Lidocaine Kinetics Research Articles

A Descriptive Tool to Characterize Nonlinear Kinetics, with Applications to Meperidine and Lidocaine

AbstractWe describe an explorative data analysis tool which can detect and describe the presence of nonlinearities in multiple dose kinetics studies. The method is nonparametric (i.e. not dependent on modeling assumptions), uses regression to estimate the functions representing the kinetics, and makes the detection of nonlinearity a part of the model selection process. Flexible functions (splines) are used to describe the kinetics corresponding to the lowest given dose, and to describe the (possible) departure of the kinetics corresponding to higher doses from the reference kinetics. The estimated kinetics and departures can be examined to offer possible insight into the nature of the nonlinearity. The methodology is applied to the analysis of meperidine and lidocaine kinetics through the lungs and the heart. We find that the lung kinetics of lidocaine and meperidine are linear. However their myocardial kinetics are complex and nonlinear.

Prognostic value of indocyanine green and lidocaine kinetics for survival and chronic hepatic encephalopathy in cirrhotic patients following elective end-to-side portacaval shunt.

The objective of this study was to assess the prognostic value of spontaneous portosystemic shunting and liver function for survival and spontaneous hepatic encephalopathy after end-to-side portacaval shunt in cirrhotic patients. One hundred ninety-eight patients with variceal hemorrhage as shown by endoscopy were evaluated. Forty-five were excluded because of uncontrollable hemorrhage; 84 were rejected because they were poor operative risk, had portal vein thrombosis or had been previously treated with beta-blockers, sclerotherapy or surgery. The remaining 69 patients were enrolled in this prospective study. There were 43 patients with alcoholic cirrhosis, 23 with cryptogenic cirrhosis and three with primary biliary cirrhosis. The severity of liver disease was assessed according to the Pugh classification: 37 patients (54%) had Pugh's score 5 to 7, 26 (38%) had 8 to 10 and six (8%) had 11 to 12. Indocyanine green intrinsic clearance was used as a probe of preoperative liver function and lidocaine systemic availability as an index of spontaneous preoperative shunting. All the patients underwent an elective end-to-side portacaval shunt. The length of minimal follow-up was 40 months. One-year survival was 76% and 5-year survival was 46%. During follow-up, 25 patients died from their liver disease and 11 patients died from various causes unrelated to their liver disease. Spontaneous chronic encephalopathy occurred in 16 patients (23%). Age, Pugh's score, active alcoholism, indocyanine green intrinsic clearance and lidocaine systemic availability were tested as prognostic factors in a multivariate analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Compartmental analysis of lidocaine kinetics during extracorporeal circulation

The aim of this study was to measure the effects of extracorporeal circulation (ECC) on lidocaine disposition and to determine if therapeutic concentrations were achieved during ECC. Anesthesia was obtained by administration of fentanyl (50 μg/kg plus 0.3 μg/kg/min) and pancuronium bromide (0.1 mg/kg) along with controlled ventilation (10 mL/kg, PaCO 2, 30 to 34 mmHg). Lidocaine was administered to ten patients in bolus doses of 2 mg/kg at the time of endotracheal intubation and during ECC at aortic declamping. Samples were collected at 20 and 40 seconds, and at 1, 3,5,10.15,20,25, and 30 minutes after drug administration. Blood sampling was arterial during anesthesia induction and from the oxygenator during ECC. Blood levels of lidocaine were determined by the immunofluorescence method. The kinetic studies of lidocaine showed increases in plasma volume and in the volume of the peripheral compartment, along with decreased volume in the compartment of well-perfused tissues during ECC. The fraction of the dose of lidocaine administered during ECC behaved accordingly, showing a decrease in the quantity of drug in the well-perfused tissues, and an increase in the other two compartments when compared to values before ECC. The doses administered gave plasma concentrations of 1.55 μg/mL, which are considered therapeutic. Thus, it is not recommended to increase the lidocaine dosage during ECC.

Effects of Cardiac Surgery with Cardiopulmonary Bypass on Lidocaine Disposition

We investigated lidocaine kinetics after cardiac surgery to elucidate the effects of cardiopulmonary bypass (CPB) and major surgery on its disposition. In five patients lidocaine kinetics were unchanged 15 min and 1 day after CPB, but lidocaine clearance decreased 42% and volume of distribution was reduced by 40% in eight patients 3 days after surgery. Seven days after surgery lidocaine kinetics had returned to baseline in five patients. These changes correlated with a doubling of the alpha 1-acid glycoprotein concentration and a 46% decrease in lidocaine free fraction on day 3, effects that persisted on day 7. Our results suggest that the use of lidocaine need not be altered in the first day after uncomplicated coronary artery surgery, but, in light of our findings the use of lidocaine and the interpretation of measured total lidocaine concentrations 3 to 7 days thereafter should be reexamined.

Effects of cardiac surgery with cardiopulmonary bypass on lidocaine disposition.

We investigated lidocaine kinetics after cardiac surgery to elucidate the effects of cardiopulmonary bypass (CPB) and major surgery on its disposition. In five patients lidocaine kinetics were unchanged 15 min and 1 day after CPB, but lidocaine clearance decreased 42% and volume of distribution was reduced by 40% in eight patients 3 days after surgery. Seven days after surgery lidocaine kinetics had returned to baseline in five patients. These changes correlated with a doubling of the alpha 1-acid glycoprotein concentration and a 46% decrease in lidocaine free fraction on day 3, effects that persisted on day 7. Our results suggest that the use of lidocaine need not be altered in the first day after uncomplicated coronary artery surgery, but, in light of our findings the use of lidocaine and the interpretation of measured total lidocaine concentrations 3 to 7 days thereafter should be reexamined.

Effect of the hour of administration on the pharmacokinetics of lidocaine in the rat.

The aim of the present study was to investigate an eventual influence of the hour of administration on lidocaine kinetics in the rat. 280 Wistar AF-SPF adult male rats were used for this study and maintained under controlled environmental conditions (LD: 06.00-18.00) during the month of October. A single 50 mg X kg-1 dose of lidocaine was given by intramuscular route, at four different fixed time points of a 24 hour period (i.e.: 10.00, 16.00, 22.00 and 04.00) to 70 rats. Blood samples were taken at the following time points: 5, 15, 30 min., 1, 2, 4 and 6 hours after the drug administration. Lidocaine plasma levels (free and bound) were determinated according to a specific gas chromatographic method. The data showed circadian variations of pharmacokinetic parameters:--Elimination half-life: max. 2.12 +/- 0.05 h at 10.00, min. 1.50 +/- 0.03 h at 16. --Initial concentration: max. 5.05 +/- 0.65 micrograms X ml-1 at 16.00; min. 2.97 +/- 0.29 micrograms X ml-1 at 04.00.--Elimination constant rate: max. 0.4618 +/- 0.0094 h-1 at 16.00, min 0.3279 +/- 0.0079 h-1 at 10.00.--Area under curve (experimental): max. 11.11 +/- 1.07 micrograms X kg-1 X h-1 at 16.00, min. 7.45 +/- 0.84 micrograms X kg-1 X h-1 at 04.00.--Apparent volume of distribution: max. 16.67 +/- 1,67 L X kg-1 at 04.00, min. 9.75 +/- 1.04 L X kg-1 at 16.00. The lidocaine-free fraction varied with time and the protein binding of lidocaine showed a circadian variation.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of long-term infusions on lidocaine kinetics.

Lidocaine kinetics were examined during continuous infusions in five healthy subjects using stable isotope lidocaine labeled with two deuterium atoms. During phase 1, lidocaine and stable isotope lidocaine (50 mg IV each) were given as a bolus to confirm that the two species were kinetically identical. Phase 2 consisted of a long-term (30 hr) lidocaine infusion designed to produce a steady-state concentration equal to 1.5 microgram/ml. Twenty-four hours into the infusion, stable isotope lidocaine (50 mg) was given as an intravenous bolus and kinetic parameters were calculated. Phase 3 differed from phase 2 in that target steady-state lidocaine concentration was 4 microgram/ml and the stable isotope lidocaine dose was reduced to 40 mg. A gas chromatograph-mass spectrometer was used to determine lidocaine and stable isotope lidocaine serum concentrations. Compared to phase 1, clearance decreased (P less than 0.05) and half-life increased (P less than 0.025) during phases 2 and 3. The volume of distribution at steady-state remained constant during all three phases. Lidocaine cumulated in serum during long-term infusions in all five patients; repeated decreases in infusion rate were necessary to avoid exceeding desired target concentrations in phases 2 and 3.

Lidocaine kinetics: relationships between early lidocaine kinetics and indocyanine green clearance.

Lidocaine plasma levels and indocyanine green clearance were measured in five normal volunteers and eight patients admitted to the coronary care unit. All individuals received lidocaine as a 1 mg/kg bolus and a 35 microgram/kg/min constant infusion for 180 minutes. Eight of the 13 (62 per cent) individuals studied (all normal volunteers and three patients) developed early, potentially subtherapeutic plasma lidocaine levels (less than or equal to 2.4 microgram/ml) within 15 minutes after starting therapy. Those individuals with subtherapeutic levels had either minimal (American Heart Association Class) or no clinical evidence of congestive heart failure. The use of indocyanine green (ICG) clearance as an estimate of hepatic plasma flow showed that individuals with early, subtherapeutic lidocaine levels had higher ICG clearance (9.33 +/- 0.32 ml/min . kg versus 2.90 +/- 1.74 ml/min . kg) and shorter ICG t 1/2 (2.02 +/- 0.99 minutes versus 3.6 +/- 0.69 minutes) and larger volume of distribution (36.1 +/- 16.3 ml/kg versus 19.5 +/- 12.8 ml/kg) than patients without subtherapeutic levels. This study suggests that early lidocaine kinetics may be significantly altered by clinical conditions that alter hepatic blood flow. The reappearance of arrhythmias shortly after initiating lidocaine therapy in patients without heart failure may be due to rapid hepatic clearance and subtherapeutic blood levels rather than lidocaine-resistant arrhythmias.

Lidocaine kinetics predicted by indocyanine green clearance.

To evaluate the importance of hepatic blood flow in lidocaine kinetics, we compared indocyanine green clearance, an estimate of hepatic plasma flow, to lidocaine clearance in 26 patients, half with and half without congestive heart failure, who received a lidocaine infusion for 24 hours as clinically indicated. The results demonstrated that patients with congestive heart failure had significantly higher steady-state lidocaine levels (6.8 +/- 3.6(S.D.) vs. 2.9 +/- 0.9 microgram per milliliter, P less than 0.005) and reduced lidocaine clearance (3.8 +/- 1.4 vs. 10.9 +/- 3.1 ml per minute per kilogram, P less than 0.005) than patients without heart failure. Potentially subtherapeutic or toxic lidocaine levels were found in 10 patients. The regression line (y = 0.3 + 1.07 x) relating clearance of lidocaine to that of indocyanine green was linear (r = 0.95, P less than 0.001). Since indocyanine green clearance can be determined rapidly and noninvasively, it offers the potential of predicting lidocaine dosage requirements with avoidance of toxicity or suboptimum therapy.

Multiple bolus technique for lidocaine administration during the first hours of an acute myocardial infarction

All patients in the San Pedro and Peninsula Hospital suspected of having a myocardial infarction are routinely given an initial bolus injection of 75 mg of lidocaine and concomitant constant infusion. Those who continue to exhibit serious ventricular ectopy are subjected to a precise treatment protocol employing 50 mg bolus injections of lidocaine every 5 minutes, if necessary, to a total of 225 mg. The clinical success of this treatment program in 1,000 consecutive patients with acute myocardial infarction prompted more extensive study of lidocaine kinetics in 23 patients receiving lidocaine with the multiple bolus technique. Plasma lidocaine levels were determined 1, 3 and 5 minutes after an initial 75 mg bolus injection and after three subsequent 50 mg bolus injections given at 5 minute intervals. The mean peak plasma concentration was 2.3 μg/ml, and no level exceeded 4.8 μg/ml. Save for a single plasma value of 1.1 μg, 5 minutes after the initial 75 mg bolus dose, the mean plasma levels were within the accepted therapeutic range at all times. The effect of clinical left ventricular failure on plasma lidocaine levels and drug distribution was examined. Although plasma levels 1 minute after the first bolus injection were 1.0 ± 0.2 and 2.0 ± 0.4 μgml (mean ± standard error of the mean) in class 0–1 and class II-III heart failure, respectively ( P < 0.05), mean concentrations were not significantly different ( P < 0.2) 5 minutes after the last bolus dose. A dosage schedule employing multiple bolus injections of lidocaine every 5 minutes, if ventricular extrasystoles are not controlled, to a total of 225 mg over 16 minutes provides adequate blood levels, results in no significant toxicity and may be safely employed with excellent results in patients with infarction irrespective of the presence of moderate congestive heart failure.