Clinical trial NCT03089905: A Study to Compare the Long-term Outcomes After Two Different Anaesthetics
Official title: Neurodevelopmental Outcome After Standard Dose Sevoflurane Versus Low-dose Sevoflurane/Dexmedetomidine/Remifentanil Anaesthesia in Young Children- The TREX Trial
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Anesthesia
Neurotoxicity
Child Development
Lead sponsor: Murdoch Childrens Research Institute
Sponsor class: OTHER
Collaborators: name: Sydney Children's Hospitals Network
name: Baylor College of Medicine
name: Boston Children's Hospital
name: The Cleveland Clinic
name: University of Texas, Southwestern Medical Center at Dallas
name: Royal Children's Hospital
name: Children's Hospital of Philadelphia
name: Queensland Children's Hospital
name: Perth Children's Hospital
name: Women and Children's Hospital
name: Istituto Giannina Gaslini
name: Flinders Medical Centre
First posted: 2017-03-24
Enrollment: 450
Sex: ALL
Maximum age (years): 2
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Participants will be randomised to receive either low-dose sevoflurane/dexmedetomidine/remifentanil OR standard dose sevoflurane anaesthesia.
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Full Scale IQ
timeFrame: 3 years of age
Secondary outcomes:
measure: incidence of intra-operative hypotension
timeFrame: 150 minutes- duration of surgery (baseline)
measure: incidence of intra-operative bradycardia
timeFrame: 150 minutes- duration of surgery (baseline)
measure: Post-operative pain
timeFrame: 60 minutes- after surgery
measure: Time to recovery
timeFrame: 60 minutes- after surgery
measure: Language outcomes
timeFrame: 3 years of age
measure: Attention/Executive Function/impulse control
timeFrame: 3 years of age
measure: Memory
timeFrame: 3 years of age
measure: Adaptive behaviour
timeFrame: 3 years of age
measure: Clinical Behavior
timeFrame: 3 years of age
measure: Executive Function
timeFrame: 3 years of age
measure: Social Skills
timeFrame: 3 years of age
Other outcomes:
Locations:
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Philadelphia
country: United States
facility: The Children's Hospital of Philadelphia
state: Pennsylvania
city: Dallas
country: United States
facility: The University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Randwick
country: Australia
facility: Sydney Children's Hospital
state: New South Wales
city: Westmead
country: Australia
facility: Children's Hospital at Westmead
state: New South Wales
city: Brisbane
country: Australia
facility: Queensland Children's Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Women's and Children's Hospital
state: South Australia
city: Bedford Park
country: Australia
facility: Flinders Medical Centre
state: South Australia
city: Parkville
country: Australia
facility: Royal Children's Hospital
state: Victoria
city: Perth
country: Australia
facility: Perth Children's Hospital
state: Western Australia
city: Alessandria
country: Italy
facility: Presidio Ospedale Infantile C.Arrigo Azienda Ospedaliera
city: Bologna
country: Italy
facility: Azienda ospedaliero-universitaria di Bologna
city: Firenze
country: Italy
facility: Azienda Ospedaliero-Universitaria Meyer
city: Genova
country: Italy
facility: Istituto Giannina Gaslini
city: Milano
country: Italy
facility: Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico - Clinica Mangiagalli
city: Milano
country: Italy
facility: Vittore Buzzi Children's Hospital
city: Pisa
country: Italy
facility: Azienda Ospedaliero Universitaria Pisana
city: Roma
country: Italy
facility: Ospedale Bambino Gesù
city: Madrid
country: Spain
facility: La Paz University Hospital
Study officials:
affiliation: Royal Children's Hospital
name: Andrew J Davidson, MD
role: STUDY_CHAIR
References: