Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood (RESTORE-cog)

June 17, 2019 updated by: University of Pennsylvania

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.

Study Overview

Status

Completed

Conditions

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.

Study Type

Observational

Enrollment (Actual)

360

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Alabama
      • Birmingham, Alabama, United States, 35233
        • Children's Hospital of Alabama
    • Arizona
      • Tucson, Arizona, United States, 85724
        • University Medical Center, The University of Arizona
    • California
      • Oakland, California, United States, 94609-1809
        • Children's Hospital and Research Center at Oakland
      • Orange, California, United States, 92868
        • Children's Hospital of Orange County
      • Palo Alto, California, United States, 94304-0126
        • Lucile Salter Packard Children's Hospital at Stanford
      • Sacramento, California, United States, 95817
        • University of California Davis Medical Center
      • San Francisco, California, United States, 94143
        • Children's Hospital at University of California San Francisco Medical Center
    • Connecticut
      • Hartford, Connecticut, United States, 06106
        • Connecticut Children's Medical Center
      • New Haven, Connecticut, United States, 06520-8064
        • Yale-New Haven Children's Hospital
    • Delaware
      • Wilmington, Delaware, United States, 19803
        • Nemours/Alfred I. duPont Hospital for Children
    • Florida
      • Miami, Florida, United States, 33136
        • Holtz Children's Hospital
      • Orlando, Florida, United States, 32803
        • Florida Hospital for Children
    • Illinois
      • Chicago, Illinois, United States, 60614-3363
        • Children's Memorial Hospital, Chicago
      • Oak Lawn, Illinois, United States, 60453
        • Advocate Hope Children's Hospital
    • Maryland
      • Baltimore, Maryland, United States, 21287
        • Johns Hopkins Children's Center
      • Baltimore, Maryland, United States, 21201-1595
        • University of Maryland Hospital for Children
    • Massachusetts
      • Worcester, Massachusetts, United States, 01655
        • University of Massachusetts Memorial Children's Medical Center
    • Michigan
      • Ann Arbor, Michigan, United States, 48109-0243
        • C. S. Mott Children's Hospital of the University of Michigan
    • Missouri
      • Kansas City, Missouri, United States, 84108
        • Children's Mercy Hospital, Kansas City
      • Saint Louis, Missouri, United States, 63110
        • St. Louis Children's Hospital
    • Nebraska
      • Omaha, Nebraska, United States, 68114
        • University of Nebraska Medical Center
    • New Hampshire
      • Lebanon, New Hampshire, United States, 03756-0001
        • Dartmouth-Hitchcock Medical Center
    • New York
      • Bronx, New York, United States, 10467
        • The Children's Hospital at Montefiore
      • New Hyde Park, New York, United States, 11040
        • Cohen Children's Medical Center of New York
    • North Carolina
      • Durham, North Carolina, United States, 27710
        • Duke Children's Hospital and Health Center
    • Oregon
      • Portland, Oregon, United States, 97239
        • Doernbecher Children's Hospital
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104
        • Children's Hospital of Philadelphia
    • Tennessee
      • Nashville, Tennessee, United States, 37232-9075
        • Monroe Carell, Jr. Children's Hospital at Vanderbilt
    • Texas
      • Dallas, Texas, United States, 75235
        • Children's Medical Center Dallas
      • Dallas, Texas, United States, 75230
        • Medical City Children's Hospital
    • Utah
      • Salt Lake City, Utah, United States, 84113
        • Primary Children's Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

2 years to 13 years (Child)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

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.

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
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
Time Frame: 2.5 to 5 years post-discharge
2.5 to 5 years post-discharge

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Pennsylvania

Collaborators

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Institutes of Health (NIH)

Investigators

  • Principal Investigator: R. Scott Watson, MD, Seattle Childrens Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 1, 2014

Primary Completion (Actual)

December 1, 2018

Study Completion (Actual)

December 1, 2018

Study Registration Dates

First Submitted

July 25, 2014

First Submitted That Met QC Criteria

August 21, 2014

First Posted (Estimate)

August 25, 2014

Study Record Updates

Last Update Posted (Actual)

June 18, 2019

Last Update Submitted That Met QC Criteria

June 17, 2019

Last Verified

June 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 1R01HD074757-01A1 (U.S. NIH Grant/Contract)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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