Dexmedetomidine Use in Infants undergoing Cooling due to Neonatal Encephalopathy (DICE trial)

项目摘要 右美托咪定在因新生儿脑病接受冷却的婴儿中的应用（DICE试验） 缺氧缺血性脑病（HIE，通常称为“出生窒息”）是一种大脑 得不到足够的氧气每1,000个婴儿中就有2个患有HIE。尽管早期干预使用大脑 冷却，死亡或严重残疾的结果，如脑瘫和智力迟钝，仍然发生在 近30%的婴儿没有其他疗法已被证明可以进一步减少这些高血压患者的脑损伤。 风险婴儿此外，伴随使用吗啡等药物可能会导致额外的脑损伤 来治疗这个人群的疼痛和镇静。在动物模型中使用吗啡可增加神经元凋亡 并对神经发育产生负面影响。开发可改善婴儿结局的替代疗法 是一个迫切的、未得到满足的公共卫生需求。 右美托咪定是一种有效的α2-肾上腺素能受体激动剂，可能是吗啡的更好替代品， 新生儿缺氧缺血性脑病的治疗与冷却。右美托咪定提供镇静、镇痛和 防止颤抖，但不抑制呼吸。重要的是，右美托咪定已被证明可以保护 脑损伤动物模型中的大脑。最近的临床研究也表明， 右美托咪定给药在成人脑损伤患者中的应用。尽管数据有限， 右美托咪定在婴儿中的安全性和有效性以及药代动力学（PK;血液中的药物水平） 它已越来越多地在许多中心管理。 我们的中心假设是，右美托咪定用于新生儿缺氧缺血性脑病的镇静 接受冷却将是安全的（AIM 1），并将与改善的短期和长期结果相关 (AIM 3）。为了验证这一假设，我们设计了一项II期多中心、随机、安全性和PK试验。 50名需要镇静的HIE婴儿（每组n=25）将随机接受 右美托咪定（负荷剂量1 μg/kg，随后连续输注0.1 - 0.5 μg/kg/h）或吗啡 （0.02-0.03 mg/kg/剂，间歇给药，每4小时一次，IV或连续输注剂量为0.005- 0.01 mg/kg/剂 mg/kg/hr）。两份机会性PK样本（常规实验室检查时）和一份PRN PK样本（任何时间） 将获得不良事件用于测量右美托咪定血浆浓度（AIM 2）。 有希望的初步数据显示，右美托咪定可能改善结局，但最佳剂量、安全性和 但仍需建立有效性。我们建议通过收集 机会性血液样本用于PK数据，并确定右美托咪定在该人群中的安全性， II期安全性试验。这些数据将为一项更大规模的III期试验提供信息，以评估这种疗法在以下患者中的疗效： 降低存活超过新生儿期的HIE婴儿的长期残疾风险。

PROJECT SUMMARY Dexmedetomidine Use in Infants undergoing Cooling due to Neonatal Encephalopathy (DICE trial) Hypoxia-ischemia encephalopathy (HIE, commonly called “birth asphyxia”) is a condition where the brain doesn’t get enough oxygen. HIE affects 2 out of every 1,000 babies. Despite early intervention using brain cooling, outcomes of death or major disability, such as cerebral palsy and mental retardation, still occurs in nearly 30% of these babies. No other therapies have been proven to further reduce brain injury for these high risk infants. Furthermore, additional brain injury may be caused by concomitant use of drugs such as morphine to treat pain and sedation in this population. Morphine use in animal models can increase neuronal apoptosis and negatively affect neurodevelopment. Developing adjunctive therapies that improve outcomes in infants with HIE is an urgent, unmet public health need. Dexmedetomidine is a potent α2-adrenergic receptor agonist that may be a better alternative to morphine for newborns with neonatal HIE treated with cooling. Dexmedetomidine provides sedation, analgesia, and prevents shivering but does not suppress breathing. Importantly, dexmedetomidine has been shown to protect the brain in animal models of brain injury. Recent clinical studies also suggest improved brain outcomes after dexmedetomidine administration in adult patients with brain injury. Even though there are limited data on dexmedetomidine safety and usefulness as well as pharmacokinetics (PK; drug levels in blood) in infants with HIE it has been increasingly administered in many centers. Our central hypothesis is that dexmedetomidine administered for sedation to full-term infants with HIE undergoing cooling will be safe (AIM 1) and will be associated with improved short and long-term outcomes (AIM 3). To test this hypothesis, we have designed a Phase II multicenter, randomized, safety and PK trial. Fifty infants (n=25 in each arm) with HIE and requiring sedation will be randomized to receive either dexmedetomidine (1 μg/kg for loading dose followed by 0.1 to 0.5 μg/kg/h continuous infusion) or morphine (0.02-0.03 mg/kg/dose intermittent dosing q 4 hours IV or as continuous infusion dose of 0.005- 0.01 mg/kg/hr). Two opportunistic PK samples (at time of routine laboratories) and a PRN PK sample any time there is an adverse event will be obtained for measurement of Dexmedetomidine plasma concentrations (AIM 2). Promising preliminary data show that dexmedetomidine may improve outcomes but optimal dosing, safety, and efficacy still need to be established. We propose to confirm dexmedetomidine optimal dosing by collecting opportunistic blood samples for PK data and determine safety of dexmedetomidine in this population in a phase II safety trial. These data will inform a larger phase III trial to assess the efficacy of this therapy in reducing the risk of long-term disabilities in infants with HIE who survive beyond the newborn period.