Anesthesia, Child Development, Neurotoxicity
Conditions
Brief summary
There is considerable evidence that most general anaesthetics modulate brain development in animal studies. The impact is greater with longer durations of exposure and in younger animals. There is great controversy over whether or not these animal data are relevant to human clinical scenarios. The changes seen in preclinical studies are greatest with GABA agonists and NMDA antagonists such as volatile anaesthetics (eg sevoflurane), propofol, midazolam, ketamine, and nitrous oxide. There is less evidence for an effect with opioid (such as remifentanil) or with alpha 2 agonists (such as dexmedetomidine). Some, but not all, human cohort studies show an association between exposure to anaesthesia in infancy or early childhood and later changes in cognitive tests, school performance or risk of developing neurodevelopmental disorders. The evidence is weak due to possible confounding. A recent well designed cohort study (the PANDA study) comparing young children that had hernia repair to their siblings found no evidence for a difference in a range of detailed neuropsychological tests. In that study most children were exposed to up to two hours of anaesthesia. The only trial (the GAS trial) has compared children having hernia repair under regional or general anesthesia and has found no evidence for a difference in neurodevelopment when tested at two years of age. The GAS and PANDA studies confirm the animal data that short exposure is unlikely to cause any neurodevelopmental impact. The impact of longer exposures is still unknown. In humans the strongest evidence for an association between surgery and poor neurodevelopmental outcome is in infants having major surgery. However, this is also the group where confounding is most likely. The aim of our study is to see if a new combination of anaesthetic drugs results in a better long-term developmental outcome than the current standard of care for children having anaesthesia expected to last 2 hours or longer. Children will be randomised to receive either a low dose sevoflurane/remifentanil/dexmedetomidine or standard dose sevoflurane anaesthetic. They will receive a neurodevelopmental assessment at 3 years of age to assess global cognitive function.
Interventions
DRUGSevoflurane
Experimental arm: end tidal concentration of 0.6 -0.8% or less. Active comparator arm: end tidal concentration of 2.5-3.0% or greater.
DRUGRemifentanil
Experimental arm: loading dose: 1 mcg/kg, infusion starting at 0.1 mcg/kg/min or greater.
DRUGDexmedetomidine
Experimental arm: loading dose:1mcg/kg, infusion: 1 mcg/kg/hr.
Sponsors
Murdoch Childrens Research Institute
Sydney Children's Hospitals Network
Baylor College of Medicine
Boston Children's Hospital
The Cleveland Clinic
University of Texas, Southwestern Medical Center at Dallas
Royal Children's Hospital
Children's Hospital of Philadelphia
Queensland Children's Hospital
Perth Children's Hospital
Women and Children's Hospital
Istituto Giannina Gaslini
Flinders Medical Centre
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
Randomisation 1:1 will be stratified by site and age at exposure (less than 12 months and greater than or equal to 12 months). Randomisation will be in blocks of variable size. The treating anaesthetist will not be blinded to treatment arm. The assessing neuropsychologist and parents will be blinded to treatment arm.
Intervention model description
Participants will be randomised to receive either low-dose sevoflurane/dexmedetomidine/remifentanil OR standard dose sevoflurane anaesthesia.
Eligibility
Sex/Gender
ALL
Age
No minimum to 2 Years
Healthy volunteers
No
Inclusion criteria
* Younger than 2 years (chronological age) * Scheduled for anaesthesia that is expected to last at least 2 hours (and/or total operating room time is scheduled to be at least 2.5 hours) * Has a legally acceptable representative capable of understanding the informed consent document and providing consent on the participant's behalf.
Exclusion criteria
* Known neurologic, chromosomal or congenital anomaly which is likely to be associated with poor neurobehavioural outcome * Existing diagnosis of behavioural or neurodevelopmental disability * Prematurity (defined as \< 36 weeks gestational age at birth) * Birth weight less than 2 kg. * Congenital cardiac disease requiring surgery * Intracranial neurosurgery and intracranial craniofacial surgery (isolated cleft lip is not an exclusion) * Previous cumulative exposure to general anaesthesia exceeding 2 hours * Planned future cumulative exposure to anaesthesia exceeding 2 hours before the age of 3 years. * Any specific contra-indication to any aspect of the protocol * Previous adverse reaction to any anaesthetic * Circumstances likely to make long term follow-up impossible * Living in a household where the primary language spoken at home is not a language in which we can administer the Wechsler Preschool and Primary School Intelligence Scale * Planned postoperative sedation with any agent except opioids (e.g. benzodiazepines, dexmedetomidine, ketamine, barbiturates, propofol, clonidine, chloral hydrate, and other non-opioid sedatives). For example if such sedation is planned for post-operative ventilation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Full Scale IQ | 3 years of age | Global cognitive function as assessed by the full scale IQ score of the Wechsler Preschool and Primary School Intelligence Scale. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| incidence of intra-operative hypotension | 150 minutes- duration of surgery (baseline) | Blood pressure measurements will be recorded during surgery |
| incidence of intra-operative bradycardia | 150 minutes- duration of surgery (baseline) | Heart rate will be recorded during surgery |
| Post-operative pain | 60 minutes- after surgery | Pain scores will be recorded after surgery |
| Time to recovery | 60 minutes- after surgery | Time of removal of airway, eye-opening and discharge from PACU will be recorded. |
| Language outcomes | 3 years of age | Clinical Evaluation of Language Fundamentals- Preschool, Version 2 (CELF-P2) |
| Attention/Executive Function/impulse control | 3 years of age | A Developmental NEuroPSYchological Assessment- Second Edition (NEPSY-2): Statue Subtest |
| Memory | 3 years of age | A Developmental NEuroPSYchological Assessment- Second Edition (NEPSY-2): Narrative memory |
| Adaptive behaviour | 3 years of age | Adaptive Behavior Assessment System - Third Edition (ABAS-III) |
| Clinical Behavior | 3 years of age | Child Behavior Checklist (CBCL) |
| Executive Function | 3 years of age | Behavior Rating of Executive Function- Preschool (BRIEF-P) |
| Social Skills | 3 years of age | Social Skills Improvement System (SSIS) |
Countries
Australia, Italy, Spain, United States
Contacts
STUDY_CHAIRAndrew J Davidson, MD
Royal Children's Hospital
Outcome results
None listed