Anesthetics for Child Development Outcomes

(TREX Trial)

Recruiting at 21 trial locations

Overseen By Suzette J Sheppard, Bsc (Hons)

Age: < 18

Sex: Any

Trial Phase: Phase 3

Sponsor: Murdoch Childrens Research Institute

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 2

Duration: 150 minutes

450 Participants Needed

Trial Summary

What is the purpose of this 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.

Will I have to stop taking my current medications?

The trial protocol does not specify whether participants must stop taking their current medications. However, it does mention that planned postoperative sedation with non-opioid sedatives is not allowed, which might imply some restrictions on certain medications.

What data supports the effectiveness of the drug Dexmedetomidine for child development outcomes?

Research shows that Dexmedetomidine can reduce emergence delirium (confusion and agitation after waking from anesthesia) in children when used with sevoflurane, making it effective in improving recovery after anesthesia. ^{1 2 3 4 5}

Is dexmedetomidine safe for use in children during sedation?

Dexmedetomidine is generally well-tolerated in children for sedation, but some may experience side effects like respiratory depression (slowed breathing) and hypotension (low blood pressure). Most side effects are manageable and consistent with its known safety profile. ^{2 4 6 7 8}

How is the drug combination of Dexmedetomidine, Remifentanil, and Sevoflurane unique for child development outcomes?

This drug combination is unique because it uses Dexmedetomidine and Remifentanil to potentially reduce the risk of emergence agitation (a state of confusion and restlessness after waking from anesthesia) and shorten recovery time when used with Sevoflurane in children, which is not consistently achieved with other drugs. ^{1 2 9 10 11}

Research Team

Andrew J Davidson, MD

Principal Investigator

Royal Children's Hospital

Eligibility Criteria

This trial is for children under 2 years old who are scheduled for an anesthesia expected to last at least 2 hours. They must have a guardian to consent and cannot have been born prematurely, had certain surgeries, or be planned for postoperative sedation with non-opioid agents.

Inclusion Criteria

I am under 2 years old.

I have someone who can legally consent for me if I'm unable to.

My upcoming surgery is expected to last at least 2 hours under anesthesia.

Exclusion Criteria

I have a condition linked to poor brain function outcomes.

I have no health issues that prevent me from following the study's procedures.

My household speaks a language not supported by the Wechsler test.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Children are randomized to receive either a low dose sevoflurane/remifentanil/dexmedetomidine or standard dose sevoflurane anaesthetic during surgery expected to last 2 hours or longer

150 minutes

1 visit (in-person)

Post-operative Monitoring

Participants are monitored for post-operative pain and recovery, including blood pressure, heart rate, and time to recovery

60 minutes

1 visit (in-person)

Follow-up

Participants receive a neurodevelopmental assessment at 3 years of age to assess global cognitive function and other developmental outcomes

3 years

Treatment Details

Interventions

• Dexmedetomidine
• Remifentanil
• Sevoflurane

Trial Overview The study tests if a low dose combination of sevoflurane, remifentanil, and dexmedetomidine leads to better long-term cognitive outcomes compared to standard dose sevoflurane in young children requiring lengthy anesthesia.

Participant Groups

Group I: Sevoflurane/dexmedetomidine/remifentanil Experimental Treatment 3 Interventions

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.

Group II: Sevoflurane Active Control 1 Intervention

End tidal concentration of 2.5-3.0% or greater.

Dexmedetomidine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Precedex for:

• Sedation in intensive care settings
• Procedural sedation

Approved in United States as Precedex for:

• Sedation in intensive care settings
• Procedural sedation

Approved in Canada as Precedex for:

• Sedation in intensive care settings
• Procedural sedation

Approved in Japan as Precedex for:

• Sedation in intensive care settings
• Procedural sedation

Who Is Running the Clinical Trial?

Murdoch Childrens Research Institute

Lead Sponsor

Trials

90

Recruited

1,303,000+

Royal Children's Hospital

Collaborator

Trials

38

Recruited

232,000+

Boston Children's Hospital

Collaborator

Trials

801

Recruited

5,584,000+

The Cleveland Clinic

Collaborator

Trials

1,072

Recruited

1,377,000+

University of Texas, Southwestern Medical Center at Dallas

Collaborator

Trials

18

Recruited

21,200+

Children's Hospital of Philadelphia

Collaborator

Trials

749

Recruited

11,400,000+

Queensland Children's Hospital

Collaborator

Trials

4

Recruited

9,700+

Perth Children's Hospital

Collaborator

Trials

3

Recruited

114,000+

Women and Children's Hospital

Collaborator

Trials

1

Recruited

450+

Istituto Giannina Gaslini

Collaborator

Trials

47

Recruited

140,000+

Findings from Research

In a study involving 91 pediatric patients, dexmedetomidine was found to be a well-tolerated alternative sedative for non-intubated moderate or deep sedation, with a low incidence of serious adverse events.

While respiratory depression and hypotension were the most common treatment-emergent adverse events, they were manageable and consistent with dexmedetomidine's known safety profile, indicating its potential for safe use in children during elective procedures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase IV, Open-Label, Safety Study Evaluating the Use of Dexmedetomidine in Pediatric Patients Undergoing Procedure-Type Sedation. Jooste, EH., Hammer, GB., Reyes, CR., et al.[2020]

References

1. United States pubmed.ncbi.nlm.nih.gov

Effects of Pharmacological Intervention on Recovery After Sevoflurane Anesthesia in Children: a Network Meta-analysis of Randomized Controlled Trials. [2023]

2. France pubmed.ncbi.nlm.nih.gov

Postoperative recovery in preschool-aged children: A secondary analysis of a randomized controlled trial comparing premedication with midazolam, clonidine, and dexmedetomidine. [2023]

3. Italy pubmed.ncbi.nlm.nih.gov

Influence of dexmedetomidine to cognitive function during recovery period for children with general anesthesia. [2022]

4. France pubmed.ncbi.nlm.nih.gov

Hemodynamic and respiratory changes following dexmedetomidine administration during general anesthesia: sevoflurane vs desflurane. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Fentanyl Versus Dexmedetomidine for the Prevention of Emergence Agitation in Children After Sevoflurane Anaesthesia: A Comparative Clinical Study. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Comparison of oral transmucosal fentanyl citrate and an oral solution of meperidine, diazepam, and atropine for premedication in children. [2019]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Routines for reducing the occurrence of emergence agitation during awakening in children, a national survey. [2021]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Phase IV, Open-Label, Safety Study Evaluating the Use of Dexmedetomidine in Pediatric Patients Undergoing Procedure-Type Sedation. [2020]

9. United States pubmed.ncbi.nlm.nih.gov

Summary of the Update Session on Clinical Neurotoxicity Studies. [2023]

10. United States pubmed.ncbi.nlm.nih.gov

Network Meta-Analysis on the Efficacy of Dexmedetomidine, Midazolam, Ketamine, Propofol, and Fentanyl for the Prevention of Sevoflurane-Related Emergence Agitation in Children. [2022]

11. United States pubmed.ncbi.nlm.nih.gov

Preventing Emergence Agitation Using Ancillary Drugs with Sevoflurane for Pediatric Anesthesia: A Network Meta-Analysis. [2021]