A Study to Compare the Long-term Outcomes After Two Different Anaesthetics
- Conditions
- AnesthesiaChild DevelopmentNeurotoxicity
- Interventions
- Registration Number
- NCT03089905
- Lead Sponsor
- Murdoch Childrens Research Institute
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 450
- 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.
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Sevoflurane/dexmedetomidine/remifentanil Remifentanil Dexmedetomidine: loading dose of 1mcg/kg over 10 minutes followed by an infusion of at 1 mcg/kg/hr. Remifentanil: loading dose 1 mcg/kg over 2 minutes followed by an infusion starting at 0.1 mcg/kg/min or greater. Sevoflurane: end tidal concentration of 0.6 -0.8% or less. Sevoflurane/dexmedetomidine/remifentanil Sevoflurane Dexmedetomidine: loading dose of 1mcg/kg over 10 minutes followed by an infusion of at 1 mcg/kg/hr. Remifentanil: loading dose 1 mcg/kg over 2 minutes followed by an infusion starting at 0.1 mcg/kg/min or greater. Sevoflurane: end tidal concentration of 0.6 -0.8% or less. Sevoflurane/dexmedetomidine/remifentanil Dexmedetomidine Dexmedetomidine: loading dose of 1mcg/kg over 10 minutes followed by an infusion of at 1 mcg/kg/hr. Remifentanil: loading dose 1 mcg/kg over 2 minutes followed by an infusion starting at 0.1 mcg/kg/min or greater. Sevoflurane: end tidal concentration of 0.6 -0.8% or less. Sevoflurane Sevoflurane End tidal concentration of 2.5-3.0% or greater.
- Primary Outcome Measures
Name Time Method 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 Outcome Measures
Name Time Method Clinical Behavior 3 years of age Child Behavior Checklist (CBCL)
Social Skills 3 years of age Social Skills Improvement System (SSIS)
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)
Memory 3 years of age A Developmental NEuroPSYchological Assessment- Second Edition (NEPSY-2): Narrative memory
incidence of intra-operative hypotension 150 minutes- duration of surgery (baseline) Blood pressure measurements will be recorded during surgery
Attention/Executive Function/impulse control 3 years of age A Developmental NEuroPSYchological Assessment- Second Edition (NEPSY-2): Statue Subtest
Adaptive behaviour 3 years of age Adaptive Behavior Assessment System - Third Edition (ABAS-III)
incidence of intra-operative bradycardia 150 minutes- duration of surgery (baseline) Heart rate will be recorded during surgery
Executive Function 3 years of age Behavior Rating of Executive Function- Preschool (BRIEF-P)
Trial Locations
- Locations (21)
Boston Children's Hospital
🇺🇸Boston, Massachusetts, United States
The University of Texas Southwestern Medical Center
🇺🇸Dallas, Texas, United States
Cleveland Clinic
🇺🇸Cleveland, Ohio, United States
The Children's Hospital of Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
Texas Children's Hospital
🇺🇸Houston, Texas, United States
Children's Hospital at Westmead
🇦🇺Westmead, New South Wales, Australia
Women's and Children's Hospital
🇦🇺Adelaide, South Australia, Australia
Queensland Children's Hospital
🇦🇺Brisbane, Queensland, Australia
Sydney Children's Hospital
🇦🇺Randwick, New South Wales, Australia
Perth Children's Hospital
🇦🇺Perth, Western Australia, Australia
Flinders Medical Centre
🇦🇺Bedford Park, South Australia, Australia
La Paz University Hospital
🇪🇸Madrid, Spain
Royal Children's Hospital
🇦🇺Parkville, Victoria, Australia
Presidio Ospedale Infantile C.Arrigo Azienda Ospedaliera
🇮🇹Alessandria, Italy
Azienda ospedaliero-universitaria di Bologna
🇮🇹Bologna, Italy
Istituto Giannina Gaslini
🇮🇹Genova, Italy
Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico - Clinica Mangiagalli
🇮🇹Milano, Italy
Vittore Buzzi Children's Hospital
🇮🇹Milano, Italy
Azienda Ospedaliero Universitaria Pisana
🇮🇹Pisa, Italy
Ospedale Bambino Gesù
🇮🇹Roma, Italy
Azienda Ospedaliero-Universitaria Meyer
🇮🇹Firenze, Italy