Physiological Disturbances Associated with Neonatal Intraventricular Hemorrhage

描述（由申请人提供）：美国每年有近5，000例极低出生体重（ELBW;出生体重=1000 g）婴儿发生重度（III级和IV级）脑室内出血（IVH）。这些婴儿中约有75%发展为智力迟钝和/或脑瘫，导致严重的个人和家庭后果。此外，这些受严重影响的婴儿在一年内出生的终身护理费用超过30亿美元，这突出了这一重大公共卫生问题的财政影响。巨大的个人和社会成本强调需要制定限制严重IVH的护理策略。此外，前瞻性预测ELBW婴儿即将发生IVH的能力将使临床医生和研究人员能够在IVH发生之前进行干预，并可能降低不良神经发育后遗症的发生率。因此，我们以患者为导向的临床研究的长期目标是前瞻性地评估与脑自动调节和IVH相关的紊乱的生理现象，以预测那些风险最大的婴儿，并制定可能限制严重脑损伤的最佳护理临床实践。虽然IVH的病因是多因素的，但脑自动调节障碍起着重要作用。增加的高碳酸血症与进行性受损的脑自动调节有关。低血压可能导致脑灌注不足，导致缺血/再灌注机制导致脑自动调节受损的婴儿IVH。自主神经功能障碍可能减弱脑小动脉的血管舒张能力，损害ELBW婴儿的脑自动调节。由于二氧化碳、血压和自主神经功能紊乱在接受重症监护的ELBW婴儿中很常见，我们的中心假设是，这些影响ELBW婴儿大脑自动调节的生理因素的改变和极端可能引发IVH，并作为IVH的重要预测因子，从而可以识别出可能从干预中获益最多的高危婴儿亚组。将通过一系列临床研究对这一假设进行研究，这些研究将解决：1）ELBW婴儿中IVH的发展是否受容许性高碳酸血症的影响，2）当用多巴胺使BP正常化时，膨胀性ELBW婴儿中受损的脑自动调节是否恢复，以及自动调节能力是否受高碳酸血症的影响，ELBW婴儿自主神经功能改变是否可预测IVH的发生。我们将使用我们在K23研究中开发的连续生理监测系统来确定脑自动调节能力。将测定出生后第一天的心律动力学，并评价其作为即将发生IVH的预测因子的价值。如果成功，我们提出的临床研究将通过开发更好的护理临床实践和提供即将发生IVH的新的准确预测因子来减少新生儿ELBW婴儿神经系统疾病的负担，从而可以识别高危婴儿并进行干预以限制IVH的发展。 公共卫生相关性 每年，近5,000名极低出生体重（<2磅，3盎司）的婴儿出生在 美国生存与严重出血的大脑（脑室内出血）;这 早产儿的毁灭性并发症与长期的神经系统疾病有关， 问题，包括智力迟钝，脑瘫，行为和学习 残疾。这些在一年内出生的严重受影响婴儿的终身护理费用 超过30亿美元，这强调了这一重大公共卫生的财政影响， 问题.我们研究的总体目标是评估脑血流的紊乱 为了预测哪些婴儿的风险最高， 更好的重症监护技术，将限制严重的脑损伤。

DESCRIPTION (provided by applicant): Annually, nearly 5,000 extremely low birth weight (ELBW; birth weight =1000 g) infants in the US develop severe (grades III and IV) intraventricular hemorrhage (IVH). Approximately 75% of these infants develop mental retardation and/or cerebral palsy, resulting in profound individual and familial consequences. In addition, lifetime care costs for these severely affected infants born in a single year exceed $3 billion dollars, which emphasizes the financial impact of this major public health problem. The huge individual and societal costs underscore the need for developing care strategies that limit severe IVH. Further, the ability to prospectively predict impending IVH in ELBW infants would enable clinicians and researchers to intervene before IVH occurs and possibly decrease the incidence of adverse neurodevelopmental sequelae. Therefore, the long-term goal of our patient-oriented clinical research is to prospectively evaluate disturbed physiological phenomena associated with cerebral autoregulation and IVH in order to predict those infants most at risk and to develop best care clinical practices that may limit severe brain injuries. While the etiology of IVH is multifactorial, disturbances of cerebral autoregulation play an important role. Increasing hypercapnia has been associated with progressively impaired cerebral autoregulation. Hypotension may cause cerebral hypoperfusion, leading to IVH in infants with impaired cerebral autoregulation by an ischemia/reperfusion mechanism. Autonomic dysfunction may attenuate vasodilatory capacity of cerebral arterioles and impair cerebral autoregulation in ELBW infants. Because disturbances of carbon dioxide, blood pressure, and autonomic function are common in ELBW infants undergoing intensive care, our central hypothesis is that alterations and extremes of these physiological factors that influence cerebral autoregulation in ELBW infants may initiate IVH and serve as important predictors of IVH, thereby allowing identification of a high-risk subgroup of infants who may benefit most from intervention. This hypothesis will be investigated through a series of clinical studies that will address: 1) whether development of IVH in ELBW infants in influenced by permissive hypercapnia, 2) whether impaired cerebral autoregulation in hypotensive ELBW infants is restored when BP is normalized with dopamine and whether autoregulatory capacity is influenced by hypercapnia, and 3) whether impending IVH may be predicted by altered autonomic function in ELBW infants. We will use our continuous physiological monitoring system developed during our K23 studies to determine cerebral autoregulatory capacity. Heart rhythm dynamics on the first day of life will be determined and its value as a predictor of impending IVH will be evaluated. If successful, our proposed clinical studies will reduce the burden of neurological disease in newborn ELBW infants by developing better care clinical practices and by providing a new accurate predictor of impending IVH, so that high-risk infants may be identified and interventions applied to limit development of IVH. PUBLIC HEALTH RELEVANCE Annually, almost 5,000 extremely low birth weight (<2 lbs, 3 ounces) infants born in the US survive with severe bleeding in the brain (intraventricular hemorrhage); this devastating complication of prematurity is associated with long-term neurological problems, including mental retardation, cerebral palsy, and behavioral and learning disabilities. Lifetime care costs for these severely affected infants born in a single year exceed $3 billion, which emphasizes the financial impact of this major public health problem. The overall goal of our research is to evaluate disturbances of brain blood flow regulation in these tiny infants in order to predict which are at highest risk and to develop better intensive care techniques that will limit severe brain injury.