Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
Condition: Intellectual Disability; Perceptual Disorders; Memory Disorders
MeSH terms: Intellectual Disability; Memory Disorders; Perceptual Disorders; Critical Illness
Study type: Observational

Summary: 
      The purpose of this study is to determine the relationships between sedative exposure during
      pediatric critical illness and long-term neurocognitive outcomes. We will test for drug- and
      dose-dependent relationships between sedative exposure and neurocognitive outcomes along the
      early developmental spectrum and will control for baseline and environmental factors, as well
      as the severity and course of illness.

      Hypotheses:

        1. Greater exposure to benzodiazepines and/or ketamine will be associated with lower IQ
           even when controlling for severity of illness, hospital course, and baseline factors. In
           addition, benzodiazepines and/or ketamine will negatively affect other aspects of
           neurocognitive function.

        2. Younger children exposed to benzodiazepines and/or ketamine will have worse
           neurocognitive outcomes than older children with similar sedative exposure and severity
           of illness.
    

Detailed description: 
      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 in >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 has 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 determined whether
      the trial's sedation protocol used at intervention sites decreased the duration of mechanical
      ventilation and sedative exposure among children with acute respiratory failure due to a
      primary pulmonary process. Control sites continued usual sedation practice. We collected
      detailed data on doses and durations of sedative medications, in-hospital course, and
      post-discharge quality of life.

      The purpose of RESTORE-cognition 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 2.5-5 years post-discharge in 500 RESTORE
      subjects with normal baseline cognitive function aged 2 weeks to 8 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, critical illness, and long-term neurocognitive
      outcomes in infants and young children.
    

Observational model: Case-Control
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        RESTORE subjects who consented for 6-month follow-up with normal baseline cognitive
        function aged 2 weeks to 8 years at PICU admission. In addition, we will study matched,
        healthy siblings of these subjects to provide data on an unexposed group with similar
        baseline biological characteristics and environment. If more than one sibling meets
        enrollment criteria, the one closest in age will be selected.
      
Keywords: intensive care; critical care; child; family; survivors