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Pharmacodynamic Safety Endpoints for Propofol Anesthesia in Children by Age and Sex: A Multicohort Observational
Lindy Moxham1,2, Aanisah Golam3, Nicholas C West2,3
1Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Insights
This study found that propofol doses for loss of eyelash reflex (LOER) were similar across pediatric age and sex. However, apnea occurred at lower doses in older children and males, indicating a narrower therapeutic index in these groups.
Area of Science:
- Pediatric Anesthesiology
- Pharmacology
- Clinical Trial Research
Background:
- Propofol is a widely used anesthetic with a narrow therapeutic index, posing risks due to dose variability, especially in children.
- Understanding propofol dosing in pediatric populations is crucial for enhancing anesthetic safety and efficacy.
Purpose of the Study:
- To determine the precise propofol doses needed for inducing loss of consciousness and apnea in children, stratified by age and sex.
- To inform the development of tailored propofol dosing guidelines for pediatric anesthesia.
Main Methods:
- A stratified and purposive sampling study enrolled children aged 3-18 years, grouped by sex and age (3-5, 6-10, 11-18 years), with a target of 60 per group.
- Propofol was administered at a constant rate until apnea (20s absence of end-tidal CO2) or a maximum dose of 10 mg/kg was reached.
- Key pharmacodynamic endpoints, including loss of eyelash reflex (LOER) and apnea, were measured to assess the effects of sex and age on propofol dosage.
Main Results:
- Data from 318 children (162 female, median age 8.1 years) were analyzed.
- The mean propofol dose for LOER was 2.65 mg/kg, with no significant influence of sex or age.
- The mean propofol dose for apnea was 6.82 mg/kg, significantly affected by sex (higher in males) and age (lower in older children).
Conclusions:
- Older children and females demonstrated a narrower therapeutic index between LOER and apnea, necessitating increased vigilance during anesthesia.
- These findings highlight the need for careful propofol titration in specific pediatric subgroups to maintain respiratory function.
- Future research, including genome-wide association studies, may elucidate pharmacogenetic factors influencing propofol response in children.
Background:
Propofol is a commonly used intravenous sedative and general anesthetic, with rapid onset and short duration of action. It has a narrow therapeutic index and significant interindividual variability in dosing requirements, which may elevate risks of its use, particularly in children.
Aims:
We aimed to quantify the doses required to induce loss of consciousness and apnea in children by age and sex to contribute to tailored propofol dosing recommendations for improved safety and efficacy in pediatric anesthesia.
Methods:
In this stratified- and purposive-sampling study, we enrolled children in six groups based on sex and age (3- to 5-year-olds, 6- to 10-year-olds, 11- to 18-year-olds), targeting 60 participants per group. For induction of anesthesia, we administered propofol at a constant rate until apnea was reached (absence of end-tidal CO2 for 20 s) up to a maximum dose of 10 mg/kg. We measured the propofol dose required to reach pharmacodynamic endpoints, including loss of eyelash reflex (LOER) and apnea, and estimated the effect of sex and age on these doses.
Results:
Data were available for 318 participants, with 162 females and a median (interquartile range) age of 8.1 (5.3-12.9) years. The mean (SD) propofol dose to LOER was 2.65 (0.69) mg/kg with no effect of sex (-0.10 mg/kg for male, 95% confidence interval (CI) -0.26 to 0.05, p = 0.183) or age (0.0 mg/kg per year, 95% CI -0.02 to 0.02, p = 0.876). The mean (SD) propofol dose to apnea was 6.82 (1.64) mg/kg, with significant effects of both sex (+0.67 mg/kg for male, 95% CI 0.30 to 1.03, p < 0.001) and age (-0.14 mg/kg per year, 95% CI -0.19 to -0.1, p < 0.001). Apnea was not reached in 62 participants.
Conclusions:
Older and female children exhibited narrower therapeutic indices for the margin between LOER and apnea. This requires heightened vigilance, especially when maintaining spontaneous respiration. A planned genome-wide association study may identify pharmacogenetic-pharmacodynamic relationships and correlations with genetic ancestry.
Trial Registration:
The trial was registered on clinicaltrials.gov before enrolment (NCT04164264; date of registration 2019-11-15).
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