Intellectual DisabilityRESTORE-cogNCT02225041
Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
An observational study of Intellectual Disability and Perceptual Disorders, run by University of Pennsylvania at 31 sites in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 30 months to 13 yearsHealthy volunteers can take part
- Conditions the study is for
- Intellectual Disability, Perceptual Disorders, Memory Disorders
- How many people
- 360 participants
- Where
- 31 sitesUnited States
- Study dates
- Aug 2014to Dec 2018
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 30 months to 13 years
- All sexes
- Healthy volunteers accepted
- Child
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.
Who may be able to join
- RESTORE subjects
- Age ≤8 years and PCPC=1 at RESTORE PICU admission
- PCPC ≤3 at RESTORE hospital discharge Sibling control subjects
- Age 4 to 17 years at time of testing
- PCPC=1
- Same biological parents as primary subject
- Lives with the primary subject
Who cannot join
- 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.
Trial locations and contacts
31 sites in 1 country.
31 sites in 1 country
United States31 sites
C. S. Mott Children's Hospital of the University of Michigan
Ann Arbor, Michigan, 48109-0243
University of Maryland Hospital for Children
Baltimore, Maryland, 21201-1595
Johns Hopkins Children's Center
Baltimore, Maryland, 21287
Children's Hospital of Alabama
Birmingham, Alabama, 35233
Children's Memorial Hospital, Chicago
Chicago, Illinois, 60614-3363
Medical City Children's Hospital
Dallas, Texas, 75230
Children's Medical Center Dallas
Dallas, Texas, 75235
Duke Children's Hospital and Health Center
Durham, North Carolina, 27710
Connecticut Children's Medical Center
Hartford, Connecticut, 06106
Children's Mercy Hospital, Kansas City
Kansas City, Missouri, 84108
Dartmouth-Hitchcock Medical Center
Lebanon, New Hampshire, 03756-0001
Holtz Children's Hospital
Miami, Florida, 33136
Monroe Carell, Jr. Children's Hospital at Vanderbilt
Nashville, Tennessee, 37232-9075
Yale-New Haven Children's Hospital
New Haven, Connecticut, 06520-8064
Cohen Children's Medical Center of New York
New Hyde Park, New York, 11040
Advocate Hope Children's Hospital
Oak Lawn, Illinois, 60453
Children's Hospital and Research Center at Oakland
Oakland, California, 94609-1809
University of Nebraska Medical Center
Omaha, Nebraska, 68114
Children's Hospital of Orange County
Orange, California, 92868
Florida Hospital for Children
Orlando, Florida, 32803
Lucile Salter Packard Children's Hospital at Stanford
Palo Alto, California, 94304-0126
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, 19104
Doernbecher Children's Hospital
Portland, Oregon, 97239
University of California Davis Medical Center
Sacramento, California, 95817
Primary Children's Medical Center
Salt Lake City, Utah, 84113
Children's Hospital at University of California San Francisco Medical Center
San Francisco, California, 94143
St. Louis Children's Hospital
St Louis, Missouri, 63110
The Children's Hospital at Montefiore
The Bronx, New York, 10467
University Medical Center, The University of Arizona
Tucson, Arizona, 85724
Nemours/Alfred I. duPont Hospital for Children
Wilmington, Delaware, 19803
University of Massachusetts Memorial Children's Medical Center
Worcester, Massachusetts, 01655
About this study
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:
- 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.
- Younger children exposed to benzodiazepines and/or ketamine will have worse neurocognitive outcomes than older children with similar sedative exposure and severity of illness.
Read the 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.
- Keywords
- intensive care, critical care, child, family, survivors
- Medical subject headings
- Intellectual Disability, Perceptual Disorders, Memory Disorders
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 2.5 to 5 years post-discharge
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Aug 2014 (estimated)
- Study startAug 2014
- Primary completionDec 2018
- Study completionDec 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Intellectual DisabilityStudies of the same condition, open and under way.
- More trials run by University of PennsylvaniaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Cross-sectional
- Enrolment
- 360 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Pennsylvania
- Sponsor type
- University, hospital or other
- Collaborators
- National Institutes of Health (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- Responsible party
- Sponsor
- Investigators
- Martha AQ Curley, RN, PhD, Principal investigator, University of PennsylvaniaR. Scott Watson, MD, Principal investigator, Seattle Childrens Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02225041
- Sponsor's protocol ID
- 1R01HD074757-01A1
- Other IDs
- 1R01HD074757-01A1
- Acronym
- RESTORE-cog
- Status last verified
- Jun 2019
- First submitted
- 25 Jul 2014
- Last updated
- 18 Jun 2019
- Results posted
- No
- Data monitoring committee
- No
Publications
Curley MAQ, Beers SR, Asaro LA, Burns C, Koh MJ, Angus DC, Wypij D, Watson RS; RESTORE-Cognition Study Investigators. Sedative Choice and Neurocognitive Outcomes After Critical Illness in Early Childhood. JAMA Netw Open. 2026 May 1;9(5):e2613599. doi: 10.1001/jamanetworkopen.2026.13599.
PubMed 42154465Curley 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.
PubMed 30017814
Study at a glance
From the registry record, last updated by the sponsor on 18 Jun 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
- ClinicalTrials.gov ID
- NCT02225041
- Acronym / sponsor ID
- RESTORE-cog / 1R01HD074757-01A1
- Keywords
- intensive care, critical care, child, family, survivors
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 360 participants (actual)
- Lead sponsor
- University of PennsylvaniaUniversity, hospital or other
- Collaborators
- National Institutes of Health (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- Study start
- Aug 2014 (actual)
- Primary completion
- Dec 2018 (actual)
- Study completion
- Dec 2018 (actual)
- First posted
- 25 Aug 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- 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.
- 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.
Study design
- Observational model
- Case-control
- Time perspective
- Cross-sectional
Who may qualify
- Ages
- 30 months to 13 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child
- 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.
Key inclusion criteria (7 listed)
- RESTORE subjects
- Age ≤8 years and PCPC=1 at RESTORE PICU admission
- PCPC ≤3 at RESTORE hospital discharge Sibling control subjects
- Age 4 to 17 years at time of testing
- PCPC=1
Key exclusion criteria (5 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
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
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Jun 2019.
- Derived from this study: PubMed 42154465Curley MAQ, Beers SR, Asaro LA, Burns C, Koh MJ, Angus DC, Wypij D, Watson RS; RESTORE-Cognition Study Investigators. Sedative Choice and Neurocognitive Outcomes After Critical Illness in Early Childhood. JAMA Netw Open. 2026 May 1;9(5):e2613599. doi: 10.1001/jamanetworkopen.2026.13599.
- Derived from this study: PubMed 30017814Curley 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.
Related trials for Intellectual Disability
RecruitingObservational study
Longitudinal Study of Ultra-rare Inherited Metabolic and Degenerative Neurological Diseases.
Inherited Disease, Rare Diseases
Not yet recruiting
Advancing Cardiovascular Health Among Adolescents With Intellectual Disabilities: Co-Development of Technology Interventions to Enhance Physical Activity
Physical Activity, Intellectual Disabilities
RecruitingObservational study
Clinical and Basic Investigations Into Known and Suspected Congenital Disorders of Glycosylation
Congenital Disorders of Glycosylation
RecruitingObservational study
Genome Medical Sequencing for Gene Discovery
Intellectual Disabilities, Congenital Anomaly
RecruitingObservational study
Adrenal Diseases in the Population of Modena: A Clinical-Epidemiological Database of Patients Referred to the Adrenal Disorders Outpatient Clinic of the Clinical Unit of Endocrinology at the Modena University Hospital (AOU Modena)
Cushing s Syndrome, Cushing Disease
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Martha AQ Curley, RN, PhD principal investigator
University of Pennsylvania
R. Scott Watson, MD principal investigator
Seattle Childrens Hospital
31 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Intellectual Disability and Perceptual Disorders, run by University of Pennsylvania at 31 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 18 Jun 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 31 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome 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 (time frame: 2.5 to 5 years post-discharge). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02225041, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Jun 2019.