Halothane and Diazepam Inhibit Ketamine-induced c-fos Expression in the Rat Cingulate Cortex

Background: Ketamine, a noncompetitive N-methyl-D-aspartate antagonist, has psychotomimetic side effects. Recent studies have shown that noncompetitive N-methyl-D-aspartate antagonists cause morphologic damage to the cingulate and retrosplenial cortices and induce c-fos protein (c-Fos) in the same regions. Although benzodiazepines are effective in preventing these side effects, the neural basis of the drug interactions has not been established.

Methods: The effects of diazepam and halothane on c-Fos expression induced by ketamine were studied. Diazepam (1 and 5 mg/kg) or vehicle were administered subcutaneously, followed 7 min later by 100 mg/kg ketamine given intraperitoneally. Halothane (1.0 and 1.8%), was administered continuously from 10 min before ketamine administration until brain fixation. Two hours after ketamine injection, rats were perfused and their brains fixed and extracted. Brain sections were prepared in a cryostat and c-Fos expression was detected using immunohistochemical methods.

Results: Ketamine induced c-Fos-like immunoreactivity in the cingulate and retrosplenial cortices, thalamus, and neocortex. Diazepam suppressed the ketamine-induced c-Fos-like immunoreactivity in the cingulate and retrosplenial cortices in a dose-dependent manner, leaving the thalamus and neocortex less affected. Halothane suppressed the ketamine-induced c-Fos-like immunoreactivity in the cingulate and retrosplenial cortices and the neocortex in a dose-dependent manner, leaving the thalamus relatively unaffected.     

Inhibitory effect of propofol on ketamine-induced c-Fos expression in the rat posterior cingulate and retrosplenial cortices is mediated by GABAA receptor activation

BACKGROUND: Non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists, including ketamine, have psychotomimetic activities and cause neuronal damage in the posterior cingulate and retrosplenial cortices (PC/RS), which are suggested to be the brain regions responsible for their psychotomimetic activities. We previously demonstrated that ketamine induced marked c-Fos (c-fos protein) expression in the rat PC/RS, which was inhibited by propofol, and the expression was closely related to ketamine-induced abnormal behavior. In the present study, we investigated whether the inhibition by propofol was mediated by GABAA receptor receptor activation. METHODS: Using Wistar rats, propofol alone, propofol with bicuculline or propofol with flumazenil was injected intravenously and then continuously infused. Fifteen minutes later, 100 mg kg-1 of ketamine or normal saline was injected intraperitoneally. Two hours after the ketamine or saline injection, the brain was extracted and brain sections were prepared, and c-Fos expression was detected using immunohistochemical methods. RESULTS: Ketamine induced marked c-Fos expression in the PC/RS (171 +/- 9/0.4 mm2), which was significantly inhibited by propofol (5 +/- 5/0.4 mm2). The inhibition by propofol was disinhibited dose-dependently by both bicuculline (0.5 and 1.0 mg kg-1 bicuculline groups: 46 +/- 15 and 143 +/- 16, respectively) and flumazenil (0.1 and 1.0 mg kg-1 flumazenil groups: 79 +/- 6 and 130 +/- 15, respectively). CONCLUSION: These results demonstrate that the inhibitory effect of propofol on ketamine-induced c-Fos expression in the PC/RS is mediated by GABAA receptor activation, and suggests that ketamine-induced psychoneuronal adverse effects may be suppressed by propofol via the activation of GABAA receptors.     

Neuroprotective and neurotoxic properties of the 'inert' gas,xenon

Background. Antagonists of the N-methyl-D-aspartate (NMDA) subtypeof glutamate receptors have been shown not only to have neuroprotectiveeffects but also to exhibit neurotoxic properties. In this study,we used c-Fos, a protein product of an immediate early gene,as a marker of neuronal injury to compare the neuroprotectiveeffects of xenon and the neurotoxic properties of xenon, nitrousoxide, and ketamine, three anaesthetics with NMDA receptor antagonistproperties. Methods. We used an in vivo rat model of brain injury in whichN-methyl-DL-aspartic acid (NMA) is injected subcutaneously (s.c.)and c-Fos expression in the arcuate nucleus is used as a measureof injury. To examine the neurotoxic potential of each of thethree anaesthetics with NMDA receptor antagonist properties,c-Fos expression in the posterior cingulate and retrosplenial(PC/RS) cortices was measured. Results. Xenon dose-dependently suppressed NMA-induced c-Fosexpression in the arcuate nucleus with an IC₅₀ of 47 (2)% atm.At the highest concentration tested (75% atm) NMA-induced neuronalinjury was decreased by as much as that observed with the prototypicalNMDA antagonist MK801 (0.5 mg kg^–1 s.c.). Both nitrousoxide and ketamine dose-dependently increased c-Fos expressionin PC/RS cortices; in contrast, xenon produced no significanteffect. If the dopamine receptor antagonist haloperidol wasgiven before either nitrous oxide or ketamine, their neurotoxiceffects were eliminated. Conclusions. Uniquely amongst anaesthetics with known NMDA receptorantagonist action, xenon exhibits neuroprotective propertieswithout co-existing neurotoxicity. The reason why ketamine andnitrous oxide, but not xenon, produce neurotoxicity may involvetheir actions on dopaminergic pathways. Br J Anaesth 2002; 89: 739–46     

NMDA receptor antagonist neurotoxicity and psychotomimetic activity

Non-competitive NMDA receptor antagonists, in spite of their neuroprotective effects against neuronal ischemia, brain trauma, etc., cause neuronal damage in the rodent posterior cingulate and retrosplenial cortices (PC/RS), which are thought to be responsible brain regions for their psychotomimetic activity in humans. A number of anesthetics have not only GABAA receptor activating properties but also NMDA receptor antagonist properties. On the other hand, ketamine and nitrous oxide, both of which are potent non-competitive NMDA receptor antagonists and have little GABAA activating properties, are demonstrated to induce neuronal damage in the rat PC/RS. Furthermore, ketamine potentiates the neuronal damage by nitrous oxide. Although many anesthetics, such as halothane, isoflurane, barbiturates and benzodiazepines, inhibit the neuronal damage in the PC/RS by NMDA receptor antagonists, probably through GABAA receptor activation, we anesthesiologists should be aware of the risk of ketamine or nitrous oxide anesthesia, not to speak of the combined use of them, without using GABAA receptor activating agents.     

Propofol acts at the sigma-1 receptor and inhibits pentazocine-induced c-Fos expression in the mouse posterior cingulate and retrosplenial cortices

BACKGROUND: The sigma-1 receptor is functionally linked with psychotomimetic effects of various drugs. A sigma-1 receptor agonist enhances bradykinin-induced intracellular Ca(2+) concentration ([Ca(2+)]i) increase and induces c-Fos expression in a part of the brain. The aim of this study was to investigate the effects of several intravenous anaesthetics on the sigma-1 receptor. METHODS: First, using Wistar rat brains, (+)[(3)H]SKF-10,047, a selective sigma-1 receptor agonist was displaced by propofol, dexmedetomidine, droperidol, and thiopental. Second, Fura-2 loaded NG-108 cells were incubated with (+)pentazocine, a selective sigma-1 receptor agonist, and propofol and then its fluorescence was observed after stimulation with bradykinin. Third, male ICR mice received Intrafat or propofol intraperitoneally (i.p.), followed by pentazocine i.p. Brain slices were prepared and Fos-like immunoreactivity was detected using an immunohistochemical method. results: Propofol, droperidol, and dexmedetomidine displaced (+)[(3)H]SKF-10,047 binding in a concentration-dependent manner with Ki50s of 10.2 +/- 0.6, 0.17 +/- 0.03, 5.73 +/- 1.2 microM, respectively. Thiopental sodium was practically ineffective. Propofol produced a statistically significant reduction in the maximal binding capacity (Bmax) but did not affect the dissociation constant (K(d)). (+)Pentazocine significantly enhanced bradykinin-induced [Ca(2+)]i increases, but propofol did not affect it. Pentazocine induced marked Fos-LI positive cells in the posterior cingulate and retrosplenial cortices (PC/RS), which was significantly reduced by propofol. CONCLUSIONS: These results suggest that propofol may be a sigma-1 receptor antagonist, and that various effects of propofol on the brain may be mediated, at least partly, by the sigma-1 receptor.     

Continuous arterial P(O2) and P(CO2) measurements in swine during nitrous oxide and xenon elimination: prevention of diffusion hypoxia

BACKGROUND: During nitrous oxide (N2O) elimination, arterial oxygen tension (PaO2) decreases because of the phenomenon commonly called diffusive hypoxia. The authors questioned whether similar effects occur during xenon elimination. METHODS: Nineteen anesthetized and paralyzed pigs were mechanically ventilated randomly for 30 min using inspiratory gas mixtures of 30% oxygen and either 70% N2O or xenon. The inspiratory gas was replaced by a mixture of 70% nitrogen and 30% oxygen. PaO2 and carbon dioxide tensions were recorded continuously using an indwelling arterial sensor. RESULTS: The PaO2 decreased from 119+/-10 mm Hg to 102+/-12 mm Hg (mean+/-SD) during N2O washout (P<0.01) and from 116+/-9 mm Hg to 110+/-8 mm Hg during xenon elimination (P<0.01), with a significant difference (P<0.01) between baseline and minimum PaO2 values (deltaPaO2, 17+/-6 mm Hg during N2O washout and 6+/-3 mm Hg during xenon washout). The PaCO2 value also decreased (from 39.3+/-6.3 mm Hg to 37.6+/-5.8 mm Hg) during N2O washout (P<0.01) and during xenon elimination (from 35.4+/-1.6 mm Hg to 34.9+/-1.6 mm Hg; P< 0.01). The deltaPaCO2 was 1.7+/-0.9 mm Hg in the N2O group and 0.5+/-0.3 mm Hg in the xenon group (P<0.01). CONCLUSION: Diffusive hypoxia is unlikely to occur during recovery from xenon anesthesia, probably because of the low blood solubility of this gas.     

咪唑安定对氯胺酮诱导的c-fos基因在大鼠后扣带回皮质区表达的影响

目的 观察咪唑安定对氯胺酮诱导的c-fos基因在大鼠后扣带回皮质区表达的影响，探讨咪唑安定预防或减轻氯胺酮所致精神症状及神经损害的机制。方法 雄性Wistar大鼠30只，随机分为生理盐水5ml组、咪唑安定15mg／kg组、氯胺酮100mg／kg组、咪唑安定15mg／kg加氯胺酮100mg／kg组、氯胺酮100mg／kg加咪唑安定15mg／kg组。咪唑安定与氯胺酮两药间隔15min给药，所用药物均由腹腔注射。各组动物于用药后2h开胸经心脏灌流脑固定，用免疫组织化学方法检测后扣带回皮质区c-fos蛋白的表达，用彩色病理图像分析系统测定c-fos阳性细胞的百分率和阳性细胞的密度。结果氯胺酮可明显诱导c-fos蛋白在大鼠后扣带回皮质区的表达；咪唑安定自身不能诱导c-fos的表达；咪唑安定预处理可显著抑制氯胺酮诱导的c-fos在这一区域的表达；先用氯胺酮后给予咪唑安定仅能部分抑制c-fos的表达。结论 咪唑安定预处理可抑制氯胺酮诱导的c-fos基因在大鼠后扣带回皮质区的表达，这可能是其预防或减轻氯胺酮所致精神症状和神经损害的机制之一。     

The Neuroprotective Effect of Xenon Administration during Transient Middle Cerebral Artery Occlusion in Mice

Background: Xenon has been shown to be neuroprotective in several models of in vitro and in vivo neuronal injury. However, its putative neuroprotective properties have not been evaluated in focal cerebral ischemia. The purpose of this study was to determine if xenon offers neuroprotection in a mouse model of middle cerebral artery occlusion.

Methods: C57BL/6 mice underwent 60 min of middle cerebral artery occlusion. The animals (n = 21 per group) were randomized to receive either 70% xenon + 30% O2, 70% N2O + 30% O2, or 35% xenon + 35% N2O + 30% O2. After 24 h, functional neurologic outcome (on three independent scales: four-point, general, and focal deficit scales) and cerebral infarct size were evaluated.

Results: The 70% xenon + 30% O2 group showed improved functional outcome (median [interquartile range], four-point scale: 2 [2], 70% xenon + 30% O2versus 3 [2], 70% N2O + 30% O2, P = 0.0061; general deficit scale: 9 [6], 70% xenon + 30% O2versus 10 [4], 70% N2O + 30% O2, P = 0.0346). Total cerebral infarct volumes were reduced in the 70% xenon + 30% O2 group compared with the 70% N2O + 30% O2 group (45 +/- 17 mm3versus 59 +/- 11 mm3, respectively; P = 0.0009).     

Continuous Arterial PO(2) and PCO(2) Measurements in Swine during Nitrous Oxide and Xenon Elimination: Prevention of Diffusion Hypoxia

Background: During nitrous oxide (N2 O) elimination, arterial oxygen tension (PaO(2)) decreases because of the phenomenon commonly called diffusive hypoxia. The authors questioned whether similar effects occur during xenon elimination.

Methods: Nineteen anesthetized paralyzed pigs were mechanically ventilated randomly for 30 min using inspiratory gas mixtures of 30% oxygen and either 70% N2 O or xenon. The inspiratory gas was replaced by a mixture of 70% nitrogen and 30% oxygen. PaO(2) and carbon dioxide tensions were recorded continuously using an indwelling arterial sensor.

Results: The PaO(2) decreased from 119 +/- 10 mmHg to 102 +/- 12 mmHg (mean +/- SD) during N2 O washout (P < 0.01) and from 116 +/- 9 mmHg to 110 +/- 8 mmHg during xenon elimination (P < 0.01), with a significant difference (P < 0.01) between baseline and minimum PaO(2) values (Delta PaO(2), 17 +/- 6 mmHg during N2 O washout and 6 +/- 3 mmHg during xenon washout). The PaCO(2) value also decreased (from 39.3 +/- 6.3 mmHg to 37.6 +/- 5.8 mmHg) during N2 O washout (P < 0.01) and during xenon elimination (from 35.4 +/- 1.6 mmHg to 34.9 +/- 1.6 mmHg; P < 0.01). The Delta PaCO(2) was 1.7 +/- 0.9 mmHg in the N2 O group and 0.5 +/- 0.3 mmHg in the xenon group (P < 0.01).     

The neuroprotective effect of xenon administration during transient middle cerebral artery occlusion in mice

BACKGROUND: Xenon has been shown to be neuroprotective in several models of in vitro and in vivo neuronal injury. However, its putative neuroprotective properties have not been evaluated in focal cerebral ischemia. The purpose of this study was to determine if xenon offers neuroprotection in a mouse model of middle cerebral artery occlusion. METHODS: C57BL/6 mice underwent 60 min of middle cerebral artery occlusion. The animals (n = 21 per group) were randomized to receive either 70% xenon + 30% O2, 70% N2O + 30% O2, or 35% xenon + 35% N2O + 30% O2. After 24 h, functional neurologic outcome (on three independent scales: four-point, general, and focal deficit scales) and cerebral infarct size were evaluated. RESULTS: The 70% xenon + 30% O2 group showed improved functional outcome (median [interquartile range], four-point scale: 2 [2], 70% xenon + 30% O2 versus 3 [2], 70% N2O + 30% O2, P = 0.0061; general deficit scale: 9 [6], 70% xenon + 30% O2 versus 10 [4], 70% N2O + 30% O2, P = 0.0346). Total cerebral infarct volumes were reduced in the 70% xenon + 30% O2 group compared with the 70% N2O + 30% O2 group (45 +/- 17 mm3 versus 59 +/- 11 mm3, respectively; P = 0.0009). CONCLUSIONS: In this model of transient focal cerebral ischemia, xenon administration improved both functional and histologic outcome.     

Minimum Alveolar Concentration-Awake of Xenon Alone and in Combination with Isoflurane or Sevoflurane

Background: The minimum alveolar concentration (MAC)-awake is a traditional index of hypnotic potency of an inhalational anesthetic. The MAC-awake of xenon, an inert gas with anesthetic properties (MAC = 71%), has not been determined. It is also unknown how xenon interacts with isoflurane or sevoflurane on the MAC-awake.

Methods: In the first part of the study, 90 female patients received xenon, nitrous oxide (N2O), isoflurane, or sevoflurane supplemented with epidural anesthesia (n = 36 for xenon and n = 18 per group for other anesthetics). In the second part, 72 additional patients received either xenon or N2O combined with the 0.5 times MAC-awake concentration of isoflurane or sevoflurane (0.2% and 0.3%, respectively, based on the results of the first part; n = 18 per group). During emergence, the concentration of an assigned anesthetic (xenon or N2O only in the second part) was decreased in 0.1 MAC decrements every 15 min from 0.8 MAC or from 70% in the case of N2O until the patient followed the command to either open her eyes or to squeeze and release the investigator's hand. The concentration midway between the value permitting the first response to command and that just preventing it was defined as the MAC-awake.

Results: The MAC-awake were as follows: xenon, 32.6 +/- 6.1% (mean +/- SD) or 0.46 +/- 0.09 MAC; N2O, 63.3 +/- 7.1% (0.61 +/- 0.07 MAC); isoflurane, 0.40 +/- 0.07% (0.35 +/- 0.06 MAC); and sevoflurane, 0.59 +/- 0.10% (0.35 +/- 0.06 MAC). Addition of the 0.5 MAC-awake concentrations of isoflurane and sevoflurane reduced the MAC-awake of xenon to 0.50 +/- 0.15 and 0.51 +/- 0.16 times its MAC-awake as a sole agent, but that of N2O to the values significantly greater than 0.5 times its MAC-awake as a sole agent (0.68 +/- 0.12 and 0.66 +/- 0.14 times MAC-awake;P < 0.01, analysis of variance and Dunnett's test).     

Minimum alveolar concentration-awake of Xenon alone and in combination with isoflurane or sevoflurane

BACKGROUND: The minimum alveolar concentration (MAC)-awake is a traditional index of hypnotic potency of an inhalational anesthetic. The MAC-awake of xenon, an inert gas with anesthetic properties (MAC = 71%), has not been determined. It is also unknown how xenon interacts with isoflurane or sevoflurane on the MAC-awake. METHODS: In the first part of the study, 90 female patients received xenon, nitrous oxide (N2O), isoflurane, or sevoflurane supplemented with epidural anesthesia (n = 36 for xenon and n = 18 per group for other anesthetics). In the second part, 72 additional patients received either xenon or N2O combined with the 0.5 times MAC-awake concentration of isoflurane or sevoflurane (0.2% and 0.3%, respectively, based on the results of the first part; n = 18 per group). During emergence, the concentration of an assigned anesthetic (xenon or N2O only in the second part) was decreased in 0. 1 MAC decrements every 15 min from 0.8 MAC or from 70% in the case of N2O until the patient followed the command to either open her eyes or to squeeze and release the investigator's hand. The concentration midway between the value permitting the first response to command and that just preventing it was defined as the MAC-awake. RESULTS: The MAC-awake were as follows: xenon, 32.6 +/- 6.1% (mean +/- SD) or 0.46 +/- 0.09 MAC; N2O, 63.3 +/- 7.1% (0.61 +/- 0.07 MAC); isoflurane, 0.40 +/- 0.07% (0.35 +/- 0.06 MAC); and sevoflurane, 0.59 +/- 0.10% (0.35 +/- 0.06 MAC). Addition of the 0.5 MAC-awake concentrations of isoflurane and sevoflurane reduced the MAC-awake of xenon to 0.50 +/- 0.15 and 0.51 +/- 0.16 times its MAC-awake as a sole agent, but that of N2O to the values significantly greater than 0.5 times its MAC-awake as a sole agent (0.68 +/- 0.12 and 0.66 +/- 0.14 times MAC-awake; P < 0.01, analysis of variance and Dunnett's test). CONCLUSIONS: The MAC-awake of xenon is 33% or 0.46 times its MAC. In terms of the MAC-fraction, this is smaller than that for N2O but greater than those for isoflurane and sevoflurane. Unlike N2O, xenon interacts additively with isoflurane and sevoflurane on MAC-awake.     

Evaluation of the safety of recent surgical microscopes equipped with xenon light sources

Although recent surgical microscopes for neurosurgery are equipped with xenon light sources to obtain bright fields of vision, the safety of a xenon beam, which has strong energy intensity in a long ultraviolet light, for cortical neurons has not been evaluated. Cranial windows were made in the parietal bones of gerbils. The skull of each gerbil was covered with warmed saline (0.5 mm in depth) to maintain the brain temperature. Ultraviolet irradiation (365-nm) was performed for 30 minutes at energy levels of 9.6, 4.4, 1.3, and 0.3 mwatts/cm(2), and neuronal damage was observed in 90 +/- 4%, 42 +/- 23%, 9 +/- 6%, and 0 +/- 0% of pyramidal cells in the parietal cortex 24 hours later. With the use of a logistic regression curve, the energy level causing 50% of neuronal damage was estimated to be 5.4 mwatts/cm(2). By increasing the thickness of the saline layer over the skull surface (1 mm and 2 mm), neuronal damages were significantly attenuated (21 +/- 18% and 10 +/- 8%, respectively, 4.4 mwatts/cm(2). Because the highest energy levels of 365-nm ultraviolet rays emitted from surgical microscopes measured in the present study (0.379 mwatts/cm (2)) were much closer to the dose causing 0% damage than to the dose causing 9% damage, the risk of neuronal injury occurring during microsurgery could be negligible. However, care should be taken in patients who take medicine classified as photosensitizing agents, such as diphenylhydantoin, which are thought to concentrate ultraviolet energy. The use of saline over the cortical surface may be beneficial for reducing the detrimental effects of 365-nm ultraviolet light.     

The effects of xenon or nitrous oxide supplementation on systemic oxygenation and pulmonary perfusion during one-lung ventilation in pigs

During experimental one-lung ventilation (OLV), the type of anesthesia may alter systemic hemodynamics, lung perfusion, and oxygenation. We studied whether xenon (Xe) or nitrous oxide (N(2)O) added to propofol anesthesia would affect oxygenation, lung perfusion, and systemic and pulmonary hemodynamics during OLV in a pig model. Nine pigs were anesthetized, tracheally intubated, and mechanically ventilated. After placement of arterial and pulmonary artery catheters, a left-sided double-lumen tube was placed via tracheotomy. IV anesthesia with propofol was supplemented in random order with N(2)O/O(2) 60:40 or Xe/O(2) 60:40 or N(2)/O(2) 60:40. All measurements were made after stabilization at each concentration. Differential lung perfusion was measured with colored microspheres. Oxygenation (Pao(2): 90 +/- 17, 95 +/- 20, and 94 +/- 20 mm Hg for N(2)/O(2), N(2)O/O(2), and Xe/O(2)) and left lung perfusion (16% +/- 5%, 14% +/- 6%, and 18.8% for N(2)/O(2), N(2)O/O(2), and Xe/O(2)) during OLV did not differ among the 3 groups. However, mean arterial blood pressure (78 +/- 25, 62 +/- 23, and 66 +/- 23 mm Hg for N(2)/O(2), N(2)O/O(2), and Xe/O(2)) and mixed venous saturation (55% +/- 12%, 48% +/- 12%, and 50% +/- 12% for N(2)/O(2), N(2)O/O(2), and Xe/O(2)) were reduced during N(2)O/O(2) as compared with the control group (N(2)/O(2)). Supplementation of IV anesthesia with Xe or N(2)O does not impair oxygenation nor alter lung perfusion during experimental OLV.     

Xenon does not reduce opioid requirement for orthopedic surgery

PURPOSE: Is to test the hypothesis that 70% xenon has a relevant opioid sparing effect compared to a minimum alveolar concentration (MAC)-equivalent combination of N(2)O and desflurane. METHODS: In this randomized, controlled study of 30 patients undergoing major orthopedic surgery, we determined the plasma alfentanil concentration required to suppress response to skin incision in 50% of patients (Cp(50)) anesthetized with xenon (70%) or a combination of N(2)O (70%) and desflurane (2%). A response was defined as movement, pressor response > 15 mmHg, heart rate > 90 beats x min(-1), autonomic reactions or a combination of these. At skin incision, alfentanil was administered at a randomly selected target plasma concentration thereafter the concentration was increased or decreased according to the patient's response. After skin incision, desflurane was adjusted to maintain the bispectral index below 60 and prevent responsiveness in both groups. RESULTS: The Cp(50) (+/- standard error) of alfentanil was 83 +/- 48ng x mL(-1) with xenon and 49 +/- 26 ng x mL(-1) with N(2)O/desflurane (P =0.451). During surgery five xenon and 15 N(2)O/desflurane patients were given desflurane at 1.0 +/- 0.5 volume % and 2.5 +/- 0.7 volume %. The total age adjusted MAC was 0.97 +/- 0.07 and 0.94 +/- 0.07 respectively (P = 0.217). The intraoperative plasma alfentanil concentrations were 95 +/- 80 and 93 +/- 60 ng x mL(-1) respectively (mean +/- SD; P = 0.451). Patients given xenon were slightly more bradycardic, whereas blood pressure was similar. CONCLUSION: Xenon compared to a MAC-equivalent combination of N(2)O and desflurane does not substantially reduce opioid requirement for orthopedic surgery. A small but clinically irrelevant difference cannot be excluded, however.     

The influence of xenon, nitrous oxide and nitrogen on gas bubble expansion during cardiopulmonary bypass

BACKGROUND AND OBJECTIVE: Xenon may have favourable applications in the setting of cardiac surgery. Its advantages include a desirable haemodynamic profile as well as potential cardiac and neuroprotective properties. However, its low solubility may lead to enhanced diffusion into enclosed gas spaces. The purpose of this study was to compare the effects of xenon (Xe), nitrous oxide (N2O) and nitrogen (N2) on gas bubble size during cardiopulmonary bypass (CPB). METHODS: Rats were randomized to receive 70% Xe, 26% oxygen (O2), 4% carbon dioxide (CO2) (xenon group); 70% N2O, 26% O2, 4% CO2 (nitrous oxide group) or 70% N2, 26% O2, 4% CO2 (nitrogen group) during 90 min of normothermic CPB. Small gas bubbles (300-500 microL; n = 12 per group) were injected into a bubble chamber on the venous side of the bypass circuit. After 10 min of equilibration, they were removed for volumetric analysis. RESULTS: The increase in bubble size was 2 +/- 2% with nitrogen, 17 +/- 6% with xenon (P = 0.0192 vs. nitrogen) and 63 +/- 23% with nitrous oxide (P = 0.0001 vs. nitrogen). The nitrous oxide group had significantly increased bubble size compared to the xenon group (P = 0.0001). CONCLUSIONS: During CPB, xenon anaesthesia produced a small increase in gas bubble size compared to nitrogen. Nitrous oxide resulted in significantly larger bubbles compared to both nitrogen and xenon.     

The effects of nitrous oxide and ketamine on the bispectral index and 95% spectral edge frequency during propofol-fentanyl anaesthesia

In this study, we have sought to establish whether N2O and ketamine alter the bispectral index during propofol-fentanyl anaesthesia. Fourteen surgical patients were randomly assigned to one of two groups: the N2O group (n = 7) and the ketamine group (n = 7). In both groups, anaesthesia was induced with propofol 1.5-2 mg kg-1 and fentanyl 2 micrograms kg-1 and maintained with propofol 5-7 mg kg-1 hr-1 to target the bispectral index between 40 and 50. After the bispectral index value had stabilized the propofol infusion rate was fixed. In the N2O group, the following concentrations of N2O were subsequently inhaled at 20-min intervals; 20, 40, 60 and 70%, and then N2O was terminated. In the ketamine group, ketamine (0.4 mg kg-1 + 1.0 mg kg-1h-1) was given. The bispectral index and 95% spectral edge frequency were recorded 20 min after each change in concentration of N2O or ketamine infusion. The bispectral index and 95% spectral edge frequency did not change significantly in the N2O group, but increased significantly from 44.1 +/- 0.7 and 16.0 +/- 0.5 to 58.6 +/- 1.4 and 19.5 +/- 0.3 (P < 0.01), respectively, in the ketamine group. Additional N2O or ketamine did not decrease the bispectral index and 95% spectral edge frequency values. The depth of sedation should be assessed carefully using a bispectral index monitor when these anaesthetic agents are used together.     

Evidence for the involvement of spinal cord alpha1 adrenoceptors in nitrous oxide-induced antinociceptive effects in Fischer rats

BACKGROUND: In a previous study, the authors found that nitrous oxide (N2O) exposure induces c-Fos (an immunohistochemical marker of neuronal activation) in spinal cord gamma-aminobutyric acid-mediated (GABAergic) neurons in Fischer rats. In this study, the authors sought evidence for the involvement of alpha1 adrenoceptors in the antinociceptive effect of N2O and in activation of GABAergic neurons in the spinal cord. METHODS: Adult male Fischer rats were injected intraperitoneally with alpha1 adrenoceptor antagonist, alpha2 adrenoceptor antagonist, opioid receptor antagonist, or serotonin receptor antagonist and, 15 min later, were exposed to either air (control) or 75% N2O. In some animals, nociception was investigated with the plantar test after 30 min of exposure, while in other animals, gas exposure was continued for 90 min and the spinal cord was examined for c-Fos immunostaining. In a separate experiment, animals were exposed to the above gases alone, after which the spinal cords were examined immunohistochemically for c-Fos and alpha1 adrenoceptor by double-staining methods. RESULTS: The antinociceptive effect of N2O was attenuated by prazosin (an alpha1 adrenoceptor antagonist), yohimbine (an alpha2 adrenoceptor antagonist), and naloxone (an opioid receptor antagonist) but not by methysergide and tropisetron (serotonin receptor antagonists). N2O exposure induced c-Fos expression in the spinal cord, which was blocked by prazosin and naloxone but not by other drugs. N2O-induced c-Fos expression was colocalized with alpha1 adrenoceptor immunoreactivity in laminae III-IV. CONCLUSIONS: These findings support the hypothesis that N2O activates GABAergic interneurons through alpha1 adrenoceptors to produce its antinociceptive effect.     

Xenon Provides Faster Emergence from Anesthesia than Does Nitrous Oxide-sevoflurane or Nitrous Oxide-isoflurane

Background: Xenon, an inert gas with anesthetic properties (minimum alveolar concentration [MAC] = 71%), has an extremely low blood:gas partition coefficient (0.14). Therefore, we predicted that xenon would provide more rapid emergence from anesthesia than does N2 O + isoflurane or N2 O + sevoflurane of equivalent MAC.

Methods: Thirty American Society of Anesthsiologists class I or II patients undergoing total abdominal hysterectomy were randomly assigned to receive 60% xenon, 60% N2 O + 0.5% isoflurane, or 60% N2 O + 0.7% sevoflurane (all concentrations are end-tidal: n = 10 per group). After placement of an epidural catheter, anesthesia was induced with standardized doses of midazolam, thiopental, and fentanyl. Thirty minutes later, xenon, N2 O + isoflurane, or N2 O + sevoflurane was started as previously assigned. These regimens were supplemented with epidural anesthesia with mepivacaine so that the mean arterial pressure and heart rate were controlled within 20% of the preoperative values. At the end of operation lasting approximately 2 h, all inhalational anesthetics were discontinued, and the patients were allowed to awaken while breathing spontaneously on an 8 l/min inflow of oxygen. A blinded investigator recorded the time until the patient opened her eyes on command (T1), was judged ready for extubation (T2), could correctly state her name, her date of birth, and the name of the hospital (T3), and could count backward from 10 to 1 in less than 15 s (T4).

Results: Emergence times from xenon anesthesia were: T1, 3.4 +/- 0.9 min; T2, 3.6 +/- 1 min; T3, 5.2 +/- 1.4 min; and T4, 6.0 +/- 1.6 min (mean +/- SD). These were one half to one third of those from N2 O + sevoflurane (T1, 6.0 +/- 1.7 min; T4, 10.5 +/- 2.5 min) or N2 O + isoflurane (T1, 7.0 +/- 1.9 min; T4, 14.3 +/- 2.8 min) anesthesia. The three groups did not differ in terms of patient demographics, the duration of anesthesia, the amount of epidural mepivacaine administered, or the postoperative pain rating. No patient could recalls intraoperative events.     

Evidence for the Involvement of Spinal Cord α1 Adrenoceptors in Nitrous Oxide-induced Antinociceptive Effects in Fischer Rats

Background: In a previous study, the authors found that nitrous oxide (N2O) exposure induces c-Fos (an immunohistochemical marker of neuronal activation) in spinal cord [gamma]-aminobutyric acid-mediated (GABAergic) neurons in Fischer rats. In this study, the authors sought evidence for the involvement of [alpha]1 adrenoceptors in the antinociceptive effect of N2O and in activation of GABAergic neurons in the spinal cord.

Methods: Adult male Fischer rats were injected intraperitoneally with [alpha]1 adrenoceptor antagonist, [alpha]2 adrenoceptor antagonist, opioid receptor antagonist, or serotonin receptor antagonist and, 15 min later, were exposed to either air (control) or 75% N2O. In some animals, nociception was investigated with the plantar test after 30 min of exposure, while in other animals, gas exposure was continued for 90 min and the spinal cord was examined for c-Fos immunostaining. In a separate experiment, animals were exposed to the above gases alone, after which the spinal cords were examined immunohistochemically for c-Fos and [alpha]1 adrenoceptor by double-staining methods.

Results: The antinociceptive effect of N2O was attenuated by prazosin (an [alpha]1 adrenoceptor antagonist), yohimbine (an [alpha]2 adrenoceptor antagonist), and naloxone (an opioid receptor antagonist) but not by methysergide and tropisetron (serotonin receptor antagonists). N2O exposure induced c-Fos expression in the spinal cord, which was blocked by prazosin and naloxone but not by other drugs. N2O-induced c-Fos expression was colocalized with [alpha]1 adrenoceptor immunoreactivity in laminae III-IV.