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.
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