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

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.

Conditions

• Anesthesia
• Neurotoxicity
• Child Development

Interventions

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.

DRUG

Remifentanil

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

DRUG

Dexmedetomidine

Experimental arm: loading dose:1mcg/kg, infusion: 1 mcg/kg/hr.

Sponsors & Collaborators

• Sydney Children's Hospitals Network

  collaborator OTHER

• Baylor College of Medicine

  collaborator OTHER

• Boston Children's Hospital

  collaborator OTHER

• The Cleveland Clinic

  collaborator OTHER

• University of Texas, Southwestern Medical Center at Dallas

  collaborator OTHER

• Royal Children's Hospital

  collaborator OTHER

• Children's Hospital of Philadelphia

  collaborator OTHER

• Queensland Children's Hospital

  collaborator OTHER_GOV

• Perth Children's Hospital

  collaborator UNKNOWN

• Women and Children's Hospital

  collaborator UNKNOWN

• Istituto Giannina Gaslini

  collaborator OTHER

• Flinders Medical Centre

  collaborator OTHER_GOV

• Murdoch Childrens Research Institute

  lead OTHER

Principal Investigators

• Andrew J Davidson, MD · Royal Children's Hospital

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

SINGLE

Model

PARALLEL

Eligibility

Max Age

2 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2017-08-10

Primary Completion

2026-03-31

Completion

2026-06-30

FDA Drug

Yes

Countries

• United States
• Australia
• Italy
• Spain

Study Locations