The need for mechanical ventilation (MV) following acute respiratory and myocardial failure is the leading cause of admission to the pediatric intensive care unit (PICU). Over 90% of MV pediatric patients receive continuous sedation, most commonly with gamma-aminobutyric acid (GABA) agonist benzodiazepines. Recently, we demonstrated that exposure to the benzodiazepine midazolam contributed to iatrogenic harm in pediatric patients?prolonging PICU length of stay and increasing the prevalence and duration of delirium. Delirium, itself a manifestation of acute brain dysfunction, is prevalent in the PICU with rates of up to 30% in older children, over 50% in infants and toddlers, and over 60% in pediatric patients requiring MV. Delirium in children is a significant contributor to longer duration on MV, prolonged PICU length of stay, and death, with significant consequential costs. Adult studies have shown that an alternative sedation paradigm using dexmedetomidine, an alpha-2 agonist, decreases the duration of delirium and coma, length of MV, ICU length of stay, cost, and infection rates compared to benzodiazepine-based sedation. Dexmedetomidine has unique anti-inflammatory and anti-oxidant characteristics, making it an appealing sedative agent as inflammation, endothelial and blood-brain barrier (BBB) injury are mechanistically associated with prolonged delirium and worse cognitive impairment in adults. Though sedation may be unavoidable in PICUs, a dexmedetomidine- based regimen may complement goal-directed sedation, as over-sedation (30%) rather than under-sedation (10%) is common in the PICU setting, and thus far, sedation protocolization alone have not demonstrated significant impact on improving outcomes in pediatric patients. The FDA recently published warnings regarding the possible role of anesthetics, including benzodiazepines, on cognitive development in children. We therefore propose mini-MENDS (Maximizing the Efficacy of Goal-Directed Sedation to Reduce Neurological Dysfunction in Mechanically Ventilated Infants and Children Study), in which we will test the hypotheses that sedation of MV pediatric patients with an alpha-2 agonist (dexmedetomidine) versus a GABA- ergic agent (midazolam) will (Aim 1A) decrease daily delirium prevalence, (Aim 1B) decrease length of MV, (Aim 2A) improve functional and behavioral recovery, (Aim 2B) be associated with fewer symptoms of post- traumatic stress, (Aim 2C) decrease the incidence of cognitive impairment, and (Aim 3) reduce levels of pro- inflammatory cytokines and biomarkers of endothelial and blood brain barrier injury. We will randomize 372 pediatric patients on MV, aged 6 months to 11 years, to receive goal-directed continuous sedation with either dexmedetomidine or midazolam for up to 10 days. The study will have 80% power to detect at least a 10% absolute reduction in daily delirium prevalence between groups, this a clinically meaningful outcome; extrapolation of current pediatric data would estimate a 10% decrease in delirium prevalence to be associated with a 1.2-day (20%) decrease in PICU LOS and 15% lower odds of dying.
Ventilated pediatric patients are frequently over-sedated and the majority suffer from delirium, a form of acute brain dysfunction that is an independent predictor of increased risk of dying, length of stay, and costs. Universally prescribed sedative medications?the GABA-ergic benzodiazepines?worsen this brain organ dysfunction and independently prolong duration of ventilation and ICU stay, and the available alternative sedation regimen using dexmedetomidine, an alpha-2 agonist, has been shown to be superior to benzodiazepines in adults, and may mechanistically impact outcomes through positive effects on innate immunity, bacterial clearance, apoptosis, cognition and delirium. The mini-MENDS trial will compare dexmedetomidine and midazolam, and determine the best sedative medication to reduce delirium and improve duration of ventilation, and functional, psychiatric, and cognitive recovery in our most vulnerable patients? survivors of pediatric critical illness.