在该研究中，我们将测试 假设MV儿科患者使用α-2激动剂（右美托咪定）与GABA- 咪达唑仑能（目的1A）降低每日谵妄发生率，（目的1B）缩短MV长度， (Aim 2A）改善功能和行为恢复，（目的2B）与较少的术后症状相关， 创伤应激，（目的2C）降低认知障碍的发生率，（目的3）降低前 炎性细胞因子和内皮和血脑屏障损伤的生物标志物。我们将随机抽取372名 接受MV的6个月至11岁的儿科患者，接受目标导向的持续镇静， 右美托咪定或咪达唑仑治疗长达10天。该研究将有80%的把握度检测至少10%的 两组间每日谵妄患病率的绝对降低，这是一个有临床意义的结果; 目前儿科数据的外推估计谵妄患病率降低10%， 与PICU LOS减少1.2天（20%）和死亡几率降低15%相关。