mini-MENDS

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 and over 50% in infants and toddlers. Among pediatric patients on MV, brain dysfunction (delirium/coma) has been reported in up to two-thirds of patients. 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 alpha2-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 and simulates a more moderate rather than deep level of sedation. Inflammation, endothelial and blood-brain barrier (BBB) injury are mechanistically associated with prolonged delirium and worse cognitive impairment in adults, and hence dexmedetomidine’s anti-inflammatory properties make it an appealing sedative agent. 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 Sedation and Reducing Neurological Dysfunction in Mechanically Ventilated Infants and Children Study), in which we will randomize ~400 pediatric patients on MV, aged 6 months to 10 years, to receive goal-directed continuous sedation with either dexmedetomidine or midazolam for up to 10 days. This study will test the hypotheses that sedation of MV pediatric patients with an alpha2 agonist (dexmedetomidine) versus a GABA-ergic agent (midazolam) will decrease daily prevalence of delirium and MV, and ICU/hospital LOS, improve functional and behavioral recovery, be associated with fewer symptoms of post-traumatic stress, decrease the incidence of cognitive impairment, and reduce levels of pro-inflammatory cytokines and biomarkers of endothelial and blood brain barrier injury.