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NCT Number: NCT03089905

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

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.

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Key information

Conditions

Anesthesia Chemically-Induced Disorders Child Development Nervous System Diseases Neurotoxicity Neurotoxicity Syndromes Poisoning

Age range

Up to 2 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

Sydney Children's Hospital, Randwick, New South Wales, Australia

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Sevoflurane

Drug

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.

Other names: Sevorane

Remifentanil

Drug

Experimental arm: loading dose: 1 mcg/kg, infusion starting at 0.1 mcg/kg/min or greater.

Other names: Ultiva

Dexmedetomidine

Drug

Experimental arm: loading dose:1mcg/kg, infusion: 1 mcg/kg/hr.

Other names: Precedex, Dexmedetomidine Ever Pharma

Primary outcomes

  1. 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

  1. incidence of intra-operative hypotension

    Time frame: 150 minutes- duration of surgery (baseline)

    Blood pressure measurements will be recorded during surgery

  2. incidence of intra-operative bradycardia

    Time frame: 150 minutes- duration of surgery (baseline)

    Heart rate will be recorded during surgery

  3. Post-operative pain

    Time frame: 60 minutes- after surgery

    Pain scores will be recorded after surgery

  4. Time to recovery

    Time frame: 60 minutes- after surgery

    Time of removal of airway, eye-opening and discharge from PACU will be recorded.

  5. Language outcomes

    Time frame: 3 years of age

    Clinical Evaluation of Language Fundamentals- Preschool, Version 2 (CELF-P2)

  6. Attention/Executive Function/impulse control

    Time frame: 3 years of age

    A Developmental NEuroPSYchological Assessment- Second Edition (NEPSY-2): Statue Subtest

  7. Memory

    Time frame: 3 years of age

    A Developmental NEuroPSYchological Assessment- Second Edition (NEPSY-2): Narrative memory

  8. Adaptive behaviour

    Time frame: 3 years of age

    Adaptive Behavior Assessment System - Third Edition (ABAS-III)

  9. Clinical Behavior

    Time frame: 3 years of age

    Child Behavior Checklist (CBCL)

  10. Executive Function

    Time frame: 3 years of age

    Behavior Rating of Executive Function- Preschool (BRIEF-P)

  11. Social Skills

    Time frame: 3 years of age

    Social Skills Improvement System (SSIS)

Sponsors and collaborators

Lead sponsor

Murdoch Childrens Research Institute

Other

Collaborators

  • Baylor College of Medicine
  • Boston Children's Hospital
  • Children's Hospital of Philadelphia
  • Flinders Medical Centre
  • Istituto Giannina Gaslini
  • Perth Children's Hospital
  • Queensland Children's Hospital
  • Royal Children's Hospital
  • Sydney Children's Hospitals Network
  • The Cleveland Clinic
  • University of Texas, Southwestern Medical Center at Dallas
  • Women and Children's Hospital

Registry information

Official study title

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

Acronym: TREX

Important dates

Study start
2017
Primary completion
2026
Study completion
2026
First posted
Mar 24, 2017
Registry last updated
Aug 1, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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