Intermittent Hypoxia and Caffeine in Infants Born Preterm

项目摘要/摘要 咖啡因是治疗早产儿呼吸模式不成熟的常规药物。我们 记录了持续的间歇性血氧水平下降(间歇性低氧，IH) 在预产期前约6周停止常规咖啡因治疗(月经后34-35周， PMA)。IH是促炎的，并与患者的认知和脑结构的不良影响有关 睡眠呼吸暂停综合征和早产儿呼吸暂停的啮齿动物模型。我们解决了两个重要问题 在≤30周出生的婴儿：1)在34-35周停止常规咖啡因和 持续42周的PMA会导致损伤，以及2)这种损伤是否可以通过将咖啡因治疗扩展到 42周PMA？创新包括高分辨率连续脉搏血氧仪记录到43周PMA到 量化IH、炎性生物标记物的测量和定量磁共振成像(MRI) 以及磁共振波谱(MRS)，以评估结构性和功能性脑损伤。我们之前的研究证实，IH 经常发生在停止常规咖啡因后，并在适当的年龄延长咖啡因治疗 给药可减弱IH的程度。我们的假设是，与安慰剂相比，接受咖啡因治疗的婴儿 在34-34周和42周的PMA期间将有较低的整体IH暴露，2)咖啡因组将有较少的 持续炎症的生物标志物证据，这些影响将通过减少IH暴露而介导，3) 咖啡因组急性脑损伤的结构、微结构和代谢生物标记物将较少，因为 由MRI和MRS确定，这些影响将通过减少长期的IH暴露而介导 咖啡因组。我们将招收220名PT婴儿。符合条件的受试者最早将在PMA的32周内注册，届时 不再有与呼吸模式不成熟有关的明显症状。注册，婴儿将开始连续 脉搏血氧仪记录血氧饱和度。我们将对110名婴儿随机服用10毫克/公斤的咖啡因 每日体重两次，服用等量的安慰剂后第二天开始服用等量咖啡因 治疗，通常是34-35周的PMA。研究药物将持续到42周PMA，脉搏 血氧计记录将继续到43周PMA。将获得两个咖啡因水平，第一个是出院前 主场和第二场主场比赛。在研究登记和完成43-45周PMA时，炎性生物标志物 并进行脑部MRI/MRS检查。数据收集还将包括人口统计数据、出生后病史、 以及出院时的医疗状况和学习完成情况。我们的结果将为以下结论提供依据 后续研究评估与持续高血压相关的长期神经发育结果 大脑持续成熟的关键时期，以及延长咖啡因治疗的效果。这个 所获得的知识将建立高度相关和易于翻译的新的成本效益战略，以 显著改善≤妊娠30周时早产婴儿的临床实践和公共健康。

Project Summary/Abstract Caffeine is routinely used in the treatment of preterm (PT) infants with immature breathing patterns. We have documented persisting intermittent decreases in blood oxygen levels (intermittent hypoxia, IH) after stopping routine caffeine treatment about 6 weeks before the due date (34-35 weeks postmenstrual age, PMA). IH is pro-inflammatory and is associated with adverse effects on cognition and brain structure in patients with sleep apnea syndrome and in rodent models of apnea of prematurity. We address 2 significant questions in infants born at ≤ 30 wks gestation: 1) does IH occurring after stopping routine caffeine at 34-35 wks and persisting to 42 wks PMA cause injury, and 2) can this injury be attenuated by extending caffeine treatment to 42 wks PMA? Innovations include high resolution continuous pulse oximeter recordings to 43 wks PMA to quantify IH, measurement of inflammatory biomarkers, and quantitative magnetic resonance imaging (MRI) and MR spectroscopy (MRS) to assess structural and functional brain injury. Our prior studies confirm that IH occurs frequently after cessation of routine caffeine, and that extended caffeine treatment at age-appropriate dosing attenuates the extent of IH. Our hypotheses are that, compared to placebo, 1) caffeine-treated infants will have lower overall IH exposure between 34-34 and 42 weeks PMA, 2) the caffeine group will have less biomarker evidence of continuing inflammation, and these effects will be mediated by reduced IH exposure, 3) the caffeine group will have less structural, microstructural and metabolic biomarkers of acute brain injury as determined by MRI and MRS, and these effects will be mediated by reduced IH exposure in the extended caffeine group. We will enroll 220 PT infants. Eligible subjects will be enrolled as early as 32 wks PMA, when no longer having overt symptoms related to immature breathing pattern. Enrolled, infants will begin continuous pulse oximeter recordings of oxygen (O2) saturation. We will randomize 110 infants to caffeine at 10 mg/kg body weight twice daily and 110 to equal volume placebo starting the day after last dose of routine caffeine treatment, typically by 34-35 weeks PMA. Study drug will be continued until 42 weeks PMA, and pulse oximeter recordings will continue to 43 wks PMA. Two caffeine levels will be obtained, the 1st before discharge home and the 2nd at home. At study enrollment and completion at 43-45 wks PMA, inflammatory biomarkers and brain MRI/MRS will be obtained. Data collection will also include demographics, postnatal medical history, and medical status at hospital discharge and study completion. Our results will provide the justification for subsequent studies to assess longer term neurodevelopmental outcomes associated with persisting IH during a critical period of continuing brain maturation, and the attenuating effects of extended caffeine treatment. The knowledge gained will establish highly relevant and easily translatable new cost-effective strategies to significantly improve clinical practice and public health in infants born preterm at ≤ 30 wks gestation.