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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Child Development; Anesthesia; Neurotoxicity
• Intervention / Treatment: Drug: Sevoflurane; Drug: Remifentanil; Drug: Dexmedetomidine

• Study Type: Interventional
• Enrollment (Actual): 450
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Randwick, New South Wales, Australia, 2031
      • Sydney Children's Hospital
    • Westmead, New South Wales, Australia, 2145
      • Children's Hospital at Westmead
  • Queensland
    • Brisbane, Queensland, Australia, 4101
      • Queensland Children's Hospital
  • South Australia
    • Adelaide, South Australia, Australia, 5006
      • Women's and Children's Hospital
    • Bedford Park, South Australia, Australia, 5042
      • Flinders Medical Centre
  • Victoria
    • Parkville, Victoria, Australia, 3052
      • Royal Children's Hospital
  • Western Australia
    • Perth, Western Australia, Australia, 6008
      • Perth Children's Hospital
• Italy
  • Alessandria, Italy
    • Presidio Ospedale Infantile C.Arrigo Azienda Ospedaliera
  • Bologna, Italy
    • Azienda Ospedaliero-Universitaria di Bologna
  • Firenze, Italy
    • Azienda Ospedaliero-Universitaria Meyer
  • Genova, Italy
    • Istituto Giannina Gaslini
  • Milano, Italy
    • Vittore Buzzi Children's Hospital
  • Milano, Italy
    • Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico - Clinica Mangiagalli
  • Pisa, Italy
    • Azienda Ospedaliero Universitaria Pisana
  • Roma, Italy
    • Ospedale Bambino Gesu
• Spain
  • Madrid, Spain
    • La Paz University Hospital
• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • The Children's Hospital of Philadelphia
  • Texas
    • Dallas, Texas, United States, 75390
      • The University of Texas Southwestern Medical Center
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 2 years (Child)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Sevoflurane; 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; Drug: Remifentanil; Experimental arm: loading dose: 1 mcg/kg, infusion starting at 0.1 mcg/kg/min or greater.; Other Names: Ultiva; Drug: Dexmedetomidine; Experimental arm: loading dose:1mcg/kg, infusion: 1 mcg/kg/hr.; Other Names: Precedex; Dexmedetomidine Ever Pharma
Active Comparator: Sevoflurane; End tidal concentration of 2.5-3.0% or greater.	Drug: Sevoflurane; 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Murdoch Childrens Research Institute
• Collaborators: Baylor College of Medicine; Children's Hospital of Philadelphia; Boston Children's Hospital; The Cleveland Clinic; Queensland Children's Hospital; Sydney Children's Hospitals Network; Perth Children's Hospital; Royal Children's Hospital; Istituto Giannina Gaslini; Flinders Medical Centre; University of Texas, Southwestern Medical Center at Dallas; Women and Children's Hospital
• Investigators: Study Chair: Andrew J Davidson, MD, Royal Children's Hospital, Melbourne

Study record dates

Study Major Dates

• Study Start (Actual): August 10, 2017
• Primary Completion (Actual): April 21, 2023
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: March 8, 2017
• First Submitted That Met QC Criteria: March 19, 2017
• First Posted (Actual): March 24, 2017

Study Record Updates

• Last Update Posted (Actual): October 12, 2023
• Last Update Submitted That Met QC Criteria: October 9, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Nervous System Diseases; Poisoning; Neurotoxicity Syndromes; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, General; Anesthetics; Analgesics, Non-Narcotic; Platelet Aggregation Inhibitors; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Analgesics, Opioid; Narcotics; Hypnotics and Sedatives; Anesthetics, Inhalation; Remifentanil; Dexmedetomidine; Sevoflurane
• Other Study ID Numbers: TREX TRIAL

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

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.

• IPD Sharing Time Frame: 6 months after publication of primary outcome
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No