NEOPAIN MULTICENTER TRIAL: DATA COORDINATING CENTER

新生儿重症监护期间经常发生侵入性手术，导致早产儿在大脑可塑性增加的关键时期出现疼痛和压力。 早产儿反复的疼痛经历或长期暴露于镇痛药物可能会显著改变其临床和神经行为结局。在109个新生儿重症监护室（NICU）中前瞻性记录的镇痛实践表明，阿片类药物和苯二氮卓类药物是最常用的，在临床实践中存在很大差异。 73.5%的新生儿在NICU护理或侵入性手术期间没有给予镇痛/镇静。 在69名早产儿中进行的一项吗啡、咪达唑仑或安慰剂治疗的初步随机试验显示，吗啡组对疼痛的行为反应减少，死亡或神经损伤发生率降低。 体重增加、提前出院和其他临床结局的趋势支持确定性随机试验的必要性和可行性。NEOPAIN多中心试验将从11个NICU随机抽取940名接受机械通气的新生儿（妊娠24-32周），接受吗啡或安慰剂持续输注。 该设计将提供80%的功效，用于检测新生儿死亡、III级或IV级脑室内出血或脑室周围白质软化的复合结局降低30%。 数据收集将包括（孕产妇/婴儿）人口统计学、临床和行为数据。 其他临床结局包括体重增加、新生儿疾病的严重程度、NICU和住院时间。 行为结果包括出院时的神经行为和心理测量测试。 本申请中描述了NOPAIN试验的试验协调、数据管理和统计分析。早产儿使用阿片类药物（吗啡和芬太尼）的情况正在增加，但没有科学评估，关于其临床或不良反应的数据也很少。 在NICU中延长镇痛的需要和临床影响必须在广泛使用之前确定。 为了提供关于阿片类药物使用安全性的数据，必须将早期疼痛/应激对未使用镇痛剂的早产儿的长期神经行为结局的影响与使用镇痛剂对新生儿的影响进行比较。 这项试验可以提供这些数据。 因此，本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.