Theophylline Prophylaxis during Hypothermia to Limit Neonatal Nephron Damage

项目摘要/摘要 急性肾损伤(AKI)常见于被诊断为缺氧缺血性脑病(HIE)的婴儿 并与发病率和死亡率的增加有关。目前，还没有得到批准的治疗方法。 以预防AKI为目标。对患有HIE的婴儿进行的几项小规模试验表明，单剂量的 出生后不久给予茶碱可减弱AKI的发展。然而，这些研究并不是 在接受治疗性低温治疗的婴儿中实施(目前对中度至 严重的缺氧缺血性脑病)，而且只报告了短期结果。因此，很少有临床医生使用茶碱治疗 这些病人的管理。我们的长期目标是建立一个适当的多中心 对妊娠35周的婴儿进行治疗性亚低温治疗的临床试验 HIE，出生后12小时内静脉注射茶碱(或氨茶碱)将导致 急性肾损伤的发生率和/或严重程度或死亡(综合主要结果)和改善的长期(2年)肾脏 结果。在进行大型试验之前，实施干预的可行性和能力 衡量相关的临床结果需要得到证明。因此，我们建议进行一项小型试点， 可行性临床试验，以i)评估招募，方案遵守，和数据收集程序在 与安慰剂相比，茶碱降低AKI发生率或死亡率的治疗试验 HIE接受治疗性亚低温治疗；ii)评估既定措施的实用性和适用性 (血肌酐、尿量、液体平衡)和新的探索性方法(尿液生物标记物、大肾 肾小管细胞外小泡和肾血氧饱和度)以确定婴儿的AKI；以及iii)确定 茶碱两种不同制剂的药代动力学、药效学、安全性及初步疗效 茶碱给药方案降低急性心肌梗死发生率和死亡率的临床研究 与安慰剂相比。使用混合方法数据分析策略对研究和干预进行评估 为了处理和检查干预的结果，我们将生成必要的数据，为发展提供信息 并实施适当的动力研究，以确定茶碱是否降低了风险 新生儿缺氧缺血性脑病亚低温治疗后AKI的严重程度。

PROJECT SUMMARY/ABSTRACT Acute kidney injury (AKI) is commonly seen in infants diagnosed with hypoxic-ischemic encephalopathy (HIE) and is associated with increased rates of morbidity and mortality. Currently, there are no approved therapies that target the prevention of AKI. Several small trials in infants with HIE suggest that a single dose of theophylline given soon after birth attenuates the development of AKI. However, these studies were not performed in infants being treated with therapeutic hypothermia (the current standard of care for moderate to severe HIE), and only reported short-term outcomes. Therefore, few clinicians use theophylline in the management of these patients. Our long-term goal is to undertake an appropriately powered multicenter clinical trial to test the hypothesis that for infants > 35 weeks gestation treated with therapeutic hypothermia for HIE, intravenous theophylline (or aminophylline) within the first 12 hours after birth will result in a decreased incidence and/or severity of AKI or death (composite primary outcome) and improved long-term (2 year) renal outcomes. Before the conduct of a large trial, the feasibility of implementing the intervention and ability to measure relevant clinical outcomes need to be demonstrated. Therefore, we propose a small pilot and feasibility clinical trial to i) evaluate recruitment, protocol adherence, and data collection procedures in a therapeutic trial of theophylline to decrease the incidence of AKI or death compared to placebo in infants with HIE being treated with therapeutic hypothermia; ii) evaluate the utility and applicability of established measures (serum creatinine, urine output, fluid balance) and novel, exploratory approaches (urine biomarkers, large renal tubular extracellular vesicles and renal oxygen saturation) to identify AKI in infants; and iii) determine theophylline pharmacokinetic, pharmacodynamic, safety and preliminary effectiveness profiles of two different theophylline dosing regimens in a therapeutic trial of theophylline to decrease the incidence of AKI or death compared to placebo. Using a mixed methods data analysis strategy to assess the research and intervention process and examine outcomes of the intervention, we will generate the requisite data to inform development and implementation of an appropriately powered study to determine whether theophylline attenuates the risk and severity of AKI in infants with HIE treated with therapeutic hypothermia.