Genetic Differences in Propofol Pharmacodynamics in Children

Genetic Differences in Pharmacodynamic Safety Endpoints With Propofol Anaesthesia in Children

Patrocinadores

Patrocinador principal: University of British Columbia

Colaborador: BC Children's Hospital Research Institute

Fuente University of British Columbia
Resumen breve

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.

Descripción detallada

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.

Estado general Recruiting
Fecha de inicio March 11, 2020
Fecha de Terminación December 2022
Fecha de finalización primaria November 2022
Fase Phase 4
Tipo de estudio Interventional
Resultado primario
Medida Periodo de tiempo
Dose of propofol required to produce loss of consciousness 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 expected to occur within 10 min after commencing the induction infusion.
Resultado secundario
Medida Periodo de tiempo
Self-identified countries of family origin up to 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. Saliva sample collected immediately after apnea, within 10min of propofol infusion start. Genomic analysis will be performed post-hoc.
Inscripción 360
Condición
Intervención

Tipo de intervención: Drug

Nombre de intervención: Propofol

Descripción: 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.

Etiqueta de grupo de brazo: Intravenous Propofol Infusion

Otro nombre: Propofol Injection 1%

Elegibilidad

Criterios:

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

Género: All

Edad mínima: 3 Years

Edad máxima: 18 Years

Voluntarios Saludables: No

Oficial general
Apellido Papel Afiliación
Simon Whyte, MBBS, FRCA Principal Investigator BC Children's Hospital, Department of Anesthesia
Contacto general

Apellido: Andrew Poznikoff, BSc

Teléfono: 604-875-2000

Teléfono Ext.: 1989

Email: [email protected]

Ubicación
Instalaciones: Estado: Contacto: Investigador: BC Children's Hospital - Department of Anesthesia Andrew Poznikoff, BSc 604-875-2000 1989 [email protected] Simon Whyte, MD Principal Investigator Bruce Carleton, PharmD Sub-Investigator Sem Lampotang, PhD Sub-Investigator Matthias Gorges, PhD Sub-Investigator Andrew Poznikoff, BSc Sub-Investigator
Ubicacion Paises

Canada

Fecha de verificación

July 2020

Fiesta responsable

Tipo: Principal Investigator

Afiliación del investigador: University of British Columbia

Nombre completo del investigador: Simon Whyte

Título del investigador: Staff Anesthesiologist

Palabras clave
Tiene acceso ampliado No
Número de brazos 1
Grupo de brazo

Etiqueta: Intravenous Propofol Infusion

Tipo: Experimental

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

Datos del paciente No
Información de diseño del estudio

Asignación: N/A

Modelo de intervención: Single Group Assignment

Propósito primario: Supportive Care

Enmascaramiento: None (Open Label)

Fuente: ClinicalTrials.gov