通过群体药代动力学分析优化1-3级肥胖患者静脉注射利多卡因的剂量

Dosing optimisation of intravenous lidocaine in patients with class 1-3 obesity by population pharmacokinetic analysis.

作者信息

Tognolini Angela R, Liu Xin, Pandey Saurabh, Roberts Jason A, Wallis Steven C, Jackson Dwane, Eley Victoria A

机构信息

Department of Anaesthesia and Perioperative Medicine, The Royal Brisbane and Women's Hospital, Brisbane, Australia.

Faculty of Medicine, The University of Queensland, Brisbane, Australia.

出版信息

Anaesthesia. 2025 May;80(5):511-521. doi: 10.1111/anae.16531. Epub 2025 Jan 2.

DOI:10.1111/anae.16531

PMID:39745506

Abstract

INTRODUCTION

Evidence to support intra-operative lidocaine infusion regimens in patients with obesity is lacking, risking underdosing or toxicity. We aimed to measure the plasma concentrations of lidocaine and its active metabolites to develop a pharmacokinetic model and optimised dosing regimen in patients with obesity.

METHODS

A standardised weight-based intravenous lidocaine regimen was administered to patients with a BMI ≥ 30 kg.m undergoing elective laparoscopic abdominal surgery. Using lean body weight, a 1.5 mg.kg loading dose over 10 min and infusion of 1.5 mg.kg.h was administered intra-operatively. Arterial blood was sampled during and after the infusion. The total and unbound plasma concentrations of lidocaine, monoethylglycinexylidide and glycinexylidide were measured using liquid chromatography-mass spectrometry. Monolix was used for population pharmacokinetic analysis. Dosing simulations were performed using Simulx to develop a regimen that best targeted a therapeutic plasma concentration between 2.5 and 5 μg.ml.

RESULTS

Thirty patients provided 221 plasma samples (median (IQR [range]) age 51 (44-61 [32-76]) y and 21 female). Median (IQR [range]) total body weight was 107.0 (91.8-132.5 [80.0-189.0]) kg and BMI was 37.7 (33.6-46.5 [30.2-58.4]) kg.m. Using total and unbound plasma concentrations of lidocaine, monoethylglycinexylidide and glycinexylidide, a four-compartment model was developed. Unbound lidocaine volume of distribution was 2.1 l.kg and clearance 1.7 l.kg.h. Simulations showed that doses used currently had a low probability of target attainment of 0%. A loading dose of 2 mg.kg over 20 min followed by an infusion of 3 mg.kg.h based on lean body weight improved probability of target attainment to 18.6%. The infusion should be reduced to 2 mg.kg.h after 80 min.

DISCUSSION

Our simulated dosing regimen achieved therapeutic concentrations more successfully in patients with obesity. Further studies should evaluate the clinical safety and efficacy of this dosing regimen.

摘要

引言

缺乏支持肥胖患者术中输注利多卡因方案的证据，存在剂量不足或毒性风险。我们旨在测量利多卡因及其活性代谢物的血浆浓度，以建立肥胖患者的药代动力学模型并优化给药方案。

方法

对体重指数（BMI）≥30kg/m²且接受择期腹腔镜腹部手术的患者给予基于体重的标准化静脉注射利多卡因方案。根据瘦体重，术中给予1.5mg/kg的负荷剂量，10分钟内输注完毕，随后以1.5mg·kg·h的速度持续输注。在输注期间和之后采集动脉血样。使用液相色谱 - 质谱法测量利多卡因、单乙基甘氨酰二甲苯胺和甘氨酰二甲苯胺的总血浆浓度和游离血浆浓度。使用Monolix进行群体药代动力学分析。使用Simulx进行给药模拟，以制定最能将治疗性血浆浓度靶向在2.5至5μg/ml之间的方案。

结果

30例患者提供了221份血浆样本（年龄中位数（四分位间距[范围]）为51（44 - 61[32 - 76]）岁，女性21例）。总体重中位数（四分位间距[范围]）为107.0（91.8 - 132.5[80.0 - 189.0]）kg，BMI为37.7（33.6 - 46.5[30.2 - 58.4]）kg/m²。利用利多卡因、单乙基甘氨酰二甲苯胺和甘氨酰二甲苯胺的总血浆浓度和游离血浆浓度，建立了一个四室模型。游离利多卡因的分布容积为2.1L/kg，清除率为1.7L·kg·h。模拟结果显示，目前使用的剂量达到目标浓度的概率较低，为0%。基于瘦体重，先在20分钟内给予2mg/kg的负荷剂量，随后以3mg·kg·h的速度输注，可将达到目标浓度的概率提高到18.6%。80分钟后输注速度应降至2mg·kg·h。