G. Richard Arthur

Bupivacaine Toxicity in Pregnant and Nonpregnant Ewes

The relative central nervous system and cardiovascular toxicity of bupivacaine was compared in pregnant and nonpregnant ewes during continuous infusion of bupivacaine into the jugular vein at the rate of 0.5 mg. kg-1. min-1. In all animals, identical symptoms of toxicity occurred in the following order: convulsions, hypotension, respiratory arrest, and circulatory collapse. The dose of bupivacaine required to produce central nervous system (CNS) toxicity in the pregnant ewe tended to be lower than in the nonpregnant animal, although the difference was not statistically significant (P < 0.1). However, the mean dose of bupivacaine resulting in cardiovascular collapse was significantly lower in pregnant ewes (5.1 ± 0.7 mg/kg) than in nonpregnant animals (8.9 ± 0.9 mg/kg). Similarly, bupivacaine blood concentrations at the onset of respiratory arrest and circulatory collapse were lower in the pregnant group, being 5.2 ± 0.7 μg/ml and 5.5 ± 0.8 μg/ml, respectively, versus 7.5 ± 1.0 μg/ml and 8.0 ± 0.9 μg/ml, respectively, in the nonpregnant group (P < 0.05). The concentration of bupivacaine in the brain of pregnant ewes at the time of cardiovascular collapse was significantly lower (P < 0.01) than in the nonpregnant group (7.5 ± 1.5 vs. 16.3 ± 1.7 μg/g). The myocardial tissue concentration of bupivacaine also tended to be lower in the pregnant group, although the differences were not statistically significant (P < 0.1). Comparisons of bupivacaine doses and blood concentrations associated with the onset of convulsions and circulatory collapse (CC/CNS ratio) with those of lidocaine, reported previously, indicate that a narrower margin of safety exists following administration of bupivacaine in nonpregnant sheep. These ratios were 3.7 ± 0.5 and 1.6 ± 0.1, respectively, for bupivacaine and 7.1 ± 1.1 and 3.6 ± 0.3, respectively, for lidocaine. In addition, the data indicate that the pregnant sheep may be more sensitive to the cardiotoxic effects of bupivacaine than the nonpregnant animal.

Does Pregnancy Alter the Systemic Toxicity of Local Anesthetics

The toxicity of mepivacaine in chronically instrumented nonpregnant and pregnant sheep was evaluated, and compared with data from previous studies of the toxicity of other local anesthetics. Thirteen preparations were studied, seven nonpregnant (NP) and six pregnant (P). Mepivacaine 2 mg.kg-1.min-1 was infused at a constant rate into the femoral vein until toxic manifestations occurred, in the following sequence: convulsions, hypotension, respiratory arrest, and circulatory collapse. The doses and plasma concentrations of mepivacaine necessary to produce toxic symptoms were similar in NP and P animals, whereas, in a previous study, pregnancy enhanced the cardiotoxicity of bupivacaine. No malignant ventricular arrhythmias were observed throughout the study. Protein binding of mepivacaine was also determined in sera from nonpregnant and pregnant ewes and compared with that for bupivacaine. Serum protein binding of mepivacaine was not reduced in pregnancy at the drug concentrations associated with toxic symptoms; at circulatory collapse, it was approximately 22% in NP and P. In contrast, the proportion of bound bupivacaine was 73% in NP and 51% in P, a significant difference. These protein binding data suggest that, although lethal concentrations of bupivacaine, determined in the previous study, were higher in NP than in P animals, concentrations of free drug were similar. Thus, the difference between the two drugs may be related to gestational increases in the availability of free drug in the case of bupivacaine.

Pharmacokinetics of local anaesthetics

Utilizing the pharmacokinetics of local anesthetic agents has different emphasis than for most other drugs, as these agents are applied directly to the site of their action rather than being transported in the blood stream to this site. Toxic reactions to local anesthetics are usually associated with the accidental intravenous injection of drug, but toxic effects can occur in normal usage. A knowledge of how the body handles these agents will help in understanding why these reactions can occur and also their different pharmacological behaviour.

Bupivacaine for intercostal nerve blocks in children: blood concentrations and pharmacokinetics

A pharmacokinetic evaluation of bupivacaine was carried out after intercostal nerve blocks performed on 28 occasions in 27 children varying in age from 3 months to 16 yr. Bupivacaine HCl, 0.5%, with epinephrine 1: 200,000 was employed. Doses of 2 mg/kg, 3 mg/kg, and 4 mg/kg resulted in peak whole blood arterial bupivacaine (base) concentrations (mean ± SD) of 0.77 ± 0.25 μg/ml, 1.37 ± 0.23 μg/ml, and 1.87 ± 0.53 μg/ml, respectively. Calculated pharmacokinetic parameters (mean ± SD) were the following: apparent volume of distribution (VDβ), 2.8 ± 0.8 L/kg; steady-state volume of distribution (VDss), 2.7 ± 0.7 L/kg; elimination half-life (t1/2β), 147 ± 80 min; and total body clearance (Cl), 16.0 ± 7.4 ml·min−1·kg−1 or 382 ± 201 ml·min−1·m−2. Compared with data reported for adult patients, our data indicate that the volume of distribution is greater and clearance is more rapid in children than in adults. The absorption of local anesthetic from the intercostal space appears to be more rapid in children than adults. In an additional group of 11 children, the relationship of the bupivacaine blood: plasma concentration ratio (γ) to hema-tocrit was investigated. Hematocrit in this group ranged from 30 to 59, and γ varied from 0.47 to 0.82. There was a significant relationship between γ and hematocrit defined by the equation γ = −0.0079 Hct + 1.028 (r = 0.72, P < 0.05). Reporting bupivacaine concentration in terms of plasma concentration may introduce an artifact that is dependent on the hematocrit, and we therefore suggest that whole blood concentration values be reported by investigators in the future.

Adverse Effects of Maternally Administered Lidocaine on the Asphyxiated Preterm Fetal Lamb

Lidocaine was infused at a constant rate of 0.1 mg.kg-1.min-1 for 180 min into 12 chronically prepared pregnant sheep while asphyxia, induced by partial umbilical cord occlusion, was maintained in the premature fetus (80% of gestation). In five similar preparations saline instead of lidocaine was infused into the mother for 180 min. Maternal and fetal arterial blood pressure, heart rate, pHa, PaCO2, and PaO2 were monitored, and fetal cardiac output and the distribution of blood flow to fetal organs were measured, using labeled microspheres, before and after asphyxia and again after maternal infusion of lidocaine or saline. Maternal and fetal arterial blood and maternal urine were obtained at intervals for determination of lidocaine concentrations and urinary drug clearance. At the end of infusion, these animals were killed and tissues dissected for determination of lidocaine concentrations and organ blood flow. Maternal and fetal lidocaine plasma concentrations at steady state were 2.32 +/- 0.12 and 1.23 +/- 0.17 microgram/ml, respectively, similar to those seen during human epidural anesthesia. Asphyxia resulted in a significant drop in fetal heart rate and increased blood flow to the brain, heart, and adrenals. Asphyxia and saline did not produce additional deterioration of the fetus, but asphyxia and lidocaine led to a significant increase in PaCO2 and decreases in pHa, mean arterial pressure, and blood flows to the brain, heart, and adrenals. It is concluded that the immature fetus loses its cardiovascular adaptation to asphyxia when exposed to clinically acceptable plasma concentrations of lidocaine obtained transplacentally from the mother.

Pregnancy does not alter lidocaine toxicity

Pregnant sheep are more vulnerable to the toxic effects of bupivacaine, a potent local anesthetic, than are nonpregnant sheep. In contrast, ovine pregnancy does not enhance the toxicity of mepivacaine, a drug with properties similar to lidocaine. We studied the central nervous and cardiovascular toxicity of lidocaine in pregnant sheep receiving a continuous intravenous drug infusion at the rate of 2 mg/kg/min and compared our results with data previously obtained in nonpregnant ewes. In all animals, toxic manifestations occurred in the following sequence: convulsions, hypotension, respiratory arrest, and circulatory collapse. The doses of lidocaine required to produce these symptoms in pregnant and nonpregnant ewes were similar. Convulsions occurred at 5.9 +/- 0.6 mg/kg (mean +/- SE) in the pregnant ewe and 5.8 +/- 1.8 mg/kg in the nonpregnant ewe, whereas circulatory collapse occurred at 40.7 +/- 2.6 and 36.7 +/- 3.3 mg/kg in the pregnant and nonpregnant animals, respectively. Lidocaine plasma concentrations associated with the onset of convulsions in both pregnant and nonpregnant ewes were almost identical (12.1 +/- 0.7 and 11.7 +/- 2.0 micrograms/ml, respectively). At circulatory collapse, these concentrations were 35.1 +/- 3.2 and 41.2 +/- 6.7 micrograms/ml, respectively. It appears that pregnancy does not enhance the toxic effects of lidocaine. These findings are similar to those for mepivacaine but not for bupivacaine, and may be related in part to differences in the way pregnancy affects serum protein binding of these drugs.

Effect of Lidocaine on the Asphyxial Responses in the Mature Fetal Lamb

: The effects of lidocaine on the fetal circulatory responses to asphyxia were evaluated in chronically instrumented pregnant sheep. Twenty-six preparations were studied. Animals were assigned to one of three groups. The animals in group I (N = 10) did not have umbilical cord occluders placed. Lidocaine at 0.1 mg X kg-1 X min-1 was infused to the mother for 180 min. The animals in group II (N = 11) had an umbilical cord occluder, which was inflated to induce fetal asphyxia (PaO2 15 mmHg) for 90 min. Occlusion was then maintained for an additional 180 min while lidocaine at 0.1 mg X kg-1 X min-1 was infused. The animals in group III (N = 5) also had an umbilical cord occluder inflated for 90 min. While occlusion was maintained for an additional 180 min, saline was infused, in place of lidocaine. The infusion rate of lidocaine of 0.1 mg X kg-1 X min-1 over 180 min resulted in a steady-state arterial lidocaine blood concentration in the mother of approximately 2.15 micrograms/ml. Fetal circulatory responses to asphyxia were evaluated before and after maternal infusion of lidocaine or normal saline. Measurements included heart rate, blood pressure, arterial pH, and blood gases. Cardiac output and organ blood flow were determined using the radio-labelled microsphere technique. In general, arterial and tissue lidocaine concentrations in asphyxiated fetuses were higher than those in the nonasphyxiated ones, the differences being significant in the brain, heart, liver, and adrenal glands.(ABSTRACT TRUNCATED AT 250 WORDS)

Estrogen-induced Changes in Protein Binding of Bupivacaine during in Vitro Fertilization

Background: Patients having in vitro fertilization (IVF) procedures that use gonadotropin‐releasing hormone agonist down‐regulation undergo hormonal manipulation of estrogen concentrations to induce oocyte maturation. After achieving minimal estrogen concentrations (baseline), stimulation increases estrogen concentrations to supraphysiologic levels, leading to egg retrieval. The isolated effect of estrogen on protein binding has not previously been reported. This study was conducted to measure the effect of estrogen concentrations on protein binding of two concentrations of bupivacaine, 1 micro gram/ml and 5 micro gram/ml, corresponding, respectively, to systemic concentrations expected after administration of epidural anesthesia and associated with bupivacaine toxicity. Serum proteins were measured to address the mechanism. Methods: Twenty‐nine healthy women undergoing IVF procedures were enrolled and venous samples were drawn at times of minimal and maximal estrogen concentrations. The percentage of free bupivacaine was determined at fixed concentrations of 1 and 5 micro gram/ml. Serum albumin and alpha1 ‐acid glycoprotein concentrations were measured at baseline and at retrieval in a group of 24 women. Results: The percentage of free bupivacaine increased between times of minimal and maximal serum estrogen concentrations, corresponding to decreased protein binding. Concentrations of serum albumin and alpha1 ‐acid glycoprotein decreased between baseline and retrieval times. Conclusions: Patients undergoing IVF procedures demonstrate a decrease in protein binding of bupivacaine from baseline concentrations. These changes may be explained by a decrease in albumin and alpha1 ‐acid glycoprotein. During anesthesia for egg retrieval, clinicians should consider the implications of increased free fraction of drug, especially for highly protein‐bound agents.

Does Gestational Age Affect the Pharmacokinetics and Pharmacodynamics of Lidocaine in Mother and Fetus

The pharmacokinetics and pharmacodynamics of lidocaine were studied in nine chronically prepared pregnant ewes and their fetuses at a mean ( +/- SE) gestation of 119 +/- 1.0 days, and the results were compared to the data previously published for ten animals at 138 +/- 1.2 days of gestation (term 148 days). Lidocaine was infused intravenously to the mother at a constant rate of 0.1 mg.kg-1.min-1 over a period of 180 min, in order to reach a steady-state maternal plasma lidocaine concentration of approximately 2 micrograms/ml. Maternal and fetal blood samples and maternal urine were collected at intervals throughout the infusion for determination of pH, blood gases, and lidocaine concentrations. Maternal and fetal heart rate, blood pressure, and intraamniotic pressure were continuously recorded. Fetal cardiac output and organ blood flow were determined before and at the end of lidocaine infusion using radionuclide-labeled microspheres. Lidocaine tissue concentrations were determined in several maternal and fetal organs excised at the end of infusion. In both groups, the steady-state plasma concentrations of lidocaine were similar; namely, 2.3 +/- 0.17 and 2.1 +/- 0.21 micrograms/ml in preterm and term ewes, respectively. There were also no significant differences in steady-state plasma drug concentrations in preterm and term fetuses (1.3 +/- 0.11 and 1.2 +/- 0.15 micrograms/ml). The mean fetal maternal concentration ratios (F/M) were the same; namely, 0.6. Maternal urinary excretion of lidocaine correlated with urine pH, being greater in the more acid urine. Tissue uptake of drug tended to be higher in the preterm than term mothers, but only significantly so in the brain and adrenals.(ABSTRACT TRUNCATED AT 250 WORDS)