Lindy Moxham, Aanisah Golam, Nicholas C West, Matthias Görges, Simon D Whyte
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It has a narrow therapeutic index and significant interindividual variability in dosing requirements, which may elevate risks of its use, particularly in children.</p><p><strong>Aims: </strong>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.</p><p><strong>Methods: </strong>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 CO<sub>2</sub> 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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p><p><strong>Trial registration: </strong>The trial was registered on clinicaltrials.gov before enrolment (NCT04164264; date of registration 2019-11-15).</p>","PeriodicalId":19745,"journal":{"name":"Pediatric Anesthesia","volume":" ","pages":""},"PeriodicalIF":1.7000,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Pharmacodynamic Safety Endpoints for Propofol Anesthesia in Children by Age and Sex: A Multicohort Observational Study.\",\"authors\":\"Lindy Moxham, Aanisah Golam, Nicholas C West, Matthias Görges, Simon D Whyte\",\"doi\":\"10.1111/pan.70031\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Aims: </strong>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.</p><p><strong>Methods: </strong>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 CO<sub>2</sub> for 20 s) up to a maximum dose of 10 mg/kg. 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引用次数: 0
摘要
背景：异丙酚是一种常用的静脉镇静和全身麻醉剂，起效快，作用时间短。它具有狭窄的治疗指数和显著的个体间剂量需求差异，这可能会增加其使用的风险，特别是在儿童中。目的：我们的目的是按年龄和性别量化引起儿童意识丧失和呼吸暂停所需的剂量，以有助于定制异丙酚剂量建议，以提高儿科麻醉的安全性和有效性。方法：在这项分层和目的抽样研究中，我们根据性别和年龄将儿童分为6组（3- 5岁，6- 10岁，11- 18岁），每组60名参与者。为了诱导麻醉，我们以恒定速率给药异丙酚，直到达到呼吸暂停（无潮末CO2 20 s），最大剂量为10 mg/kg。我们测量了达到药效学终点所需的异丙酚剂量，包括睫毛反射丧失（LOER）和呼吸暂停，并估计了性别和年龄对这些剂量的影响。结果：318名参与者的数据可用，其中162名女性，年龄中位数（四分位数间距）为8.1（5.3-12.9）岁。LOER的平均异丙酚剂量（SD）为2.65 (0.69)mg/kg，性别（男性为-0.10 mg/kg， 95%可信区间(CI) -0.26 ~ 0.05, p = 0.183）或年龄（每年0.0 mg/kg, 95% CI -0.02 ~ 0.02, p = 0.876）无影响。异丙酚对呼吸暂停的平均（SD）剂量为6.82 (1.64)mg/kg，男女均有显著影响（男性+0.67 mg/kg, 95% CI 0.30 ~ 1.03, p）结论：年龄较大和女性儿童在LOER和呼吸暂停之间的界限表现出较窄的治疗指标。这需要高度警惕，特别是在维持自主呼吸时。计划中的全基因组关联研究可能会确定药物遗传学-药效学关系以及与遗传祖先的相关性。试验注册：试验入组前已在clinicaltrials.gov上注册(NCT04164264；注册日期2019-11-15)。
Pharmacodynamic Safety Endpoints for Propofol Anesthesia in Children by Age and Sex: A Multicohort Observational Study.
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).
期刊介绍：
Devoted to the dissemination of research of interest and importance to practising anesthetists everywhere, the scientific and clinical content of Pediatric Anesthesia covers a wide selection of medical disciplines in all areas relevant to paediatric anaesthesia, pain management and peri-operative medicine. The International Editorial Board is supported by the Editorial Advisory Board and a team of Senior Advisors, to ensure that the journal is publishing the best work from the front line of research in the field. The journal publishes high-quality, relevant scientific and clinical research papers, reviews, commentaries, pro-con debates, historical vignettes, correspondence, case presentations and book reviews.
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