NEOPAIN MULTICENTER TRIAL: DATA COORDINATING CENTER

在新生儿重症监护期间，在大脑可塑性增强的关键时期，频繁的侵入性手术会给早产儿带来疼痛和压力。早产儿反复的疼痛经历或长期接触止痛药可能会显著改变他们的临床和神经行为结果。109个新生儿重症监护病房(NICU)的前瞻性记录显示，阿片类药物和苯二氮卓类药物是最常用的止痛药物，临床应用的差异很大。在NICU护理或侵入性手术期间，73.5%的新生儿没有给予止痛/镇静。一项对69名早产儿进行的吗啡、咪达唑仑或安慰剂治疗的先导性随机试验显示，吗啡组对疼痛的行为反应减少，死亡或神经损伤的发生率降低。体重增加、更早出院和其他临床结果的趋势支持了明确的随机试验的必要性和可行性。NeOPAIN多中心试验将从11个NICU中随机选择940名有呼吸机的新生儿(孕24-32周)，接受持续的吗啡或安慰剂输注。这一设计将为检测新生儿死亡、III或IV级脑室出血或脑室周围白质软化症的综合结果减少30%提供80%的功率。数据收集将包括(产妇/婴儿)人口统计、临床和行为数据。其他临床结果包括体重增加、新生儿疾病严重程度、NICU持续时间和住院时间。行为结果包括出院时的神经行为和心理测试。本申请描述了NOPAIN试验的试验协调、数据管理和统计分析。阿片类药物(吗啡和芬太尼)在早产儿中的使用正在增加，没有科学的评估，也缺乏关于其临床或不良反应的数据。在广泛使用之前，必须现在就确定NICU中延长止痛时间的必要性和临床影响。为了提供阿片类药物使用安全性的数据，必须将早期疼痛/应激对早产儿无镇痛的长期神经行为结果的影响与新生儿使用止痛药的效果进行比较。这项试验可以提供这些数据。因此，这项试验的结果有可能显著改变NICU的临床实践，并减少新生儿严重发病率和死亡率的一个主要原因。

Frequent invasive procedures occur during neonatal intensive care causing pain and stress in preterm neonates during a critical period of increased brain plasticity. Repetitive painful experiences or prolonged exposure to analgesic drugs in preterm neonates may significantly alter their clinical and neurobehavioral outcomes. Analgesic practices recorded prospectively in 109 Neonatal Intensive Care Units (NICUs) showed that opioids and benzodiazepines were most commonly used, with large variations in clinical practice. No analgesia/sedation was given to 73.5 percent of neonates during NICU care or invasive procedures. A pilot randomized trial of morphine, midazolam, or placebo therapy in 69 preterm neonates showed reduced behavioral responses to pain and evidence of decreased incidence of death or neurologic injury in the morphine group. Trends for increased weight gain, earlier discharge, and other clinical outcomes support the need for and the feasibility of a definitive randomized trial. The NEOPAIN Multicenter Trial will randomize 940 ventilated neonates (24-32 weeks gestation) from 11 NICUs to receive continuous infusions of morphine or placebo. This design will provide 80 percent power for the detection of a 30 percent reduction in the composite outcome of neonatal death, Grade III or IV intraventricular hemorrhage, or periventricular leukomalacia. Data collection will include (maternal/infant) demographic, clinical and behavioral data. Other clinical outcomes include weight gain, severity of neonatal illness, and durations of NICU and hospital stay. Behavioral outcomes include neurobehavioral and psychometric testing at the time of hospital discharge. Trial coordination, data management and statistical analyses for the NOPAIN Trial are described in this application. The use of opioids (morphine and fentanyl) in preterm neonates is increasing without scientific evaluation and with scarce data on their clinical or adverse effects. The need for and clinical impact of prolonged analgesia in the NICU must be defined now before widespread use occurs. To provide data about the safety of opioid use, the effects of early pain/stress on the long-term neurobehavioral outcomes of prematurity in neonates without analgesia must be compared to the effects of analgesia use in neonates. This trial can provide those data. Thus, the results of this trial have the potential to significantly alter clinical practice in the NICU and reduce a major cause of severe morbidity and mortality in neonates.