Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood

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.

Inclusion Criteria:

RESTORE subjects

- Age ≤8 years and PCPC=1 at RESTORE PICU admission

- PCPC ≤3 at RESTORE hospital discharge Sibling control subjects

Inclusion criteria:

- Age 4 to 17 years at time of testing

- PCPC=1

- Same biological parents as primary subject

- Lives with the primary subject

Exclusion Criteria:

RESTORE subjects

- Hospital readmission that includes MV and sedation

- History of cardiac arrest, traumatic brain injury (TBI) with loss of consciousness,
genetic disorder, premature birth <32 weeks gestational age, or birth weight <2500 g
Sibling control subjects

- Adopted or step siblings

- History of MV and sedation, receipt of general anesthesia, cardiac arrest, TBI with
loss of consciousness, genetic disorder, premature birth <32 weeks gestational age, or
birth weight <2500 gm.