Enflurane requirement and ventilatory response to carbon dioxide during lidocaine infusion in dogs.

Arterial plasma lidocaine concentration of 1 to 3.5 microgram/ml produced dose-related decreases in enflurane requirement (MAC) ranging from 15 to 37 per cent in dogs. The ventilatory responses to carbon dioxide at comparable depths of anesthesia with enflurane alone and the enflurane-lidocaine combination were measured in each animal and compared. With both anesthetic regimens there were increases in resting arterial carbon dioxide tension (mean maximal increase = 18 torr) and a 69 per cent decrease in the slope of the ventilatory response as depth of anesthesia increased. The effect of the drug interaction appears to be additive, since the ventilatory depression produced by the enflurane-lidocaine combination was no greater than that produced by enflurane alone at equivalent levels of anesthesia.

Increase in anesthetic uptake, excretion, and blood solubility in man after eating.

Blood-gas partition coefficients of N2O, enflurane, halothane, methoxyflurane, and isoflurane were measured on blood samples from 12 healthy male volunteers before and after eating. The solubility values determined while volunteers fasted substantiate previously reported blood-gas partition coefficients for enflurane, isoflurane, and halothane. Solubility values for methoxyflurane and N2O were slightly greater and smaller, respectively, than accepted values. The uptake and excretion of N2O, enflurane, halothane, and methoxyflurane also were measured in 6 of these subjects in the fasted and postprandial states. Subjects breathed a constant, inspired mixture containing trace concentrations of all 4 gases. Eating increased blood solubility by 17 to 24 percent for all agents except N2O. Accordingly, the rates of rise of the end-tidal enflurane, halothane, and methoxyflurane concentrations were 7 to 8 percent below control, and the rates of anesthetic uptake increased 20 to 23 percent. Simulation studies showed that the increased ventilation induced by eating opposed and, therfore, minimized the impact of increased blood solubility and cardiac output on the rate of end-tidal anesthetic rise. Changes in blood solubility did not correlate with levels of plasma triglycerides and cholesterol.

Lidocaine, monoethylglycinexylidide, and isolated human uterine muscle.

The effects of lidocaine and its primary metabolite monoethylglycinexylidide (MEGX) on isolated human muscle strips from non-gravid and gravid uteri were evaluated. No differences between the effects of lidocaine and those of MEGX on gravid and non-gravid muscle strips were observed. Lidocaine produced significant (P less than 0.01) dose-related depression of uterine contractility, although significant pharamacologic depression occurred only at lidocaine concentrations in excess of 25 microgram/ml. MEGX produced no consistent changes in any of the responses measured.

Central-nervous-system toxicity of local anesthetic mixtures in monkeys.

The central-nervous-system toxicities of local anesthetic mixtures consisting of lidocaine and etidocaine or lidocaine and tetracaine, administered intravenously to four healthy, non-medicated rhesus monkeys, were evaluated. Toxicities were compared by determining seizure dosages for each drug alone and then in a lidocaine-etidocaine-tetracaine mixture. Arterial plasma levels of lidocaine and etidocaine at which electrical seizure activity occurred also were measured when the drugs were administered alone and in combination. The seizure dosages and arterial plasma levels for the drug mixtures studied were equal to the sums of the dosages and thresholds for individual constituents of the mixtures. Under the conditions of this investigation local anesthetic toxicity was additive. (Key words: Anesthetics, local, lidocaine; Anesthetics, local, etidocaine; Anesthetics, local, tetracaine; Brain, seizure thresholds; Toxicity, convulsions.)

Relation of etidocaine and bupivacaine toxicity to rate of infusion in rhesus monkeys.

The relationship between infusion rate of etidocaine and bupivacaine and central nervous system toxicity was studied in three rhesus monkeys. Increasing the infusion rate from 0.5 to 2.0 mg/kg.min-1 decreased the seizure dosage of etidocaine but had no effect on that of bupivacaine. Arterial plasma concentrations of etidocaine and bupivacaine that induced electrical seizure activity increased as the infusion rate was increased from 0.5 to 1.0 mg/kg. min-1. A plasma decay study in a fourth animal demonstrated that etidocaine decayed more rapidly than did bupivacaine. These results suggest that the rate of administration of these agents is important in determining central nervous system toxicity.

Enflurane, isoflurane, and halothane and isolated human uterine muscle.

The effects of equipotent concentrations of enflurane, isoflurane, and halothane on isolated human uterine muscle have been evaluated. Three anesthetic concentrations (0.5, 1.9, and 1.5 MAC) were studied. Specimens included myometrial strips from 45 non-gravid and seven gravid uteri. Both groups of muscle strips showed significant (P less than 0.05) and progressive depression of contractility with all anesthetics. However, the extents of depression at each anesthetic level studied were similar with all drugs. Enflurane, isoflurane, and halothane are equally depressing to isolated human uterine muscle.

Fluroxene toxicity induced by phenobarbital.

Because of reports of fluroxene toxicity in man, the effect of phenobarbital treatment on the toxicity and metabolism of fluroxene was studied in 9 rhesus monkeys. Six monkeys that were exposed to a mean calculated alveolar fluroxene concentration of 5.8% for 4-hr periods up to a total of 16 hr showed no evidence of toxicity. Two animals were sacrificed after a single 4-hr exposure to obtain control measures of fluroxene metabolites in tissues. Four monkeys that had previously survived received exposures to fluroxene and 3 monkeys that had no exposure to fluroxene died during fluroxene anesthesia after treatment with phenobarbital (mean time, 3 hr). Toxicity was manifested by arterial hypotension, pulmonary edema, and arterial hypoxemia. Phenobarbital treatment enhanced production of fluroxene metabolites, including the highly toxic trifluoroethanol. Concentrations of trifluoroethanol in mixed-expired gas, blood, and urine, and of total nonvolatile fluorine in blood, urine, and tissues of animals treated with phenobarbital were 2 to 10 times as in control animals. The results suggest that the rhesus monkey is a valuable model for the study of fluroxene pharmacology and that inclusion of an enzyme-inducing challenge in the evaluation of potential toxicity of other anesthetics seems warranted.