A Study to Compare the Long-term Outcomes After Two Different Anaesthetics

Study Overview
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Brief Summary
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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.

Official Title
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Neurodevelopmental Outcome After Standard Dose Sevoflurane Versus Low-dose Sevoflurane/Dexmedetomidine/Remifentanil Anaesthesia in Young Children- The TREX Trial

Conditions
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Anesthesia, Neurotoxicity, Child Development

Intervention / Treatment
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* Drug: Sevoflurane
* Drug: Remifentanil
* Drug: Dexmedetomidine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Maximum Age: 2 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be randomised to receive either low-dose sevoflurane/dexmedetomidine/remifentanil OR standard dose sevoflurane anaesthesia.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sevoflurane/dexmedetomidine/remifentanil<br>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. | Drug: Sevoflurane<br>* 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.<br>* Other names: Sevorane;Drug: Remifentanil<br>* Experimental arm: loading dose: 1 mcg/kg, infusion starting at 0.1 mcg/kg/min or greater.<br>* Other names: Ultiva;Drug: Dexmedetomidine<br>* Experimental arm: loading dose:1mcg/kg, infusion: 1 mcg/kg/hr.<br>* Other names: Dexmedetomidine Ever Pharma;|
| Active Comparator: Sevoflurane<br>End tidal concentration of 2.5-3.0% or greater. | Drug: Sevoflurane<br>* 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.<br>* Other names: Sevorane;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Full Scale IQ | Global cognitive function as assessed by the full scale IQ score of the Wechsler Preschool and Primary School Intelligence Scale. | 3 years of age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| incidence of intra-operative hypotension | Blood pressure measurements will be recorded during surgery | 150 minutes- duration of surgery (baseline) | 
| incidence of intra-operative bradycardia | Heart rate will be recorded during surgery | 150 minutes- duration of surgery (baseline) | 
| Post-operative pain | Pain scores will be recorded after surgery | 60 minutes- after surgery | 
| Time to recovery | Time of removal of airway, eye-opening and discharge from PACU will be recorded. | 60 minutes- after surgery | 
| Language outcomes | Clinical Evaluation of Language Fundamentals- Preschool, Version 2 (CELF-P2) | 3 years of age | 
| Attention/Executive Function/impulse control | A Developmental NEuroPSYchological Assessment- Second Edition (NEPSY-2): Statue Subtest | 3 years of age | 
| Memory | A Developmental NEuroPSYchological Assessment- Second Edition (NEPSY-2): Narrative memory | 3 years of age | 
| Adaptive behaviour | Adaptive Behavior Assessment System - Third Edition (ABAS-III) | 3 years of age | 
| Clinical Behavior | Child Behavior Checklist (CBCL) | 3 years of age | 
| Executive Function | Behavior Rating of Executive Function- Preschool (BRIEF-P) | 3 years of age | 
| Social Skills | Social Skills Improvement System (SSIS) | 3 years of age |