Mechanism of age-related and nitrous oxide-associated anesthetic sensitivity: the role of brain catecholamines

To provide a neurochemical basis for differences in their anesthetic requirements, the authors examined mice selectively bred for resistance (HI) and susceptibility (LO) to nitrous oxide anesthesia for brain levels of catecholamines. Concentrations of norepinephrine and dopamine in whole brain were 26% and 13% higher (P less than 0.001), respectively, in HI mice than in LO mice. Whole-brain levels of 3,4-dihydroxyphenylacetic acid, a major metabolite of dopamine, were the same for both HI and LO groups of mice. The authors then analyzed portions of the HI and LO mice brains for concentrations of norepinephrine and dopamine. A significant correlation was found between norepinephrine content in the medulla and nitrous oxide requirement. In other regions of the brain (cerebellum, cerebral cortex, hippocampus, pons, midbrain, hypothalamus), no significant differences in norepinephrine or dopamine levels could be detected. Differences in anesthetic requirements between resistant and susceptible mice decrease from 0.99 to 0.53 atm as they aged from 100 days to 600 days old, paralleling the decline in differences in norepinephrine levels in medulla oblongata between HI and LO mice from 1.6 to 0.73 ng/mg protein. Thus, the difference in anesthetic requirement between HI and LO mice may arise from alterations in catecholamine content in specific regions of the brain.     

Rapidly developing tolerance to acute exposures to anesthetic agents.

Following the observation that mice manifest a characteristic withdrawal syndrome after an hour of exposure to nitrous oxide, the authors reasoned that there might be a very rapidly developing tolerance to nitrous oxide. Thus, they determined the inspired concentrations that cause loss of the righting reflex in mice (i.e, the ED50), in the presence of 1 atm of oxygen, of: 1) nitrous oxide alone; 2) cyclopropane alone; 3) nitrous oxide plus 13.6 atm helium; 4) ethylene plus 13.6 atm helium. In each instance the ED50 was determined after averages of 6,34 and 64 min of exposure to the anesthetic agents. For nitrous oxide alone the ED50 at 6 min was 1.18 +/- 0.049 atm, increasing to 1.39 +/- 0.061 atm at 64 min. For ethylene plus helium the ED50 increased from 1.21 +/- 0.033 atm at 6 min to 1.31 +/- 0.039 atm at 64 min, indicating the development of acute tolerance. Neither cyclopropane alone nor nitrous oxide plus helium caused acute tolerance. This absence of tolerance may have resulted from a slower development of an alveolar anesthetic concentration.     

Potencies of barbiturates in mice selectively bred for resistance or susceptibility to nitrous oxide anesthesia

To test the possibility that mice selectively bred for resistance (HI mice) and susceptibility (LO mice) to nitrous oxide anesthesia have general differences in central nervous system sensitivity to other depressants, we examined the effects of four barbiturates in these two lines of mice. LO mice given intraperitoneal injections of barbital (275 mg/kg), hexobarbital (120 mg/kg), pentobarbital (65 mg/kg), or secobarbital (50 mg/kg) had significantly (16-46%) longer sleep times than HI mice. Concentrations of barbiturates were significantly (12-73%) greater in the serum and 3-55% greater in the brain on awakening in HI mice than in LO mice. The largest separations in potency between the HI and LO lines occurred with pentobarbital and hexobarbital and the smallest separations with barbital and secobarbital. We concluded that HI and LO mice do have a general resistance and susceptibility to barbiturates, but that the magnitude of the difference in central nervous system sensitivity between the two lines varies among barbiturates.     

Direct measurement of nitrous oxide MAC and neurologic monitoring in rats during anesthesia under hyperbaric conditions.

The minimum alveolar concentration (MAC) of nitrous oxide necessary to prevent purposeful movement in rats has not been directly measured; rather, it has been extrapolated because the required partial pressure exceeds 760 mm Hg, or 1 atm absolute pressure (ATA). Values reported have ranged from 1.36 to 2.20 ATA (136-220 vol%, or 1034-1672 mm Hg). By maintaining general anesthesia at 2.25 ATA (1710 mm Hg), we directly measured the nitrous oxide MAC in 17 Long-Evans rats during mechanical ventilation and monitoring of two-channel electroencephalogram, compressed spectral array and cortical evoked potentials, electrocardiograph, and respiratory and anesthetic gases by mass spectrometry. After a minimal stabilization period of 30 min during ventilation by 1.8 ATA nitrous oxide and 0.45 ATA oxygen, MAC measurements were begun. Each rat was given up to three noxious electrical stimulations of 50 V by 10-ms-duration pulses at 50/s for 45 s. The partial pressure of nitrous oxide was decreased by approximately 10% after each negative response. The MAC was taken as the nitrous oxide concentration midway between that at which there was no response and that at which the rat moved purposefully. The nitrous oxide MAC in Long-Evans rats was determined to be 1.55 +/- 0.16 ATA (mean +/- SD). Hyperbaric nitrous oxide decreased electroencephalogram wave frequency to a predominantly theta rhythm of increased amplitude. Cortical evoked potentials had decreased wave amplitudes and increased latencies with increasing partial pressures > 0.75 ATA.(ABSTRACT TRUNCATED AT 250 WORDS)     

Nonlinear antagonism of anesthesia in mice by pressure

Previous studies have shown a rectilinear antagonism by pressure of nitrous oxide or isoflurane anesthesia in mice (pressure reversal). Since a rectilinear pressure reversal is predicted by the critical volume hypothesis for anesthesia, we examined this phenomenon with two other gases. We measured the doses of argon or nitrogen which abolished the righting reflex in 50% of animals (ED50) at various high pressures produced by the addition of helium. The ED50 values of argon and nitrogen alone are 16.7 +/- 1.37 and 38.3 +/- 1.62 atmospheres absolute (ATA). Fifty-five percent more argon and 27% more nitrogen is needed to produce anesthesia at 100 ATA. However the increasing anesthetic requirements with pressure were curvilinearly related to pressure, rising most steeply at pressures near the ED50 without helium. This suggests that the pressure reversal of anesthesia is not simply a reciprocal anesthetic expansion-pressure compression phenomenon as predicted by the critical volume hypothesis. It suggests that anesthetics and pressure act at different sites.     

Mice with glycine receptor subunit mutations are both sensitive and resistant to volatile anesthetics

We used two mouse lines with glycine receptor mutations to determine whether glycine receptors might play an important role in anesthetic responses in vivo. Spastic (spA) mutants were slightly more sensitive (P = 0.02) to enflurane in the loss-of-righting reflex assay (50% effective concentration [EC(50)] = 1.17 +/- 0.06 atm for controls versus 0.97 +/- 0.06 atm for spA) but were also substantially more resistant (P = 0.01) to enflurane in the tail clamp assay (EC(50) = 1.96 +/- 0.10 atm for controls versus 2.58 +/- 0.25 atm for spA). spA mice were also more sensitive to halothane (P < 0.001) in the loss-of-righting reflex assay (EC(50) = 0.81 +/- 0.03 atm for controls versus 0.57 +/- 0.04 atm for spA), but the responses of mutant and control mice to tail clamp in the presence of halothane were similar. Spasmodic control and mutant mice did not differ in their responses to the two drugs. Sleep time was substantially longer in both mutant mouse lines after injection of three hypnotics (midazolam, pentobarbital, and ethanol). Our results suggest a complex involvement of glycinergic pathways in mediating anesthetic responses. Greater sensitivity to the hypnotic effect of enflurane, halothane, midazolam, pentobarbital, and ethanol in mutant mice with diminished glycinergic capacity suggests that glycinergic activity is inversely related to hypnosis, whereas resistance to enflurane in the tail clamp assay suggests that glycinergic activity potentiates the minimum alveolar anesthetic concentration response. Halothane seems to share some, but not all, of enflurane's mechanisms, indicating that not all volatile anesthetics modulate glycinergic pathways equally. IMPLICATIONS: We tested two mouse lines with glycine receptor mutations to determine whether glycine receptors might play an important role in anesthetic responses in vivo. Both sensitivity and resistance to common anesthetics were observed in mutant mice, depending on the behavioral end-point evaluated.     

Dexmedetomidine Enhances Analgesic Action of Nitrous Oxide: Mechanisms of Action

Background: Nitrous oxide and dexmedetomidine are thought to mediate analgesia (antinociception in a noncommunicative organism) via [alpha]2B- and [alpha]2A-adrenergic receptor subtypes within the spinal cord, respectively. Nitrous oxide and dexmedetomidine exert diametrically opposite effects on neuronal activity within the locus ceruleus, a pivotal site for modulation of analgesia. Because of these differences, the authors explored whether the two analgesics in combination would provide satisfactory analgesia.

Methods: The analgesic effects of nitrous oxide and dexmedetomidine given both intraperitoneally and intrathecally were evaluated using the tail-flick latency test in rats. For investigation of the interaction, rats were pretreated with dexmedetomidine, either intraperitoneally or intrathecally, immediately before nitrous oxide exposure such that peak antinociceptive effects of each drug coincided. For assessment of the effect on tolerance, dexmedetomidine was administered as tolerance to nitrous oxide developed. Expression of c-Fos was used to assess neuronal activity in the locus ceruleus.

Results: Nitrous oxide and dexmedetomidine increased tail-flick latency with an ED50 (mean +/- SEM) of 55.0 +/- 2.2% atm for nitrous oxide, 27.6 +/- 5.1 for [mu]g/kg intraperitoneal dexmedetomidine, and 2.9 +/- 0.1 [mu]g for intrathecal dexmedetomidine. Combinations of systemically administered dexmedetomidine and nitrous oxide produced an additive analgesic interaction; however, neuraxially administered dexmedetomidine interacted synergistically with nitrous oxide. Tolerance to nitrous oxide was reversed by coadministration of dexmedetomidine. Prazosin, the [alpha]1-/[alpha]2B-adrenoceptor antagonist, attenuated the analgesic effect of nitrous oxide and prevented dexmedetomidine-induced reversal of tolerance to nitrous oxide. Nitrous oxide-induced increase of neuronal activity in the locus ceruleus was reversed by dexmedetomidine.     

The minimum alveolar concentration (MAC) of sevoflurane in humans

Forty surgical patients were divided into two groups and anesthetized with either sevoflurane and oxygen or sevoflurane, oxygen, and nitrous oxide. The minimum alveolar concentration (MAC) for sevoflurane required to prevent movement in response to surgical incision in healthy patients was 1.71 +/- 0.07% (SE). The AD95 (anesthetic ED95) that prevented 95% of patients from moving was 2.07%. The addition of 63.5% end-tidal nitrous oxide allowed a reduction in the alveolar sevoflurane concentration to 0.66 +/- 0.06% (SE). The reduction in sevoflurane MAC was 61.4%. The AD95 for sevoflurane with 63.5% end-tidal nitrous oxide was 0.94%.     

Nitrous Oxide Depresses Spinal F Waves in Rats

Background: Evoked, recurrent electromyographic activity (F waves) reflect alpha-motor neuron excitability. Based on observations that other inhaled anesthetics do so, we hypothesized that nitrous oxide, alone or in combination with isoflurane, would depress F-wave activity and correlate with depression of movement response to tail clamp or electric stimulation.

Methods: In study 1, the authors examined the effect of nitrous oxide in combination with isoflurane in 13 normocapnic Sprague-Dawley rats anesthetized with 1.0% isoflurane (0.7 minimum alveolar concentration) in oxygen. The tibial nerve was stimulated at the popliteal fossa, and evoked electromyographic activity [M (direct neuromuscular junctional response) and F waves] were recorded from ipsilateral foot muscles. The effect of the addition of 30% or 70% nitrous oxide was measured. F-wave amplitude/M-wave amplitude ratio (F/M) was determined from each stimulus-electromyographic response pair. F/M vs. movement response to 60-s tail clamp was assessed after each recording session. F-wave amplitude/M-wave amplitude ratio at adjacent doses that permitted and prevented movement were compared. In study 2, the authors examined the effect of (hyperbaric) nitrous oxide as the sole anesthetic agent on F waves. In 11 rats anesthetized with isoflurane, stimulation and recording electrodes were placed as described above, with additional electrodes for stimulation placed in the tail. Rats were placed in a pressure chamber pressurized with nitrous oxide/oxygen to 3.4 atm. Thirty m were allowed for isoflurane washout. electromyographic activity was evoked and recorded at 1.0, 1.6, 2.2, and 2.7 atm N2 O (random order). Movement in response to 60 s of 15 V, 50-Hz tail stimulation was evaluated after each recording session.

Results: Nitrous oxide with or without isoflurane produced a dose-dependent decrease in F/M. By interpolation of this data, the authors found that 2 atm N2 O alone, or 44% N2 O added to 1.0% isoflurane at 1.0 atm, produced 1.0 minimum alveolar concentration anesthesia. At the deepest level of isoflurane/nitrous oxide that permitted movement, mean F/M was 20.6+/-17.5%; at the lowest concentration that blocked movement, rats had a mean F/M of 13.7 +/-13.9% (P = 0.01). At the minimal hyperbaric nitrous oxide blocking movement, rats had a mean F/M of 3.7+/-2.9%, whereas the F/M at the highest nitrous oxide dose that permitted movement was 4.4 +/-2.7% (P < 0.04).     

ANAESTHETIC REQUIREMENT IN MICE SELECTIVELY BRED FOR DIFFERENCES IN ETHANOL SENSITIVITY

Anaesthetic requirements for nitrous oxide, enflurane and isofluranewere determined in mice selectively bred for their susceptibility("long-sleep" mice) or resistance ("short-sleep" mice) to alcohol.Nitrous oxide and enflurane requirements, measured by the rolling-responsetest, were 34 and 20% greater, respectively, in short-sleepmice than in long-sleep mice. Although isoflurane requirementwas 39% greater when measured by the tail-clamp test, it wasnot significantly different when measured by the rolling-responsetest. The greater anaesthetic requirement for short-sleep micewas not associated with a different synaptic membrane phospholipid,fatty acid or cholesterol composition.     

Neuromuscular and cardiovascular effects of mivacurium chloride (BW B109OU) during nitrous oxide-narcotic, nitrous oxide-halothane and nitrous oxide-isoflurane anesthesia in surgical patients

One hundred seventeen adult surgical patients were studied to compare neuromuscular and cardiovascular effects of mivacurium chloride during nitrous oxide-narcotic (BAL, n = 45) nitrous oxide-halothane (HAL, n = 27) and nitrous oxide-isoflurane (ISF, n = 45) anesthesia. Anesthesia was maintained with nitrous oxide (60%-70%) and oxygen (30%-40%) with end-tidal concentrations of halothane or isoflurane to yield a total MAC of approximately 1.25, or with supplemental fentanyl and thiopental as clinically indicated. Twitch response of the adductor pollicis muscle was elicited by supramaximal square wave pulses of 0.2 msec duration at a frequency of 0.15 Hz (Grass S44 stimulator) to the ulnar nerve and quantitated by a Grass FT10 transducer. Nine patients in each of the HAL and ISF groups received one of four doses of mivacurium (0.03, 0.05, 0.10 or 0.15 mg/kg). Ninety patients in the balanced anesthesia group received one of seven doses of mivacurium (0.03, 0.04, 0.05, 0.08, 0.15, 0.20, 0.25 mg/kg). The ED50, ED75 and ED95 of mivacurium in each group were estimated from linear regression plots of log dose versus probit of maximum percentage depression of twitch height. The ED50, ED75 and ED95 for halothane and isoflurane are 0.040, 0.053 and 0.081 and 0.037, 0.043 and 0.053, respectively. The ED50, ED75, and ED95 for the balanced group are 0.039, 0.050, and 0.073 mg/kg respectively. There was no significant difference between the slopes of the HAL and BAL inhalation anesthetic dose-response curves. The slope of the ISF group was significantly than the slope of the BAL group. Intercepts of the HAL and BAL curves were not different. The isoflurane curve's intercept was significantly less than the other groups' intercepts, lying above the halothane curve, but below the BAL curve. For the 0.05 mg/kg dose, maximum block was greater in the ISF group (89.1 +/- 2.7%, n = 9) than in the HAL (70.3 +/- 7.6%, n = 9) or BAL (67.7 +/- 6.4%, n = 9) groups. At higher doses of mivacurium, isoflurane produces a greater potentiation of neuromuscular block than halothane or balanced anesthesia. There were no significant cardiovascular changes seen in any group following mivacurium doses up to 0.15 mg/kg (approximately 2xED95).     

MAC of desflurane in 60% nitrous oxide in infants and children.

Desflurane, an inhaled anesthetic, may be useful for outpatient procedures in pediatric patients because its blood solubility (similar to that of nitrous oxide and less than that of commercially available potent inhaled anesthetics) may facilitate emergence and recovery from anesthesia. Although the MAC of desflurane without nitrous oxide has been determined in pediatric patients, it is likely that clinicians will administer desflurane with nitrous oxide. To determine the potency of desflurane administered with 60% nitrous oxide in pediatric patients, the authors determined the minimum alveolar concentration that prevents movement in 50% of subjects (MAC) in 12 infants aged 17 weeks-12 months and 12 children aged 1-5 yr. Anesthesia was induced with desflurane in oxygen; nitrous oxide was not administered during induction of anesthesia to minimize the likelihood of hypoxia if laryngospasm occurred. Following tracheal intubation, nitrous oxide and desflurane were administered and maintained at target concentrations for a minimum of 10 min before surgical incision. No additional anesthetic, sedative/hypnotic, or analgesic drugs were administered prior to incision. Following surgical incision, anesthesia was maintained with nitrous oxide, desflurane, and fentanyl, 4 +/- 1 micrograms/kg (mean +/- SD). MAC, determined using a modification of Dixon's "up-and-down" technique, was 7.5 +/- 0.1% (mean +/- SE) for infants and 6.4 +/- 0.2% for children; similar values were obtained using logistic regression (7.5 +/- 0.01% and 6.3 +/- 0.03%, respectively). Time from discontinuation of anesthesia to eye-opening and tracheal extubation was 5.4 +/- 3.6 min (mean +/- SD).(ABSTRACT TRUNCATED AT 250 WORDS)     

Dexmedetomidine enhances analgesic action of nitrous oxide: mechanisms of action

BACKGROUND: Nitrous oxide and dexmedetomidine are thought to mediate analgesia (antinociception in a noncommunicative organism) via alpha 2B- and alpha 2A-adrenergic receptor subtypes within the spinal cord, respectively. Nitrous oxide and dexmedetomidine exert diametrically opposite effects on neuronal activity within the locus ceruleus, a pivotal site for modulation of analgesia. Because of these differences, the authors explored whether the two analgesics in combination would provide satisfactory analgesia. METHODS: The analgesic effects of nitrous oxide and dexmedetomidine given both intraperitoneally and intrathecally were evaluated using the tail-flick latency test in rats. For investigation of the interaction, rats were pretreated with dexmedetomidine, either intraperitoneally or intrathecally, immediately before nitrous oxide exposure such that peak antinociceptive effects of each drug coincided. For assessment of the effect on tolerance, dexmedetomidine was administered as tolerance to nitrous oxide developed. Expression of c-Fos was used to assess neuronal activity in the locus ceruleus. RESULTS: Nitrous oxide and dexmedetomidine increased tail-flick latency with an ED50 (mean +/- SEM) of 55.0 +/- 2.2% atm for nitrous oxide, 27.6 +/- 5.1 for microg/kg intraperitoneal dexmedetomidine, and 2.9 +/- 0.1 microg for intrathecal dexmedetomidine. Combinations of systemically administered dexmedetomidine and nitrous oxide produced an additive analgesic interaction; however, neuraxially administered dexmedetomidine interacted synergistically with nitrous oxide. Tolerance to nitrous oxide was reversed by coadministration of dexmedetomidine. Prazosin, the alpha 1-/alpha 2B-adrenoceptor antagonist, attenuated the analgesic effect of nitrous oxide and prevented dexmedetomidine-induced reversal of tolerance to nitrous oxide. Nitrous oxide-induced increase of neuronal activity in the locus ceruleus was reversed by dexmedetomidine. CONCLUSION: The synergistic analgesic interaction between nitrous oxide and dexmedetomidine within the spinal cord is obscured by a supraspinal antagonism when dexmedetomidine is administered systemically in the pretolerant state. After tolerance to nitrous oxide develops, supraspinal functional antagonism no longer obtains exposing the synergistic action at the level of the spinal cord, which expresses itself as a reversal of the tolerant state. The authors speculate that the addition of dexmedetomidine to nitrous oxide is likely to provide enhanced and more durable analgesia in settings in which nitrous oxide is currently used alone (e.g., labor and dental surgery).     

Interaction of Isoflurane and Nitrous Oxide Combinations Similar for Median Electroencephalographic Frequency and Clinical Anesthesia

Background: The volatile anesthetic sparing effect of nitrous oxide in clinical studies is less than might be expected from the additivity of minimum alveolar concentration values. Other studies identify nonadditive interactions between isoflurane and nitrous oxide. The aim of this study was to quantify the interaction of isoflurane and nitrous oxide at a constant median electroencephalographic frequency.

Methods: Twenty-five patients were studied during laparotomies. Nitrous oxide was randomly administered in concentrations of 0, 20, 40, 60, and 75 vol%, to ten patients for each nitrous oxide concentration. Isoflurane vaporizer settings were chosen so that the median electroencephalographic frequency was held between 2 and 3 Hz. The relationship between nitrous oxide concentrations and required isoflurane concentrations was examined with the method of isoboles.

Results: Nitrous oxide linearly decreased the isoflurane requirement. Addition of every 10 vol% of nitrous oxide decreases the isoflurane requirement by approximately 0.04 vol%. The total anesthetic requirement of isoflurane and nitrous oxide, expressed in terms of previously reported minimum alveolar concentration values, increased significantly with increasing nitrous oxide concentrations.     

The additive contribution of nitrous oxide to isoflurane MAC in infants and children

The purpose of this study was to determine the contribution of nitrous oxide to isoflurane MAC in pediatric patients. MAC was determined in 47 infants and small children (mean ages 16.6 +/- 6.7 months) during isoflurane and oxygen anesthesia (n = 11) and isoflurane and nitrous oxide anesthesia (25% nitrous oxide [n = 12], 50% nitrous oxide [n = 12], and 75% nitrous oxide [n = 12]). After assigning patients to one of four groups, anesthesia was induced with increasing inspired concentrations of isoflurane in oxygen. After anesthetic induction and tracheal intubation, ventilation was controlled (carbon dioxide partial pressure = 32 +/- 5 mmHg), and nitrous oxide was added to the inspired gas mixture to achieve end-expired nitrous oxide concentrations of 0, 25, 50, or 75%. Inspired and expired gas samples were obtained from a distal sampling port in the tracheal tube. The response to skin incision in each patient was assessed at a previously selected end-tidal concentration of isoflurane. The MAC of isoflurane was determined in each group using the up-and-down method described for evaluating quantal responses. The mean duration of constant end-tidal concentrations prior to skin incision was 14 +/- 7 min (range 6-46 min). The ratio of expired to inspired nitrous oxide and isoflurane concentrations during the period of constant end-tidal concentrations was 0.96 +/- 0.01 and 0.93 +/- 0.03 respectively. The MAC of isoflurane in oxygen was 1.69 +/- 0.13 vol% (mean +/- standard deviation).(ABSTRACT TRUNCATED AT 250 WORDS)     

Vecuronium-induced neuromuscular blockade during enflurane, isoflurane, and halothane anesthesia in humans

To determine the effect of the commonly used volatile anesthetics on a vecuronium-induced neuromuscular blockade, the authors studied 54 patients anesthetized with 1.2 MAC or 2.2 MAC enflurane, isoflurane, or halothane (MAC value includes contribution from 60% nitrous oxide). During 1.2 MAC enflurane, isoflurane, and halothane, the ED50S (the doses depressing twitch tension 50%) for vecuronium were 12.8, 14.7, and 16.9 micrograms/kg, respectively. During 2.2 MAC enflurane, isoflurane, and halothane, the ED50S for vecuronium were 6.3, 9.8, and 13.8 micrograms/kg, respectively (P less than 0.05). Time from injection to peak effect was the same for each anesthetic group (6.5 +/- 0.5 min, mean +/- SD), except for the group given 2.2 MAC enflurane (9.7 +/- 0.6 min) (P less than 0.05). The duration of a 50% block from injection to 90% recovery was the same for each group (mean 20 +/- 4 min), except for the group given 2.2 MAC enflurane (46.5 min) (P less than 0.05). The authors conclude that enflurane is the most potent volatile anesthetic, followed by isoflurane and then halothane, in augmenting a vecuronium-induced neuromuscular blockade. Increasing the concentration of volatile anesthetic has less effect on a neuromuscular blockade produced by vecuronium than on one produced by other nondepolarizing relaxants (e.g., pancuronium and d-tubucurarine).     

Mivacurium infusion requirements in pediatric surgical patients during nitrous oxide-halothane and during nitrous oxide-narcotic anesthesia

We were interested in determining the infusion rate of mivacurium required to maintain approximately 95% neuromuscular blockade during nitrous oxide-halothane (0.8% end-tidal) or nitrous oxide-narcotic anesthesia. Neuromuscular blockade was monitored by recording the electromyographic activity (Datex NMT) of the adductor pollicis muscle resulting from supramaximal stimulation of the ulnar nerve at 2 Hz for 2 s at 10-s intervals. Mivacurium steady-state infusion requirements averaged 315 +/- 26 micrograms.m-2.min-1 during nitrous oxide-halothane anesthesia and 375 +/- 19 micrograms.m-2.min-1 (mean +/- SEM) during nitrous oxide-narcotic anesthesia. Higher levels of pseudocholinesterase activity were generally associated with a higher mivacurium infusion requirement. During both anesthetics, younger age was associated with a higher infusion requirement when the infusion requirement was calculated in terms of micrograms.kg-1.min-1. This difference was not present when the infusion rate was calculated in terms of micrograms.m-2.m-1. There was no evidence of cumulation during prolonged mivacurium infusion. There was no difference in the rates of spontaneous or reversal-mediated recovery between anesthetic groups. After the termination of the infusion, spontaneous recovery to T4/T1 greater than or equal to 0.75 occurred in 9.8 +/- 0.4 min, with a recovery index, T25-75, of 4.0 +/- 0.2 min (mean +/- SEM). In summary, pseudocholinesterase activity is the major factor influencing mivacurium infusion rate in children during nitrous oxide-narcotic or nitrous oxide-halothane (0.8% end-tidal) anesthesia.     

Nitrous oxide potentiates vecuronium neuromuscular blockade in humans

This study was designed to measure the potency of vecuronium with and without nitrous oxide. Anaesthesia was induced with thiopentone and fentanyl in 56 adult patients. The subjects were randomly assigned to receive nitrous oxide, 70%, or intermittent boluses of thiopentone and fentanyl for maintenance of anaesthesia. Train-of-four stimulation was applied to the ulnar nerve every 20 sec, and the force of contraction of the adductor pollicis muscle was measured. Vecuronium, 20, 30 or 40 micrograms.kg-1 was given by random allocation five minutes after induction of anaesthesia. Maximum depression of the first response (T1) in the train-of-four was measured, and dose-response curves were constructed. In the absence of nitrous oxide, the ED50 and ED95 were mean +/- standard error of the mean (SEM), 29.2 +/- 1.8 and 59.3 +/- 3.6 micrograms.kg-1, respectively. In the group receiving nitrous oxide, these values were 25.3 +/- 1.2 and 42.3 +/- 2.0 micrograms.kg-1 respectively. By analysis of covariance, the dose-response curves were shown to be shifted with respect to one another (P less than 0.05). Administration of nitrous oxide was associated with a 19.5% increase in potency (95% confidence limits: 1.7 to 40.4%). It is concluded that nitrous oxide has a slight potentiating effect on neuromuscular blockade, and that this effect occurs within five to ten minutes after the beginning of its administration.     

Anesthesia Sensitivity in Mice that Lack the beta 3 Subunit of the gamma-Aminobutyric Acid Type A Receptor

Background: The mammalian gamma-aminobutyric acid type A (GABAA) receptor, a likely target of anesthetic action, exhibits remarkable subunit heterogeneity. In vitro expression studies suggest that there is subunit specificity to anesthetic responses at the GABAA receptor. The authors tested whether genetically engineered mice that lack the beta 3 subunit of the GABAA receptor differed in their sensitivities to several general anesthetic agents.

Methods: Median effective concentrations for loss-of-righting reflex and tail clamp/withdrawal for enflurane and halothane were determined in mice with and without the beta 3 gene and gene product. Sleep time was measured after intraperitoneal injection of pentobarbital, ethanol, etomidate, and midazolam.

Results: Null allele mice (beta 3 -/-) did not differ from wild-type mice (beta 3 +/+) in the obtunding response to enflurane and halothane but were significantly more resistant to enflurane (null allele half-effect concentrations [EC50] of 2.59 +/- 0.10 vs. wild-type EC50 of 2.06 +/- 0.12 atm %, P < 0.001) and halothane (null allele EC50 of 1.73 +/- 0.04 vs. wild-type EC50 of 1.59 +/- 0.05 atm %, P = 0.01) as determined by tail clamp response. Wild-type and null allele mice exhibited divergent responses to other sedative agents active at the GABAA receptor. No differences were noted in sleep times after administration of pentobarbital and ethanol, but null allele mice were more resistant to etomidate (null allele EC sub 50 of 17.8 +/- 1.9 min vs. wild-type EC50 of 26.2 +/- 2.4 min, P < 0.02) and midazolam (null allele EC50 of 14.2 +/- 7.8 min vs. wild-type EC50 of 41.3 +/- 10.4 min, P < 0.05).     

Reduced anesthetic requirement after electrical stimulation of periaqueductal gray matter

To determine whether electrical stimulation of the periaqueductal gray region decreases anesthetic requirement, the authors studied the effect of such stimulation on the MAC of halothane and 60% nitrous oxide in 33 patients. These patients, who were undergoing implantation of a radio-frequency-coupled receiver and connection of that receiver to electrodes previously implanted in the periaqueductal gray area, were assigned randomly to receive (n = 16) or not receive (n = 17) electrical stimulation 1 h before surgery. The mean value (+/- SEM) for the minimum alveolar concentration of halothane combined with 60% nitrous oxide was significantly less (P less than 0.001) for patients who were stimulated preoperatively (0.15 +/- 0.05%) than for those who were not (0.51 +/- 0.02%). The authors conclude that stimulation of the periaqueductal gray region decreases anesthetic requirements and believe that at least three mechanisms are possible: a nonspecific narcotic-like effect, a specific effect on a pain pathway, or an effect on specific neural pathways that affect anesthetic requirements secondary to changes in regional concentrations of neurotransmitters.