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

Sponsor
Murdoch Childrens Research Institute (Other)
Overall Status
Recruiting
CT.gov ID
NCT03089905
Collaborator
Sydney Children's Hospitals Network (Other), Baylor College of Medicine (Other), Boston Children's Hospital (Other), The Cleveland Clinic (Other), University of Texas, Southwestern Medical Center at Dallas (Other), Royal Children's Hospital, Melbourne (Other), Children's Hospital of Philadelphia (Other), Queensland Children's Hospital (Other), Perth Children's Hospital (Other), Women's and Children's Hospital, Adelaide (Other), Istituto Giannina Gaslini, Genoa, Italy (Other), Flinders Medical Centre (Other)
450
Enrollment
20
Locations
2
Arms
99.7
Anticipated Duration (Months)
22.5
Patients Per Site
0.2
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 3

Study Design

Study Type:
Interventional
Anticipated Enrollment :
450 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Intervention Model Description:
Participants will be randomised to receive either low-dose sevoflurane/dexmedetomidine/remifentanil OR standard dose sevoflurane anaesthesia.Participants will be randomised to receive either low-dose sevoflurane/dexmedetomidine/remifentanil OR standard dose sevoflurane anaesthesia.
Masking:
Single (Outcomes Assessor)
Masking Description:
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.
Primary Purpose:
Treatment
Official Title:
Neurodevelopmental Outcome After Standard Dose Sevoflurane Versus Low-dose Sevoflurane/Dexmedetomidine/Remifentanil Anaesthesia in Young Children- The TREX Trial
Actual Study Start Date :
Aug 10, 2017
Anticipated Primary Completion Date :
Dec 1, 2022
Anticipated Study Completion Date :
Dec 1, 2025

Arms and Interventions

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

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Full Scale IQ [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 Outcome Measures

    1. incidence of intra-operative hypotension [150 minutes- duration of surgery (baseline)]

      Blood pressure measurements will be recorded during surgery

    2. incidence of intra-operative bradycardia [150 minutes- duration of surgery (baseline)]

      Heart rate will be recorded during surgery

    3. Post-operative pain [60 minutes- after surgery]

      Pain scores will be recorded after surgery

    4. Time to recovery [60 minutes- after surgery]

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

    5. Language outcomes [3 years of age]

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

    6. Attention/Executive Function/impulse control [3 years of age]

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

    7. Memory [3 years of age]

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

    8. Adaptive behaviour [3 years of age]

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

    9. Clinical Behavior [3 years of age]

      Child Behavior Checklist (CBCL)

    10. Executive Function [3 years of age]

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

    11. Social Skills [3 years of age]

      Social Skills Improvement System (SSIS)

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    N/A to 2 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Boston Children's Hospital Boston Massachusetts United States 02115
    2 Cleveland Clinic Cleveland Ohio United States 44195
    3 The Children's Hospital of Philadelphia Philadelphia Pennsylvania United States 19104
    4 The University of Texas Southwestern Medical Center Dallas Texas United States 75390
    5 Texas Children's Hospital Houston Texas United States 77030
    6 Sydney Children's Hospital Randwick New South Wales Australia 2031
    7 Children's Hospital at Westmead Westmead New South Wales Australia 2145
    8 Queensland Children's Hospital Brisbane Queensland Australia 4101
    9 Women's and Children's Hospital Adelaide South Australia Australia 5006
    10 Flinders Medical Centre Bedford Park South Australia Australia 5042
    11 Royal Children's Hospital Parkville Victoria Australia 3052
    12 Perth Children's Hospital Perth Western Australia Australia 6008
    13 Presidio Ospedale Infantile C.Arrigo Azienda Ospedaliera Alessandria Italy
    14 Azienda ospedaliero-universitaria di Bologna Bologna Italy
    15 Azienda Ospedaliero-Universitaria Meyer Firenze Italy
    16 Istituto Giannina Gaslini Genova Italy
    17 Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico - Clinica Mangiagalli Milano Italy
    18 Vittore Buzzi Children's Hospital Milano Italy
    19 Azienda Ospedaliero Universitaria Pisana Pisa Italy
    20 Ospedale Bambino Gesù Roma Italy

    Sponsors and Collaborators

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

    Investigators

    • Study Chair: Andrew J Davidson, MD, Royal Children's Hospital, Melbourne

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Murdoch Childrens Research Institute
    ClinicalTrials.gov Identifier:
    NCT03089905
    Other Study ID Numbers:
    • TREX TRIAL
    First Posted:
    Mar 24, 2017
    Last Update Posted:
    Mar 2, 2022
    Last Verified:
    Feb 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    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
    Additional relevant MeSH terms:
    Neurotoxicity Syndromes
    Dexmedetomidine
    Remifentanil
    Sevoflurane

    Study Results

    No Results Posted as of Mar 2, 2022