Cosmo A. DiFazio

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.

Effects of lidocaine on the anesthetic requirements for nitrous oxide and halothane.

The effects of various plasma concentrations of lidocaine on nitrous oxide anesthesia in man and halothane requirements in the dog were studied. The response to incision of the skin was observed in 20 patients who were anesthetized with nitrous oxide, 70% inspired, and oxygen, 30%, plus various plasma levels of lidocaine. In addition, changes in the MAC of halothane in dogs were observed at various levels of lidocaine. In both circumstances lidocaine concentrations of 3 to 6 microgram/ml decreased anesthetic requirements approximately 10 to 28%. At clinically common concentrations of lidocaine, significant decreases in anesthetic requirements should be anticipated.

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.

Lidocaine constricts or dilates rat arterioles in a dose-dependent manner

The microvascular effects of varying concentrations of lidocaine were evaluated with the use of videomicroscopy in an in vivo rat cremaster muscle preparation. Animals were anesthetized with chloralose and urethane and breathed room air spontaneously. Mean areterial pressure and heart rate were measured via a carotid artery cannula. The cremaster muscle was suffused with a balanced electrolyte solution and pH, temperature, Po2, Pco2, and osmolarity were controlled. Internal diameters of fourth-order arterioles in the cremaster muscle were measured with an electronic vernier system. In one group of animals (n = 7), arteriolar diameters were measured every 30 s during a 10-min control period, a 10-min period of topical application of lidocaine hydrochloride, and a 10-min recovery period. Lidocaine hydrochloride, 100, 101, 102, 103, or 104 μg·ml−1, produced changes in arteriolar diameters to 88.9 ± 0.9, 79.0 ± 1.3, 67.5 ± 2.4, 60.1 ± 3.4, and 127.1 ± 7.2 per cent of control, respectively (P < 0.001). In a second group of animals (n = 4), fourth-order arteriolar diameters were measured during administration of intravenous lidocaine, 1.2 mg·kg−1 bolus plus 0.3 mg·kg−1 · min−1. Vasoconstriction to 91.3 ± 0.9% of control was observed (P < 0.001). These results demonstrate a biphasic dose-dependent response to lidocaine. At lesser concentrations, including those that occur in the plasma of patients during intravenous infusion or nerve blocks, dose-related vasoconstriction occurred. Lidocaine, 104 μg · ml−1, a concentration similar to that which occurs at the site of injection during infiltration, nerve block, or epidural anesthesia, produced vasodilation. It appears likely that the observed effects are a result of peripheral rather than central actions of the drug.

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)

Prolonged Antagonism of Opioid Action with Intravenous Nalmefene in Man

To identify the opioid antagonist activity of nalmefene and to determine its duration in man, six healthy male subjects were pretreated on separate days with a saline placebo, 0.5 mg, 1 mg, or 2 mg nalmefene intravenously in a randomized double-blind fashion. Opioid challenges with fentanyl, 2 μg/kg, then were administered 1,2,4,6, and 8 h afterward. Respiratory depression was monitored by ventilatory and occlusion pressure responses during CO2 re-breathing, while analgesia to experimental pain was identified with the submaximal effort tourniquet ischemia test. One hour following placebo pretreatment, the initial fentanyl dose produced marked respiratory depression. Minute ventilation and occlusion pressure at a PCO2 60 mmHg during rebreathing (VE60 and P0.160) were reduced to 29 and 41% of control, respectively. The slopes of the ventilatory and occlusion pressure responses also decreased significantly to 51 and 55% of control. Respiratory effects were similar with all subsequent fentanyl doses. Pretreatment with 2 mg nalmefene completely prevented the subjective and respiratory effects of fentanyl for the entire 8 h of the experiment. Nalmefene, 1 mg, significantly blunted the fentanyl effects for the same period, but VE60 values at 6 and 8 h were depressed significantly (P < 0.05) to 66 and 61% of control. The antagonist effects of the lowest nalmefene dose, 0.5 mg, persisted for about 4 h, at which time V E60 was 64% of control. Fentanyl administration produced consistent increases in pain tolerance (44–55% above control) throughout the experiment. Nalmefene pretreatment abolished this analgesic response in a dose-related time course that mirrored the respiratory effects almost exactly. These findings demonstrate that nalmefene is an effective opioid antagonist with a duration of action far in excess of naloxone and more clearly related to dose.

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.

Naloxone versus nalbuphine infusion for prophylaxis of epidural morphine-induced pruritus.

This randomized, double-blind study compared the efficacy of two mu-receptor antagonists, naloxone and nalbuphine, in the prophylactic management of pruritus in postcesarean section patients receiving epidural morphine. Dosages of study drugs were individualized by the use of a patient self-administration (PSA) device. All 51 patients were healthy women who received a uniform epidural anesthetic and epidural morphine (5 mg). Coded solutions were infused for 24 h, with 5-min PSA lockout times: Group A (n = 17), nalbuphine 2.5 mg/h, PSA nalbuphine 1 mg; Group B (n = 16), naloxone 50 micro gram/h, PSA saline; Group C (n = 18), naloxone 50 micro gram/h, PSA naloxone 40 micro gram. Patients were assessed for pruritus and pain every 8 h for 24 h. Both naloxone and nalbuphine provided good relief for pruritus; median pain and pruritus scores were in the none-to-mild range (0-3) for all groups at all assessment intervals. The pruritus scores of the PSA saline group were higher during the 16- to 24-h period (P < 0.05) than the scores of either group receiving mu-receptor antagonist by PSA. There was evidence of shortening of the duration of analgesia in patients receiving naloxone who required treatment for pruritus after 16 h. Patients who self-administered large doses of nalbuphine over the first 8 h also reported pain scores consistent with reversal of analgesia. The potency ratio for naloxone:nalbuphine for antagonism of the pruritic effects of epidural morphine was approximately 40:1. Intervention to treat either unrelieved pruritus or pain, respectively, was necessary in the following numbers of patients: Group A, 0/1; Group B, 1/1; Group C, 2/2. Prophylactic infusions offer the potential for labor cost savings by minimizing the need for episodic therapeutic interventions to treat pruritus. (Anesth Analg 1996;82:641-7)

Effects of ph on Protein Binding of Lidocaine

Protein binding of lidocaine (2.5, 5, 10, and 20 μg/ml) in fresh plasma was studied from pH 5.6 to pH 9.8. Percent binding of lidocaine was inversely related to hydrogen-ion and lidocaine concentrations.

Dose-dependent Effects of Bupivacaine on Rat Muscle Arterioles

The dose-dependent actions of bupivacaine on the microvasculature were evaluated by television microscopy in an in vivo rat cremaster muscle preparation. Animals were anesthetized with chloralose and urethane. Mean arterial pressure was measured via a carotid artery cannula; heart rate was calculated from the phasic pressure trace. The cremaster muscle was suffused with a balanced electrolyte solution that was controlled for temperature, pH, PO2, PCO2, and osmolarity to provide a physiologic environment. Internal diameters of fourth-order arterioles were measured with an electronic vernier displayed on the video monitor. Arteriolar diameters were measured every 30 s during a 10-min control period, a 10-min period of topical application of bupivacaine hydrochloride, and a 30-min recovery period. Bupivacaine 10−1, 100, 101, and 102 μg · ml−1 produced progressive vasoconstriction to 82.7 ± 2.9%, 75.0 ± 5.6%, 71.0 ± 7.0%, and 65.7 ± 9.4% of control (P ≤ 0.05 for each), respectively. Bupivacaine, 103 and 2.5 X 103 μg · ml−1, did not alter arteriolar diameters significantly, although there was a tendency for vasodilation. In a second group of animals, arteriolar diameters were measured during intravenous bupivacaine infusion that produced stable plasma concentrations of 2.3 ± 0.2 μg · ml−1. Vasoconstriction of 91.4 ± 2.2%, of control (P ≤ 0.01) was observed. These results demonstrate that dose-dependent arteriolar constriction occurs even with blood bupivacaine levels that are at the upper limits of those expected to occur during regional anesthesia.