The Plasma Concentration of Lidocaine's Principal Metabolite Increases During Continuous Epidural Anesthesia in Infants and Children

Abstract

Continuous epidural anesthesia is frequently used for anesthesia and analgesia during and after surgery in infants and children. Nevertheless, there are no data on the pharmacokinetics of repeatedly administered epidural lidocaine in children. We measured the concentrations of lidocaine and its principal active metabolite, monoethylglycinexylidide (MEGX), in plasma samples obtained in a group of infants and children during continuous epidural anesthesia with lidocaine. Methods After obtaining approval from the local ethics committee and parental consent, we studied 10 infants and children, aged 3 mo to 4 yr and weighing 5-19 kg, who underwent abdominal or thoracic surgeries lasting >5 h. After induction of general anesthesia, the epidural spaces were entered via the caudal route or via the lumbar or thoracic interspaces using Tuohy 19-gauge needles (Portex Minipak[registered sign]; Hythe, Kent, England) and 22-gauge epidural catheters. The loss of resistance technique with saline was used to identify lumbar and thoracic epidural spaces. An initial dose of 1% lidocaine (5 mg/kg) without epinephrine was injected into the epidural space, followed by an infusion of the same solution (2.5 mg [center dot] kg-1 [center dot] h-1) using a motor-driven syringe pump. Anesthesia was maintained with epidural anesthesia and oxygen (33%), nitrous oxide (67%), and isoflurane (0%-1%) or sevoflurane (0%-1.5%). Blood samples were drawn at 30 min and every hour after the epidural injection for 5 h. Plasma samples were separated by centrifugation at 4[degree sign]C and stored at -20[degree sign]C until analyzed. The total plasma concentrations of lidocaine and MEGX were simultaneously measured by using high-performance liquid chromatography with ultraviolet detection; a variable wavelength ultraviolet detector (Model UV-8020; Tosoh, Tokyo, Japan) set for 210 nm was used. Analytic recoveries of lidocaine and MEGX were 97% and 90%, respectively; coefficients of variation were <5%, and compounds at concentrations as low as 0.01 [micro sign]g/mL could be detected in 250-[micro sign]L plasma samples. Results The time-dependent changes in the concentrations of plasma lidocaine, MEGX, or the sum of lidocaine and MEGX that occurred during lidocaine infusion were assessed using linear regression, and the statistical significance of the changes were determined by using multiple regression analysis. We observed that increases in plasma lidocaine were minimal during surgery, whereas MEGX levels and the sum of lidocaine and MEGX both increased significantly as a function of time (Figure 1).Figure 1: Time-dependent changes in plasma lidocaine ([large circle]), monoethylglycinexylidide (MEGX; [up triangle, open]), and the sum of lidocaine and MEGX ([square]) during continuous epidural lidocaine infusion. Data are expressed as mean +/- SD. Regression lines are defined by the equations Y = 2.6 + 0.4 h (r = 0.82, P = 0.0001) for the sum of lidocaine and MEGX; Y = 2.5 + 0.12 h (r = 0.42, P = 0.0008) for lidocaine; and Y = 0.1 + 0.28 h (r = 0.88, P = 0.0001) for MEGX, where Y is plasma concentration and h is time after the initial epidural injection. Increases in plasma lidocaine concentration were minimal; MEGX and the sum of lidocaine and MEGX were each significantly increased as a function of time.Discussion Analysis of lidocaine pharmacokinetics during epidural anesthesia for surgery in infants and children has been limited to single-dose caudal administration [1]. In their study, Ecoffey et al. [1] observed that plasma lidocaine levels peaked 28 min after the caudal administration of 5 mg/kg lidocaine; the average plasma level was 2 [micro sign]g/mL, and the average half-life was 155 min. Based on these findings, they recommended that initial doses of epidural lidocaine in infants and children should be reduced by one-third to one-half [2]. In our study, we administered epidural lidocaine as a 5-mg/kg bolus followed by infusion of 2.5 mg [center dot] kg-1 [center dot] h-1. Using this protocol, plasma lidocaine concentrations were maintained well below 5.3 [micro sign]g/mL, which is considered toxic in adults [3]. Other authors have suggested that the accumulation of lidocaine metabolites during prolonged IV administration may account for the development of toxicity even when blood lidocaine concentrations are within the therapeutic range [4-6]. Indeed, the convulsant potency of MEGX is approximately equal to that of lidocaine itself [7]. MEGX levels also increased with repeated administration of lidocaine during epidural anesthesia. The additive effects of MEGX and lidocaine have been suggested to play an important role in the development of toxic side effects associated with lidocaine administration [8]. Our findings indicate that MEGX continuously increases with time during lidocaine infusion in children and infants. Therefore, plasma MEGX accumulation must be considered when repeated or continuous administration of epidural lidocaine is used for anesthesia in pediatric patients. In conclusion, during continuous epidural anesthesia, local anesthetic accumulation may occur even when plasma lidocaine is maintained within the normal range. We observed that plasma MEGX, an active metabolite of lidocaine, increases continuously.