Genetic Differences in Propofol Pharmacodynamics in Children

NCT ID: NCT04164264

Last Updated: 2024-04-22

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 360 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-03-11
• Study Completion Date: 2024-12-31

Brief Summary

Propofol is an extensively utilized intravenous sedative and general anesthetic. However, propofol has a narrow therapeutic index, and this means that there is only a small difference in the dose required to produce loss of consciousness and the dose required to produce potentially life-threatening effects such as loss of protective airway reflexes and cessation of spontaneous breathing. Moreover, there is substantial variation between individuals in the doses required to achieve these pharmacodynamic endpoints.

Given the inexorable rise in demand for pediatric sedation and the increasing use of propofol in sedation protocols by non-anaesthesiologists, the purpose of this study is to refine the propofol dosing recommendations to account for pharmacogenomic variability to make procedural sedation safer for children. Experienced users already adjust for age and body weight. This study may enable further refinements according to sex and - novelly - ancestry.

Detailed Description

Hypothesis:

The investigators hypothesize that examination of genome-wide association study (GWAS) findings will enable the investigators to provide pharmacogenomic insights into clinically observed - and, with this study, quantified - differences in propofol requirements for loss of consciousness (LOC) and apnea in children. It is further hypothesized that the distribution of allelic variants in these pharmacogenes may differ between children of different genomic ancestry.

Objectives:

Primary: (i) To describe and quantify doses of propofol required to produce loss of consciousness and apnea in children of differing ages, sex and self-identified countries of origin. (ii) To identify genomic associations that may explain variability, and generate hypotheses for further study. (iii) To identify genomic ancestry and examine how pharmacogene allele variants that may explain the findings of (i) above are distributed across genomic ancestries.

Secondary: To examine the correlation between self-identified countries of family origin and genomic ancestry.

Methods:

Prospective, non-randomized, single cohort study of two pharmacodynamic endpoints (loss of consciousness and apnea), in children requiring propofol anesthesia, with subsequent genome-wide association study (GWAS) and principal component analysis (PCA) to examine, respectively, pharmacogenomic explanations for pharmacodynamic variability and genomic ancestry.

Conditions

Anesthesia

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: SUPPORTIVE_CARE
• Blinding Strategy: NONE

Study Groups

Intravenous Propofol Infusion

Quantification of the dose of propofol required to produce loss of consciousness and apnea.

Group Type: EXPERIMENTAL

Propofol

Intervention Type: DRUG

At T0, a propofol infusion at a rate of 1.5 mg/kg/min will be started until apnea is achieved. Loss of consciousness will be defined clinically using loss of eyelash reflex (TLOER) and tolerance of nasal cannulae (TNC), tested every 10 sec., and by a BIS \<60 for 30 sec. (TBIS). Apnea will be defined as absence of end-tidal CO2 for at least 20 seconds (TAPNEA). A saliva sample with be taken under anesthesia for genome-wide association study and principal component analysis.

Interventions

Propofol

At T0, a propofol infusion at a rate of 1.5 mg/kg/min will be started until apnea is achieved. Loss of consciousness will be defined clinically using loss of eyelash reflex (TLOER) and tolerance of nasal cannulae (TNC), tested every 10 sec., and by a BIS \<60 for 30 sec. (TBIS). Apnea will be defined as absence of end-tidal CO2 for at least 20 seconds (TAPNEA). A saliva sample with be taken under anesthesia for genome-wide association study and principal component analysis.

Intervention Type: DRUG

Other Intervention Names

Propofol Injection 1%

Eligibility Criteria

Inclusion Criteria

• Age ≥ 3 to ≤ 18
• ASA physical status classification I-III
• Intravenous induction resulting in apnea clinically appropriate and indicated

Exclusion Criteria

• Age < 3 or >18
• ASA physical status IV-V
• Propofol induction to apnea not indicated or feasible
• Sedative premedication
• Severe neurological impairment, expected to reduce propofol requirement as judged by the clinical experience of the anaesthetist
• Weight <3%ile or >97%ile for age

• Minimum Eligible Age: 3 Years
• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

BC Children's Hospital Research Institute

OTHER

Sponsor Role: collaborator

University of British Columbia

OTHER

Sponsor Role: lead

Responsible Party

Simon Whyte

Staff Anesthesiologist

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Simon Whyte, MBBS, FRCA

Role: PRINCIPAL_INVESTIGATOR

BC Children's Hospital, Department of Anesthesia

Locations

BC Children's Hospital - Department of Anesthesia

Vancouver, British Columbia, Canada

Countries

Canada

References

Moxham L, Golam A, West NC, Gorges M, Whyte SD. Pharmacodynamic Safety Endpoints for Propofol Anesthesia in Children by Age and Sex: A Multicohort Observational Study. Paediatr Anaesth. 2025 Aug 11. doi: 10.1111/pan.70031. Online ahead of print.

Reference Type: DERIVED

PMID: 40788031 (View on PubMed)

Related Links

http://bcchr.ca/PART

Pediatric Anesthesia Research Team website

Other Identifiers

H19-00188

Identifier Type: -

Identifier Source: org_study_id