Metoclopramide prevents PICU nosocomial infection

描述（由申请人提供）：院内感染和败血症是危重儿童发病率和死亡率的主要因素。B细胞、T细胞和自然杀伤细胞淋巴细胞是宿主免疫系统的重要组成部分，其预防和杀死医院感染。淋巴细胞减少症（绝对淋巴细胞计数<1，000）在危重儿童中很常见，并使发生院内败血症的风险增加5.5倍。危重病会引起压力，而压力激素皮质醇会诱导淋巴细胞凋亡。催乳素是一种反调节性应激激素，可增加Bcl-2的表达，防止皮质醇诱导的淋巴细胞凋亡。虽然催乳素在手术应激后增加，但在危重病期间通常会减少，部分原因是多巴胺能活性增加，抑制了垂体催乳素的释放。患有危重病引起的低催乳素血症的儿童发生长期淋巴细胞减少症的可能性高8倍，发生淋巴细胞增生介导的淋巴细胞耗竭的可能性高12倍。拟定研究的目的是确定甲氧氯普胺（一种胃肠道促动力药和中枢多巴胺拮抗剂，可将全身催乳素水平维持在正常高水平范围内）作为每日预防性给药用于危重患儿时，是否可预防低催乳素血症、淋巴细胞减少症和院内败血症。拟议的随机双盲安慰剂对照试验的三个具体目标是确定每日甲氧氯普胺给药是否1）维持催乳素水平，2）维持绝对淋巴细胞计数和淋巴细胞亚群，3）降低医院感染和败血症的发生率。本研究的次要目的是确定甲氧氯普胺预防治疗是否能减少这些儿童的机械通气时间、器官功能障碍/衰竭评分、重症监护病房住院时间和发病率评分。该项目的长期目标是开发创新策略，以提高免疫功能，减少危重儿童的医院感染和败血症。

DESCRIPTION (provided by applicant): Nosocomial infection and sepsis is a predominant contributor to morbidity and mortality in critically ill children. The B-cell, T- cell, and natural killer cell lymphocytes are important components of the host immune system which prevent and kill nosocomial infection. Lymphopenia (absolute lymphocte count < 1,000) is common in critically ill children and increases the risk of developing nosocomial sepsis 5.5 fold. Critical illness causes stress, and the stress hormone cortisol induces lymphocyte apoptosis. Prolactin is the counter-regulatory stress hormone which increase Bcl-2 expression and prevents cortisol-induced lymphocyte apoptosis. Although prolactin is increased after surgical stress, it is commonly decreased during critical illness, in part due to increased dopaminergic activity which inhibits prolactin release from the pituitary gland. Children with critical illness induced hypoprolactinemia have an 8-fold higher likelihood of prolonged lymphopenia and a 12 -fold higher likelihood of apoptosis-mediated lymphoid depletion. The objective of the proposed study is to determine if Metoclopramide, a gastrointestinal pro-kinetic and central dopamine-antagonist which maintains systemic prolactin levels in the high normal range, can prevent hypoprolactinemia, lymphopenia, and nosocomial sepsis when given as daily prophylaxis to critically ill children. The three specific aims of the proposed randomized double-blinded placebo-controlled trial are to determine if daily metoclopramide administration 1) maintains prolactin levels, 2) maintains absolute lymphocyte counts and lymphocyte subsets, and 3) reduces rates of nosocomial infection and sepsis. The secondary objective of the study is to determine if metoclopramide prophylaxis reduces duration of mechanical ventilation, organ dysfunction/failure scores, intensive care unit length of stay, and morbidity scores in these children. The long term goal of the project is to develop innovative strategies to improve immune function and reduce nosocomial infection and sepsis in critically ill children.