发展性照顾阻碍HPA轴程序化改善早产儿新生儿期操作性疼痛对儿童神经行为发育的影响研究

Pain management is a critical issue in current neonatal practice. Disadvantages of pharmacologic analgesia include side effects, questionable efficacy, and possible negative impact on neonatal outcomes. As an alternative approach, non-pharmacologic interventions are recommended for pain management. Our previous study revealed that non-pharmacologic interventions (eg, sucrose, sucrose plus non-nutritive sucking, massage plus music) could reduce the repeated procedural pain in preterm infants. However, our result simultaneously demonstrated that preterm infants still show stress behaviors and activity during and after the painful procedure even through using non-pharmacologic interventions. Therefore, we hypothesize that the combination of non-pharmacologic interventions and supportive care (developmental care) may have additive effects by stimulating infants in a multisensorial way to cope with the repeated painful experience. The hypothalamic pituitary adrenal (HPA) axis is responsible for the neuroendocrine adaptation component of the stress response. Our pilot study has demonstrated that developmental care in repeated procedural pain could decrease the change in cortisol concentration for preterm infants hospitalized in neonatal intensive care unit for 2 weeks. This study will examine the efficacy of developmental care in neonatal pain management on the cortisol concentration and neurobehavioral development in preterm infants at 12 and 24 months of corrected age. Furthermore, this study will determine the relation between cortisol concentration and neurobehavioral development in preterm infants at 12 and 24 months of corrected age, which will provide health-care professionals with the necessary information for premature prognosis management.

新生儿期操作性疼痛管理是新生儿医学领域关注的热点问题。非药物镇痛疗法具有低风险、简单易行等优势。我们研究发现，“蔗糖液”、“蔗糖液+非营养性吸吮”、“宁握+音乐”能够减轻新生儿期操作性疼痛，但是，早产儿在致痛性操作过程中、甚至操作结束后仍然存在压力性行为。因此，本课题组提出假设，将上述非药物疗法联合使用的同时，配合减轻压力性行为的支持性护理，即发展性照顾，能够从更大程度上减轻早产儿操作性疼痛。HPA轴在应激反应调控过程中发挥着重要作用。我们初步证实，发展性照顾能够改善早产儿入院2周操作性疼痛对皮质醇水平的影响。本项目拟进一步以新生儿期疼痛干预为重点，在验证发展性照顾对新生儿期疼痛干预效果的基础上，动态观察其对婴幼儿期皮质醇及神经行为发育的影响，深入分析皮质醇与神经行为发育之间的相关性，明确发展性照顾阻断HPA轴程序化改善新生儿期疼痛对神经行为发育的影响，为制定早产儿预后优化策略提供新思路。

世界卫生组织（WHO）报道，全球每年约有1500万早产儿出生。其中，中国早产儿发生率为7.8%。随着新生儿重症医学的飞速发展，早产儿救治存活率明显上升。但是，早产儿为了达到诊断、治疗的目的，必需经历很多操作性疼痛。这些操作性疼痛引发HPA轴程序化足以影响早产儿日后神经行为发育。因此，新生儿期疼痛管理是医学领域关注的问题。. 新生儿期疼痛管理包括药物干预与非药物干预。吗啡是新生儿期常用的阿片类药物之一。本研究采用循证医学系统评价的研究方法，全面评价了新生儿时期应用吗啡与后期神经心理发育的相关性。研究发现，新生儿期使用吗啡可能会影响8月龄时的运动发育与20月龄时的认知发育。. 蔗糖液与非营养性吸吮是目前研究最多的非药物疗法。本研究评估了蔗糖液与非营养性吸吮单独应用或联合应用的效果，结果发现，蔗糖液与非营养性吸吮联合应用的镇痛效果明显优于单独应用的效果。但是，早产儿仍然存在啼哭、肢体过度频繁伸展、手指张开等压力行为。因此，本研究在此基础上构建了用于减轻早产儿反复操作性疼痛的发展性照顾干预方案（减少声光刺激+“鸟巢护理”+抚触+音乐+蔗糖液+非营养性吸吮+宁握），采用随机对照试验评价了发展性照顾对早产儿新生儿期反复操作性疼痛的干预效果，测量了发展性照顾干预早产儿新生儿期反复操作性疼痛对HPA轴发育的影响，验证了发展性照顾干预早产儿新生儿期反复操作性疼痛对婴幼儿期神经行为发育的影响，揭示了发展性照顾干预早产儿新生儿期反复操作性疼痛改善神经行为发育结局与HPA轴发育的相关性。研究结果显示，发展性照顾能够减轻早产儿新生儿期经历的反复操作性疼痛评分，能够降低早产儿住院期间及1岁时的基础状态皮质醇浓度，能够改善矫正胎龄40周时的行为神经评分、成长至1岁以及2岁时的认知发育评分与内化行为、外化行为评分。此外，本研究结果显示，发展性照顾干预早产儿新生儿期疼痛进而降低唾液皮质醇浓度可能是其能够降低疼痛对早产儿神经行为发育影响的作用机制。