H. Pedersen

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.

Incidence of visceral pain during cesarean section: the effect of varying doses of spinal bupivacaine

The safety of 0.5% hyperbaric bupivacaine, as well as the incidence and severity of visceral pain, were evaluated in 36 women undergoing elective cesarean section under spinal anesthesia who, randomly divided into two groups, received different dose ranges according to height, 7.5-10 mg in group A and 10-12.5 mg in group B. When sensory block to at least the fourth thoracic dermatome was established, surgery was begun and the occurrence and severity of visceral pain recorded (visual analog scale) by an observer unaware of patient data. The level of analgesia to pinprick was determined when and if there was onset of pain intraoperatively, and supplementary medication was administered as needed. Hypotension, the incidence of which was similar in both groups, was treated as necessary with ephedrine. No patients experienced pain until after delivery of the infant. Thereafter, moderate to severe pain, in association with peritoneal traction, occurred in 12 patients in group A (70.5%) but only in 6 patients in group B (31.6%). In patients experiencing moderate to severe pain, the mean time between induction of anesthesia and onset of pain was similar in both groups, as was the amount of systemic narcotic given. Total time for regression of sensory analgesia to L5 was longer in patients in group B (243.9 versus 195.4 min), and the incidence of complete motor blockade was greater in group B. Increasing the amount of 0.5% hyperbaric bupivacaine per spinal segment reduces the occurrence of moderate to severe visceral pain during elective cesarean section without jeopardizing mother or fetus.

Toxicity of Lidocaine in Adult, Newborn, and Fetal Sheep

The relative central nervous system and cardiovascular toxicity of lidocaine was compared in adult, newborn, and fetal sheep during continuous infusion of lidocaine into the jugular vein at the rate of 2 mg.kg−1.min−1. An identical sequence of toxic manifestations occurred in the adult, newborn, and fetus: convulsions, hypotension, respiratory arrest, and circulatory collapse. Doses necessary to produce these manifestations were highest in fetuses and lowest in adults. For example, in order to elicit convulsions, 5.8 ± 1.8 mg/kg of lidocaine was required in the adults, 18.4 ± 2.2 in the newborns, and 41.9 ± 6.0 in the fetuses. Measurements of lidocaine concentrations in blood demonstrated that these toxic symptoms occurred at levels which were not significantly different among the three groups. The results indicate that fetal and newborn lambs are no more sensitive to lidocaine toxicity than are adult sheep. The fact that the highest doses were required in the fetuses is probably related to the placental clearance of the drug into mothers and better fetal maintenance of arterial PO2 despite convulsions and respiratory arrest (cessation of breathing-like movements).

Hyperbaric Bupivacaine for Spinal Anesthesia in Cesarean Section

The efficacy and safety of 0.5% hyperbaric bupivacaine (Sensorcaine, Astra) was evaluated in 22 patients undergoing elective cesarean section under spinal anesthesia. The dose varied from 7.5 to 10 mg, (depending on the patients height) which was significantly lower than previously reported. Patients were placed in head-down tilt immediately after sub-arachnoid injection. The mean spread of analgesia was to T3, which was reached in 10–15 min. Regression was complete in 258 ± 16 min. Complete motor paralysis of lower extremities occurred in only two patients. Complete recovery of motor function in all patients was evident in less than 2.5 h. All infants were vigorous at birth and there were no serious maternal complications. The incidence of hypotension was 4.5%, the lowest reported as a consequence of spinal anesthesia in this group of patients, A technique involving the use of reduced doses of hyperbaric bupivacaine (0.5%) in conjunction with head-down tilt appears to be useful for spinal anesthesia for cesarean section.

Systemic toxicity of ropivacaine during ovine pregnancy.

Ropivacaine is a new amide local anesthetic structurally related to bupivacaine and mepivacaine. Its potency and duration of action are similar to those of bupivacaine but its therapeutic index may be greater. Since pregnancy enhances the cardiotoxicity of bupivacaine, the current study was devised to compare the toxicity of ropivacaine in chronically instrumented nonpregnant and pregnant ewes during continuous intravenous infusion of the drug at the rate of 0.5 mg.kg-1.min-1. In all animals, symptoms of local anesthetic toxicity occurred in the usual order--convulsions, hypotension, apnea, and circulatory collapse. There were no significant differences between the two groups of animals in the doses and plasma concentrations of ropivacaine associated with each toxic manifestations. For example, circulatory collapse occurred at a mean dose of 11.3 +/- 1.1 mg.kg-1 in nonpregnant and 12.4 +/- 0.9 mg.kg-1 in pregnant animals, with corresponding plasma concentrations of 7.3 +/- 0.3 and 9.6 +/- 2.1 micrograms.ml-1 (P = not significant). Protein binding of ropivacaine in the concentration range associated with toxic manifestations was similar in sera obtained from nonpregnant and pregnant ewes. In conclusion, ovine pregnancy does not enhance the systemic toxicity of ropivacaine, possibly because of an absence of gestation-related increase in the availability of free drug.

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.

Pharmacokinetics of Lidocaine in Fetal and Neonatal Lambs and Adult Sheep

The pharmacokinetics of lidocaine were studied in fetal and neonatal lambs and in pregnant and nonpregnant adult sheep. Catheters were implanted in the femoral vessels and in the urinary bladders of animals prepared for chronic study. Lidocaine, 5–10 mg/kg, was injected intravenously either into the fetus or newborn lamb or into nonpregnant adult sheep. Serial samples of arterial blood and urine were obtained over four hours and analyzed for unchanged lidocaine using a gas chromatographic technique. The elimination half-lives of lidocaine in the bloods of nonpregnant ewe, neonate and fetus were 31, 51 and 33 min, respectively. Total-body clearances in the neonate and adult were 53 and 41 ml/min/kg. The metabolic clearances of lidocaine were the same in both, and approximated hepatic blood flow. Renal clearance was greater in the neonate, which was attributed to differences in urinary pH values and extents of protein binding. Thus, despite differences in half-lives, the newborn lamb is as capable as the adult of clearing lidocaine.

Current controversies in obstetric anesthesia

ontroversies in obstetric anesthesia are difficult to resolve for several reasons. Ethical considC erations often preclude the initiation of prospective, randomized studies, so that most authors have had to rely on retrospective analyses of patient records, disregarding selection bias and the multiplicity of uncontrolled variables. This has led to some highly questionable conclusions, as is well illustrated in the large number of studies attempting to determine the effects of epidural analgesia on the progress of labor, and the incidence of instrumental or operative delivery. Until recently, clinical studies assessing the integrity of uteroplacental perfusion, so crucial to fetal well-being, were often limited to the evaluation of the neonate by such insensitive means as the Apgar scoring system. With technologic advances in Doppler velocimetry, more precise information on the effects of drugs, such as vasopressors, can be expected. Animal studies, although allowing for more controlled conditions, may not be clinically applicable, due to species differences and the drug dose chosen. For example, the risk of teratogenic effects from nitrous oxide, although well documented in mice and rats, was probably exaggerated in humans. This review will address the following controversial issues: cardiotoxicity of local anesthetics during pregnancy, the choice of an epidural test dose, vasopressors and uteroplacental blood flow, the effects of epidural analgesia on the progress of labor, and, finally, the teratogenic risk to humans of nitrous oxide.

Effect of ropivacaine and bupivacaine on uterine blood flow in pregnant ewes.

The effects of ropivacaine, a new amide local anesthetic, on uterine blood flow and fetal well-being were compared with those of bupivacaine in 10 chronically instrumented pregnant ewes. In random sequence, animals received two intravenous infusions of each drug. The low infusion rate regimens were chosen to result in clinically relevant maternal plasma concentrations of local anesthetics, whereas the more rapid rates of infusions were given to assess the safety of higher maternal drug concentrations. An epinephrine infusion was given to demonstrate the appropriateness of the animal model for the measurement of uterine blood flow. Maternal and fetal heart rates, arterial blood pressure, and the ewes central venous pressure, intraamniotic pressure, and uterine blood flow were recorded continuously. Arterial blood samples were taken from mother and fetus at frequent intervals to determine acid-base status and local anesthetic concentrations. A total of 39 studies were performed. None of the infusions of either local anesthetic resulted in a significant decrease in uterine blood flow or deterioration in fetal condition. The mean maternal plasma concentrations at the end of infusions were as follows: ropivacaine low dose, 1.60 +/- 0.35 micrograms/mL; bupivacaine low dose, 1.55 +/- 0.15 micrograms/mL; ropivacaine high dose, 2.50 +/- 0.37 micrograms/mL; and bupivacaine high dose, 1.83 +/- 0.19 micrograms/mL. Epinephrine infusion resulted in a 25% decrease in uterine blood flow without adverse fetal effects. We conclude that neither ropivacaine nor bupivacaine, as administered in this study, led to any ill effects on uterine artery blood flow or fetal well-being.

Etidocaine Toxicity in the Adult, Newborn, and Fetal Sheep

The systemic toxicity of etidocaine was compared in adult, newborn, and fetal sheep during continuous infusion of the drug into the jugular vein at the rate of 0.5 mg·kg-1·min-1. All recipients exhibited symptoms of toxicity in the following order: convulsions, hypotension, respiratory arrest, and circulatory collapse. The dose of etidocaine required to produce CNS and cardiovascular toxicity was significantly different among the three age groups, being the highest in the fetus and the lowest in the adult. In contrast, no significant difference in etidocaine blood concentrations at the onset of each toxic symptom was observed among the groups except that convulsions and hypotension occurred at lower blood levels in the fetus as compared with the newborn and adult. Comparisons of etidocaine 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 exists in adults and newborn following administration of etidocaine.