Jeffrey C. Moscicki

Comparison of pH-adjusted lidocaine solutions for epidural anesthesia

One hundred forty-eight adult patients having epidural anesthesia for cesarean section, postpartum tubal ligation, lower extremity orthopedic procedures, or lithotriptic therapy were assigned to five groups. Group 1 patients were given a commercially prepared 1.5% lidocaine solution with 1:200,000 epinephrine plus 1 ml of normal saline per 10 ml of lidocaine; the solution pH was 4.6. Group 2 patients were given commercially prepared 1.5% lidocaine solution plus 1:200,000 epinephrine, with 1 mEq (1 ml) NaHCO3 per 10 ml of lidocaine; the solution pH was 7.15. Group 3 patients received the commercial solution of 1.5% lidocaine with 1:200,000 epinephrine; the solution pH was 4.55. Group 4 patients were given a mixture of 18 ml of 2% lidocaine with 30 ml of 1.5% lidocaine, both commercially packaged with 1:200,000 epinephrine, plus 1 mEq (1 ml) of NaHCO3 added per 10 ml of solution; the solution pH was 7.2. Group 5 patients received 1.5% plain lidocaine to which epinephrine was added to a final concentration of 1:200,000; the solution pH was 6.35. Times of onset of analgesia (time between the completion of the anesthetic injection and loss of scratch sensation at the right hip (L-2 dermatome)) and of surgical anesthesia (time between completion of injection and loss of discomfort following tetanic stimulation produced by a nerve stimulator applied to skin on the right hip) were significantly more rapid in the groups that received the pH-adjusted solutions (groups 4 and 2). Group 4 had the fastest mean onset time, 1.92 ± 0.17 min, followed by group 2, 3.31 ± 0.23 min. Onset times were progressively longer in group 5 at 4.27 ± 0.51 min, group 3 at 4.73 ± 0.37 min, and group 1 at 7.11 ± 0.82 min. The spread of sensory blockade was also significantly more rapid in the pH-adjusted groups 5, 10, and 15 min after epidural injection. In patients having cesarean sections in groups 1 and 2, plasma lidocaine levels in the maternal peripheral venous and in umbilical cord blood and Apgar scores were similar in both groups.

Analgesic and respiratory depressant activity of nalbuphine: a comparison with morphine.

To compare the respiratory depressant and analgesic effects of nalbuphine and morphine, six healthy male subjects were given the drugs as single 0.15-mg/kg doses, and as four successive doses of 0.15 mg/kg. Respiratory depression was monitored by ventilatory and mouth occlusion pressure responses during CO2 rebreathing, while analgesia to experimental pain was tested with the submaximal effort tourniquet ischemia test. When given as single 0.15-mg/kg doses, both drugs significantly increased the threshold and tolerance for experimental pain. The analgesic effect was similar for both drugs at this dosage, as was depression of the ventilatory and occlusion pressure responses to CO2. Morphine administered in multiple doses progressively increased pain tolerance from 30 ± 13% above control with the first dose of 0.15 mg/kg to 107 ± 13% above control after the fourth dose (cumulative total 0.60 mg/kg). Nalbuphine produced a 40 ± 12% increase in pain tolerance with an initial dose of 0.15 mg/kg, but additional increments of nalbuphine did not result in significantly greater analgesia. The increasing morphine dosage was associated with progressive rightward displacement and ultimately decreases in the slope of the CO2 response curves. Nalbuphine produced an initial rightward displacement of the CO2 response curves similar to morphine, but continued administration of the drug did not result in further displacement or changes in slope. These findings demonstrate that nalbuphine, in contrast to morphine, exhibits a ceiling effect for respiratory depression which is paralleled by its limited analgesic effect on experimental pain.

Nitric Oxide Synthase Inhibitor Dose-dependently and Reversibly Reduces the Threshold for Halothane Anesthesia: A Role for Nitric Oxide in Mediating Consciousness?

Nitric oxide is a newly recognized cell messenger for the activation of soluble guanylate cyclase and is produced from L-arginine by the enzyme nitric oxide synthase in a wide variety of tissues, including vascular endothelium and brain. Inhalational anesthetics inhibit nitric oxide production from vascular endothelium and also decrease resting cyclic guanosine monophosphate content in multiple brain regions. Halothane has been shown to depress neurotransmission by L-glutamate and N-methyl-D-aspartate. These amino acid neurotransmitters are known to increase neuronal cyclic guanosine monophosphate content by stimulation of nitric oxide production. To investigate the possible involvement of the L-arginine-to-nitric oxide pathway in the anesthetic state, the effect of a specific nitric oxide synthase inhibitor, nitroG-L-arginine methyl ester, on the minimum alveolar concentration (MAC) for halothane anesthesia was determined in Sprague-Dawley rats. Bolus injection of nitroG-L-arginine methyl ester at 0, 1, 5, 10, 20, and 30 mg/kg resulted in a dose-dependent reduction in MAC for halothane of 0 +/- 0, 2.3 +/- 0.4, 21.5 +/- 3.9, 30.5 +/- 2.4, 51.0 +/- 7.8, and 26.0 +/- 2.8%, respectively. NitroG-L-arginine methyl ester had no effect on MAC for halothane. Bolus infusion of L-arginine 300 mg/kg after MAC reduction by nitroG-L-arginine methyl ester 10 mg/kg resulted in an immediate and complete reversal of the MAC reduction. No reversal was observed after infusion of D-arginine 300 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

The Decrease of the Minimum Alveolar Anesthetic Concentration Produced by Sufentanil in Rats

The anesthetic potency of sufentanil was established by determining its effect on the minimal alveolar anesthetic concentration (MAC) of halothane. Each of eight selected doses of sufentanil was administered to a group of four to five mechanically ventilated rats anesthetized with halothane. Sufentanil was administered as a constant infusion preceded by an intravenous bolus dose that was three times that of the infusion rate per minute. The tail-clamp technique was used to establish control MAC and the MAC of halothane with sufentanil. Increasing sufentanil dosages were nonlinearly related to reductions in the MAC of halothane. A sigmoidal dose-response curve was described. An abrupt, steep response follows the initial upward deflection of the curve with an additional 62% MAC reduction occurring between doses of 1·10−5 mg·kg−1·min−1 and 1·10−4 mg·kg−1·min−1. Essentially complete anesthesia was seen at the latter dosage. No significant adverse side effects were seen with sufentanil at doses up to 1·10−2 mg·kg−1·min−1.

Anesthetic potency of nalbuphine and interaction with morphine in rats.

The contribution to anesthesia by nalbuphine was determined in rats by measurement of the reduction in the anesthetic requirement for cyclopropane produced by increasing doses of nalbuphine while maintaining a constant level of anesthesia (MAC). The respiratory effect of nalbuphine was evaluated by measurement of arterial Pco2 at this constant MAC level. The response produced by the addition of morphine to a constant dose of nalbuphine in further reducing the cyclopropane anesthetic requirement was also evaluated, as was the effect on arterial Pco2. The anesthetic contribution of nalbuphine was dose dependent until a plateau contribution of 0.22 MAC was achieved. Arterial Pco2 increased to a plateau level of 48 torr with nalbuphine administration from a Pco2 of 41 torr with cyclopropane alone. Further increases in Pco2 did not occur until exceedingly high nalbuphine doses were used. Morphine did not supplement the anesthetic contribution of nalbuphine, and there was no increase in Pco2 when morphine was added to nalbuphine during cyclopropane anesthesia. These results suggest that nalbuphine produces analgesia by acting at kappa opioid receptors and that nalbuphine binds but produces minimal effects on mu opioid receptors within the central nervous system.

Propofol Sedation Produces Dose-dependent Suppression of Lidocaine-induced Seizures in Rats

The association of propofol with excitatory motor activity, such as myoclonic jerking and opisthotonus, in humans and in animals suggests that it may aggravate clinical seizure activity in some circumstances, although evidence suggests that under other circumstances, propofol inhibits seizure activity.In the current study, we assessed the effect of sedating doses of propofol on lidocaine-induced seizure activity in spontaneously breathing rats receiving no other anesthetics. Adult Sprague-Dawley male rats, 300-400 g, were divided into a control group and three experimental groups representing three graded levels of propofol sedation. The control rats then received a lidocaine infusion at the rate of 150 mg [center dot] kg-1 [center dot] h (-1), resulting in a slow, progressive increase in systemic lidocaine concentrations. At the onset of electroencephalographic (EEG) seizure activity, arterial lidocaine concentrations were obtained. The treated rats received propofol according to three different dose schedules: Dose 1 = 10 mg [center dot] kg-1 [center dot] h-1 after a 2.5-mg/kg bolus; Dose 2 = 20 mg [center dot] kg-1 [center dot] h (-1) after a 5-mg/kg bolus; Dose 3 = 40 mg [center dot] kg-1 [center dot] h-1 after a 10-mg/kg bolus. After 30 min, a steady level of sedation, dependent on the dose of propofol, was achieved. The lidocaine infusion was then started, and systemic lidocaine levels were obtained at the onset of EEG seizure activity. The lidocaine was continued until the onset of death by cardiac arrest. Plasma lidocaine was measured by gas chromatography. Analysis of variance and Dunnetts t-test were used for comparisons with the control values. Continuous propofol sedation increased the seizure dose of lidocaine from 37.7 +/- 3.5 mg/kg (mean +/- SEM) to 52.5 +/- 2.6 mg/kg (Dose 1, P < 0.05) and 67.9 +/- 8.6 mg/kg (Dose 2, P < 0.05), and completely abolished lidocaine seizures at Dose 3. The lethal dose of lidocaine, 89.4 +/- 10.5 mg/kg control versus 108.7 +/- 10.3 mg/kg (Dose 1), 98.3 +/- 10.1 mg/kg (Dose 2), and 93.5 +/- 10.4 mg/kg (Dose 3) did not differ among groups. The lidocaine levels at seizure threshold were increased in the propofoltreated rats: 16.9 +/- 0.5 [micro sign]g/mL control versus 19.2 +/- 0.7 [micro sign]g/mL (Dose 1, P = not significant) and 23.7 +/- 1.8 [micro sign]g/mL (Dose 2, P < 0.05). Continuous propofol sedation in spontaneously breathing rats receiving no other anesthetics exerts a protective effect against lidocaine-induced seizures in a monotonic, dose-dependent fashion. The cardiac arrest dose of lidocaine is unaffected by propofol under these conditions. Implications: The IV anesthetic drug propofol, given to rats to produce sedation, was found to suppress seizure activity caused by overdosage of the local anesthetic lidocaine. (Anesth Analg 1998;86:652-7)

The anesthetic contribution of magnesium sulfate and ritodrine hydrochloride in rats.

The anesthetic effects of the tocolytic agents, magnesium sulfate and ritodrine hydrochloride, were investigated by determining their effect on the minimal alveolar anesthetic concentration (MAC) of halothane in male and in pregnant and nonpregnant female rats. Magnesium and ritodrine were administered by continuous intravenous infusion to mechanically ventilated rats anesthetized with halothane. The tail-clamp technique was used to establish the MAC of halothane before and then again during the infusion of either magnesium or ritodrine. Ritodrine produced no change in halothane MAC. Increasing magnesium dosages and magnesium plasma levels were associated with nonlinear reductions in halothane MAC that were unrelated to sex or pregnancy. The alveolar halothane MAC concentration in pregnant rats (0.85 +/- 0.02) was not significantly different from the halothane MAC in nonpregnant female or male rats. At the highest plasma magnesium concentrations (15.8 +/- 1.57 mg/dl) achieved in the pregnant rats, the alveolar halothane MAC was 0.36 +/- 0.13, a 61.6% reduction in MAC. The anesthetic effects of magnesium were not attributable to cardiovascular, respiratory, or neuromuscular depression. Major decreases in blood pressure occurred only in the pregnant rats with the highest magnesium concentrations.

Lidocaine pharmacokinetics in children during general anesthesia.

In spite of the increasing use of intravenous lidocaine in the operating room, no pharmacokinetic data exist for intravenous lidocaine in children. We studied ten children, ages 0.5–3 yr, and eight adults to determine lidocaine pharmacokinetics during anesthesia with halothane, nitrous oxide, and oxygen. After induction of anesthesia, tracheal intubation, and insertion of venous and arterial catheters, lidocaine, 1 mg/kg, was infused intravenously over 30 sec. Arterial samples were drawn at 0.5, 1, 2, 4, 5, 10, 15, 30, 60, 90, and 120 min. Plasma was separated and analyzed for lidocaine, using gas chromatography. Plasma concentration vs time data were fitted to a two-compartment model.Using standard formulas, we derived the following data: Children: distribution half-life (t1/2α) 3.2 min, elimination half-life (t1/2β) 58 min, volume of the central compartment (V1) 0.22 L/kg, volume of distribution (Vd area) 1.1 L/kg, and total plasma clearance (Cl) 11.1 ml·kg−1·min−1. Adults: t1/2α 3.6 min, t1/243 min, V1 0.16 L/kg, Vd area 0.71 L/kg, and Cl 9.8 ml·kg−1·min−1. No significant differences were found between children and adults for all parameters analyzed. We conclude that children older than 6 months of age distribute and eliminate intravenous lidocaine in the same manner as adults.

Reduction in halothane MAC: comparison of morphine and alfentanil.

The anesthetic potency and effectiveness of alfentanil and morphine were established by determining the effects of increasing drug doses on the alveolar anesthetic requirement of halothane to maintain a constant anesthetic (MAC) level. Six selected doses of alfentanil and four of morphine were administered to groups of mechanically ventilated rats anesthetized with halothane. Alfentanil was given as a loading dose followed by an intravenous infusion of 0.01–100 μg. kg −1.min −1, and morphine was administered as a subcutaneous dose of 4–20 mg/kg. The reduction in halothane requirement after morphine was biphasic, with a rapid linear increase occurring up to an 8 mg/kg subcutaneous dose, followed by a further, slower reduction in halothane requirement after doses of 8–20 mg/kg. At a 20 mg/kg dose, the halothane MAC was reduced approximately 84%. With alfentanil, a curvilinear reduction in halothane MAC occurred up to an alfentanil dose of 15μg. kg −1.min −1, where a 48% reduction was found. Larger doses produced severe truncal, chest wall, and abdominal rigidity, precluding adequate ventilation and the determination of MAC

Thiopental reduces halothane MAC in rats

The anesthetic contribution of specific plasma concentrations of thiopental has not been previously defined in laboratory animals. The plasma thiopental concentrations needed to reduce the anesthetic requirement for halothane by fractions of the minimum alveolar anesthetic concentration (MAC) were assessed in the rat. After steady-state thiopental plasma concentrations were established with a constant infusion, the tail-clamp technique was used to determine control MAC and the MAC of halothane with increasing concentrations of thiopental. We observed progressive reductions in halothane MAC. This required logarithmic increases in thiopental concentration rather than linear ones. A nonlinear reduction in anesthetic requirement was noted with an approximate 50% reduction in MAC at a thiopental plasma concentration of 7.4 μg/mL and an approximate 90% reduction at 32 μg/mL. Thiopental appears to provide essentially complete anesthesia in the rat model with a logarithmic contribution of increasing plasma concentrations.