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PubMed1995

Volatile anesthetics and glutamate activation of N-methyl-D-aspartate receptors.

Several studies have indicated important functional interactions between volatile anesthetics and the N-methyl-D-aspartate (NMDA) class of glutamate receptors. In the present study, we examined the effects of diethyl ether, chloroform, methoxyflurane, halothane, enflurane, and isoflurane on (1) glutamate activation of the NMDA receptor complex, including glycine reversal of anesthetic action, as revealed by [3H]-(5R, 10S)-(+)methyl-10,11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine, dizocilpine (MK-801) binding to the cation channel, and (2) [3H]cis-4-( phosphonomethyl)piperidine-2-carboxylic acid (CGS 19755) binding to the glutamate recognition site of the NMDA receptor In agreement with previous studies, glutamate increased the binding of 1 nM [3H]MK-801, measured after a 1-hr incubation at 37 degrees, by up to several hundred fold. This stimulation was blocked by glutamate antagonists and potentiated by glycine with an EC50 of approximately 0.03 muM. Glycine also had a direct stimulatory effect on [3H]MK-801 binding at much higher concentrations ( > or = 10 muM). All of the anesthetics examined depressed glutamate stimulation of [3H]MK-801 binding in a concentration-dependent manner with the following order of potency: halothane > or = enflurane > methoxyflurane > chloroform > diethyl ether. This inhibition of [3H]MK-801 binding was observed at concentrations that are routinely attained in the cerebrospinal fluid during surgical anesthesia. Moreover, the inhibition was reversed rapidly following removal of the anesthetics from the assay medium. Inclusion of glycine in the incubation medium markedly attenuated anesthetic-induced inhibition of glutamate-sensitive [3H]MK-801 binding with an EC50 of between 0.1 and 1 muM. Thus, this reversal by glycine correlated with its potentiating as opposed to its direct stimulatory, effect on NMDA receptors. Anesthetic inhibition of [3H]MK-801 binding could not be overcome by raising the glutamate concentration (i.e. the interaction did not appear to be competitive with respect to glutamate) unless glycine was present. Binding of [3H]CGS 19755 to the glutamate recognition site was also inhibited by each of the anesthetics examined. However, with the exception of chloroform, all of the anesthetics were more potent inhibitors of glutamate-stimulated [3H]MK-801 binding than they were of [3H]CGS 19755 binding. [3H]CGS 19755 binding saturation curves in the presence of halothane and enflurane indicated a decrease in the density of [3H]-CGS 19755 binding sites with no change in binding affinity (i.e. the inhibition did not appear to be competitive). These findings support the idea that anesthetic drugs disrupt NMDA receptor transmission through multiple allosteric effects on the receptor-channel activation mechanisms and the glutamate binding site.

Anesthetics, Inhalation↗
PubMed2000

Direct inhibition of microtubule-based kinesin motility by local anesthetics.

Local anesthetics are known to inhibit neuronal fast anterograde axoplasmic transport (FAAT) in a reversible and dose-dependent manner, but the precise mechanism has not been determined. FAAT is powered by kinesin superfamily proteins, which transport membranous organelles, vesicles, or protein complexes along microtubules. We investigated the direct effect of local anesthetics on kinesin, using both in vitro motility and single-molecule motility assays. In the modified in vitro motility assay, local anesthetics immediately and reversibly stopped the kinesin-based microtubule movement in an all-or-none fashion without lowering kinesin ATPase activity. QX-314, a permanently charged derivative of lidocaine, exerted an effect similar to that of lidocaine, suggesting that the effect of anesthetics is due to the charged form of the anesthetics. In the single-molecule motility assay, the local anesthetic tetracaine inhibited the motility of individual kinesin molecules in a dose-dependent manner. The concentrations of the anesthetics that inhibited the motility of kinesin correlated well with those blocking FAAT. We conclude that the charged form of local anesthetics directly and reversibly inhibits kinesin motility in a dose-dependent manner, and it is the major cause of the inhibition of FAAT by local anesthetics.

Adenosine Triphosphatases↗
PubMed1997

Contrasting membrane localization and behavior of halogenated cyclobutanes that follow or violate the Meyer-Overton hypothesis of general anesthetic potency.

The membrane localization and properties of two halogenated cyclobutanes were examined using 2H and 19F NMR. The common predictors of potency indicate that these two compounds will have anesthetic activity; however, 1,2-dichlorohexafluorocyclobutane (c(CCIFCCIFCF2CF2)) is not an effective anesthetic, whereas 1-chloro-1,2,2-trifluorocyclobutane (c(CCIFCF2CH2CH2)) is an effective general anesthetic. Using 2H NMR, the effect of these compounds on the acyl chain packing in palmitoyl (d31) oleoylphosphatidylcholine membranes was examined. The addition of the anesthetic c(CCIFCF2CH2CH2) results in small increases in the segmental order near the headgroup, whereas segments deeper in the bilayer show decreases in order. These results are consistent with those obtained previously for halothane, isoflurane, and enflurane. On the addition of the nonanesthetic c(CCIFCCIFCF2CF2), the segmental order in vitually unchanged, except for a slightly changed order near the segents 10-12 of the palmitoyl chains. These results, and the 19F chemical shifts, indicate that the anesthetic c(CCIFCF2CH2CH2) exhibits a preference for the membrane interface, as do the other general anesthetics, whereas the nonanesthetic c(CCIFCIFCF2CF2) resides within the membrane hydrocarbon core. The compound c(CCIFCCIFCF2CF2) and other nonanesthetic halocarbons have lower molecular dipole moments compared to effective anesthetic halocarbons, which may account for their altered distribution within the membrane. These data strongly suggest that preferential localization of a halocarbon within the membrane interface is a predictor of anesthetic potency. Furthermore, the data indicate that the properties and forces in the membrane interface deserve consideration as mediators of anesthetic activity.

Anesthetics↗
PubMed1975

The biochemical basis of anesthetic toxicity.

The inhalational anesthetics reversibly inhibit mitochondrial electron transport from NADH-linded substrates at the level of the enzyme NADH-dehydrogenase. The effect of this inhibition on ATP production is probably not the basis of the anesthetic state, as the level of high-energy phosphate in the brain does not decrease during anesthesia. Anesthetics, therefore, interfere with brain energy untilization, in addition to brain energy production. Inhibition by anesthetics of mitochondrial calcium uptake, which results from the inhibition of electron transport, may be an important anesthetic effect if it raises the intracellular calcium level. Other areas of investigation which have not been discussed here include the effects of anesthetics on glycolytic and other enzyme systems, ion fluxes, neurotransmitter synthesis and release, and on the structure of natural and artificial membranes. It is now appreciated that most of the inhalational anesthetics are metabolized by the endoplasmic reticulum of hepatocytes. The biotransformation of several anesthetics can be increased by drugs which induce hepatic microsomal enzymes. The organ toxicities of chloroform, trichloroethylene, fluroxene, methoxyflurane, and possibly of halothane and enflurane are related to their intermediary or final metabolites. It is of anesthetic drugs for an individual patient.

Anesthesia, Inhalation↗
PubMed1987

Allergy to local anesthetics: comparison of patch test with prick and intradermal test results.

The interrelation between immediate and delayed hypersensitivity reactions to local anesthetics is poorly understood. Especially, the relevance of positive patch test reactions to local anesthetics with regard to the compatibility of injected local anesthetics is unclear. We therefore subjected 104 patch test-positive probands to prick and intradermal tests with seven local anesthetic agents. All prick tests were negative. Only 14 patients showed positive reactions in intradermal tests: 11 with the ester local anesthetic procaine, one with the amide local anesthetic butanilicaine, and two with both. Procaine yielded both immediate and delayed reactions; butanilicaine, only immediate reactions. All other local anesthetics showed negative reactions. It is concluded that in patients with positive patch test reactions to local anesthetics and negative history of anaphylactoid reactions, positive skin test reactions to intradermal application are rare and that, therefore, the risk of anaphylactic reactions to injection anesthesia with amide local anesthetics, except butanilicaine, appears low in these patients.

Adult↗
PubMed2001

Severity of airway hyperreactivity associated with laryngeal mask airway removal: correlation with volatile anesthetic choice and depth of anesthesia.

STUDY OBJECTIVE: To compare the influence of anesthetic depth and choice of volatile anesthetic drug on the incidence and severity of airway hyperreactivity associated with Laryngeal Mask Airway (LMA) removal. DESIGN: Randomized observer-blinded study. SETTING: Ambulatory Surgical Center at a University Medical Center. PATIENTS: 123 ASA physical status I and II children undergoing infraumbilical procedures. INTERVENTIONS: Patients were randomly assigned to one of four treatment groups: Group 1 = anesthetic induction with halothane, maintenance with isoflurane, nitrous oxide (N(2)O), and oxygen (O(2)), LMA removed when child awakened; Group 2 =anesthetic induction and maintenance as in Group 1, LMA removed while child anesthetized with age adjusted 2 minimum alveolar concentration (MAC) end-tidal concentration of isoflurane; Group 3 = anesthetic induction and maintenance with sevoflurane, N(2)O, and O(2), LMA removed when child awakened; Group 4 = anesthetic induction and maintenance as in Group 3, but LMA removed while child anesthetized with age-adjusted 2 MAC end-tidal concentration of sevoflurane. MEASUREMENTS AND MAIN RESULTS: Severity of airway hyperreactivity was graded as mild, moderate, or severe. A significant difference was not found amongst the four groups with respect to mild and moderate airway hyperreactivity. Severe airway hyperreactivity leading to a critical event [partial or complete laryngospasm with oxygen saturation (SPO(2)) < 85%] was only encountered in Group 1 patients (incidence 13%). Adverse airway events (SPO(2) < 90%, vomiting and bronchospasm) were also significantly higher in Group 1 (p < 0.05). Isoflurane use was independently associated with significantly higher airway hyperreactivity when compared with sevoflurane (p < 0.05). CONCLUSIONS: Depth of anesthesia during LMA removal does not appear to affect the incidence or severity of airway hyperreactivity when sevoflurane is the maintenance anesthetic. However, awake LMA removal during isoflurane anesthesia results in a higher incidence of adverse airway events and carries the risk of severe airway hyperreactivity.

Anesthesia↗
PubMed1997

Entropy-driven interactions of anesthetics with membrane proteins.

Thermodynamic analysis of anesthetic effects on Ca2+-ATPase activity was performed to evaluate the feasibility of anesthetic binding and gain insight into the molecular events underlying the anesthetic-enzyme interactions. The Ca2+-ATPases, integral membrane proteins vital in cellular Ca2+ regulation, are suitable models for investigation of the mechanism of anesthetic action on membrane proteins that are targeted by the anesthetics. Ca2+-ATPase of plasma membrane, PMCA, and SERCA1 in the intracellular sarcoplasmic reticulum membrane were used to study two general anesthetics: halothane, a halogenated two-carbon alkane; and propofol, an intravenous, strongly lipophilic-substituted phenol. Interactions of both anesthetics result in a negative Gibbs free energy change, which in both enzymes is more favorable for the more lipophilic propofol than halothane. Temperature dependence (more negative change in Gibbs free energy at increased temperature) is in agreement with predominantly nonpolar interactions. The interactions are entropy-driven, characterized by positive enthalpy which is overcompensated by positive entropy changes. This is in contrast to the reported in literature enthalpy-driven anesthetic binding to soluble proteins. The possible contributions to the observed positive entropy change are discussed including displacement of ordered water molecules by anesthetic binding in nonpolar cavities in the membrane proteins and subtle structural rearrangements.

Anesthetics↗
PubMed1990

Differential effects of anesthetic regimens on gentamicin pharmacokinetics in the rat: a comparison with chronically catheterized conscious animals.

The intravenous disposition of gentamicin was compared in the conscious chronically catheterized rat with that in rats anesthetized using five injectable laboratory anesthetics. Gentamicin plasma clearance in the conscious rat was significantly higher than in animals anesthetized with urethane, fentanyl/fluanisone/midazolam, pentobarbitone, or ketamine/midazolam but similar to that in rats anesthetized with alphaxolone/alphadolone. Urethane anaesthesia resulted in a significantly lower gentamicin clearance than in all other groups. Gentamicin clearance in rats anesthetized with alphaxolone/alphadolone was significantly higher than in rats anesthetized with either fentanyl/fluanisone/midazolam or urethane. No significant differences in the volume of distribution of gentamicin were observed between any of the groups studied, either anesthetized or conscious. Carboxyinulin blood clearance in the conscious group was significantly higher than that with urethane, fentanyl/fluanisone/midazolam, pentobarbitone, or ketamine/midazolam but not significantly different from alphaxolone/alphadolone-anesthetized animals. The differences in carboxyinulin clearance were noted to be proportional to the differences in gentamicin clearance (r2 = 0.98). These results demonstrate that the choice of anesthetic used in laboratory pharmacokinetic studies is important. Gentamicin clearance was higher in conscious than anesthetized rats, and it may be prudent to use chronically catheterized animals in pharmacokinetic studies.

Anesthetics↗
PubMed1999

Percutaneous penetration of local anesthetic bases: pharmacodynamic measurements.

Local anesthetics do not penetrate readily through human skin if applied in their salt form; however, if applied in their base form various effects may be observed, such as a decrease in pricking pain and a change in burning, itch, and thermal sensations. These effects occur after skin penetration and may be attributed to the action of the anesthetics on nociceptors and thermoreceptors, i.e., on C and Adelta nerve fiber respectively. As there is little known about the time course of the pharmacodynamic response of cutaneously applied local anesthetic bases, this study was conducted to characterize various local anesthetics pharmacodynamically by measuring thermal thresholds over time with a thermal sensory analyzer. The results show that the investigated local anesthetics affect thermal thresholds to a different extent, with tetracaine and lidocaine being most efficient. From the response versus time profiles of all eight study subjects various response parameters were obtained: only the cold sensation parameters proved suitable for characterization of the local anesthetics, possibly because cold receptors are located in the epidermis and can easily be reached. Lag times of onset are short and the maximum anesthetic effect is reached within 2-3 h. Cold sensation parameters correlate linearly with the solubility of the local anesthetic bases in medium chain triglycerides and with the drug flux of 50% saturation, indicating that medium chain triglycerides may have similar properties with regard to the local anesthetics solubility as the stratum corneum lipids.

Anesthetics, Local↗
PubMed2004

Pharmacoeconomics of inhaled anesthetic agents: considerations for the pharmacist.

PURPOSE: Types of economic analyses used for inhaled anesthetic agents, factors to consider in calculating the cost of inhaled anesthetics, limitations of pharmacoeconomic studies of these agents, and strategies for controlling inhaled anesthetic costs are discussed. SUMMARY: Inhaled anesthetic agents comprise a substantial component of drug budgets. Calculation of the cost of administering an inhaled anesthetic should take into consideration the cost per mL, potency, waste, concentration and duration of gas delivery, fresh gas flow rate, molecular weight, and density. The use of newer inhaled anesthetic agents with low solubility in blood and tissue provides a more rapid recovery from anesthesia than older, more soluble agents, and also provides the same level of control of depth of anesthesia at a lower fresh gas flow rate and possibly a lower cost than older agents at a higher fresh gas flow rate. A more rapid recovery may facilitate fast-track recovery and yield cost savings if it allows the completion of additional surgical cases or allows a reduction in personnel overtime expenses. Interpretation of pharmacoeconomic studies of inhaled anesthetics requires an appreciation of the limitations in methodology and ability to extrapolate results from one setting to another. Pharmacists' efforts to reduce anesthetic waste and collaborate with anesthesiologists to improve the use of these agents can help contain costs, but improving scheduling and efficiency in the operating room has a greater potential to reduce operating room costs. CONCLUSION: Much can be done to control costs of anesthetic agents without compromising availability of these agents and patient care.

Administration, Inhalation↗
PubMed1998

Variations in the composition of spinal anesthetic solutions: the effects of drug addition order and preparation methods.

UNLABELLED: Adjuvants such as opioids or epinephrine are commonly added in small volumes to multicomponent spinal anesthetic solutions. In this study, we tested the hypothesis that final adjuvant concentrations vary depending on the devices and techniques used to prepare the anesthetic solution. We compared two aspiration devices, the filter needle and the filter straw, in a laboratory study. Two techniques for drawing up and estimating adjuvant volumes were assessed, as was variation in the composition of a model spinal anesthetic solution resulting from intra- and interindividual variability. A model hyperbaric anesthetic solution consisting of tetracaine, dextrose, and methylene blue (MB) as a small-volume tracer solution was studied. The components were drawn up into a syringe through one of two commercially supplied aspiration devices, a filter straw or a filter needle. The effect of the order of aspiration of the components into the syringe was measured by determining the MB concentration in the final solution by optical absorbance. Ten experienced anesthesiologists then prepared samples of the test solution using one of two different techniques to estimate tracer volume in the aspiration syringe. In comparison studies, the MB tracer was added to the hyperbaric solution with a tuberculin syringe. The order of aspiration of the solution components had a large effect on the final concentration of the MB tracer in the ultimate mixture. Variation in the MB concentration was on the order of four- to fivefold. Effects were larger for the filter straw compared with the filter needle. A comparison of 10 anesthesiologists revealed large intra- and interindividual variations in the final composition of the model anesthetic solution. The concentration of tracer added to the mixture with a tuberculin syringe approximated the planned yield. We conclude that the devices and techniques used to prepare mixtures of drugs for delivery to the cerebrospinal fluid may influence the concentrations of drugs in the anesthetic and, thus, the dose supplied to the patient receiving spinal anesthesia. Variation in clinical effects of spinal anesthetics may be attributable, in part, to variation in the composition of the anesthetic. IMPLICATIONS: This laboratory study demonstrates the potential for large variation in the composition of spinal anesthetic mixtures.

Adjuvants, Anesthesia↗
PubMed1999

Pretreatment with dexmedetomidine: altered indices of anesthetic depth for halothane in the neuraxis of cats.

UNLABELLED: The sedative and anesthetic-sparing ability of the alpha2-adrenergic agonist dexmedetomidine is well documented. In this study, we identified the effects of halothane, with and without dexmedetomidine, on hemodynamic and electroencephalographic (EEG) variables and quantified the concentration of halothane resulting in various anesthetic depth indices mediated through the central nervous system (CNS) in chronically instrumented cats. Halothane was given alone or after dexmedetomidine (15 microg/kg p.o.). In both groups, four indices of anesthetic depth--minimum alveolar anesthetic concentration (MAC; no movement to noxious stimuli), MAC(BAR) (no autonomic response to noxious stimuli), MAC(BS) (EEG burst suppression), and MAC(ISOELECTRIC) (EEG isoelectricity)--were determined. Halothane decreased arterial blood pressure, heart rate, and higher frequency components of the EEG before the onset of burst suppression and isoelectricity. Dexmedetomidine pretreatment augmented the actions of halothane on arterial pressure, heart rate, and the EEG. Dexmedetomidine reduced the halothane concentrations resulting in MAC (from 1.22% +/- 0.06% to 0.89% +/- 0.08%) and MAC(BAR) (from 1.81% +/- 0.05% to 1.1% +/- 0.10%), but not those resulting in MAC(BS) (3.01% +/- 0.17% vs 3.14% +/- 0.10%) or MAC(ISOELECTRIC) (4.39% +/- 0.26% vs 4.65% +/- 0.12%). These results suggest that dexmedetomidine does not alter various CNS-mediated indices of anesthetic action to equivalent degrees and that there are dissimilar degrees of an anesthetic-sparing action at different levels of the neuraxis. IMPLICATIONS: The anesthetic adjuvant dexmedetomidine seems to differentially alter central nervous system-mediated indices of anesthetic action. Lower brainstem or spinal determinants of anesthetic depth (movement and hemodynamic responses) are more attenuated than those of higher brain functions, such as the electroencephalogram.

Adrenergic alpha-Agonists↗
PubMed1999

Methylene blue, a soluble guanylyl cyclase inhibitor, reduces the sevoflurane minimum alveolar anesthetic concentration and decreases the brain cyclic guanosine monophosphate content in rats.

UNLABELLED: The nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signal pathway plays an important role in anesthetic and analgesic effects. We sought to determine the involvement of inhibition of soluble guanylyl cyclase (sGC) in the anesthetic mechanism and site of action of volatile anesthetics. We examined the effect of intracerebroventricular (ICV) administration of methylene blue (MB), a sGC inhibitor, on the minimum alveolar anesthetic concentration (MAC) of sevoflurane and the brain cGMP content in rats in vivo. We also investigated the effect of sevoflurane on NO-stimulated sGC activity in vitro. The rats were divided into three groups. After the ICV administration of MB, sevoflurane MAC and brain cGMP contents were measured in the first group and the second group, respectively. In the third group, brain cGMP contents were determined after sevoflurane anesthesia without the ICV administration of MB to examine the direct effect of sevoflurane on brain cGMP contents. MB significantly decreased sevoflurane MAC and brain cGMP content in a dose-dependent manner. Sevoflurane itself also dose-dependently decreased cGMP contents in brain in vivo and inhibited the NO-stimulated sGC activity in vitro. These results suggest that the inhibition of the NO-cGMP signal pathway at the sGC level could be involved in anesthetic or analgesic effects, and the inhibitory effect of sevoflurane on sGC would be one of the sites of action of this anesthetic. IMPLICATIONS: Because the nitric oxide-cyclic guanosine monophosphate signal pathway mediates nociception and the site of action of halogenated volatile anesthetics in uncertain, we examined the possible involvement of inhibition of soluble guanylyl cyclase in the anesthetic mechanism. The inhibitory effect of sevoflurane on soluble guanylyl cyclase could be one of sites of this anesthetic.

Anesthetics, Inhalation↗
PubMed2002

The repolarizing effects of volatile anesthetics on porcine tracheal and bronchial smooth muscle cells.

UNLABELLED: This study was conducted to determine the effects of volatile anesthetics (potent bronchodilators) on membrane potentials in porcine tracheal and bronchial smooth muscle cells. We used a current-clamp technique to examine the effects of the volatile anesthetics isoflurane (1.5 minimum alveolar anesthetic concentration [MAC]) and sevoflurane (1.5 MAC) on membrane potentials of porcine tracheal and bronchial (third- to fifth-generation) smooth muscle cells depolarized by a muscarinic agonist, carbachol (1 microM). The effects of volatile anesthetics on muscarinic receptor binding affinity were also investigated by using a radiolabeled receptor assay technique. The volatile anesthetics isoflurane and sevoflurane induced significant repolarization of the depolarized cell membranes in the trachea (from -19.8 to -23.6 mV and to -24.8 mV, respectively) and bronchus (from -24.7 to -29.3 mV and -30.4 mV, respectively) without affecting carbachol binding affinity to the muscarinic receptor. The repolarizing effect was abolished by a Ca(2+)-activated Cl(-) channel blocker, niflumic acid. These results indicate that volatile anesthetic-induced repolarization of airway smooth muscle cell membranes might be caused by a change in Ca(2+)-activated Cl(-) channel activity and that the different repolarized effects of the volatile anesthetics could in part contribute to the different effects of volatile anesthetics on tracheal and bronchial smooth muscle contractions. IMPLICATIONS: By use of a current-clamp technique, the volatile anesthetics isoflurane and sevoflurane repolarized porcine airway smooth muscle cell membranes depolarized by a muscarinic agonist. This effect might be caused mainly by change in Ca(2+)-activated Cl(-) channel activity, not in K(+) channel activity.

Anesthetics, Inhalation↗
PubMed2002

Autoantibodies associated with volatile anesthetic hepatitis found in the sera of a large cohort of pediatric anesthesiologists.

UNLABELLED: Anesthetic-induced hepatitis is thought to have an immune-mediated basis, in part because many patients who develop hepatitis have serum autoantibodies that react with specific hepatic proteins. The present study shows that pediatric anesthesiologists also have these serum autoantibodies. Moreover, levels of these autoantibodies are higher than those of general anesthesiologists. We collected sera from 105 pediatric and 53 general anesthesiologists (including 3 nurse anesthetists), 20 halothane hepatitis patients, and 20 control individuals who were never exposed to inhaled anesthetics. Serum cytochrome P450 2E1 (P450 2E1) and 58-kd hepatic endoplasmic reticulum protein (ERp58) autoantibodies were measured by enzyme-linked immunosorbent assays. Positive values were 2 SD above median control values. Two multiple regression models were constructed. Pediatric anesthesiologists, like halothane hepatitis patients, had higher serum autoantibody levels of ERp58 and P450 2E1 than general anesthesiologists and controls, which was possibly because of their increased occupational exposures to anesthetics. Female anesthesiologists had higher levels of ERp58 autoantibodies than male anesthesiologists, whereas female pediatric anesthesiologists had higher levels of P450 2E1 autoantibodies than all other anesthesiologists. One female pediatric anesthesiologist had symptoms of hepatic injury. Because most anesthesiologists do not develop volatile anesthetic-induced hepatic injury, the findings suggest that pathogenic ERp58 and P450 2E1 autoantibodies may not directly cause volatile anesthetic hepatitis. Female anesthesiologists have high levels of these autoantibodies; however, the majority of these individuals do not develop hepatitis, suggesting that autoantibodies may not have a pathological role in volatile anesthetic-induced hepatitis. IMPLICATIONS: Environmental exposure of anesthesiology personnel to certain inhaled anesthetics can induce the formation of autoantibodies that have been associated with anesthetic hepatitis. Female anesthesiologists have high levels of these autoantibodies; however, the majority of these individuals do not develop hepatitis, suggesting that autoantibodies may not have a pathological role in volatile anesthetic-induced hepatitis.

Adult↗
PubMed2002

Nonhalogenated anesthetic alkanes and perhalogenated nonimmobilizing alkanes inhibit alpha(4)beta(2) neuronal nicotinic acetylcholine receptors.

UNLABELLED: The nonhalogenated anesthetic alkanes, cyclopropane and butane, do not enhance gamma-aminobutyric acid-elicited GABAergic currents, suggesting that these agents produce anesthesia via interactions with other molecular targets. Perhalogenated nonimmobilizing alkanes, such as 1,2-dichlorohexafluorocyclobutane and 2,3-dichlorooctafluorobutane, also fail to enhance GABAergic currents, but display specific behavioral effects that are distinct from those of structurally similar anesthetics. At concentrations predicted to be anesthetic, 1,2-dichlorohexafluorocyclobutane and 2,3-dichlorooctafluorobutane produce amnesia but fail to produce immobility. Neuronal nicotinic acetylcholine (nACh) receptors are sensitive to many anesthetics and are thought to have an important role in learning and memory. We postulated that neuronal nACh receptors might mediate the common amnestic action of nonhalogenated and perhalogenated alkanes. To test the hypothesis that neuronal nACh receptors have a role in mediating the behavioral effects of general anesthetics and nonimmobilizers, we quantified the inhibitory potencies of nonhalogenated anesthetic alkanes and perhalogenated nonimmobilizing alkanes on currents mediated by alpha(4)beta(2) neuronal nACh receptors. Our studies reveal that anesthetics and nonimmobilizers significantly inhibit alpha(4)beta(2) neuronal nACh receptors at concentrations that suppress learning and with potencies that correlate with their hydrophobicities. These results support the hypothesis that alpha(4)beta(2) neuronal nACh receptors mediate the amnestic actions of alkanes but not their immobilizing actions. IMPLICATIONS: The results of this study suggest that the immobilizing actions of general anesthetics do not result from the inhibition of alpha(4beta2) neuronal nicotinic acetylcholine receptors. However, the inhibition of neuronal nicotinic acetylcholine receptors may account for the amnestic activities of general anesthetics and nonimmobilizers.

Algorithms↗
PubMed1986

The extent of metabolism of inhaled anesthetics in humans.

To determine the percentage of anesthetic metabolized and to assess the role of metabolism in the total elimination of inhaled anesthetics, the authors administered isoflurane, enflurane, halothane, and methoxyflurane simultaneously, for 2 h, to nine healthy patients. Total anesthetic uptake during the 2 h of washin and total recovery of unchanged anesthetic in exhaled gases during 5 to 9 days of washout were measured, and from these the per cent of anesthetic uptake that was recovered was calculated. Of the isoflurane taken up, 93 +/- 4% (mean +/- SE) was recovered. To compensate for factors other than metabolism that limit complete recovery of unchanged anesthetic, the percentage recovery of each anesthetic was normalized to the percentage recovery of isoflurane (which it was assumed undergoes no metabolism). Deficits in normalized recovery were assumed to be due to metabolism of the anesthetics. The resulting estimates of metabolism of anesthetic taken up were: enflurane 8.5 +/- 1.0%, halothane 46.1 +/- 0.9%, and methoxyflurane 75.3 +/- 1.6%. These results indicate that elimination is primarily via the lungs for isoflurane and enflurane, equally via the lungs and via metabolism for halothane, and primarily via metabolism for methoxyflurane.

Adult↗
PubMed1989

Randomized trial of primary anesthetic agents on outcome of coronary artery bypass operations.

To examine the role of primary anesthetic agent on outcome of coronary artery bypass grafting operations, 1,012 patients were prospectively randomized to receive enflurane (257), halothane (253), isoflurane (248), or sufentanil (254). Except for administration of the primary anesthetic, anesthesia management was standardized for all patients. The randomized groups did not differ in demographic characteristics, extent of coronary artery disease, chronic antianginal therapy, hemodynamic characteristics including new myocardial ischemia at arrival to the operating room, and surgical characteristics that might influence the rate of postoperative myocardial infarction or death. From anesthetic induction to start of cardiopulmonary bypass, new ST segment depression appeared in 310 (30.4%) patients and was not different among primary anesthetic groups (28.0-33.5%). Similarly, the incidence of postoperative myocardial infarction (3.6-4.7%) and death (1.2-2.4%) was not different. Although intraoperative hypotension was twice as common in patients receiving any volatile anesthetic and hypertension twice as common with sufentanil, tachycardia (greater than or equal to 110 bpm) was not related to any primary anesthetic (4.3-9.1%) and was the only hemodynamic abnormality significantly related to intraoperative ischemia. The strongest predictor of intraoperative ischemia was ischemia on arrival to the operating room. The authors postulate that approximately 90% of new myocardial ischemia observed during anesthesia is the manifestation of silent ischemia observed in patients before operation and only 10% is related to anesthetic management. They conclude that, despite differences in the hemodynamic consequences of the primary anesthetics studied, none of the primary anesthetics influenced outcome and the primary role of the anesthesiologist in management of these patients is control of heart rate.

Adult↗