Neurodevelopmental Outcome After Standard Dose Sevoflurane Versus Low-dose Sevoflurane/Dexmedetomidine/Remifentanil Anaesthesia in Young Children- The TREX Trial
Overview
- Phase
- Phase 3
- Intervention
- Sevoflurane
- Conditions
- Anesthesia
- Sponsor
- Murdoch Childrens Research Institute
- Enrollment
- 450
- Locations
- 21
- Primary Endpoint
- Full Scale IQ
- Status
- Active, not recruiting
- Last Updated
- 9 months ago
Overview
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.
Investigators
Eligibility Criteria
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
Arms & Interventions
Sevoflurane/dexmedetomidine/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.
Intervention: Sevoflurane
Sevoflurane/dexmedetomidine/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.
Intervention: Remifentanil
Sevoflurane/dexmedetomidine/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.
Intervention: Dexmedetomidine
Sevoflurane
End tidal concentration of 2.5-3.0% or greater.
Intervention: Sevoflurane
Outcomes
Primary Outcomes
Full Scale IQ
Time Frame: 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 Outcomes
- Clinical Behavior(3 years of age)
- Social Skills(3 years of age)
- Post-operative pain(60 minutes- after surgery)
- Time to recovery(60 minutes- after surgery)
- Language outcomes(3 years of age)
- Memory(3 years of age)
- incidence of intra-operative hypotension(150 minutes- duration of surgery (baseline))
- Attention/Executive Function/impulse control(3 years of age)
- Adaptive behaviour(3 years of age)
- incidence of intra-operative bradycardia(150 minutes- duration of surgery (baseline))
- Executive Function(3 years of age)