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

Status:	Recruiting
Conditions:	Hospital, Neurology
Therapuetic Areas:	Neurology, Other
Healthy:	No
Age Range:	Any - 2
Updated:	2/6/2019
Start Date:	August 10, 2017
End Date:	April 2022
Contact:	Andrew J Davidson, MD
Email:	andrew.davidson@rch.org.au
Phone:	+61393455233

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

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.

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

We found this trial at

sites

Children's Hospital of Philadelphia

South 34th Street
Philadelphia, Pennsylvania 19104

215-590-1000