Genetic Differences in Propofol Pharmacodynamics in Children

Genetic Differences in Pharmacodynamic Safety Endpoints With Propofol Anaesthesia in Children

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Anesthesia
• Intervention / Treatment: Drug: Propofol

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.

• Study Type: Interventional
• Enrollment (Actual): 360
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3V4
      • BC Children's Hospital - Department of Anesthesia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Intravenous Propofol Infusion; Quantification of the dose of propofol required to produce loss of consciousness and apnea.

Drug: 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.; Other Names: Propofol Injection 1%

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose of propofol required to produce loss of consciousness	Loss of consciousness will be defined clinically when there is a loss of eyelash reflex, a tolerance of nasal cannulae, and when the Bispectral Index <60 for 30 sec.	Loss of consciousness will be expected to occur somewhere between 120-180 seconds after commencing the induction infusion.
Dose of propofol required to produce apnea	Apnea will be defined as absence of end-tidal CO2 for at least 20 seconds.	Apnea will be expected to occur within 10 min after commencing the induction infusion.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Self-identified countries of family origin up to grandparents	The participant will report the countries which make up the participant's ancestral background, up to the country of origin of the grandparents.	Within 10 minutes after consent to participate.
A genotyped/imputed dataset of 8 million genetic variants aggregated using SHAPEIT (v2), IMPUTE2 (v2.3.2), Phase 3 1000 Genomes Project reference panel, SNP2HLA (v1.0.2), and the Type 1 Diabetes Genetics Consortium reference panel.	Extensive genome-wide genotyping to determine genetic variants of the pathways involved in propofol biotransformation. The array captures both common and rare variation collected from large-scale sequencing projects.	Saliva sample collected immediately after apnea, within 10min of propofol infusion start. Genomic analysis will be performed post-hoc.

Collaborators and Investigators

• Sponsor: University of British Columbia
• Collaborators: BC Children's Hospital Research Institute
• Investigators: Principal Investigator: Simon Whyte, MBBS, FRCA, BC Children's Hospital, Department of Anesthesia

Publications and helpful links

Helpful Links

• Pediatric Anesthesia Research Team website

Study record dates

Study Major Dates

• Study Start (Actual): March 11, 2020
• Primary Completion (Actual): October 26, 2023
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: November 6, 2019
• First Submitted That Met QC Criteria: November 12, 2019
• First Posted (Actual): November 15, 2019

Study Record Updates

• Last Update Posted (Estimated): April 22, 2024
• Last Update Submitted That Met QC Criteria: April 19, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Propofol
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Central Nervous System Depressants; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Hypnotics and Sedatives; Propofol
• Other Study ID Numbers: H19-00188

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes