A Study to Compare the Long-term Outcomes After Two Different Anaesthetics (TREX)
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| ClinicalTrials.gov Identifier: NCT03089905 |
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Recruitment Status :
Recruiting
First Posted : March 24, 2017
Last Update Posted : February 9, 2023
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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 |
|---|---|---|
| Anesthesia Neurotoxicity Child Development | Drug: Sevoflurane Drug: Remifentanil Drug: Dexmedetomidine | Phase 3 |
| Study Type : | Interventional (Clinical Trial) |
| Estimated 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. |
| 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 : | August 10, 2017 |
| Estimated Primary Completion Date : | June 2023 |
| Estimated Study Completion Date : | June 2026 |
| Arm | Intervention/treatment |
|---|---|
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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 Name: Sevorane Drug: Remifentanil Experimental arm: loading dose: 1 mcg/kg, infusion starting at 0.1 mcg/kg/min or greater.
Other Name: Ultiva Drug: Dexmedetomidine Experimental arm: loading dose:1mcg/kg, infusion: 1 mcg/kg/hr.
Other Names:
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Active Comparator: Sevoflurane
End tidal concentration of 2.5-3.0% or greater.
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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 Name: Sevorane |
- 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.
- incidence of intra-operative hypotension [ Time Frame: 150 minutes- duration of surgery (baseline) ]Blood pressure measurements will be recorded during surgery
- incidence of intra-operative bradycardia [ Time Frame: 150 minutes- duration of surgery (baseline) ]Heart rate will be recorded during surgery
- Post-operative pain [ Time Frame: 60 minutes- after surgery ]Pain scores will be recorded after surgery
- Time to recovery [ Time Frame: 60 minutes- after surgery ]Time of removal of airway, eye-opening and discharge from PACU will be recorded.
- Language outcomes [ Time Frame: 3 years of age ]Clinical Evaluation of Language Fundamentals- Preschool, Version 2 (CELF-P2)
- Attention/Executive Function/impulse control [ Time Frame: 3 years of age ]A Developmental NEuroPSYchological Assessment- Second Edition (NEPSY-2): Statue Subtest
- Memory [ Time Frame: 3 years of age ]A Developmental NEuroPSYchological Assessment- Second Edition (NEPSY-2): Narrative memory
- Adaptive behaviour [ Time Frame: 3 years of age ]Adaptive Behavior Assessment System - Third Edition (ABAS-III)
- Clinical Behavior [ Time Frame: 3 years of age ]Child Behavior Checklist (CBCL)
- Executive Function [ Time Frame: 3 years of age ]Behavior Rating of Executive Function- Preschool (BRIEF-P)
- Social Skills [ Time Frame: 3 years of age ]Social Skills Improvement System (SSIS)
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| Ages Eligible for Study: | up to 2 Years (Child) |
| 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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03089905
| Contact: Andrew J Davidson, MD | +61393455233 | andrew.davidson@rch.org.au | |
| Contact: Suzette J Sheppard, Bsc (Hons) | +61393454901 | suzette.sheppard@mcri.edu.au |
Show 21 study locations
| Study Chair: | Andrew J Davidson, MD | Royal Children's Hospital, Melbourne |
| Responsible Party: | Murdoch Childrens Research Institute |
| ClinicalTrials.gov Identifier: | NCT03089905 |
| Other Study ID Numbers: |
TREX TRIAL |
| First Posted: | March 24, 2017 Key Record Dates |
| Last Update Posted: | February 9, 2023 |
| Last Verified: | February 2023 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| 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. |
| Supporting Materials: |
Study Protocol Statistical Analysis Plan (SAP) Informed Consent Form (ICF) Clinical Study Report (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. |
| 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 |
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Neurotoxicity Syndromes Nervous System Diseases Poisoning Chemically-Induced Disorders Dexmedetomidine Remifentanil Sevoflurane Hypnotics and Sedatives Central Nervous System Depressants Physiological Effects of Drugs Analgesics, Non-Narcotic Analgesics Sensory System Agents |
Peripheral Nervous System Agents Adrenergic alpha-2 Receptor Agonists Adrenergic alpha-Agonists Adrenergic Agonists Adrenergic Agents Neurotransmitter Agents Molecular Mechanisms of Pharmacological Action Analgesics, Opioid Narcotics Platelet Aggregation Inhibitors Anesthetics, Inhalation Anesthetics, General Anesthetics |