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

Anesthesia Clinical Trial

— TREX  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03089905
• Other study ID #: TREX TRIAL
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: August 10, 2017
• Est. completion date: June 2026

Study information

• Verified date: October 2023
• Source: Murdoch Childrens Research Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 450
• Est. completion date: June 2026
• Est. primary completion date: April 21, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 2 Years

Eligibility

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

Related Conditions & MeSH terms

• Anesthesia
• Child Development
• Neurotoxicity
• Neurotoxicity Syndromes

Intervention

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

Locations

Country	Name	City	State
Australia	Women's and Children's Hospital	Adelaide	South Australia
Australia	Flinders Medical Centre	Bedford Park	South Australia
Australia	Queensland Children's Hospital	Brisbane	Queensland
Australia	Royal Children's Hospital	Parkville	Victoria
Australia	Perth Children's Hospital	Perth	Western Australia
Australia	Sydney Children's Hospital	Randwick	New South Wales
Australia	Children's Hospital at Westmead	Westmead	New South Wales
Italy	Presidio Ospedale Infantile C.Arrigo Azienda Ospedaliera	Alessandria
Italy	Azienda ospedaliero-universitaria di Bologna	Bologna
Italy	Azienda Ospedaliero-Universitaria Meyer	Firenze
Italy	Istituto Giannina Gaslini	Genova
Italy	Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico - Clinica Mangiagalli	Milano
Italy	Vittore Buzzi Children's Hospital	Milano
Italy	Azienda Ospedaliero Universitaria Pisana	Pisa
Italy	Ospedale Bambino Gesù	Roma
Spain	La Paz University Hospital	Madrid
United States	Boston Children's Hospital	Boston	Massachusetts
United States	Cleveland Clinic	Cleveland	Ohio
United States	The University of Texas Southwestern Medical Center	Dallas	Texas
United States	Texas Children's Hospital	Houston	Texas
United States	The Children's Hospital of Philadelphia	Philadelphia	Pennsylvania

Sponsors (13)

Lead Sponsor	Collaborator
Murdoch Childrens Research Institute	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

Countries where clinical trial is conducted

United States,  Australia,  Italy,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	incidence of intra-operative hypotension	Blood pressure measurements will be recorded during surgery	150 minutes- duration of surgery (baseline)
Secondary	incidence of intra-operative bradycardia	Heart rate will be recorded during surgery	150 minutes- duration of surgery (baseline)
Secondary	Post-operative pain	Pain scores will be recorded after surgery	60 minutes- after surgery
Secondary	Time to recovery	Time of removal of airway, eye-opening and discharge from PACU will be recorded.	60 minutes- after surgery
Secondary	Language outcomes	Clinical Evaluation of Language Fundamentals- Preschool, Version 2 (CELF-P2)	3 years of age
Secondary	Attention/Executive Function/impulse control	A Developmental NEuroPSYchological Assessment- Second Edition (NEPSY-2): Statue Subtest	3 years of age
Secondary	Memory	A Developmental NEuroPSYchological Assessment- Second Edition (NEPSY-2): Narrative memory	3 years of age
Secondary	Adaptive behaviour	Adaptive Behavior Assessment System - Third Edition (ABAS-III)	3 years of age
Secondary	Clinical Behavior	Child Behavior Checklist (CBCL)	3 years of age
Secondary	Executive Function	Behavior Rating of Executive Function- Preschool (BRIEF-P)	3 years of age
Secondary	Social Skills	Social Skills Improvement System (SSIS)	3 years of age