A population pharmacokinetic model of epidural lidocaine in geriatric patients: effects of low-dose dopamine.
The purposes of this study were to develop a population pharmacokinetic (PK) model of epidural lidocaine in geriatric patients, to search for any difference in the PK behavior of epidural lidocaine when dopamine is given concurrently, and to develop a descriptive PK model from which to calculate dosage and infusion regimens of epidural lidocaine to define and achieve desired target goals in either the epidural or the serum compartment. Twenty patients over age 65 years, undergoing peripheral vascular surgery using continuous epidural lidocaine anesthesia, were studied. Ten patients also received an intravenous infusion of placebo (normal saline), whereas 10 other patients received an intravenous infusion of dopamine at 2 mug/kg per minute. Total plasma lidocaine concentrations (gas-chromatographic assay) were measured from arterial samples just before injecting the first epidural dose (baseline) and then at 5, 15, 30, 60, 90, and 120 minutes and hourly thereafter. Samples were also taken when the lidocaine infusion was stopped at the end of the surgery and at 30 minutes, 60 minutes, 90 minutes, 2 hours, 3 hours, 4 hours, and 5 hours after surgery. The nonparametric adaptive grid (BigNPAG) computer program in the MM-USCPACK collection was used for population PK modeling to obtain the entire discrete maximum likelihood joint parameter distribution. The assay error polynomial was determined to be 0.2 + 0.05 C. The structural population PK model was linear and had three compartments, each with first-order transfer kinetics. Lidocaine had a very fast transfer rate constant (Ka part + K20) from the epidural space to the serum compartment. This rate was slowed, by over 41%, by dopamine. The mean rate constant of elimination from the serum compartment (K20) was increased by 9.7% by dopamine. The mean rate constant for drug movement from central to peripheral compartment (K23) was increased by 47% in the patients receiving dopamine. The mean rate constant back from the peripheral to the central compartment (K32) was slowed 46% by dopamine. There was no obvious difference in the apparent volume of distribution of the central compartment between the patients given placebo and the patients receiving dopamine. In this model, there was no specific compartment for lidocaine in the cerebrospinal fluid. Cerebrospinal fluid is probably one of the components of the overall peripheral, nonserum compartment in our model. In this first population model of epidural lidocaine using a statistically consistent method, low-dose dopamine appears to decrease the rate of transfer of lidocaine from the epidural to the serum compartment and to increase both the rate of elimination of lidocaine as well as its transfer between the central (serum) and peripheral compartment presumably by increasing tissue perfusion. Serum lidocaine concentrations were slightly less in the patients receiving dopamine. Dosage requirements (overall hourly weight-adjusted infusion rates) were slightly less for the patients receiving dopamine, consistent with the slower removal of lidocaine from the epidural compartment. This model should be useful to design more optimal and individualized epidural lidocaine infusion regimens to define and achieve desired target goals in the epidural or the serum compartment.
Department of Pharmacy, Singapore General Hospital, Singapore.
Andrea
A
Kwa
Juraj
J
Sprung
Michael Van
MV
Guilder
Roger W
RW
Jelliffe
D000368:Aged; D000767:Anesthesia, Epidural; D000779:Anesthetics, Local / Q000493:pharmacokinetics*; D004298:Dopamine / Q000494:pharmacology*; D004311:Double-Blind Method; D004347:Drug Interactions; D006801:Humans; D008012:Lidocaine / Q000493:pharmacokinetics*; D016014:Linear Models; D015233:Models, Statistical; D011153:Population
D000779:Anesthetics, Local; D008012:Lidocaine; D004298:Dopamine