Perioperative lidocaine infusions show potential as a systemic analgesic and to enhance postoperative recovery. This study characterised the pharmacokinetics (PK) of lidocaine and its metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX), in adult surgical patients using non-linear mixed-effects modelling. Thirty-four donor nephrectomy and 64 cholecystectomy patients received intraoperative IV lidocaine. Plasma samples were collected perioperatively and analysed in NONMEM. Covariate effects and alternative dosing regimens were investigated. 1,520 concentration-timepoints were analysed. Lidocaine PK was best fitted with a 3-compartment model, while MEGX and GX used a 2-compartment model. All parameters were scaled allometrically with total body mass and fat-free mass (FFM). Lidocaine had a typical clearance of 45.9 L/h, decreasing by 60% postoperatively, and a central volume of 25.2 L. Peripheral compartments 1 and 2 exhibited intercompartmental clearances of 142 L/h and 5.81 L/h, with volumes of 44.4 L and 29.3 L, respectively. Peripheral compartment 1's volume expanded with intraoperative fluid administration. Simulations suggested an FFM-based dosing regimen (bolus: 2.5 mg/kg over 30 min, single infusion: 2 mg/kg over 1 h, maintenance infusion: 1.5 mg/kg/h) quickly achieved and maintained a lidocaine target plasma concentration of 1.5 mg/L. The joint parent-metabolites model adequately describes the disposition of lidocaine and its metabolites, incorporating allometric scaling and key covariates. It provides a foundation for optimising lidocaine dosing and guiding investigations to establish target plasma concentrations for safe and effective use in the general surgical population. Further research is warranted to refine and evaluate the model's utility in other surgical populations.
To review the relationship between drug concentrations of perioperative intravenous lidocaine and their analgesic effects. We systematically searched SCOPUS, Medline, EMBASE, CENTRAL, and Web of Science (inception to March 2024) for randomized controlled trials comparing intraoperative lidocaine to placebo or control in adults undergoing non-cardiac surgery. Studies reported pain outcomes and plasma lidocaine concentrations. Bias was assessed using the Cochrane risk-of-bias tool, and data was analyzed with a random-effects model to determine mean difference (MD) and 95% confidence intervals (CI). Fifteen studies (445 lidocaine, 453 control patients) were included. Lidocaine lowered post-anesthetic care unit (PACU) opioid use (8 studies, MD: -3.00, 95% CI [-5.00, -1.01], = 0.0092, I = 57%), with meta-regression indicating greater reduction at higher plasma concentrations (regression coefficient: -3.05, 95% CI [-4.48, -1.61], = 0.002). However, 11 studies found no significant difference in 24-hour postoperative opioid consumption or pain scores. Nausea and vomiting incidence were similar between groups, and a few patients experienced lidocaine-related adverse events. Perioperative lidocaine infusion reduces PACU opioid consumption, with greater effects at higher concentrations, although significant heterogeneity was noted. Further research is needed to identify optimal concentrations for clinically significant analgesic benefits. International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY) ID: INPLASY202180046, DOI: 10.37766/inplasy2021.8.0046.
The establishment of optimal dosing regimens for intravenous (IV) lidocaine in the perioperative setting, aiming to balance effective pain relief with minimisation of potential side effects, is a topic of ongoing debate. This discussion stems from the significant variability in lidocaine's pharmacokinetic (PK) parameters and its relatively narrow safety margin. Population pharmacokinetic (popPK) modelling has emerged as a valuable tool for understanding the factors contributing to this observed variability in drug kinetics. This systematic review compiles the existing knowledge on lidocaine's PK properties and published popPK models, with a focus on significant covariates. A systematic search on Cochrane CENTRAL, Medline, and EMBASE was performed from inception to June 2023. Original clinical studies that administered IV lidocaine to adults and performed PK analyses using a nonlinear mixed effects modelling approach were included. The quality of the included studies was assessed by compliance with the Clinical Pharmacokinetics (ClinPK) statement checklist. Seven studies were included, which involved a diverse adult population, including both volunteers and patients with various comorbidities. Lidocaine PK was primarily characterised by a two- or three-compartment model. The volume of distribution at steady state ranged from 66 to 194 L, and the total clearance ranged from 22 to 49 L/h. Despite adjusting for significant covariates like heart failure status, alpha-1-acid glycoprotein, duration of lidocaine infusion, and body weight, each study revealed substantial variability in PK parameters. The potential impact of hepatic or renal function biomarkers on these PK parameters calls for further investigation. Incomplete reporting of key aspects of developed models may hinder the models' reliability and clinical application. The findings emphasise the importance of tailoring drug dosage to ensure the safe and effective use of intravenous lidocaine. Optimal design methodologies may be incorporated for a more efficient identification of important covariates. Utilising contemporary model evaluation methods like visual predictive checks and bootstrapping would enhance the robustness of popPK models and the reliability of their predictions. This comprehensive review advances our understanding of lidocaine's pharmacokinetics and lays the groundwork for further research in this critical area of perioperative pain management. Review protocol registered on 25 August 2023 in PROSPERO (CRD42023441113). This work was supported by the Fundamental Research Grant Scheme, the Ministry of Higher Education, Malaysia (FRGS/1/2020/SKK01/UM/02/2).