A Study to Compare the Long-term Outcomes After Two Different Anaesthetics
TREX
Neurodevelopmental Outcome After Standard Dose Sevoflurane Versus Low-dose Sevoflurane/Dexmedetomidine/Remifentanil Anaesthesia in Young Children- The TREX Trial
2 other identifiers
interventional
450
4 countries
21
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P50-P75 for phase_3
Started Aug 2017
Longer than P75 for phase_3
21 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
March 8, 2017
CompletedFirst Posted
Study publicly available on registry
March 24, 2017
CompletedStudy Start
First participant enrolled
August 10, 2017
CompletedPrimary Completion
Last participant's last visit for primary outcome
March 1, 2026
CompletedStudy Completion
Last participant's last visit for all outcomes
June 1, 2026
ExpectedAugust 1, 2025
July 1, 2025
8.6 years
March 8, 2017
July 30, 2025
Conditions
Outcome Measures
Primary Outcomes (1)
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 Outcomes (11)
incidence of intra-operative hypotension
150 minutes- duration of surgery (baseline)
incidence of intra-operative bradycardia
150 minutes- duration of surgery (baseline)
Post-operative pain
60 minutes- after surgery
Time to recovery
60 minutes- after surgery
Language outcomes
3 years of age
- +6 more secondary outcomes
Study Arms (2)
Sevoflurane/dexmedetomidine/remifentanil
EXPERIMENTALDexmedetomidine: 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
ACTIVE COMPARATOREnd tidal concentration of 2.5-3.0% or greater.
Interventions
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.
Experimental arm: loading dose: 1 mcg/kg, infusion starting at 0.1 mcg/kg/min or greater.
Experimental arm: loading dose:1mcg/kg, infusion: 1 mcg/kg/hr.
Eligibility Criteria
You may qualify if:
- 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.
You may not qualify if:
- 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
- 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
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- Murdoch Childrens Research Institutelead
- Sydney Children's Hospitals Networkcollaborator
- Baylor College of Medicinecollaborator
- Boston Children's Hospitalcollaborator
- The Cleveland Cliniccollaborator
- University of Texas, Southwestern Medical Center at Dallascollaborator
- Royal Children's Hospitalcollaborator
- Children's Hospital of Philadelphiacollaborator
- Queensland Children's Hospitalcollaborator
- Perth Children's Hospitalcollaborator
- Women and Children's Hospitalcollaborator
- Istituto Giannina Gaslinicollaborator
- Flinders Medical Centrecollaborator
Study Sites (21)
Boston Children's Hospital
Boston, Massachusetts, 02115, United States
Cleveland Clinic
Cleveland, Ohio, 44195, United States
The Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, 19104, United States
The University of Texas Southwestern Medical Center
Dallas, Texas, 75390, United States
Texas Children's Hospital
Houston, Texas, 77030, United States
Sydney Children's Hospital
Randwick, New South Wales, 2031, Australia
Children's Hospital at Westmead
Westmead, New South Wales, 2145, Australia
Queensland Children's Hospital
Brisbane, Queensland, 4101, Australia
Women's and Children's Hospital
Adelaide, South Australia, 5006, Australia
Flinders Medical Centre
Bedford Park, South Australia, 5042, Australia
Royal Children's Hospital
Parkville, Victoria, 3052, Australia
Perth Children's Hospital
Perth, Western Australia, 6008, Australia
Presidio Ospedale Infantile C.Arrigo Azienda Ospedaliera
Alessandria, Italy
Azienda ospedaliero-universitaria di Bologna
Bologna, Italy
Azienda Ospedaliero-Universitaria Meyer
Florence, Italy
Istituto Giannina Gaslini
Genova, Italy
Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico - Clinica Mangiagalli
Milan, Italy
Vittore Buzzi Children's Hospital
Milan, Italy
Azienda Ospedaliero Universitaria Pisana
Pisa, Italy
Ospedale Bambino Gesù
Roma, Italy
La Paz University Hospital
Madrid, Spain
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- STUDY CHAIR
Andrew J Davidson, MD
Royal Children's Hospital
Study Design
- Study Type
- interventional
- Phase
- phase 3
- Allocation
- RANDOMIZED
- Masking
- SINGLE
- Who Masked
- OUTCOMES ASSESSOR
- Masking Details
- 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.
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- OTHER
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
March 8, 2017
First Posted
March 24, 2017
Study Start
August 10, 2017
Primary Completion
March 1, 2026
Study Completion (Estimated)
June 1, 2026
Last Updated
August 1, 2025
Record last verified: 2025-07
Data Sharing
- IPD Sharing
- Will share
- Shared Documents
- STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
- Time Frame
- 6 months after publication of primary outcome
- Access Criteria
- Prior to releasing any data the following are required: a data access agreement must be signed between relevant parties, the TREX Trial Steering Committee must see and approve the analysis plan describing how the data will be analysed, there must be an agreement around appropriate acknowledgement and any additional costs involved must be covered. Data will only be shared with a recognised research institution which has approved the proposed analysis plan.
The de-identified data set collected for this analysis of the TREX trial will be available six months after publication of the primary outcome. The study protocol, analysis plan and consent forms will also be available. The data may be obtained from the Murdoch Children's Research Institute by emailing andrew.davidson@rch.org.au.