MAC Halothane Research Articles

Baseline Cerebral Metabolic Rate Is a Critical Determinant of the Cerebral Vasodilating Potency of Volatile Anesthetic Agents.

A Comparison of the Direct Cerebral Vasodilating Potencies of Halothane and Isoflurane in the New Zealand White Rabbit. By Drummond JC, Todd MM, Scheller MS, and Shapiro HM. ANESTHESIOLOGY 1986; 65:462-7. Reprinted with permission.Halothane is commonly viewed as a more potent cerebral vasodilator than isoflurane. It was speculated that the lesser vasodilation caused by isoflurane might be the result of the greater reduction in cerebral metabolic rate (CMR) that it causes, and that the relative vasodilating potencies of halothane and isoflurane would be similar if the two agents were administered in a situation that precluded volatile-agent-induced depression of CMR. To test this hypothesis, cerebral blood flow (CBF) and the cerebral metabolic rate for oxygen (CMRO2) were measured in two groups of rabbits before and after the administration of 0.75 MAC halothane or isoflurane. One group received a background anesthetic of morphine and N2O, which resulted in an initial CMRO2 of 3.21 ± 0.17 (SEM) ml · 100 g · min; second group received a background anesthetic of high-dose pentobarbital, which resulted in an initial CMRO2 of 1.76 ± 0.16 ml · 100 g · min. In rabbits receiving a background of morphine sulfate/N2O, halothane resulted in a significantly greater CBF (65 ± 10 ml · 100 g · min) than did isoflurane (40 ± 5 ml · 100 g · min). Both agents caused a reduction in CMRO2, but CMRO2 was significantly less during isoflurane administration. By contrast, with a background of pentobarbital anesthesia, CBF increased by significant and similar amounts with both halothane and isoflurane. With halothane, CBF increased from 22 ± 2 ml · 100 g · min in the control stage to 39 ± 3, and with isoflurane from 24 ± to 38 ± 2 ml · 100 g · min. CMRO2 was not depressed further by either halothane or isoflurane. These results suggest that the relative effects of halothane and isoflurane on CBF are dependent on the CMR present prior to their administration. When the preexistent CMR is not markedly depressed, isoflurane decreases CMR and causes less cerebral vasodilation than does halothane. When initial CMR is depressed, halothane and isoflurane have similar vasodilating potencies.

From Bench to Bedside and Back Again: A Personal Journey with Dexmedetomidine.

Dexmedetomidine Diminishes Halothane Anesthetic Requirements in Rats Through a Postsynaptic Alpha 2 Adrenergic Receptor. By Segal IS, Vickery RG, Walton JK, Doze VA, and Maze M. ANESTHESIOLOGY 1988; 125:590-4. Abstract reprinted with permission.The effect of 4(5)-[1-(2,3-dimethylphenyl)ethyl]imidazole (medetomidine), the α2 adrenergic agonist, on anesthetic requirements was investigated in rats anesthetized with halothane. Halothane MAC was determined before and after either dexmedetomidine (D-enantiomer) or levomedetomidine (L-enantiomer) 10, 30, and 100 μg/kg, or vehicle intraperitoneally. There was a dose-dependent increase in MAC with the D-, but not the L-, stereoisomer. At the highest dose of dexmedetomidine (100 μg/kg), halothane could be discontinued for up to 30 min with no response to tail clamping. To determine whether α2 adrenoreceptors mediated this effect of dexmedetomidine on MAC, cohorts of rats were pretreated with idazoxan, 10 mg/kg intraperitoneally, a highly selective α2 antagonist. This completely prevented the reduction of MAC caused by dexmedetomidine. To determine whether the reduction of MAC caused by dexmedetomidine was mediated in part through either opiate or adenosine receptors, groups of rats were pretreated with either naltrexone, 5 mg/kg intraperitoneally, an opiate antagonist, or 8-phenyltheophylline, 2.5 mg/kg intraperitoneally, an A1 adenosine antagonist. These two pretreatments did not alter the reduction of MAC by dexmedetomidine. To determine whether postsynaptic mechanisms mediate the anesthetic effect of dexmedetomidine, rats were depleted of central catecholamine stores with either n-(2-chloroethyl)-n-ethyl-2-bromobenzylamine or reserpine and α-methyl-para-tyrosine, and MAC was determined before and after each dose of dexmedetomidine. While the catecholamine-depleted rats had a lower basal MAC than the vehicle controls, there was still a profound reduction in halothane MAC after administration of dexmedetomidine. The reduction of MAC by dexmedetomidine was blocked with idazoxan in the catecholamine-depleted rats. These data indicate that the reduction of MAC caused by dexmedetomidine is mediated through α2 adrenoreceptors with no apparent involvement of either opiate or A1 adenosine receptors. Data from catecholamine-depleted rats suggest that the mediating mechanism must involve site(s) other than or in addition to the presynaptic α2 adrenergic receptors on noradrenergic neurons. The authors conclude that central postsynaptic α2 adrenergic receptors mediate a significant part of the reduction of anesthetic requirements caused by dexmedetomidine.

From the Journal archives: Be alert to the risk of unexpected prolonged postoperative hypoxemia!

In 1978, Drs. R Knill and A. Gelb published the results of a study to measure the effect of subanesthetic levels of halothane on the ability of fit volunteers to respond to sustained hypoxia, and to determine how long potentially hazardous levels of halothane persist after a brief non-complex surgical procedure in healthy patients. The purpose of this commentary is to highlight the historical context of their findings and the impact of their work on our modern day practice of anesthesia. In six fit male volunteers, steady states of halothane reduced the ventilatory response to normocapnic hypoxemia (PETO2 40 mmHg) by ~ 50% at 0.05 MAC and by 70% at 0.10 MAC without affecting resting levels of ventilation. Subjects remained easily rousable and coherent with full memory of events. Symptoms of hypoxemia were markedly reduced or totally absent during hypoxic periods. In five patients recovering from dental procedures (mean duration 59 min), 0.10 MAC halothane levels persisted in the recovery room for approximately one hour. Patients emerging from a brief (about one hour) halothane anesthetic, although appearing conscious, may have a hazardous degree of depression of the usually protective ventilatory response to hypoxemia for about one hour in the recovery room. Both the symptoms and signs of hypoxemia will be substantially reduced during this emergence phase, enhancing the risk that severe hypoxic episodes may go unrecognized. Gelb AW, Knill RL. Subanaesthetic halothane: Its effect on regulation of ventilation and relevance to the recovery room. Can Anaesth Soc J 1978; 25: 488-94.

Insertion of laryngeal mask airway does not increase the intraocular pressure in children with glaucoma

It is hypothesized that in children with glaucoma, the insertion of laryngeal mask airway (LMA) will cause lesser rise in intraocular pressure (IOP) than tracheal tube (TT). To compare the IOP response to LMA and TT insertion in children with glaucoma. A prospective, randomized, single-blind study was conducted in 30 glaucomatous ASA-1 children, aged 1-10 years scheduled to undergo trabeculectomy. Anesthesia was induced with halothane and maintained for 5 min with 1 MAC of halothane after administering atracurium 0.5 mg·kg(-1) following which LMA or TT was introduced. IOP was measured in both the eyes before and after insertion of airway device for 5 min. The IOP increased significantly from 27.3 ± 5.2 to 31.2 ± 5.4 mmHg (P < 0.001) after tracheal intubation but returned to baseline within 5 min. The IOP did not change from the baseline after insertion of LMA. The IOP was significantly higher in group TT compared to group LMA at 2 min (P = 0.004) and 5 min (P = 0.01) after the device insertion. The heart rate (HR) increased significantly after tracheal intubation and returned to baseline 4 min after intubation. The HR increase was significantly more in TT group compared to LMA group at all times of observation. Both systolic blood pressure (SBP; P = 0.01) and diastolic blood pressure (DBP; P = 0.02) showed an increase at 1 min in children in group TT. Insertion of LMA in glaucomatous children is not associated with an increased IOP response or cardiovascular changes.

Theoretical context-sensitive elimination times for inhalation anaesthetics

Context-sensitive times to 50%, 80%, and 90% elimination from the brain have been calculated for volatile anaesthetics. This does not represent complete recovery because there are important residual effects even at 90% elimination, and the effect of anaesthetic metabolism on the rate of elimination has not been considered. A physiologically based model of anaesthetic uptake and distribution was elaborated to include anaesthetic metabolism and fluoride kinetics. It was validated by comparing its predictions with real data, then experiments were undertaken to calculate the partial pressure of anaesthetic in the brain after the administration of 1 MAC of halothane, enflurane, isoflurane, sevoflurane or desflurane, or 50% of inspired nitrous oxide or xenon, for up to 6 h. The model generated data that were compatible with many published measurements of anaesthetic kinetics and fluoride production. Metabolism had a negligible effect on kinetics. After 4 h of anaesthesia, the model predicted body content to be 28 g nitrous oxide, 26 g desflurane, 14 g sevoflurane, or 15 g isoflurane, and 99.9% brain elimination times were then 9 h for nitrous oxide, 33 h for desflurane, 52 h for sevoflurane, and 71 h for isoflurane. At this stage of elimination, the whole body still retained between 4% and 13% of the absorbed dose. Differences between sevoflurane and desflurane were obvious only during the final stages of elimination (>99% from the vessel-rich group). Large amounts of anaesthetics are absorbed during anaesthesia and significant amounts remain in the body for days after apparent recovery.

The acute hypoxic ventilatory response under halothane, isoflurane, and sevoflurane anaesthesia in rats*

The relative order of potency of anaesthetic agents on the hypoxic ventilatory response has been tested in humans, but animal data are sparse. We examined the effects of 1.4, 1.6, 1.8, and 2.0 MAC halothane, isoflurane, and sevoflurane on phrenic nerve activity in euoxia (baseline) and during acute normocapnic hypoxia (inspired oxygen fraction 0.09) in adult male Sprague-Dawley rats. With halothane, all animals became apnoeic even in euoxia, and the hypoxic response was completely abolished at all anaesthetic levels. With isoflurane, 5 of 14 animals exhibited phrenic nerve activity in euoxia at 1.4 MAC and demonstrated a hypoxic response (302% of baseline activity), but all became apnoeic and lost the hypoxic response at higher doses. With sevoflurane, phrenic nerve activity and a hypoxic response was preserved in at least some animals at all doses (i.e. even the highest dose of 2.0 MAC). Similar to the rank order of potency previously observed in humans, the relative order of potency of depression of the hypoxic ventilatory response in rats was halothane (most depressive) > isoflurane > sevoflurane (p = 0.01 for differences between agents).

Amino acid residues involved in agonist binding and its linking to channel gating, proximal to transmembrane domain of 5-HT3Areceptor for halothane modulation

The 5-hydroxytryptamine type 3 (5-HT3) receptor is a member of the Cys-loop superfamily of ligand-gated ion channels (LGICs) and modulated by pharmacologic relevant concentrations of volatile anesthetics or n-alcohols like most receptors of LGICs. The goal of this study was to reveal whether the site-directed single mutations of E-106, F-107 and R-222 in 5-HT3 receptor may affect the anesthetic modulation of halothane known as positive modulator. The wild-type and mutant receptors, E106D, F107Y, R222F, R222V, were expressed in Xenopus Laevis oocytes and receptor function was assessed using two electrode voltage clamp techniques. E106D, F107Y, R222F, R222V mutant 5-HT3A receptors were functionally expressed. F107Y mutant 5-HT3A receptors displayed decreased sensitivity to 5-HT compared to the wild type 5-HT3A receptor (P < 0.05). Halothane showed positive modulation in both wild and F107Y mutant 5-HT3A receptors but F107Y mutant 5-HT3 receptor showed greater enhancing modulation comparing to wild-type receptor. Meanwhile, R222F and R222V mutant 5-HT3 receptor lost positive modulation with 1 and 2 MAC of halothane. Most interestingly, positive modulation by halothane was converted into negative modulation in E106D mutant 5-HT3A receptor. The present study implicate the amino acid residues known for agonist binding and linking agonist binding to channel gating might also have important role for anesthetic modulation in 5-HT3A receptor.

Lidocaine, MK-801, and MAC

Previous studies have found that the local anesthetic/sodium channel blocker lidocaine decreased MAC by maximum amounts approximately equal to the decreases produced by dizocilpine (MK-801), a N-methyl-d-aspartate (NMDA) receptor antagonist. Blockade of sodium channels by inhaled anesthetics has been suggested as a possible cause for impairment of transmission through NMDA receptors. We postulated that the net effect of lidocaine and MK-801 on MAC would be the same, albeit by affecting NMDA neurotransmission at different points. We measured the effect of various lidocaine infusions on the MAC of cyclopropane, halothane, isoflurane, and o-difluorobenzene in rats. We also measured the effect of concurrent lidocaine-MK-801 infusion on the MAC of isoflurane and o-difluorobenzene. Our data contradicted our predictions. (a) We found no limit to the effect of lidocaine infusion, in some cases finding that lidocaine, alone, produced immobility; (b) lidocaine infusion did not decrease the MAC of o-difluorobenzene differently from the MAC of other inhaled anesthetics; and (c) the addition of MK-801 equally affected the decrease in MAC produced by lidocaine infusion for isoflurane versus o-difluorobenzene. Lidocaine does not primarily decrease MAC by decreasing the release of glutamate from nerve terminals.

Cardiac rhythm and left ventricular function of infants at 1 MAC sevoflurane and halothane

The implementation of sevoflurane in pediatric anesthesia practice led to a decrease in the incidence of cardiac arrest previously reported with halothane. Nevertheless, the effects of sevoflurane on cardiac rhythm and function have not been systematically investigated in infants. Thus, we compared cardiac rhythm and left ventricular function at 1 MAC sevoflurane and halothane anesthesia and investigated the potential benefit effect of atropine. Twenty infants ASA physical status I or II were randomly assigned to have anesthesia induced with either sevoflurane (up to 5%) or halothane (up to 1.5%). After insertion of an i.v. line, anesthesia was maintained at 1 MAC sevoflurane (group S) or 1 MAC halothane (group H) with infants breathing spontaneously in 100% oxygen. Cardiac output and contractility were measured by transthoracic echocardiography. Three sets of hemodynamic parameters were averaged prior to and after administration of 20 microg x kg(-1) of i.v. atropine. Infants breathing spontaneously 1 MAC halothane or 1 MAC sevoflurane were found to have comparable hemodynamic parameters. After atropine administration, heart rate and cardiac index (CI) increased significantly in both groups (19.6 +/- 7.6% in group H and 21.3 +/- 13.1% in group S, 18.6 +/- 8.8% in group H and 17.7 +/- 12% in group S respectively). Moreover, atropine induced an increase in left ventricular shortening fraction with no difference between groups. In contrast, only infants in group S presented a significant increase in ejection fraction. Indices of left ventricular function were comparable between groups with no clinically significant change following atropine administration. The present study confirms the favorable hemodynamic profile of sevoflurane in infants breathing spontaneously at 1 MAC concentration.

Halothane Does Not Inhibit the Functional Coupling between the β2-Adrenergic Receptor and the GαsHeterotrimeric G Protein

This study investigated whether halothane affects the functional coupling between the beta2 adrenergic receptor and the alpha subunit of its cognate stimulatory heterotrimeric guanosine-5'-triphosphate (GTP)-binding protein (Galphas). The authors hypothesized that halothane does not affect isoproterenol-promoted guanosine nucleotide exchange at Galphas and hence would not affect isoproterenol-induced relaxation of airway smooth muscle. Halothane effects on isoproterenol-induced inhibition of calcium sensitivity were measured in permeabilized porcine airway smooth muscle. Galphas nucleotide exchange was measured in crude membranes prepared from COS-7 cells transfected to transiently coexpress the human beta1 or beta2 receptor each with human short Galphas. A radioactive, nonhydrolyzable analog of GTP, [S]GTPgammaS, was used as the reporter for nucleotide exchange at Galphas. Halothane (0.75 mm, approximately 2.8 minimum alveolar concentration [MAC] in pigs) did not affect isoproterenol-induced inhibition of calcium sensitivity. Isoproterenol caused a time- and concentration-dependent increase in Galphas nucleotide exchange. Halothane, even at concentrations of 1.5 mm (approximately 5.6 MAC), had no effect on basal Galphas nucleotide exchange in the absence of isoproterenol, whereas halothane inhibited isoproterenol-promoted Galphas nucleotide exchange in both the beta1-Galphas and beta2-Galphas expressing membranes. However, the effect was significantly greater on beta1-Galphas coupling compared with beta2-Galphas coupling, with no effect on beta2-Galphas coupling at 2.8 MAC halothane. Halothane does not inhibit the biochemical coupling between the beta2 receptor and Galphas and hence does not affect the inhibition of calcium sensitivity induced by isoproterenol. Therefore, halothane should not affect the efficacy of beta2 agonists, as suggested by studies of in vivo animal models of asthma.

GABA A-R α1 subunit knockin mutation leads to abnormal EEG and anesthetic-induced seizure-like activity in mice

Gamma-aminobutyric acid-type A receptors (GABA A-Rs) have been proposed as a target for many general anesthetics. We recently created knockin (KI) mice harboring a point mutation (serine 270 to histidine) in the GABA A-R α1 subunit. This mutation abolishes sensitivity of recombinant GABA A–Rs to isoflurane while maintaining normal sensitivity to halothane and increasing the potency of GABA. KI mice showed abnormalities in the EEG baseline, including occasional spike-wave activity and spindle-like bursts. When anesthetized with isoflurane, the KI mice but not the control mice revealed repetitive 4–5Hz slow wave discharges in the cortical EEG. KI mice did not differ from controls in response to isoflurane or halothane in the standard tail clamp/withdrawal and loss of righting reflex assays. We recorded miniature inhibitory postsynaptic currents (mIPSCs) from hippocampal interneurons and pyramidal cells in brain slices. mIPSCs in neurons from KI mice were of normal amplitude, but decayed more slowly than controls. Hippocampal mIPSCs in control mice were significantly prolonged by 0.4 and 0.9 MAC isoflurane, and by 0.5 MAC halothane. In KI mice, the effect of isoflurane on mIPSC decay was dramatically reduced, while halothane prolonged mIPSCs as for controls. We conclude that the kinetic and pharmacological properties of hippocampal GABA A-Rs in the KI mouse recapitulate many features of mutant α1β2γ2 GABA A-Rs observed in vitro. GABA A-Rs containing α1 subunits do not appear to contribute to the actions of isoflurane in the spinal cord, but both EEG and synaptic recordings provide evidence for effects of isoflurane on these GABA A-R isoforms in cortical structures.

Effect of adenosine infusion on isoflurane MAC in dogs

Adenosine is a potent analgesic in people and reduces the MAC of halothane in dogs. The purpose of this study was to determine whether adenosine reduces the MAC of isoflurane in dogs. Seven beagles (four males and three females) were anesthetized and randomly assigned to receive adenosine (0.3 mg kg−1 minute−1; 6 mL kg−1 hour−1, IV) or saline (0.9%, 6 mL kg−1 hour−1IV). After an interval of ≥7 days, each dog was reanesthetized and treated with the alternate infusion. Anesthesia was induced and maintained with isoflurane in oxygen.

Cochlear implant: Anaesthesia challenges

Background: Cochlear implants are now an acceptable therapeutic option for those patients with irreversible hearing loss and deaf-mutism. The surgery is time consuming and complicated. Hence, the technique of anaesthesia plays a crucial role in success of cochlear implant surgery. Cochlear implant patients have various types of syndromes which are important from anaesthetic as well as surgical point of view. Pre-implant preparation requires objective assessment of hearing, plain X-rays of skull and a CT scan of the temporal bone. Anaesthesia is required for objective assessment of hearing in children under five years of age, to obtain X-rays of skull, magnetic resonance imaging (MRI), CT scan, brain evoked response audiometry (BERA) testing and finally for cochlear implant surgery. Anaesthetic considerations include preoperative familiarisation with the patient and his family. Syndromal illnesses have specific anaesthetic significance such as presence of difficult airway or prolonged QT interval. Parental presence is highly desirable during induction of anaesthesia. Electro-surgical instruments especially monopolar ones, should not be used once the cochlear implant is in place. Methods: In our institution, all cases (15 children) received their cochlear implants under general anaesthesia and formed the study group. Children were administered midazolam orally and inj ketamine during CT scan. Our techniques of general anaesthesia were modified to permit use of nerve stimulators during surgery. To minimise the incidence of vertigo particularly after cochleostomy, postoperative nausea and vomiting, all patients received glycopyrrolate and fentanyl citrate intravenously prior to induction. Other agents used were, thiopentone, suxamethonium and end-tidal 1.3 MAC halothane in 1:2 mixture of oxygen and nitrous oxide (O 2 and N 2O). Electro diathermy was switched off, before the cochlear device was implanted on the patient. Patients were allowed to breathe spontaneously whenever nerve stimulator was used to locate the facial nerve. Inj Ondansetron 0.1 mg/kg was used as anti-emetic agent. Postoperative pain relief was initially provided with fentanyl 1 μg/kg IV and later with syrup ibuprofen. Results: There were no remarkable anaesthetic or surgical complication in our series except perilymph leakage in two cases.

The protective effect of isoflurane and halothane on noise-induced hearing loss in mice

Problem: Production of oxygen-free radicals and apoptosis are the mechanism of inner ear damage in noise-induced hearing loss. General anesthetics can inhibit the tissue metabolic activity, production of oxygen-free radicals, and apoptosis. We conducted this study to evaluate the protective effect of general anesthetics on hearing loss in noise-exposed mice. Methods: We used BALB/c mice with normal Preyer’s reflex. Mice were anesthetized with 1 - 1.5 MAC of isoflurane and halothane using end-tidal agent monitoring system with supplement of oxygen (4 L/min). Broad band white noise (120 dB SPL, 0.2 - 7 kHz) was used for induction of noise-induced hearing loss. Mice were stimulated by noise for 3 hours daily for 3 consecutive days with or without anesthetics (control). Hearing level was evaluated by measuring auditory brainstem response before and after noise exposure. Results: The hearing level before noise exposure was 26 ± 2 dB in the control group (n = 5). The level changed to 79 ± 1 dB after 3-day noise exposure and to 82 ± 1.5 dB 1 week after noise exposure. When we anesthetized the mice with isoflurane during noise exposure (n = 5), hearing levels were 22 ± 2.5 dB before noise exposure, 48 ± 6.5 dB after exposure and 29 ± 3.5 dB 1 week after noise exposure. In the halothane anesthetics group (n = 5), hearing levels were 20 ± 1.5 dB, 39 ± 2 dB, and 25 ± 3.5 dB, respectively. Conclusion: General anesthesia with isoflurane or halothane can protect the noise-induced hearing deterioration. Significance: The mechanism of this protective effect needs further studies. Support: None reported.

Milrinone attenuates the negative inotropic effects of landiolol in halothane-anesthetized dogs.

Clinical use of high dose beta-blocker therapy is limited by excessive negative inotropic effects. Previous studies suggest that milrinone may be of utility in limiting the inotropic but not the chronotropic effects of beta blockers. We examined the hemodynamic effects of co-administration of a new potent selective beta(1) blocker, landiolol, and milrinone in halothane-anesthetized dogs. Eighteen adult mongrel dogs were anesthetized with 1.2 MAC halothane. Hemodynamic measurements were made at baseline, 30 min after starting the milrinone (0.5 micro g x kg(-1) x min(-1)) or normal saline infusion (n = 9 in each), then 30 min after each change in the dose of landiolol infusion. The tested doses of landiolol were 10, 100, and 1000 micro g x kg(-1) x min(-1). Landiolol (>/= 10 micro g x kg(-1) x min(-1)) has significant and comparable negative chronotropic effects in both groups of dogs. While it also has significant negative inotropic effects in both groups, such effects are significantly attenuated in the dogs treated with milrinone. Milrinone is effective to attenuate the negative inotropic effects of landiolol in halothane-anesthetized dogs.

Anesthetic sensitivities to propofol and halothane in mice lacking the R-type (Cav2.3) Ca2+ channel.

Because inhibition of voltage-dependent Ca(2+) channels can be a mechanism underlying general anesthesia, we examined sensitivities to propofol and halothane in mice lacking the R-type (Ca(v)2.3) channel widely expressed in neurons. Sleep time after propofol injection (26 mg/kg IV) and halothane MAC(RR) and MAC (50% effective concentrations for the loss of the righting reflex and for the tail pinch/withdrawal response, respectively) were determined. Significantly shorter propofol-induced sleep time (291.6 +/- 16.8 s versus 344.4 +/- 12.1 s) and larger halothane MAC(RR) (1.11% +/- 0.04% versus 0.98% +/- 0.03%) were observed in Ca(v)2.3 channel knockouts (Ca(v)2.3(-/-)) than in wild-type (Ca(v)2.3(+/+)) litter mates. To investigate the basis of the decreased anesthetic sensitivities in vivo, field excitatory postsynaptic potentials and population spikes (PSs) were recorded from Schaffer collateral CA1 synapses in hippocampal slices. Propofol (10-30 micro M) inhibited PSs by potentiating gamma-aminobutyric acid-ergic inhibition, and this potentiation was markedly smaller at 30 micro M in Ca(v)2.3(-/-) mice, possibly accounting for the decreased propofol sensitivity in vivo. Halothane (1.4%-2.2%) inhibited field excitatory postsynaptic potentials similarly in both genotypes, whereas 1%-2% halothane depressed PSs more in Ca(v)2.3(-/-) mice, suggesting the postsynaptic role of the R-type channel in the propagation of excitation and other mechanisms underlying the increased halothane MAC(RR) in Ca(v)2.3(-/-) mice. Because inhibition of neuronal Ca(2+) currents can be a mechanism underlying general anesthesia, we examined anesthetic sensitivities in mice lacking the R-type (Ca(v)2.3) Ca(2+) channels both in vivo and in hippocampal slices. Decreased sensitivities in mutant mice imply a possibility that agents blocking this channel may increase the requirements of anesthetics/hypnotics.

Adverse airway events during brief nasal inhalations of volatile anaesthetics: the effect of humidity and repeated exposure on incidence in volunteers preselected by response to desflurane.

Twelve volunteers known to have airways that responded adversely to 2.0 MAC desflurane were recruited. Each volunteer inhaled three single breaths of each of 0.5, 1.0 and 2.0 MAC of sevoflurane, halothane, isoflurane, desflurane and balance air, with breaths of air between, whilst breathing nasally through a face mask attached to one of three filters that provided three different levels of humidification. The incidence of any adverse airway events was recorded. The anaesthetic inhaled significantly affected the incidence of adverse airway events (p < 0.001), with the least to most irritant being sevoflurane, halothane, isoflurane and desflurane. Increasing the concentration of anaesthetic also significantly increased the incidence of adverse airway events (p < 0.001). The filter used, and hence the level of humidification, did not affect the incidence of adverse airway events (p = 0.09), but repeated exposure caused a significant reduction in the incidence of adverse airway events (p < 0.001).

Halogenated anesthetics reduce interleukin-1beta-induced cytokine secretion by rat alveolar type II cells in primary culture.

Alveolar epithelial type II (AT II ) cells participate in the intraalveolar cytokine network by secreting cytokines and are widely exposed to volatile anesthetics during general anesthesia. The aim of the current study was to evaluate the effects of halothane, enflurane, and isoflurane on rat AT II cell cytokine secretions in AT II primary cell cultures. Alveolar epithelial type II primary cell cultures were obtained from adult rat lungs. AT II cells were stimulated by recombinant murine interleukin-1beta (rmIL-1beta) to mimic an inflammatory response, and immediately exposed for various duration to different concentration of halothane, enflurane, or isoflurane. Interleukin-6, macrophage inflammatory protein-2 (MIP-2), and monocyte chemoattractant protein-1 (MCP-1) protein concentrations were then measured in cell culture supernatants. Recombinant mIL-1beta-stimulated AT II cells exposed to air served as control. Halothane, isoflurane, and enflurane (1 minimum alveolar concentration [MAC], 4 h) decreased rmIL-1beta-stimulated AT II cell secretions of interleukin-6, MIP-2, and MCP-1, but did not modify total protein secretion. Halothane exposure decreased rmIL-1beta-stimulated AT II cell secretions of interleukin-6, MIP-2, and MCP-1 in a dose- and time-dependent manner. Total protein concentrations remained unchanged except AT II 1.5 MAC of halothane, and no cytotoxic effect could be evidenced by lactate dehydrogenase release. These effects were transient as rmIL-1beta-stimulated AT II cell secretions of interleukin-6 and MIP-2 progressively reached control values between 4 and 24 h after the end of halothane exposure. However, MCP-1 inhibition persisted until 24 h. rmIL-1beta-induced MIP-2 and tumor necrosis factor-alpha mRNA expression were decreased by 36 and 24%, respectively, after halothane exposure. The current study shows that exposure of rmIL-1beta-stimulated AT II cells to volatile anesthetics reversibly alters their cytokine secretion. Therefore, volatile anesthesia, by modulating pulmonary epithelial cell secretion of inflammatory cytokines, might affect the lung inflammatory response.

Glycine receptors mediate part of the immobility produced by inhaled anesthetics.

Many inhaled anesthetics potentiate the effect of glycine on inhibitory strychnine-sensitive glycine receptors in vitro, supporting the view that this receptor could mediate the immobility produced by inhaled anesthetics during noxious stimulation (i.e., would underlie minimum alveolar anesthetic concentration [MAC]). There are quantitative differences between anesthetics in their capacity to potentiate glycine's effect in receptor expression systems: halothane (most potentiation), isoflurane (intermediate), and cyclopropane (minimal). If glycine receptors mediate MAC, then their blockade in the spinal cord should increase the MAC of halothane more than that of isoflurane and isoflurane MAC more than cyclopropane MAC; the increases in MAC should be proportional to the receptor potentiation produced in vitro. Rats with chronically implanted intrathecal catheters were anesthetized with halothane, isoflurane, or cyclopropane. During intrathecal infusion of artificial cerebrospinal fluid, MAC was determined. Then MAC was re-determined during an infusion of 3, 12, 24, or 48 (isoflurane only) micro g/min of strychnine (strychnine blocks glycine receptors) in artificial cerebrospinal fluid. Strychnine infusion increased MAC in proportion to the enhancement of glycine receptors found in vitro. The maximum effect was with an infusion of 12 micro g/min. For the combined results at 12 and 24 micro g/min of strychnine, the increase in MAC correlated with the extent of in vitro potentiation (r(2) = 0.82). These results support the hypothesis that glycine receptors mediate part of the immobilization produced by inhaled anesthetics. In vitro, halothane potentiates glycine's effect on strychnine-sensitive glycine receptors more than isoflurane and isoflurane more than cyclopropane. The present in vivo work indicates that antagonism of the glycine receptor with strychnine increases minimum alveolar anesthetic concentration for halothane more than isoflurane and isoflurane more than cyclopropane. Such results support the notion that glycine receptors may mediate part of the immobility produced by inhaled anesthetics.

The use of the cuffed oropharyngeal airway in paediatric patients

The cuffed oropharyngeal airway (COPA) is a device which has already been demonstrated to be suitable for anaesthetized adult patients undergoing either spontaneous or mechanical ventilation. There are few reports on the use of the COPA in children. In this study, the authors assessed the COPA in paediatric patients undergoing minor surgery. The same anaesthesiologist inserted the COPA in 40 consecutive paediatric patients, ASA I and II, aged 1.8-15.3 years. (7.4 +/- 3.9), after induction of anaesthesia with N2O/O2/sevoflurane. COPA size was chosen by measuring the distal tip of the device at the angle of the jaw with the COPA perpendicular to the patient's bed. The proper positioning of the COPA was assessed by observing thoracoabdominal movements, regular capnograph trace, the reservoir bag movements and SpO2 > 94% with a fraction of inspired oxygen of 0.5. Anaesthesia was maintained with 1 MAC halothane, sevoflurane, or isoflurane in N2O/O2 (50%) and the patients were spontaneously breathing. The stability of the COPA following changes in head, neck and body position was tested. We recorded the duration time for COPA insertion, the side-effects of placement of the COPA and during the intraoperative period, the number of attempts, the type of manipulation in order to provide an effective airway and postoperative symptoms, such as the presence of blood on the device, sore throat, neckache, jaw pain and PONV. Successful COPA insertion at the first attempt was 90% and at the second attempt in the remaining 10%. The most frequent airway manipulations were head tilt in 27.5% (obtained by a pillow under shoulders) and chin lift in 5%. No complications both at COPA placement nor during the intraoperative period were observed. On the basis of weight and age, the COPA size was no. 8 in 50%, no. 9 in 30%, no. 10 in 12.5%, and no. 11 in 7.5%. The COPA demonstrated stability after changes in head, neck and body position. Postoperative complications were the presence of blood stains in one case and PONV in six cases (15%). The COPA is an extratracheal airway device suitable in paediatric patients undergoing general anaesthesia with spontaneous ventilation for minor surgery and other painful procedures. This study shows that for paediatric patients: (i) complications seem to be rare; (ii) the COPA allows hands free anaesthesia; (iii) specific indication for the COPA could be obese patients with a small mouth; and (iv) COPA sizing can be easily established by the weight or age of the patients.