Patricia A. Turner

Neural Blockade and Pharmacokinetics following Subarachnoid Lidocaine in the Rhesus Monkey I. Effects of Epinephrine

A sensitive and reliable animal model for the objective physiologic and pharmacokinetic evaluation of spinal anesthesia has been developed. Using this model, spinal anesthesia using lidocaine (30 mg) in 7.5% dextrose with and without epinephrine was compared. Epinephrine did not alter the degree or duration of time to achieve maximum motor block. However, epinephrine did significantly increase the time for complete motor recovery. A significantly higher dermatome level of sensory block was achieved in the epinephrine-containing solutions, as well as a significantly longer time for complete recovery. This reflects a latent effect of epinephrine, as the time for two-segment regression was independent of epinephrine. Pharmacokinetic analysis showed no effect of epinephrine on absorption and elimination constants. The maximum plasma concentration and time to reach maximum plasma concentration were equal with and without epinephrine.

Comparison of Neural Blockade and Pharmacokinetics after Subarachnoid Lidocaine in the Rhesus Monkey. Ii: Effects of Volume, Osmolality, and Baricity

The effects of volume, osmolality, and baricity on lidocaine spinal anesthesia in the rhesus monkey were studied. Changes in neural blockade, physical properties of cerebrospinal fluid, and arterial pharmacokinetics associated with variations in injectate composition were assessed. Wide ranges of volume, baricity, and osmolality were studied using 1, 2, and 5% lidocaine prepared in either sterile water or 7.5% dextrose. Minimal changes in neural blockade were found in the ranges of osmolality and baricity studied, although 5% lidocaine in sterile water resulted in significantly shorter complete recovery times for both sensory and motor block when compared to other solutions. Samples of cerebrospinal fluid obtained after injection of lidocaine showed increases or decreases in specific gravity and osmolality depending on the physical properties of the solution injected. No differences in elimination phase pharmacokinetics were found with any of the lidocaine solutions. Rates of systemic absorption increased with decreasing osmolality. Osmotic potentiation of lidocaine spinal anesthesia could not be demonstrated.

Pharmacokinetics and Neural Blockade after Subarachnoid Lidocaine in the Rhesus Monkey III. Effects of Phenylephrine

Using a rhesus monkey model, lidocaine (30 mg) in 7.5% dextrose was compared with lidocaine (30 mg) in 7.5% dextrose containing 1.5 mg of phenylephrine (Neosynephrine). Phenylephrine increased both duration of maximum motor block and time for complete motor recovery. A significantly higher sensory dermatome level and significantly longer time for complete sensory recovery was found when the lidocaine solution contained phenylephrine. Time for two-segment regression of sensory blockade was unaffected by phenylephrine. The slope of the regression phase for motor block was parallel for both treatments, suggesting differences in neural blockade were caused by a more profound initial block when phenylephrine was added. Pharmacokinetic analysis revealed identical absorption and elimination constants. Maximum plasma concentrations of lidocaine and time to reach maximum plasma concentrations were identical with and without phenylephrine. The systemic absorption (fraction of drug absorbed from the subarachnoid space) was complete with and without phenylephrine. No lag times for systemic absorption were found for either treatment. Our data demonstrate that there are no clinically significant differences between phenylephrine and epinephrine when added to lidocaine solutions for spinal anesthesia.

Serum bupivacaine concentrations in term parturients following continuous epidural analgesia for labor and delivery

This study was undertaken to measure the blood concentrations of bupivacaine associated with a single loading dose followed by continuous epidural infusion for the management of the pain of labor and delivery with special reference to the potential for accumulation and toxicity. Four-milliliter venous blood samples were obtained every 15 min following the loading dose until delivery. If inadequate analgesia was observed just prior to delivery, an additional dose of bupivacaine was administered. Bupivacaine concentrations were measured using a double extraction technique followed by gas chro-matographic analysis using a nitrogen-specific detector. Clearance, volume of distribution, and rate of absorption were estimated from the blood concentration time data and were 43.39 ± 11.46 L/h, 67.56 ± 17.66 L, and 8.97 ± 3.69 h-1, respectively. Peak serum bupivacaine concentrations were 0.68 ± 0.14 μg/ml and occurred 0.58 ± 0.25 h following administration of the loading dose. The duration of bupivacaine infusion was 3.42 ± 0.80 h. Serum bupivacaine concentrations at delivery or just prior to administration of a supplemental delivery dose were significantly lower than the peak concentration in all patients (p < 0.001). Fetal-to-maternal serum concentration ratios were found to be 0.44 ± 0.16 for the six patients requiring a supplemental delivery dose and 0.44 ± 0.13 for the six patients receiving bupivacaine only by infusion—The data reported here illustrate that epidural analgesia for labor and delivery achieved using a single 50-mg loading dose followed by a continuous infusion of 12.5 mg/h of bupivacaine will not result in maternal or fetal accumulation or toxicity.

Evaluation of lidocaine spinal anesthesia in the rhesus monkey.

The present study was undertaken to determine whether a nonhuman primate model could be developed that would allow reproducible spinal anesthesia with determination of onset and duration of both sensory and motor anesthesia, using techniques for evaluation common in clinical practice. Recently, Feldman and Covino (1) reported the development of a chronic dog model for evaluation of spinal anesthesia. However, their model was used for determination of onset and duration of motor anesthesia only. They were not able to measure either sensory or autonomic blockade. A review of the limited Iiterature relating to spinal anesthesia in primates reveals examination of narrow aspects of the technique. Some of those studies examined systemic and regional blood flow during spinal anesthesia, but there was no attempt to measure neural blockade (2). Another study was conducted using hyperbaric ketamine in the rhesus mon-

Bupivacaine Protein Binding in the Term Parturient: Effects of Lactic Acidosis

The effects of lactic acidosis on bupivacaine serum protein binding was studied in a group of term parturients and a group of nonpregnant female control subjects. Groups were matched in age and health. Distribution characteristics of bupivacaine in pregnancy were determined. Bupivacaine protein binding was best characterized by the model for two classes of binding sites in all studies. The parturients exhibited a lower capacity for the high-affinity, low-capacity (alpha 1-acid glycoprotein) site and higher affinity for the low-affinity, high-capacity (albumin) site. Lactic acidosis decreased the affinity constant for the high-affinity, low-capacity site in the control group but did not change binding characteristics in the parturients. Free concentration of bupivacaine (Cu) was elevated at low total bupivacaine concentrations (Ct) (less than 10 micrograms/ml). No differences in Cu were detected at concentrations in the cardiotoxic range (greater than 20 micrograms/ml). The Cu values predicted by the estimated binding parameters from in vitro experiments were compared with actual Cu measured in nine parturients at delivery; they correlated significantly (r = 0.94). Distribution changes for bupivacaine in the parturients were consistent with known physiologic changes in body composition associated with pregnancy. Alterations that occur in serum protein binding during pregnancy should not result in increased risk of central nervous system or cardiovascular system toxicity since these alterations do not increase free tissue concentration.

Influence of Cimetidine on Bupivacaine Disposition in Rat and Monkey

Recent reports have appeared describing a cimetidine-induced alteration in either the input or disposition function for many drugs. The total clearance component of the disposition function is the primary perturbation. In the present investigation, the influence of cimetidine on bupivacaine disposition was studied, using in vitro and in vivo models. Since the extraction ratio for bupivacaine is low, total clearance follows the capacity-limited theory. Hence, the influence of cimetidine on the intrinsic clearance of bupivacaine was assessed using microsome and hepatocyte models. Results for both systems are in excellent agreement and indicate a noncompetitive inhibition. Additionally, the influence of cimetidine on the protein-binding profile of bupivacaine was determined. In the presence of cimetidine, the these findings was assessed in vivo in rhesus monkeys. co-administration of cimetidine resulted in an increase in the volume of distribution at steady state and no change in the total clearance of bupivacaine.