Pain and Hypoxia in Premature Neonates

描述(由申请人提供)：进入新生儿重症监护病房(NICU)的早产儿在住院期间需要进行多达数百次手术。其中许多都是会导致疼痛的组织损伤程序(TDP)。NIH资助的新生儿疼痛研究目前主要集中在疼痛、止痛和神经发育结果之间的关系上。然而，最近旨在通过减少吗啡疼痛来改善神经学结果的多中心临床研究并不确定[Bellu等人，2008；[Anand等人，2004；Simons等人，2003]。他们提出，仅预防和治疗疼痛可能不会显著减少神经损伤。尽管TDPs已知会导致低氧血症(动脉含氧量降低)，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损伤。回答这一研究问题将填补新生儿疼痛研究的这一重要空白，同时补充NIH新生儿疼痛投资组合中的其他项目。答案将使开发更安全、更有效的临床干预措施，以改善全球NICU护理的早产儿的健康结果成为可能(我们的长期目标)。这项新研究人员的RO1应用将在一项早产儿随机前瞻性临床试验中测量两种最常见的NICU程序--气管内吸引术和鞋跟刺激术--对早产儿的影响。气管内吸引术是指在不断开呼吸机连接的情况下，使用直插式导管从气管导管中清除粘液或分泌物。高跟枪是指使用专门设计的柳叶刀将新生儿的脚后跟刺穿以获取血糖。经历足跟枪的早产儿将被随机分为安慰剂组或蔗糖干预组。对于缺氧、氧化应激和细胞损伤的生化测量的血液样本将在手术前和手术后进行定时(根据临床指示进行)。我们的一般假设是，通常进行的组织损伤程序显示疼痛的生物行为标记物与缺氧、氧化应激和细胞损伤的生化标记物之间存在正相关。具体目标1将确定气管内吸引术和/或鞋跟刺激术(使用和不使用蔗糖干预)是否会增加疼痛的生物行为标记。疼痛将使用一种经过验证的疼痛评分工具--早产儿疼痛概况(PIPP)进行量化。具体目标2将确定气管内吸引术和/或高跟枪在蔗糖干预和不干预的情况下是否会增加缺氧和氧化应激的生化标记物。ATP在血浆中的分解产物--次黄嘌呤(HX)、黄嘌呤(Xa)和尿酸(UA)--将用高效液相色谱法测定。氧化应激将通过用气相色谱和质谱仪测量血浆中黄嘌呤氧化酶(XO)、黄嘌呤脱氢酶(XDH)和尿囊素的水平来量化。具体目标3将确定气管内吸痰和/或鞋跟刺刀(在有或没有蔗糖干预的情况下)是否会增加细胞损伤的生化标记物细胞损伤将通过测量血浆丙二醛(MDA)水平来量化，丙二醛(MDA)是脂质过氧化的标记物。具体目标4将确定程序性疼痛的生物行为标记物与缺氧、氧化应激和细胞损伤的生化标记物之间是否存在正相关。公共卫生相关性：早产儿的程序性疼痛及其与缺氧(缺氧)的关系是新生儿重症监护实践以及婴儿长期神经发育的重要问题。如果早期疼痛经验被证明是导致缺氧、氧化应激和细胞损伤的原因，生化标记物可能被用来在早期疼痛的细胞后果及其神经学后果之间提供生化联系。这些生物标记物随后可用于评估基于机制的干预措施，这些干预措施可能导致更有效地管理NICU程序疼痛和长期婴儿神经发育。

DESCRIPTION (provided by applicant): 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 lance in 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. PUBLIC HEALTH RELEVANCE: Procedural pain in premature infants and its relationship to hypoxia (oxygen deficiency) is an important issue for neonatal intensive care practice as well as long-term infant neurodevelopment. If early pain experiences are shown to contribute to hypoxia, oxidative stress, and cell injury, biochemical markers might be used to provide biochemical links between the cellular consequences of early pain and its neurologic consequences. These biomarkers may then be used to evaluate mechanism-based interventions that could lead to more effective management of NICU procedural pain and long-term infant neurodevelopment.