Ensuring the safety and comfort of the more than 100,000 critically ill infants and young children supported on mechanical ventilation in the US each year is integral to the practice of pediatric critical care. Humane care of these young patients requires the use of sedating medications, most commonly combinations of opioids and benzodiazepines. Unfortunately, sedative use also carries risk. Animal studies found that even transient administration of benzodiazepines and other sedatives during periods of developmental synaptogenesis caused widespread neuronal apoptosis and residual learning and memory deficits. Sedation is administered for days to weeks to >90% of acutely-ill, ventilated infants and children. Thus, a commonly used treatment in critically ill young children may itself have detrimental, age-dependent long-term effects. An opportunity to increase the understanding of the long-term cognitive effects of sedation during critical illness in children ha been provided by the cluster randomized, controlled trial of a sedation protocol, Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE), U01 HL086622, PI Curley, 31 sites, n=2,816. This trial will determine if the trial's sedation protocol used at intervention sites can decrease the duration of mechanical ventilation and sedative exposure among children with acute respiratory failure due to a primary pulmonary process. Control sites continue usual sedation practice. We are collecting detailed data on doses and durations of sedative medications, in-hospital course, and post-discharge quality of life. Testing neurocognitive outcomes was beyond the scope of the initial trial design. However, given evolving concerns about the long-lasting neurocognitive effects of some sedatives, understanding these outcomes is now crucial in this population, regardless of the protocol's short-term effects. The purpose of this study is to determine the relationships between sedative exposure during pediatric critical illness and long-term neurocognitive outcomes. We will assess multiple domains of neurocognitive function 3 years post-discharge in 500 RESTORE subjects with normal baseline cognitive function aged 2 weeks to eight years at pediatric intensive care unit admission. In addition, we will study 310 matched, healthy siblings of RESTORE subjects to provide data on an unexposed group with similar baseline biological characteristics and environment. Our goal is to increase our understanding of the relationships between sedative exposure and long-term neurocognitive outcomes in infants and young children.

Public Health Relevance

There is increasing concern that sedatives; commonly used during critical illness in young children; may harm the developing brain. This study will evaluate the long-term neurodevelopmental effects of sedation in young children and will assess whether specific sedatives; or combinations of specific sedatives; increases a child's risk of subsequent neurocognitive impairment. Given the extensive use of sedatives in critically ill young children; this information has great importance not only to patients and families; but also to society in general.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Pediatrics Subcommittee (CHHD)
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Maholmes, Valerie
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University of Pittsburgh
Internal Medicine/Medicine
Schools of Medicine
United States
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Watson, R Scott; Crow, Sheri S; Hartman, Mary E et al. (2017) Epidemiology and Outcomes of Pediatric Multiple Organ Dysfunction Syndrome. Pediatr Crit Care Med 18:S4-S16
Best, Kaitlin M; Wypij, David; Asaro, Lisa A et al. (2017) The authors reply. Crit Care Med 45:e623-e624
Scott, Megan N; Hunter, Scott J; Joseph, Robert M et al. (2017) Neurocognitive Correlates of Attention-Deficit Hyperactivity Disorder Symptoms in Children Born at Extremely Low Gestational Age. J Dev Behav Pediatr 38:249-259
Zimmerman, Jerry J; Watson, R Scott; Ely, E Wesley (2016) Daily sedation interruption in children warrants further study. Intensive Care Med 42:1101-2