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.
Patients will be eligible for enrollment if they are 1) aged 44 weeks post-menstrual age and up to 11 years, 2) planned admission to the pediatric ICU at Monroe Carell Jr. Children's Hospital at Vanderbilt (MCJCHV), and 3) requiring mechanical ventilation (MV) and sedation. Pre-pubescent children (<11 years) are typically different from older children who often behave physiologically more similar to adults. Pre-pubescent children are more likely to be admitted to the PICU and are undergoing a steeper curve of neurocognitive maturation. Therefore, these patients may be at greatest risk for worse brain dysfunction.
Receiving continuous sedation for > 72 hours prior to screening.
Rapidly resolving respiratory failure at screening, with planned immediate liberation from MV.
Severe developmental delay at baseline defined as a score of ≥ 4 (severe disability) on the Pediatric Cerebral Performance Category (PCPC) Scale, referencing cognitive status prior to critical illness.
Clinically significant 2nd or 3rd degree heart block or bradycardia < 60 beats per minute.
Parallel
Dexmedetomidine
DrugFor patients in the dexmedetomidine group, dose will range from 0.2-2.0 mcg/kg/hr. For example, a 10 kg patient on an infusion of 1 mcg/kg/hr of dexmedetomidine would receive 10 mcg of study drug per hour. This dose range have been selected after literature review and discussions with critical care practitioners, investigational pharmacists, and the mini-MENDS study steering committee.
Midazolam
DrugFor patients in the midazolam group, dose will range from 0.025-0.25 mg/kg/hr. For example, a 10 kg patient on an infusion of 0.15 mg/kg/hr of midazolam would receive 1.5 mg of midazolam per hour. This dose range have been selected after literature review and discussions with critical care practitioners, investigational pharmacists, and the mini-MENDS study steering committee.
Daily prevalence of delirium
The analysis of delirium prevalence will be conducted using a modified Intention-to-Treat (ITT) population, defined as all patients who were randomized and received study drug. The investigators chose a 14 day evaluation period for delirium, because it represents the best balance of gaining valuable clinical information, while maximizing resource utilization, given the average study drug infusion to be 5 days and maximum duration to be 10 days. Thus our follow-up period will cover 9 additional days of delirium monitoring after the study drug is stopped in the majority of our patients.
Duration of mechanical ventilation (MV)
Days of mechanical ventilation (Time vs. days) and impact of sedation will be determined.
Incidence of long-term cognitive impairment.
Maladaptive behavior and cognitive dysfunction (memory, attention, executive dysfunction) will be assessed 6 months post ICU discharge.
Incidence of post-traumatic stress symptoms in patients and parents/caregivers
Assessment of post-traumatic stress symptoms in patients and parents at 6 months post ICU discharge
Functional status
Functional status will be assessed using a parental questionnaire tool (The Functional Status Scale and Ages and Stages Questionnaire) based on a conceptual framework of adaptive behavior, activities of daily living, and global functional morbidity.
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Vanderbilt University Medical Center
Lead sponsor
Pfizer
Collaborator
National Heart, Lung, and Blood Institute (NHLBI)
Collaborator
