Pain and Hypoxia in Premature Neonates

项目摘要 新生儿重症监护室（NICU）收治的早产儿需要多达数百名 在住院期间，其中许多是组织损伤程序（TDP）， 痛苦NIH资助的新生儿疼痛研究目前主要集中在疼痛， 镇痛和神经发育结果。然而，最近的多中心临床研究旨在改善 用吗啡减轻疼痛的神经学结果尚不确定[Bellu et al，2008; [Anand et al，2004; Simons等人，2003年]。他们认为，仅仅预防和治疗疼痛可能不会显着减少 神经损伤 虽然已知TDP会导致低氧血症（动脉血氧含量降低），但尚不清楚 它们是否会导致缺氧（组织水平的缺氧），从而导致氧化应激和细胞凋亡。 损伤提出这一研究问题将填补新生儿疼痛研究的这一重要空白， 补充NIH新生儿疼痛组合中的其他项目。答案将使 制定更安全、更有效的临床干预措施，改善早产儿的健康状况 在全球NICU中得到护理（我们的长期目标）。 来自新研究者的RO 1应用程序将测量两种最常见的方法的影响 在一项随机研究中，进行了代表TDP的NICU手术-气管内吸痰和足跟穿刺。 早产儿的前瞻性临床试验。气管内吸痰是指去除粘液或 在不与呼吸机断开连接的情况下，使用在线导管从气管内导管中清除分泌物。鞋跟 柳叶刀指的是用专门设计的刺血针穿刺新生儿的脚后跟以检测血糖。 发生足跟穿刺的早产儿将随机分为安慰剂组或蔗糖干预组 组将定时采集用于缺氧、氧化应激和细胞损伤生化测量的血液样本 手术前后（根据临床指征进行）。我们的假设是 通常进行的组织损伤过程显示出生物行为标记物之间的正相关性 疼痛和缺氧，氧化应激和细胞损伤的生化标志物。 具体目标1将确定气管内抽吸和/或足跟穿刺器是否有和没有 蔗糖干预）增加疼痛的生物行为标志物。将使用经验证的 疼痛评分工具，早产儿疼痛概况（PIPP）。 具体目标2将确定气管内抽吸和/或足跟穿刺器是否有和没有 蔗糖干预）增加缺氧和氧化应激生化标记。ATP产品 血浆中的分解-次黄嘌呤（Hx），黄嘌呤（Xa）和尿酸（UA）-将使用高浓度的 高效液相色谱法氧化应激将通过测量以下物质的血浆水平来定量： 黄嘌呤氧化酶（XO）、黄嘌呤脱氢酶（XDH）和尿囊素，采用气相色谱和质谱法 谱 具体目标3将确定气管内抽吸和/或足跟穿刺器是否有和没有 蔗糖干预）增加细胞损伤生化标记细胞损伤将通过 测量丙二醛（MDA）的血浆水平，MDA是脂质过氧化的标志物。 具体目标4将确定是否有生物行为标志物之间的正相关性， 程序性疼痛和缺氧、氧化应激和细胞损伤的生化标志物。

PROJECT SUMMARY Premature infants admitted to the neonatal intensive care unit (NICU) require up to several hundred procedures during their hospitalization. Many of these are tissue damaging procedures (TDPs) that cause pain. NIH-funded neonatal pain research currently focuses primarily on the relationship between pain, analgesia, and neurodevelopmental outcomes. However, recent multicenter clinical studies aimed at improving neurologic outcome by decreasing pain with morphine were inconclusive [Bellu et al, 2008; [Anand et al, 2004; Simons et al, 2003]. They suggest that prevention and treatment of pain alone may not significantly decrease neurologic injury. Although TDPs are known to cause hypoxemia (reduced arterial oxygen content), it is not known whether they result in hypoxia (oxygen deficiency at the tissue level), which leads to oxidative stress and cell injury. Answering this research question will fill this important gap in neonatal pain research while complementing the other projects in NIH's neonatal pain portfolio. The answer will make possible the development of safer, more effective clinical interventions to improve health outcomes for premature infants cared for in NICUs worldwide (our long-term goal). This RO1 application from a new investigator will measure the effects of two of the most commonly performed NICU procedures representative of TDPs-endotracheal suctioning and heel lancein a randomized prospective clinical trial of premature neonates. Endotracheal suctioning refers to the removal of mucus or secretions from the endotracheal tube using an in-line catheter without disconnection from the ventilator. Heel lance refers to the puncture of a newborn's heel for blood glucose using a specially designed lancet. Premature infants experiencing heel lance will be randomized into either a placebo or sucrose intervention group. Blood sampling for biochemical measurement of hypoxia, oxidative stress and cell injury will be timed before and after the procedures (to be performed as clinically indicated). Our general hypothesis is that commonly performed tissue damaging procedures exhibit a positive correlation between biobehavioral markers of pain and biochemical markers of hypoxia, oxidative stress, and cell injury. Specific Aim 1 will determine whether endotracheal suctioning and/or heel lance with and without sucrose intervention) increase biobehavioral markers of pain. Pain will be quantified using a validated pain scoring tool, the Premature Infant Pain Profile (PIPP). Specific Aim 2 will determine whether endotracheal suctioning and/or heel lance with and without sucrose intervention) increase biochemical markers of hypoxia and oxidative stress. Products of ATP breakdown in plasma-hypoxanthine (Hx), xanthine (Xa), and uric acid (UA)-will be measured using high performance liquid chromatography. Oxidative stress will be quantified by measuring plasma levels of xanthine oxidase (XO), xanthine dehydrogenase (XDH), and allantoin using gas chromatography and mass spectroscopy. Specific Aim 3 will determine whether endotracheal suctioning and/or heel lance with and without sucrose intervention) increase biochemical markers of cell injury Cell injury will be quantified by measuring plasma levels of malondialdehyde (MDA), a marker for lipid peroxidation. Specific Aim 4 will determine whether there is a positive correlation between biobehavioral markers of procedural pain and biochemical markers of hypoxia, oxidative stress, and cell injury.