Pharmacodynamic Safety Endpoints for Propofol Anesthesia in Children by Age and Sex: A Multicohort Observational Study

ABSTRACT

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)

1. Introduction

The provision of sedation and anesthesia is integral to care for children undergoing painful or uncomfortable procedures, surgeries, or investigations. Propofol (2,6‐diisopropylphenol) is a widely used intravenous sedative and general anesthetic. It has a narrow therapeutic index, with only small differences in the doses required to produce loss of consciousness (LOC) and potentially life‐threatening effects, such as loss of protective airway reflexes and apnea [1]. Moreover, there is substantial interindividual variability in the doses required to achieve these pharmacodynamic endpoints [2, 3, 4]. Pharmacokinetic (PK) and pharmacodynamic (PD) factors contribute to this variability; both may be influenced by genetic variability (pharmacogenetics, PG).

Typically, children require higher weight‐adjusted doses and infusion rates of propofol than adults to maintain general anesthesia. However, “children” are not a homogeneous population; childhood is a period marked by physiological maturation, and thus, PK and PD differ significantly between children at different developmental stages [2]. These differences—for example, in body composition, weight, hepatic and renal function, and cerebral cortical effects—profoundly affect anesthetic dosing [5, 6]. For example, the intercompartmental clearance rates of propofol in a term neonate and a prepubertal child are 38% and 150% of the adult rate [7, 8]. Additional factors, such as sex and ethnicity, may impact propofol dosing [9, 10]. Our current understanding of these differences may be inadequate and has the potential to contribute to serious adverse events.

The pediatric population is at a higher risk of complications related to overly deep sedation or anesthesia [11]. Furthermore, the increasing demand for pediatric sedation has led to an expanded use of propofol by non‐anesthesia‐trained providers [12]. Given propofol's narrow therapeutic margin for safety and substantial interindividual variability in dose requirement, sedation can inadvertently become general anesthesia with life‐threatening consequences that inexperienced providers may not readily recognize or be prepared to manage [11, 13, 14].

The primary objective of this first part of our study was to quantify the doses of propofol required to achieve LOC and apnea in children of differing ages, sexes, and self‐reported ethnic backgrounds. The second part, still in progress, will include genome‐wide association data to examine the potential PG contribution of these demographic factors, which may inform future dosing recommendations.

2. Methods

2.1. Study Design and Approval

We conducted a prospective, non‐randomized, multicohort observational study. The University of British Columbia/Children's & Women's Health Centre of British Columbia Research Ethics Board granted approval (H19‐00188; date of approval 2019‐12‐09; PI Simon D Whyte) and the study was registered in clinicaltrials.gov (NCT04164264; date of registration 2019‐11‐15). Results are reported according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines [15].

2.2. Setting and Participants

We enrolled eligible children aged 3–18 years, American Society of Anesthesiologists (ASA) physical status I–III, in whom intravenous induction of anesthesia resulting in apnea was clinically appropriate and indicated. Written informed consent and age‐appropriate assent were obtained from participating families in the preoperative Anesthesia Care Unit at BC Children's Hospital, a tertiary pediatric facility in Vancouver, Canada, between March 2020 and October 2023. A total of 360 participants were enrolled in a stratified sample based on six cohorts, with 60 children in each cohort (vide infra) based on sex (male, female) and age: ≥ 3 years to < 6 years (3–5 years), ≥ 6 years to < 11 years (6–10 years), and ≥ 11 years to < 19 years (11–18 years). Exclusion criteria included the use of sedative pre‐medications, severe neurologic impairment expected to reduce propofol requirement, weight less than the 3rd or greater than the 97th percentile for age, and conversion to inhalational induction of anesthesia for any reason.

2.3. Study Procedures

Pre‐operatively, participants and their families completed an ethnicity questionnaire going back two generations from the child, based on the 2016 Canadian Census categories [16].

In the operating room, as is our routine practice, intravenous access was secured, and standard monitoring equipment was applied before the induction of anesthesia. When participant cooperation allowed, a bispectral index monitor (BIS; Covidien, Dublin, Ireland) was also applied. At T₀, the anesthesiologist started a propofol infusion at a rate of 1.5 mg/kg/min, to a maximum dose of 10 mg/kg. After 30 s, the anesthesiologist started testing for loss of eyelash reflex (LOER) at 10‐second intervals. After LOER was reached, the anesthesiologist started testing for tolerance of nasal cannulae (NC), defined as no localizing movement in response to placement in the nares, every 10 s. Once tolerated, these were left in situ. Respiration was monitored using continuous CO₂ sampling from the NC. Any airway obstruction was mitigated by gentle airway repositioning. Central apnea was defined as the absence of end‐tidal CO₂ for at least 20 s [17]. If apnea was not achieved after 10 mg/kg propofol infusion, this was recorded, and the study infusion ended. A research assistant recorded the following time points: T ₀, T _LOER, T _NC, and T _APNEA, using in‐house data logger software. The time taken to BIS < 60 for 30 s (T _BIS) was recorded automatically by the data‐logger software connected to the anesthetic machine and BIS monitor. The subsequent conduct of anesthesia was at the discretion of the attending anesthesiologist. Once the anesthesiologist secured the airway, the research assistant performed two buccal swabs and stored the samples for future PG analysis.

2.4. Outcome Measures

The constant infusion rate of propofol allowed for calculating the doses administered up to each timepoint. Primary outcomes were the propofol doses administered by T _LOER, T _NC, and T _APNEA stratified by age group, biological sex, and ethnicity; a secondary outcome was the propofol dose administered by T _BIS. Using a custom implementation of the Paedfusor model, with the elimination rate constant (k _e0) reduction by Rigby‐Jones, we calculated the PD outcomes of predicted plasma (C _p ) and effect site (C _e ) concentrations at the same endpoints [18, 19].

2.5. Sample Size

Our study was designed primarily to allow for the investigation of possible PG–PD relationships. PD endpoints relevant to propofol induction were chosen and measured, and biospecimens (saliva) were obtained for future PG analyses. We hypothesized that genetic ancestry may correlate with PG–PD relationships, as genetically influenced variations in drug responses may evolve in geographically disparate populations [20]. A sample size calculation for this study was thus challenging, given that the genetic ancestry of participants could not be determined a priori. Data and advice from the Canadian Pharmacogenetics Network for Drug Safety were solicited. Their recommendation was to recruit 60 participants to each of the six age/sex groups, for a total of 360 participants, with an understanding that once genetic ancestry was determined for these participants, and the distribution of the population understood, additional participants might need to be recruited. Our approved ethics application allows for reopening enrollment for this purpose.

2.6. Data Analysis

Doses of propofol required to achieve LOC (calculated using T _LOER‐T ₀, T _NC‐T ₀ and T _BIS‐T ₀) and apnea (T _APNEA‐T ₀) are reported as mean (standard deviation [SD]). The LOC‐apnea dose (or therapeutic) margin was calculated as the dose difference between the T _LOER and T _APNEA endpoints. For those who did not reach apnea, we used a conservative estimated mean value of 10.5 mg/kg to calculate their theoretical absolute minimum LOC‐apnea dose margin, recognizing that the true value, had we continued infusing propofol beyond the protocolized limit of 10 mg/kg, would likely have been higher.

To explore the effects of age and sex, we built linear regression models for propofol dose and estimated C _p and C _e at each of the four PD endpoints as well as the LOC‐apnea dose margin. No adjustments for potential multiple comparisons were considered due to the collinearity of the four PD endpoints.

For analysis of self‐reported ancestry, participants were reallocated into 12 categories based on the Canadian Census ethnicity categories [16]. Participants were reassigned if they indicated a country of origin that matched our predetermined categories. Participants who indicated “Canadian” as their ancestry were assigned to the “White” category if both parents were indicated or inferred as “White”. Those who did not choose a category or were uncertain of a parent's ethnicity were classified as “Unknown”. To explore the effect of self‐reported ancestry, we built a simple linear regression model for propofol dose to the four PD endpoints, but did not account for sex, age, or any interactions due to sample size and category reallocation limitations.

All data analyses were performed using R (R Foundation for Statistical Computing, Vienna, Austria).

3. Results

3.1. Participants

We enrolled 360 eligible participants; 42 were excluded, leaving 318 (88.3%) participants for analysis of the primary outcomes (Figure 1). These children had a median (interquartile range) age of 8.1 (5.3–12.9) years, with 162 females, and were balanced across our sex and age sub‐groups (Table 1). A total of 62/318 (19.5%) did not reach apnea despite receiving at least 10 mg/kg of propofol, and BIS sensor placement failed in 113/318 (35.5%) cases due to technical difficulties or discomfort with the sensor application.

FIGURE 1.

Study eligibility, enrollment, and analysis flow diagram.

TABLE 1.

Study population demographics.

	Female	Male	Overall
n	162	156	318
Age groups
3–5	53 (32.7)	47 (30.1)	100 (31.4)
6–10	52 (32.1)	53 (34.0)	105 (33.0)
11–18	57 (35.2)	56 (35.9)	113 (35.5)
Age, years	7.8 [5.2, 12.9]	8.2 [5.4, 13.0]	8.1 [5.3, 12.9]
Weight, kg	26.0 [19.2, 47.8]	28.0 [20.4, 48.1]	27.0 [20.0, 48.0]
Height, cm	127.7 [112.5, 156.5]	130.7 [113.1, 159.0]	130.0 [112.7, 158.0]
Self‐reported ethnicity
White	85 (52.5)	79 (50.6)	164 (51.6)
South Asian	14 (8.6)	13 (8.3)	27 (8.5)
Chinese	7 (4.3)	9 (5.8)	16 (5.0)
First Nations/White	8 (4.9)	6 (3.8)	14 (4.4)
Latin‐American/White	4 (2.5)	7 (4.5)	11 (3.5)
Filipino	4 (2.5)	6 (3.8)	10 (3.1)
West‐Asian	3 (1.9)	3 (1.9)	6 (1.9)
Southeast‐Asian	3 (1.9)	2 (1.3)	5 (1.6)
Chinese/White	2 (1.2)	3 (1.9)	5 (1.6)
First Nations	1 (0.6)	4 (2.6)	5 (1.6)
Black/White	2 (1.2)	3 (1.9)	5 (1.6)
Other	29 (17.9)	21 (13.5)	50 (15.7)

Note: Values are reported as median [Q1, Q3] for continuous variables and counts (percentage) for categorical variables.

3.2. Dose, C_e , and C _p Differences for Pharmacodynamic Endpoints

The mean (SD) propofol dose to T _LOER was 2.65 (0.69) mg/kg with no effect of sex or age (Figure 2, Table 2). There was similarly no effect of age or sex on the propofol dose to T _NC, but there was an effect of age on the propofol dose to T _BIS (−0.12 mg/kg per year, 95% CI –0.16 to −0.08, p < 0.001). The mean propofol dose to T _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).

FIGURE 2.

Comparison of propofol doses for each of the measured pharmacodynamic endpoints, including loss of eyelash reflex (LOER, n = 315), tolerance of nasal cannula (NC, n = 314), Bispectral Index < 60 (BIS, n = 205), and apnea (n = 256). Raw data are shown as a dot for each participant, stratified by sex (male, blue; female, red) and age in years, with a smoothed line fitted for each sex within each endpoint.

TABLE 2.

Linear regression models for dose as well as plasma concentration (Cp) and effect site concentration (Ce) calculated using the Paedfusor model [18, 19].

		Dose (mg/kg)			Cp (mcg/mL) from Paedfusor model			Ce (mcg/mL) from Paedfusor model
		Estimate	95% CI	p	Estimate	95% CI	p	Estimate	95% CI	p
LOER	Count	n = 315			n = 293			n = 293
	(Intercept)	2.69	2.5–2.89	< 0.001	3.28	2.85–3.7	< 0.001	1.80	1.46–2.15	< 0.001
	Sex: male	−0.10	−0.26 to 0.05	0.183	−0.24	−0.57 to 0.08	0.145	−0.17	−0.44 to 0.09	0.198
	Age [years]	0.00	−0.02 to 0.02	0.876	0.26	0.22–0.3	< 0.001	0.14	0.1–0.17	< 0.001
NC	Count	n = 314			n = 292			n = 292
	(Intercept)	3.35	3.12–3.58	< 0.001	4.02	3.56–4.48	< 0.001	2.50	2.1–2.91	< 0.001
	Sex: male	−0.13	−0.31 to 0.05	0.159	−0.27	−0.63 to 0.09	0.137	−0.21	−0.52 to 0.11	0.197
	Age [years]	−0.02	−0.04 to 0.00	0.106	0.26	0.22–0.31	< 0.001	0.14	0.1–0.18	< 0.001
BIS	Count	n = 205			n = 186			n = 186
	(Intercept)	5.19	4.71–5.67	< 0.001	5.90	5.16–6.63	< 0.001	4.64	3.96–5.33	< 0.001
	Sex: male	−0.24	−0.59 to 0.11	0.180	−0.42	−0.95 to 0.1	0.116	−0.40	−0.89 to 0.09	0.109
	Age [years]	−0.12	−0.16 to –0.08	< 0.001	0.19	0.13–0.26	< 0.001	0.05	−0.01 to 0.11	0.131
Apnea	Count	n = 256			n = 236			n = 236
	(Intercept)	7.85	7.36–8.34	< 0.001	7.48	6.75–8.21	< 0.001	6.39	5.64–7.15	< 0.001
	Sex: male	0.67	0.30–1.03	< 0.001	0.53	0.01–1.06	0.049	0.78	0.24–1.33	0.005
	Age [years]	−0.14	−0.19 to –0.1	< 0.001	0.33	0.26–0.4	< 0.001	0.22	0.15–0.29	< 0.001

Note: Data are split by the four measured pharmacodynamic endpoints, including loss of eyelash reflex (LOER), tolerance of nasal cannula (NC), Bispectral Index < 60 (BIS), and apnea. Statistically significant estimates for the effect of sex or age are bolded.

Regression models for propofol C _p indicated a significant effect of age, with higher C _p for older age across all four endpoints. There was also a significant effect of sex for C _p at T _APNEA (+0.53 mcg/mL for male, 95% CI 0.01–1.06, p = 0.049); but not at the other endpoints (Table 2). Regression models for propofol C _e , with a mean (SD) of 8.77 (2.32) mcg/mL at T _APNEA, indicated a significant effect of age for the C _e at T _LOER, T _NC, and T _APNEA, with higher C _e for older age, but not at T _BIS (Figure 3, Table 2). There was also a significant effect of sex for C _e at T _APNEA (+0.78 mcg/mL for male, 95% CI 0.24–1.33, p = 0.005), but not at the other endpoints (Table 2).

FIGURE 3.

Comparison of the propofol effect site concentration (Ce) estimated using the Paedfusor model for each of the measured pharmacodynamic endpoints, including loss of eyelash reflex (LOER, n = 293), tolerance of nasal cannula (NC, n = 292), Bispectral Index < 60 (BIS, n = 183), and apnea (n = 234) [18, 19]. Raw data are shown as a dot for each participant, stratified by sex (male, blue; female, red) and age in years, with a smoothed line fitted for each sex within each endpoint. Participants over 16 years of age were excluded, as their Ce cannot be calculated using the Paedfusor model.

3.3. Dose Margin Effects

The mean (SD) LOC‐apnea dose margin was 4.22 (1.64) mg/kg for those participants who reached apnea (n = 256). For those who did not (n = 62), we calculated the LOC‐apnea dose margin to be at least 3.48 mg/kg greater (95% CI 3.1–3.8, p < 0.001) in those participants who did not reach apnea compared to those who did (see Figure S1). The proportion of children who did not become apneic was most pronounced in the youngest age group (3–5 years), with 35/100 (35%) not reaching apnea compared to 15/105 (14%) for 6–10 years and 12/113 (11%) for 11–18 years.

3.4. Dose Differences by Self‐Reported Ethnicity

There were no differences in the propofol dose to T _LOER or T _APNEA based on self‐reported ancestry. However, significant differences were noted for propofol doses to T _NC among Chinese/White and First Nations compared to White participants and for propofol doses to T _BIS when comparing Chinese/White to White. These differences were confounded by outliers and small sample sizes (Figure 4). Our sample was not representative of the population in the Greater Vancouver area, as it oversampled White and Other (mixed race) participants while under‐representing South Asian, Chinese, and Filipino participants (see Figure S2).

FIGURE 4.

Comparison of propofol doses for each of the measured pharmacodynamic endpoints, including loss of eyelash reflex (LOER), tolerance of nasal cannula (NC), Bispectral Index < 60 (BIS), and apnea, stratified by self‐reported ancestry. Data are presented as box and whisker plots with a black dot for the mean, the box indicating the interquartile range, and the whisker extending to the last point within 1.5 times the SD. Raw data are overlaid as a dot for each participant (red, participants who did not reach apnea; gray, all other participants).

4. Discussion

In this prospective, non‐randomized, multicohort observational study, we found that both age and sex had significant effects on the doses of propofol required to reach apnea (T _APNEA): older children required lower doses (per kg) than younger children, and females required lower doses than males. These differences were not detected at the timepoints of our two clinical LOC indicators (T _LOER and T _NC), although age did have an effect on the propofol dose to T _BIS (older children required lower doses). These results indicate that propofol has a narrower therapeutic index between LOC and apnea in older and female children. Among those children for whom we were able to calculate PK/PD characteristics with the Paedfusor model, we found that older age generally predicted higher propofol C _p and C _e across all endpoints; additionally, male sex predicted higher propofol C _p and C _e at T _APNEA. Apnea was not reached in 62 participants, whose average LOC‐apnea dose margin was at least 3.48 mg/kg higher than their peers. Our data on dose differences by self‐reported ancestry were inconclusive.

While further research is required to understand the exact mechanisms of therapeutic differences between sexes and ages, our data support differential titration of propofol induction in children, especially when preserving spontaneous respiration. Careful consideration should be given to the narrower safety margin observed in older and female children. The results of this study are relevant to all healthcare providers who use propofol in their pediatric practice, including but not limited to specialists in anesthesiology, emergency medicine, critical care, and those who operate clinics that utilize procedural sedation, including gastroenterology, plastic surgery, and dentistry.

4.1. Pharmacokinetic and Pharmacodynamic Factors

There are multiple potential explanations for the age and sex differences in propofol response we observed. Both PK and PD factors may contribute and be affected by genetic variability. By studying intravenous induction of anesthesia, we aimed to examine an in vivo pharmacological process in which PK influence would be minimized; the rapid nature of propofol induction should theoretically limit the contributions of redistribution and elimination to dose–response variability. However, to differentiate PD endpoints in this study, we needed to “slow dow” induction sufficiently to measure discrete LOC indicators, which may have allowed for some PK contribution to variability, particularly in volume of distribution and particularly for apnea, which was observed last. Hence, we generated predicted C _p and C _e at the times of our PD endpoints (Table 2, Figure 3). If no PD variability existed (i.e., the differences in doses required to reach PD endpoints were entirely due to PK variability), we would expect these C _e values to be the same across age and sex groups. However, we found that predicted C _e values were higher in older children across three of our four endpoints and were higher in male participants when they reached apnea. While acknowledging the limitations of PKPD modeling, the observed C _e variability suggests at least some PD variability (different effect site concentrations can produce the same pharmacodynamic effect) and suggests that exploring PG variation may yield valuable insights.

The distribution of those who failed to reach apnea showed no sex difference and was heavily skewed toward the 3–5‐year group. This is important to emphasize, as these children could not be included in the T _APNEA analyses and would undoubtedly have influenced the mean values in favor of higher dose requirements and increased the true interindividual variability we would have observed. Hence, it is certain that the observed age group differences in apnea dosing would be even greater if the actual apnea dose for these participants had been measured.

4.2. Sex Differences and Other Factors

The fact that sex had a significant effect on propofol dose, C _p , and C _e at T _APNEA suggests a potential influence of sex hormones. The impact of biological sex and sex hormones alone on PK and PD mechanisms is complex and, for both pediatric patients and anesthetic drugs, largely unknown. However, studies investigating drug dose–response relationships should report or stratify by biological sex, as this leads to genetic, epigenetic, and hormonal differences at the cellular and tissue levels, which may in turn affect PK and PD [21].

Research has highlighted several factors that may contribute to interindividual variability during propofol anesthesia, including genetic factors such as cytochrome P450 enzyme and gamma‐aminobutyric acid receptor polymorphisms, as well as physiological factors such as cardiac output and cerebral blood flow [3, 22, 23].

4.3. Self‐Reported Ancestry

We did not detect differences in any PD endpoints among the self‐reported ancestry groups. This was likely due to small sample sizes in some groups and substantial variability within groups. An interesting observation is that our enrolled sample may not be representative of the pediatric surgical population served by our institution (Figure S2). There was an under‐representation of children from visible minority and Indigenous backgrounds, which may stem from language barriers, access to care issues, or differential historical or contemporary experiences in healthcare or research settings [24].

4.4. Limitations

Our study had several limitations. Our exclusion of patients with certain characteristics (e.g., severe neurologic impairment, extremes of weight‐for‐age percentile, under 3 years of age, and ASA physical status IV and V) limits the generalizability of the findings. Other patient factors that could influence propofol dosing and PD, which were not considered in our study, include underlying health conditions, environmental exposures, and specific genetic factors. Additionally, the logistics of recruiting study participants may have introduced selection bias, as the enrolled participants might have differed systematically from those who chose not to participate. This may have contributed to our unrepresentative self‐reported ancestry sampling. The limited number of participants in certain ethnic groups led to insufficient power to detect differences in propofol dosing between these groups. Furthermore, self‐reported ancestry data may be subject to inaccuracies or biases, and some participants, who identified themselves as belonging to groups not specifically listed within the Canadian Census categories, were re‐coded to the best of our ability.

4.5. Future Work

We are currently undertaking genome sequencing of the DNA collected from study participants via buccal swab and conducting a genome‐wide association study to identify potentially relevant gene polymorphisms that may influence PD responses to propofol [25]. Potential candidates identified in vitro include genes encoding the metabolizing enzyme CYP2B6 and the sex‐linked drug receptor gamma‐aminobutyric acid type A receptor subunit epsilon (GABRE) [22]. An understanding of specific genetic markers that affect propofol dose–response relationships may enable greater personalization of sedation in the future and improve safety measures in the pediatric population.

5. Conclusion

In this study, there was considerable interindividual variability in the dose requirements for achieving apnea during propofol induction of anesthesia in children. Older children and female children displayed narrower therapeutic margins between LOC and apnea and may benefit from enhanced monitoring to maintain spontaneous respiration safely. These findings demonstrate the importance of tailored dosing strategies in pediatric anesthesia to mitigate risks associated with propofol administration. Future research, including pharmacogenetic studies, may further refine these recommendations and improve safety outcomes in pediatric anesthesia.

Ethics Statement

This study was approved by the University of British Columbia/Children's & Women's Health Centre of British Columbia Research Ethics Board (H19‐00188; date of approval 2019‐12‐09; PI Simon D. Whyte).

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Figure S1: pan70031‐sup‐0001‐Appendix.pdf.

Moxham L., Golam A., West N. C., Görges M., and Whyte S. D., “Pharmacodynamic Safety Endpoints for Propofol Anesthesia in Children by Age and Sex: A Multicohort Observational Study,” Pediatric Anesthesia 35, no. 12 (2025): 1071–1079, 10.1111/pan.70031.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.