Metoclopramide prevents PICU nosocomial infection

描述(由申请人提供)：医院感染和败血症是危重儿童发病率和死亡率的主要贡献者。B细胞、T细胞和自然杀伤细胞淋巴细胞是宿主免疫系统中预防和杀死医院感染的重要组成部分。淋巴细胞减少症(淋巴细胞绝对计数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。危重疾病会导致压力，而压力荷尔蒙皮质醇会诱导淋巴细胞凋亡。催乳素是一种逆调节性应激激素，可增加Bcl2的表达，阻止皮质醇诱导的淋巴细胞凋亡。虽然手术应激后催乳素会增加，但在危重疾病期间，催乳素通常会降低，部分原因是多巴胺能活动增加，从而抑制垂体腺释放催乳素。患有危重病引起的低催乳素血症的儿童，长期淋巴细胞减少的可能性是正常儿童的8倍，而由细胞凋亡引起的淋巴系统衰竭的可能性是正常儿童的12倍。甲氧氯普胺是一种胃肠动力和中枢多巴胺拮抗剂，可将全身催乳素水平维持在较高的正常范围，该研究的目的是确定胃复安是否可以预防危重儿童的低催乳素血症、淋巴细胞减少症和医院败血症。这项拟议的随机、双盲、安慰剂对照试验的三个具体目标是确定每天服用甲氧氯普胺是否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。这项研究的次要目标是确定预防胃复安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的战略，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.