En studie for å sammenligne de langsiktige resultatene etter to forskjellige anestesimidler (TREX)
Nevroutviklingsresultat etter standarddose sevofluran versus lavdose sevofluran/dexmedetomidin/remifentanil anestesi hos små barn - TREX-studien
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.
Studieoversikt
Status
Forhold
Intervensjon / Behandling
Studietype
Registrering (Faktiske)
Fase
- Fase 3
Kontakter og plasseringer
Studiesteder
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New South Wales
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Randwick, New South Wales, Australia, 2031
- Sydney Children's Hospital
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Westmead, New South Wales, Australia, 2145
- Children's Hospital at Westmead
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Queensland
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Brisbane, Queensland, Australia, 4101
- Queensland Children's Hospital
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South Australia
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Adelaide, South Australia, Australia, 5006
- Women's and Children's Hospital
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Bedford Park, South Australia, Australia, 5042
- Flinders Medical Centre
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Victoria
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Parkville, Victoria, Australia, 3052
- Royal Children's Hospital
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Western Australia
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Perth, Western Australia, Australia, 6008
- Perth Children's Hospital
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Massachusetts
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Boston, Massachusetts, Forente stater, 02115
- Boston Children's Hospital
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Ohio
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Cleveland, Ohio, Forente stater, 44195
- Cleveland Clinic
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Pennsylvania
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Philadelphia, Pennsylvania, Forente stater, 19104
- The Children's Hospital of Philadelphia
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Texas
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Dallas, Texas, Forente stater, 75390
- The University of Texas Southwestern Medical Center
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Houston, Texas, Forente stater, 77030
- Texas Children's Hospital
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Alessandria, Italia
- Presidio Ospedale Infantile C.Arrigo Azienda Ospedaliera
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Bologna, Italia
- Azienda ospedaliero-universitaria di Bologna
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Florence, Italia
- Azienda Ospedaliero-Universitaria Meyer
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Genova, Italia
- Istituto Giannina Gaslini
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Milan, Italia
- Vittore Buzzi Children's Hospital
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Milan, Italia
- Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico - Clinica Mangiagalli
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Pisa, Italia
- Azienda Ospedaliero Universitaria Pisana
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Roma, Italia
- Ospedale Bambino Gesù
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Madrid, Spania
- La Paz University Hospital
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Deltakelseskriterier
Kvalifikasjonskriterier
Alder som er kvalifisert for studier
Tar imot friske frivillige
Kjønn som er kvalifisert for studier
Beskrivelse
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
Studieplan
Hvordan er studiet utformet?
Designdetaljer
- Primært formål: Behandling
- Tildeling: Randomisert
- Intervensjonsmodell: Parallell tildeling
- Masking: Enkelt
Våpen og intervensjoner
Deltakergruppe / Arm |
Intervensjon / Behandling |
|---|---|
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Eksperimentell: 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. |
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.
Andre navn:
Experimental arm: loading dose: 1 mcg/kg, infusion starting at 0.1 mcg/kg/min or greater.
Andre navn:
Experimental arm: loading dose:1mcg/kg, infusion: 1 mcg/kg/hr.
Andre navn:
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Aktiv komparator: Sevoflurane
End tidal concentration of 2.5-3.0% or greater. |
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.
Andre navn:
|
Hva måler studien?
Primære resultatmål
Resultatmål |
Tiltaksbeskrivelse |
Tidsramme |
|---|---|---|
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Full Scale IQ
Tidsramme: 3 years of age
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Global cognitive function as assessed by the full scale IQ score of the Wechsler Preschool and Primary School Intelligence Scale. |
3 years of age
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Sekundære resultatmål
Resultatmål |
Tiltaksbeskrivelse |
Tidsramme |
|---|---|---|
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incidence of intra-operative hypotension
Tidsramme: 150 minutes- duration of surgery (baseline)
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Blood pressure measurements will be recorded during surgery |
150 minutes- duration of surgery (baseline)
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incidence of intra-operative bradycardia
Tidsramme: 150 minutes- duration of surgery (baseline)
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Heart rate will be recorded during surgery |
150 minutes- duration of surgery (baseline)
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Post-operative pain
Tidsramme: 60 minutes- after surgery
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Pain scores will be recorded after surgery |
60 minutes- after surgery
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Time to recovery
Tidsramme: 60 minutes- after surgery
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Time of removal of airway, eye-opening and discharge from PACU will be recorded. |
60 minutes- after surgery
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Language outcomes
Tidsramme: 3 years of age
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Clinical Evaluation of Language Fundamentals- Preschool, Version 2 (CELF-P2) |
3 years of age
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Attention/Executive Function/impulse control
Tidsramme: 3 years of age
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A Developmental NEuroPSYchological Assessment- Second Edition (NEPSY-2): Statue Subtest |
3 years of age
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Memory
Tidsramme: 3 years of age
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A Developmental NEuroPSYchological Assessment- Second Edition (NEPSY-2): Narrative memory |
3 years of age
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Adaptive behaviour
Tidsramme: 3 years of age
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Adaptive Behavior Assessment System - Third Edition (ABAS-III) |
3 years of age
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Clinical Behavior
Tidsramme: 3 years of age
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Child Behavior Checklist (CBCL) |
3 years of age
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Executive Function
Tidsramme: 3 years of age
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Behavior Rating of Executive Function- Preschool (BRIEF-P) |
3 years of age
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Social Skills
Tidsramme: 3 years of age
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Social Skills Improvement System (SSIS) |
3 years of age
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Samarbeidspartnere og etterforskere
Samarbeidspartnere
Etterforskere
- Studiestol: Andrew J Davidson, MD, Royal Children's Hospital
Publikasjoner og nyttige lenker
Generelle publikasjoner
- Saynhalath R, Disma N, Taverner FJ, von Ungern-Sternberg BS, Andropoulos D, Ng AS, Shields BB, Izzo F, Lee-Archer P, McCann ME, Montagnini L, Kuppers B, Lenares E, Sheppard S, de Graaff JC, Lee KJ, Wang X, Szmuk P, Davidson AJ, Skowno JJ; TREX (Trial Remifentanil DEXmedetomidine) Consortium. Short-term Outcomes in Infants after General Anesthesia with Low-dose Sevoflurane/Dexmedetomidine/Remifentanil versus Standard-dose Sevoflurane (the TREX Trial). Anesthesiology. 2024 Dec 1;141(6):1075-1085. doi: 10.1097/ALN.0000000000005232.
- Chen DX, Tan ZM, Lin XM. General Anesthesia Exposure in Infancy and Childhood: A 10-year Bibliometric Analysis. J Perianesth Nurs. 2024 Oct;39(5):772-781. doi: 10.1016/j.jopan.2023.12.006. Epub 2024 Mar 21.
- Oltean T, Ostlund S, Rinehart J, Vandenabeele P, Kain ZN, Coeckelenbergh S. Neuronal Cell Death Modalities and Protective Mechanisms Induced By Sevoflurane: A Narrative Review. Anesth Analg. 2026 Oct 1;143(4):807-821. doi: 10.1213/ANE.0000000000008035. Epub 2026 May 6.
Studierekorddatoer
Studer hoveddatoer
Studiestart (Faktiske)
Primær fullføring (Antatt)
Studiet fullført (Antatt)
Datoer for studieregistrering
Først innsendt
Først innsendt som oppfylte QC-kriteriene
Først lagt ut (Faktiske)
Oppdateringer av studieposter
Sist oppdatering lagt ut (Faktiske)
Siste oppdatering sendt inn som oppfylte QC-kriteriene
Sist bekreftet
Mer informasjon
Begreper knyttet til denne studien
Ytterligere relevante MeSH-vilkår
- Sykdommer i nervesystemet
- Kjemisk-induserte lidelser
- Forgiftning
- Nevrotoksisitetssyndromer
- Organiske kjemikalier
- Heterocykliske forbindelser, 1-ring
- Heterocykliske forbindelser
- Ethers
- Azoler
- Hydrokarboner
- Syrer, acyklisk
- Karboksylsyrer
- Imidazoles
- Piperidines
- Hydrokarboner, halogenert
- Hydrokarboner, fluorert
- Propionater
- Metyletere
- Remifentanil
- Sevofluran
- Dexmedetomidin
Andre studie-ID-numre
- TREX TRIAL
- 2024-512385-34-00 (Ctis)
Plan for individuelle deltakerdata (IPD)
Planlegger du å dele individuelle deltakerdata (IPD)?
IPD-planbeskrivelse
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-delingstidsramme
6 months after publication of primary outcome
Tilgangskriterier for IPD-deling
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-deling Støtteinformasjonstype
- STUDY_PROTOCOL
- SEVJE
- ICF
- ANALYTIC_CODE
- CSR
Legemiddel- og utstyrsinformasjon, studiedokumenter
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