Myocardial uptake of bupivacaine: I. Pharmacokinetics and pharmacodynamics of lidocaine and bupivacaine in the isolated perfused rabbit heart.

Bupivacaine, but not lidocaine, may cause severe cardiac dysrrhythmias in case of accidental intravascular injection. In an attempt to discriminate between a pharmacokinetic and a pharmacodynamic (or both) origin to these differences, we used an isolated rabbit heart model with constant coronary inflow to compare the myocardial uptake and disposition kinetics of lidocaine and bupivacaine. Drug concentration in the outflow perfusate was assayed and surface electrocardiogram was recorded. Drug uptake and disposition kinetics were modeled with a two-compartment open model. An Emax model was used to describe the increase in QRS duration in relation with drug concentration in the central compartment. Lidocaine and bupivacaine exhibited similar myocardial pharmacokinetics (i.e., a rapid decrease in the outflow concentration upon drug administration discontinuation). Bupivacaine-induced maximum increase in QRS duration (Emax) was 15 times superior to lidocaine Emax. The steady-state perfusate concentration producing half Emax was the same for both drugs. We conclude that bupivacaine-induced QRS widening decreases almost at the same rate as does lidocaine-induced QRS widening when drug administration is terminated. Therefore, the different cardiac effects of lidocaine and bupivacaine are not due to differences in myocardial uptake and disposition kinetics.

Myocardial uptake of lignocaine: pharmacokinetics and pharmacodynamics in the isolated perfused heart of the rabbit.

1. The uptake kinetics and pharmacodynamics of lignocaine were studied in isolated perfused heart of the rabbit. 2. Six hearts were perfused with increasing concentrations of lignocaine in a modified Krebs-Henseleit buffer. The effluent concentration together with the increase in QRS duration were measured during lignocaine infusion and during 20 min after cessation of lignocaine infusion. 3. Lignocaine disposition and elimination were best described by a two-compartment open model. Terminal half-life was 11.0 +/- 2.9 min. The unidirectional transfer was slower from central to peripheral compartment than from peripheral to central compartment (T1/2.12 = 42.6 +/- 10.5 min whereas T1/2.21 = 10.7 +/- 2.8 min). The myocardium/perfusate concentration-ratio was 4.7 +/- 0.4. 4. The pharmacodynamic effect was best described in the central compartment by using the Hill equation. Calculated maximum QRS duration (Emax) was 77 +/- 8 ms. Emax was also directly measured in four additional rabbits by infusing ten times the dose of lignocaine used in the main experiment: the value of Emax measured in these conditions was 92.5 +/- 9.6 ms, i.e. a QRS widening of 150%. The steady-state perfusate concentration producing half the effect (C50) was 15.7 +/- 7.6 micrograms ml-1. 6. In conclusion, the specific lignocaine binding leading to increase in QRS duration appeared to be more closely related to the vascular stream than non specific binding leading to a deeper accumulation process.

Continuous intercostal blockade with lidocaine after thoracic surgery. Clinical and pharmacokinetic study.

The efficacy and the side effects of a continuous infusion of lidocaine in the fifth intercostal space for the management of postoperative pain after lateral thoracotomy were evaluated in 20 adults. An indwelling catheter was inserted in the appropriate intercostal space before thoracotomy closure. After recovery from general anesthesia, a loading dose of 3 mg/kg of 1.5% lidocaine with epinephrine 1:160,000 was injected through the catheter, followed by a continuous infusion of 1% lidocaine without epinephrine at a rate of 1 mg.kg-1.h-1 for 54 h. In seven patients pharmacokinetic data were obtained. Pain, assessed by visual continuous analog scale, decreased from a median score of 8 (range, 7-10) to a score of 5 (range, 2-7) 20 min after the loading dose of lidocaine and continued to decrease until the end of the study (P = 0.0001). Complete cutaneous analgesia, assessed by pinprick test, was seen in a median of three thoracic spinal segments (range, 0-6) with partial cutaneous analgesia in seven segments (range, 6-9) 40 min after the loading dose, and levels that remained unchanged for 54 h (P = 0.0001). Peak lidocaine serum concentrations, 1.9 +/- 0.7 micrograms/mL, were present 9 +/- 3 min after injection of the loading dose. Serum concentrations of lidocaine under steady state conditions averaged 4.8 +/- 0.9 micrograms/mL (range, 3.5-5.8 micrograms/mL). This level under steady state conditions, though below the toxic level, suggests that additional bolus injection of lidocaine during the course of infusion might result in potentially toxic serum levels of lidocaine.(ABSTRACT TRUNCATED AT 250 WORDS)

[Continuous block of the femoral nerve after surgery of the knee: pharmacokinetics of bupivacaine]. / Bloc crural continu après chirurgie du genou: pharmacocinétique de la bupivacaïne.

Ten ASA Class 1 and 2 patients, aged from 16 to 56 years (mean +/- SD: 37 +/- 17 years), scheduled for knee surgery were studied. At the end of the surgical procedure under general anesthesia, an epidural catheter was inserted in the femoral space. After X-ray opacification, a bolus of 2.5 mg.kg-1 of 0.5% bupivacaine with epinephrine was injected. A maintenance infusion was performed during 48 hours with 0.25 mg.kg-1.h-1 of 0.125% bupivacaine without epinephrine. Pain score recorded with an visual analogue scale was 5.0 +/- 1.9 before femoral block. Pain score decreased significantly from 6 to 48 hours. Plasma bupivacaine levels at 24, 36 and 48 hours were significantly higher than the levels obtained at 30 min, 1, 6 and 12 hours. Mean plasma bupivacaine level at steady state was 1.78 +/- 0.59 micrograms.ml-1. Clearance of bupivacaine was 2.59 +/- 0.91 ml.min-1.kg-1. No neurologic complications have been recorded.