Clinical trial NCT02225041: Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
Official title: Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Intellectual Disability
Perceptual Disorders
Memory Disorders
Keywords: intensive care
critical care
child
family
survivors
Lead sponsor: University of Pennsylvania
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2014-08-25
Enrollment: 360
Sex: ALL
Minimum age (years): 30
Maximum age (years): 13
Standard ages: CHILD
Accepts healthy volunteers: yes
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.

Brief 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Neurocognitive function at 2.5 years post-ICU discharge, as assessed using standardized tests of attention, processing speed, learning and memory, visual-spatial skills, motor skills, language, executive function, IQ, and behavior
timeFrame: 2.5 to 5 years post-discharge
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Children's Hospital of Alabama
state: Alabama
city: Tucson
country: United States
facility: University Medical Center, The University of Arizona
state: Arizona
city: Oakland
country: United States
facility: Children's Hospital and Research Center at Oakland
state: California
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: Palo Alto
country: United States
facility: Lucile Salter Packard Children's Hospital at Stanford
state: California
city: Sacramento
country: United States
facility: University of California Davis Medical Center
state: California
city: San Francisco
country: United States
facility: Children's Hospital at University of California San Francisco Medical Center
state: California
city: Hartford
country: United States
facility: Connecticut Children's Medical Center
state: Connecticut
city: New Haven
country: United States
facility: Yale-New Haven Children's Hospital
state: Connecticut
city: Wilmington
country: United States
facility: Nemours/Alfred I. duPont Hospital for Children
state: Delaware
city: Miami
country: United States
facility: Holtz Children's Hospital
state: Florida
city: Orlando
country: United States
facility: Florida Hospital for Children
state: Florida
city: Chicago
country: United States
facility: Children's Memorial Hospital, Chicago
state: Illinois
city: Oak Lawn
country: United States
facility: Advocate Hope Children's Hospital
state: Illinois
city: Baltimore
country: United States
facility: University of Maryland Hospital for Children
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins Children's Center
state: Maryland
city: Worcester
country: United States
facility: University of Massachusetts Memorial Children's Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: C. S. Mott Children's Hospital of the University of Michigan
state: Michigan
city: Kansas City
country: United States
facility: Children's Mercy Hospital, Kansas City
state: Missouri
city: Saint Louis
country: United States
facility: St. Louis Children's Hospital
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Lebanon
country: United States
facility: Dartmouth-Hitchcock Medical Center
state: New Hampshire
city: Bronx
country: United States
facility: The Children's Hospital at Montefiore
state: New York
city: New Hyde Park
country: United States
facility: Cohen Children's Medical Center of New York
state: New York
city: Durham
country: United States
facility: Duke Children's Hospital and Health Center
state: North Carolina
city: Portland
country: United States
facility: Doernbecher Children's Hospital
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Nashville
country: United States
facility: Monroe Carell, Jr. Children's Hospital at Vanderbilt
state: Tennessee
city: Dallas
country: United States
facility: Medical City Children's Hospital
state: Texas
city: Dallas
country: United States
facility: Children's Medical Center Dallas
state: Texas
city: Salt Lake City
country: United States
facility: Primary Children's Medical Center
state: Utah
Study officials:
affiliation: University of Pennsylvania
name: Martha AQ Curley, RN, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Seattle Childrens Hospital
name: R. Scott Watson, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Curley MAQ, Watson RS, Cassidy AM, Burns C, Delinger RL, Angus DC, Asaro LA, Wypij D, Beers SR; RESTORE-cognition Study Investigators. Design and rationale of the "Sedation strategy and cognitive outcome after critical illness in early childhood" study. Contemp Clin Trials. 2018 Sep;72:8-15. doi: 10.1016/j.cct.2018.07.004. Epub 2018 Jul 11.