Absence of direct antioxidant effects from volatile anesthetics in primary mixed neuronal-glial cultures

BACKGROUND: Volatile anesthetics decrease ischemic brain injury. Mechanisms for this protection remain under investigation. The authors hypothesized that volatile anesthetics serve as antioxidants in a neuronal-glial cell culture system. METHODS: Primary cortical neuronal-glial cultures were prepared from fetal rat brain. Cultures were exposed to iron, H2O2, or xanthine-xanthine oxidase for 30 min in serum-free media containing dissolved isoflurane (0-3.2 mm), sevoflurane (0-3.6 mm), halothane (0-4.1 mm), n-hexanol, or known antioxidants. Cell damage was assessed by release of lactate dehydrogenase (LDH) and trypan blue exclusion 24 h later. Lipid peroxidation was measured by the production of thiobarbituric acid-reactive substances in a cell-free lipid system. Iron and calcium uptake and mitochondrial depolarization were measured after exposure to iron in the presence or absence of isoflurane. RESULTS: Deferoxamine reduced LDH release caused by H2O2 or xanthine-xanthine oxidase, but the volatile anesthetics had no effect. Iron-induced LDH release was prevented by the volatile anesthetics (maximum effect for halothane = 1.2 mm, isoflurane = 1.2 mm, and sevoflurane = 2.1 mm aqueous phase). When corrected for lipid solubility, the three volatile anesthetics were equipotent against iron-induced LDH release. In the cell-free system, there was no effect of the anesthetics on thiobarbituric acid-reactive substance formation in contrast to Trolox, which provided complete inhibition. Isoflurane (1.2 mm) reduced mean iron uptake by 46% and inhibited mitochondrial depolarization but had no effect on calcium uptake. CONCLUSIONS: Volatile anesthetics reduced cell death induced by oxidative stress only in the context of iron challenge. The likely reason for protection against iron toxicity is inhibition of iron uptake and therefore indirect reduction of subsequent intracellular oxidative stress caused by this challenge. These data argue against a primary antioxidant effect of volatile anesthetics.     

Effects of Volatile Anesthetics on N-methyl-d-aspartate Excitotoxicity in Primary Rat Neuronal-Glial Cultures

Background: Volatile anesthetics are known to ameliorate experimental ischemic brain injury. A possible mechanism is inhibition of excitotoxic cascades induced by excessive glutamatergic stimulation. This study examined interactions between volatile anesthetics and excitotoxic stress.

Methods: Primary cortical neuronal-glial cultures were exposed to N-methyl-d-aspartate (NMDA) or glutamate and isoflurane (0.1-3.3 mm), sevoflurane (0.1-2.9 mm), halothane (0.1-2.9 mm), or 10 [mu]m (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine hydrogen maleate (MK-801). Lactate dehydrogenase release was measured 24 h later. In other cultures, effects of volatile anesthetics on Ca++ uptake and mitochondrial membrane potential were determined in the presence or absence of NMDA (0-200 [mu]m).

Results: Volatile anesthetics reduced excitotoxin induced lactate dehydrogenase release by up to 52% in a dose-dependent manner. At higher concentrations, this protection was reversed. When corrected for olive oil solubility, the three anesthetics offered equivalent protection. MK-801 provided near-complete protection. Ca++ uptake was proportionally reduced with increasing concentrations of anesthetic but did not account for reversal of protection at higher anesthetic concentrations. Given equivalent NMDA-induced Ca++ loads, cells treated with volatile anesthetic had greater lactate dehydrogenase release than those left untreated. At protective concentrations, volatile anesthetics partially inhibited NMDA-induced mitochondrial membrane depolarization. At higher concentrations, volatile anesthetics alone were sufficient to induce mitochondrial depolarization.     

Effects of volatile anesthetics on N-methyl-D-aspartate excitotoxicity in primary rat neuronal-glial cultures

BACKGROUND: Volatile anesthetics are known to ameliorate experimental ischemic brain injury. A possible mechanism is inhibition of excitotoxic cascades induced by excessive glutamatergic stimulation. This study examined interactions between volatile anesthetics and excitotoxic stress. METHODS: Primary cortical neuronal-glial cultures were exposed to N-methyl-D-aspartate (NMDA) or glutamate and isoflurane (0.1-3.3 mM), sevoflurane (0.1-2.9 mM), halothane (0.1-2.9 mM), or 10 microM (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine hydrogen maleate (MK-801). Lactate dehydrogenase release was measured 24 h later. In other cultures, effects of volatile anesthetics on Ca++ uptake and mitochondrial membrane potential were determined in the presence or absence of NMDA (0-200 microM). RESULTS: Volatile anesthetics reduced excitotoxin induced lactate dehydrogenase release by up to 52% in a dose-dependent manner. At higher concentrations, this protection was reversed. When corrected for olive oil solubility, the three anesthetics offered equivalent protection. MK-801 provided near-complete protection. Ca++ uptake was proportionally reduced with increasing concentrations of anesthetic but did not account for reversal of protection at higher anesthetic concentrations. Given equivalent NMDA-induced Ca++ loads, cells treated with volatile anesthetic had greater lactate dehydrogenase release than those left untreated. At protective concentrations, volatile anesthetics partially inhibited NMDA-induced mitochondrial membrane depolarization. At higher concentrations, volatile anesthetics alone were sufficient to induce mitochondrial depolarization. CONCLUSIONS: Volatile anesthetics offer similar protection against excitotoxicity, but this protection is substantially less than that provided by selective NMDA receptor antagonism. Peak effects of NMDA receptor antagonism were observed at volatile anesthetic concentrations substantially greater than those used clinically.     

Effects of halothane,isoflurane and sevoflurane on ischemiareperfusion injury in the perfused liver of fasted rats

Background : Although intraoperative ischemia-reperfusion of the liver generally occurs under general anesthesia, little is known about the direct effect of anesthetic agents on hepatic injury due to this phenomenon. The effect of volatile anesthetics on ischemia-reperfusion injury was studied using isolated liver perfusion. Methods : The liver was isolated from 24-h-fasted male Sprague-Dawley rats and perfused through the portal vein with a modified Krebs-Ringer bicarbonate solution in a recirculating perfusion-aeration system. Ischemia was induced by reducing the baseline perfusion pressure from 1.2 to 0.2 kPa followed by reperfusion to baseline level. The ischemia-reperfusion injury was assessed by LDH release from the perfused liver. We studied the effect of halothane, isoflurane and sevoflurane on the ischemia-reperfusion injury during 20 min of control conditions, exposure of the liver to 60 min of ischemia and reperfusion for 90 min. Results : Ischemia was evident by reduced portal vein flow and oxygen consumption, and caused an increase in lactate production. Reperfusion caused a transient reduction in lactate production and a significant increase in LDH release. All anesthetics reduced hepatic oxygen consumption and increased the net lactate production during control conditions. Volatile anesthetics also significantly attenuated LDH release during reperfusion. The suppression of LDH release was observed even when isoflurane was administered during the reperfusion period, but not when it was administered only during ischemia. Conclusion : These results indicate that volatile anesthetics may protect the fasted liver from early, neutrophil-independent, ischemia-reperfusion injury by acting during the reperfusion phase.     

Comparison of volatile anesthetic actions on intracellular calcium stores of vascular smooth muscle: investigation in isolated systemic resistance arteries

BACKGROUND: Volatile anesthetic actions on intracellular Ca2+ stores (ie., sarcoplasmic reticulum [SR]) of vascular smooth muscle have not been fully elucidated. METHODS: Using isometric force recording method and fura-2 fluorometry, the actions of four volatile anesthetics on SR were studied in isolated endothellum-denuded rat mesenteric arteries. RESULTS: Halothane (> or = 3%) and enflurane (> or = 3%), but not isoflurane and sevoflurane, increased the intracellular Ca2+ concentration ([Ca2+]i) in Ca2+-free solution. These Ca2+-releasing actions were eliminated by procaine. When each anesthetic was applied during Ca2+ loading, halothane (> or = 3%) and enflurane (5%), but not isoflurane and sevoflurane, decreased the amount of Ca2+ in the SR. However, if halothane or enflurane was applied with procaine during Ca2+ loading, both anesthetics increased the amount of Ca2+ in the SR. The caffeine-induced increase in [Ca2+], was enhanced in the presence of halothane (> or = 1%), enflurane (> or = 1%), and isoflurane (> or = 3%) but was attenuated in the presence of sevoflurane (> or = 3%). The norepinephrine-induced increase in [Ca2+], was enhanced only in the presence of sevoflurane (> or = 3%). Not all of these anesthetic effects on the [Ca2+]i were parallel with the simultaneously observed anesthetic effects on the force. CONCLUSIONS: In systemic resistance arteries, the halothane, enflurane, isoflurane, and sevoflurane differentially influence the SR functions. Both halothane and enflurane cause Ca2+ release from the caffeine-sensitive SR. In addition, both anesthetics appear to have a stimulating action on Ca2+ uptake in addition to the Ca2+-releasing action. Halothane, enflurane, and isoflurane all enhance, while sevoflurane attenuates, the Ca2+-induced Ca2+-release mechanism. However, only sevoflurane stimulates the inositol 1,4,5-triphosphate-induced Ca2+ release mechanism. Isoflurane and sevoflurane do not stimulate Ca2+ release or influence Ca2+ uptake.     

Comparative effects of halothane, isoflurane, and sevoflurane on the liver with hepatic artery ligation in the beagle.

Recently, there has been increasing interest in the alterations in splanchnic and hepatic circulation and preservation of hepatic oxygenation and function during anesthesia and surgery. However, the effects of volatile anesthetics under a condition of marginal hepatic oxygen supply are not well understood. Using a crossover design, we therefore studied the effects of equianesthetic concentrations (1.5 MAC) of halothane, isoflurane, and sevoflurane on hepatic oxygenation and function in nine beagles in which the hepatic artery had been ligated. Portal blood flow was measured by an electro-magnetic flow meter. Hepatic function was assessed by indocyanine green elimination kinetics. While cardiac output and mean arterial pressure were greater during halothane anesthesia than during isoflurane and sevoflurane anesthesia, portal blood flow and hepatic oxygen supply were significantly less during halothane and sevoflurane anesthesia than during isoflurane anesthesia. With regard to hepatic oxygen uptake, there was a significant difference between halothane (2.7 +/- 1.2 ml.min-1 x 100 g-1) and sevoflurane (3.7 +/- 2.0 ml.min-1 x 100 g-1; P less than 0.05). Consequently, the hepatic oxygen supply/uptake ratio and the hemoglobin oxygen saturation and oxygen partial pressure in hepatic venous blood during sevoflurane anesthesia were significantly less than they were with the other anesthetics. Indocyanine green clearance was better preserved during sevoflurane anesthesia (39.7 +/- 12.0 ml.min-1) than during halothane anesthesia (30.9 +/- 8.4 ml.min-1; P less than 0.05). We conclude that sevoflurane is accompanied by a smaller oxygen supply/uptake ratio than is halothane and isoflurane, while it preserves hepatic function.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of volatile anesthetics on nonadrenergic,noncholinergic depressor responses in rats

The effects of volatile anesthetics on nonadrenergic, noncholinergic (NANC) transmission mediated by calcitonin gene-related peptide (CGRP) are unclear. We studied the effects of isoflurane, halothane, and sevoflurane on NANC depressor responses to electrical spinal cord stimulation in pithed rats whose mean arterial blood pressure was maintained near 120 mm Hg by continuous infusion of methoxamine. Autonomic outflow was blocked by hexamethonium. After 30 min of inhalation of different concentrations of anesthetics, spinal cord stimulation at the lower thoracic level (10 V at 4 Hz; duration, 1 ms) was applied for 30 s to induce a NANC depressor response. Isoflurane at 2% and halothane at 1.5% attenuated NANC depressor responses significantly, whereas isoflurane at 1%, halothane at 0.75%, and sevoflurane at 2% or 4% did not. Volatile anesthetics did not attenuate the release of CGRP after spinal cord stimulation, whereas isoflurane at 2% and halothane at 1.5% significantly inhibited depressor responses to exogenously administered CGRP. Sevoflurane at 4% did not significantly affect CGRP-induced depressor responses. Thus, isoflurane and halothane at large concentrations attenuate NANC depressor responses by attenuating the depressor action of CGRP, not CGRP release. IMPLICATIONS: The anesthetics isoflurane and halothane attenuate nonadrenergic, noncholinergic depressor responses mediated by calcitonin gene-related peptide in the rat without affecting the release of the peptide.     

Minimum alveolar anesthetic concentration of volatile anesthetics in normal and cardiomyopathic hamsters

Minimum alveolar anesthetic concentrations (MAC) values of volatile anesthetics in cardiovascular diseases remain unknown. We determined MAC values of volatile anesthetics in spontaneously breathing normal and cardiomyopathic hamsters exposed to increasing (0.1%-0.3% steps) concentrations of halothane, isoflurane, sevoflurane, or desflurane (n = 30 in each group) using the tail-clamp technique. MAC values and their 95% confidence interval were calculated using logistic regression. In normal hamsters, inspired MAC values were: halothane 1.15% (1.10%-1.20%), isoflurane 1.62% (1.54%-1.69%), sevoflurane 2.31% (2.22%-2.40%), and desflurane 7.48% (7.30%-7.67%). In cardiomyopathic hamsters, they were: halothane 0.89% (0.83%-0.95%), isoflurane 1.39% (1.30%-1.47%), sevoflurane 2.00% (1.85%-2.15%), and desflurane 6.97% (6.77%-7.17%). Thus, MAC values of halothane, isoflurane, sevoflurane, and desflurane were reduced by 23% (P < 0.05), 14% (P < 0.05), 13% (P < 0.05), and 7% (P < 0.05), respectively in cardiomyopathic hamsters. IMPLICATIONS: Minimum alveolar anesthetic concentrations of volatile anesthetics were significantly lower in cardiomyopathic hamsters than in normal hamsters.     

The anticonvulsant effects of volatile anesthetics on penicillin-induced status epilepticus in cats

Volatile anesthetics may be used to treat status epilepticus when conventional drugs are ineffective. We studied 30 cats to compare the inhibitory effects of sevoflurane, isoflurane, and halothane on penicillin-induced status epilepticus. Anesthesia was induced and maintained with one of the three volatile anesthetics in oxygen. Penicillin G was injected into the cisterna magna, and the volatile anesthetic discontinued. Once status epilepticus was induced (convulsive period), the animal was reanesthetized with 0.6 minimum alveolar anesthetic concentration (MAC) of the volatile anesthetic for 30 min, then with 1.5 MAC for the next 30 min. Electroencephalogram and multiunit activity in the midbrain reticular formation were recorded. At 0.6 MAC, all anesthetics showed anticonvulsant effects. Isoflurane and halothane each abolished the repetitive spike phase in one cat; isoflurane reduced the occupancy of the repetitive spike phase (to 27%+/-22% of the convulsive period (mean +/- SD) significantly more than sevoflurane (60%+/-29%; P < 0.05) and halothane (61%+/-24%; P < 0.05), and the increase of midbrain reticular formation with repetitive spikes was reduced by all volatile anesthetics. The repetitive spikes were abolished by 1.5 MAC of the anesthetics: in 9 of 10 cats by sevoflurane, in 9 of 9 cats by isoflurane, and in 9 of 11 cats by halothane. In conclusion, isoflurane, sevoflurane, and halothane inhibited penicillin-induced status epilepticus, but isoflurane was the most potent. IMPLICATIONS: Convulsive status epilepticus is an emergency state and requires immediate suppression of clinical and electrical seizures, but conventional drugs may be ineffective. In such cases, general anesthesia may be effective. In the present study, we suggest that isoflurane is preferable to halothane and sevoflurane to suppress sustained seizure.     

Local application of halothane, isoflurane or sevoflurane increases the response to an electrical stimulus in humans

Volatile anesthetics may interfere with pain perception. This study investigates the effect of halothane, isoflurane and sevoflurane when applied locally, to the response of an electrical stimulus. METHODS: In this randomized control double-blind crossover study 70 volunteers were studied. In experiment 1 (30 subjects), equipotent liquid volumes of halothane 1 ml, isoflurane 1.5 ml and sevoflurane 2.7 ml were randomly applied on one forearm for 30 minutes. The other forearm received water. Both forearms were exposed to an electrical stimulus. The experiment was repeated the following day in a reverse fashion. In experiments 2 (20 subjects) and 3 (20 subjects) the response to the same stimulus was tested after local application of 2, 4, and 6 ml of halothane or 5 ml of sevoflurane respectively. RESULTS: Low doses of the three anesthetics were associated with an increased response to the electrical stimulus (F = 8.940, df = 1,174, P = 0.003). Higher doses of halothane and sevoflurane had no effect on the response (F = 2.358, df = 1,114, P = 0.127 and t = 0.840, df = 19, P = 0.411 respectively). CONCLUSIONS: Low liquid volumes of volatile anesthetics, when applied locally to the skin enhanced the response to an electrical stimulus but higher volumes had no effect.     

The blood/gas solubilities of sevoflurane, isoflurane, halothane, and serum constituent concentrations in neonates and adults

To determine the effect of prematurity on the solubility of volatile anesthetics in blood, the authors measured the blood/gas partition coefficients of sevoflurane, isoflurane, and halothane and the serum concentrations of albumin, globulin, cholesterol, and triglycerides in umbilical venous blood from ten preterm and eight full-term neonates and in venous blood from eight fasting adult volunteers. The authors found that the blood/gas partition coefficient of sevoflurane did not differ significantly among the three age groups. The partition coefficients of isoflurane and halothane in preterm neonates did not differ significantly from those in full-term neonates. However, the partition coefficients of both anesthetics in neonates were significantly less than those in adults. The blood/gas partition coefficients of the three volatile anesthetics in preterm neonates did not change significantly with gestational age. The blood/gas partition coefficients of sevoflurane, isoflurane and halothane for all three age groups combined correlated only with the serum concentration of cholesterol. The authors conclude that the blood/gas partition coefficients of isoflurane, halothane, and sevoflurane in preterm neonates are similar to those in full term neonates and that gestational age does not significantly affect the blood/gas solubility.     

The effects of anesthetics on cortical spreading depression elicitation and c-fos expression in rats

The effects of anesthetics on the generation of cortical spreading depression (CSD) were investigated. Volatile anesthetics halothane, isoflurane, sevoflurane (0.5, 1.0, and 2.0 MAC), and the intravenous anesthetic pentobarbital were studied. Cortical spreading depression was induced by 3M-KCl applied to a surface of brain cortex for 30 minutes. Direct current (DC) potential was recorded, and the number, amplitude, and duration of CSDs were observed. With increasing concentrations of each volatile anesthetic, there was a dose-related reduction in CSD frequency but not in CSD amplitude. At 2.0 MAC of sevoflurane the suppression of CSD was less than with the other volatile anesthetics. In addition, the influence of anesthetics on expression of c-fos mRNA was investigated. Additional animals anesthetized by isoflurane or sevoflurane were studied. Five CSDs were elicited by electric stimulation (0.5 mV, 1 second) in each animal. In situ hybridization with 35S-labeled oligonucleotides was used to evaluate the level of c-fos mRNA. The expression of c-fos was observed in the hemisphere in which CSD was elicited, but there was no difference in expression of c-fos among the groups. We conclude that volatile anesthetics can induce suppression of CSD elicitation in a dose dependent manner, but that at high concentrations sevoflurane is significantly less effective than other volatile agents. Pentobarbital has the least effect on KCl-induced CSD. These data suggest that the choice of anesthetics can impact the results of studies examining membrane depolarization and the ionic changes initiated by CSD.     

Effects of isoflurane, sevoflurane, and halothane on myofilament Ca2+ sensitivity and sarcoplasmic reticulum Ca2+ release in rat ventricular myocytes

BACKGROUND: The aim of this study was to describe and compare the effects of isoflurane, sevoflurane, and halothane at selected concentrations (i.e., concentrations that led to equivalent depression of the electrically evoked Ca2+ transient) on myofilament Ca2+ sensitivity, sarcoplasmic reticulum (SR) Ca2+ content, and the fraction of SR Ca2+ released during electrical stimulation (fractional release) in rat ventricular myocytes. METHODS: Single rat ventricular myocytes loaded with fura-2 were electrically stimulated at 1 Hz, and the Ca2+ transients and contractions were recorded optically. Cells were exposed to each anesthetic for 1 min. Changes in myofilament Ca2+ sensitivity were assessed by comparing the changes in the Ca2+ transient and contraction during exposure to anesthetic and low Ca2+. SR Ca2+ content was assessed by exposure to 20 mm caffeine. RESULTS: Isoflurane and halothane caused a depression of myofilament Ca2+ sensitivity, unlike sevoflurane, which had no effect on myofilament Ca2+ sensitivity. All three anesthetics decreased the electrically stimulated Ca2+ transient. SR Ca2+ content was reduced by both isoflurane and halothane but was unchanged by sevoflurane. Fractional release was reduced by both isoflurane and sevoflurane, but was unchanged by halothane. CONCLUSIONS: Depressed myofilament Ca2+ sensitivity contributes to the negative inotropic effects of isoflurane and halothane but not sevoflurane. The decrease in the Ca2+ transient is either responsible for or contributory to the negative inotropic effects of all three anesthetics and is either primarily the result of a decrease in fractional release (isoflurane and sevoflurane) or primarily the result of a decrease in SR Ca2+ content (halothane).     

The effects of volatile anesthetics on calcium regulation by malignant hyperthermia-susceptible sarcoplasmic reticulum.

To clarify the mechanism by which volatile anesthetics initiate malignant hyperthermia (MH), we examined the effect of halothane, isoflurane, and enflurane on Ca2+ uptake and release by sarcoplasmic reticulum vesicles isolated from MH-susceptible (MHS) and normal pig muscle. Clinical concentrations of these anesthetics (0.1-0.5 mM) stimulated sarcoplasmic reticulum ATP-dependent Ca2+ uptake (maximal at approximately 4 mM), whereas 10-20 times the clinical anesthetic concentration inhibited Ca2+ uptake. There was no significant difference between MHS and normal sarcoplasmic reticulum in any aspect of Ca2+ uptake. Ca2+ release from 45Ca(2+)-filled sarcoplasmic reticulum vesicles in a 10(-8) M Ca(2+)-containing medium (pH 7.0) was significantly stimulated at clinical concentrations of all three volatile anesthetics (anesthetic concentration for the 50% stimulation of Ca2+ release = 0.096-0.22 mM); however, the rate constant for Ca2+ release from MHS sarcoplasmic reticulum was in all cases significantly greater than that from normal sarcoplasmic reticulum. Furthermore, 0.5 mM halothane had no effect on Ca2+ release from normal sarcoplasmic reticulum at pH values less than 6.8, although it could still significantly stimulate Ca2+ release from MHS sarcoplasmic reticulum even at pH 6.4; similar results were obtained for isoflurane and enflurane. These studies thus demonstrate that the interaction of volatile anesthetics with the sarcoplasmic reticulum Ca(2+)-release channel is altered in MHS porcine muscle such that the channel may be activated even at a Ca2+ concentration or pH that would be expected to maintain the channel in the closed state.     

Minimum Alveolar Concentration of Volatile Anesthetics in Rats during Postnatal Maturation

Background: Although neonatal rats have become widely used as experimental laboratory animals, minimum alveolar concentration (MAC) values of volatile anesthetics in rats during postnatal maturation remain unknown.

Methods: We determined MAC values of volatile anesthetics in spontaneously breathing neonatal (2-, 9-, and 30-day-old) and adult Wistar rats exposed to increasing (in 0.1-0.2% steps) concentrations of halothane, isoflurane, or sevoflurane (n = 12-20 in each group), using the tail-clamp technique. MAC and its 95% confidence intervals were calculated using logistic regression and corrected for body temperature (37[degrees]C).

Results: In adult rats, inspired MAC values corrected at 37[degrees]C were as follows: halothane, 0.88% (confidence interval, 0.82-0.93%); isoflurane, 1.12% (1.07-1.18%); and sevoflurane, 1.97% (1.84-2.10%). In 30-day-old rats, the values were as follows: halothane, 1.14% (1.07-1.20%); isoflurane, 1.67% (1.58-1.76%); and sevoflurane, 2.95% (2.75-3.15%). In 9-day-old rats, inspired MAC values were as follows: halothane, 1.68% (1.58-1.78%); isoflurane, 2.34% (2.21-2.47%); and sevoflurane, 3.74% (3.64-3.86%). In 2-day-old rats, inspired MAC values were as follows: halothane, 1.54% (1.44-1.64%); isoflurane, 1.86% (1.72-2.01%); and sevoflurane, 3.28% (3.09-3.47%).     

In vitro effects of desflurane, sevoflurane, isoflurane, and halothane in isolated human right atria

BACKGROUND: Direct myocardial effects of volatile anesthetics have been studied in various animal species in vitro. This study evaluated the effects of equianesthetic concentrations of desflurane, sevoflurane, isoflurane, and halothane on contractile parameters of isolated human atria in vitro. METHODS: Human right atrial trabeculae, obtained from patients undergoing coronary bypass surgery, were studied in an oxygenated (95% O2-5% CO2) Tyrode's modified solution ([Ca2+]o = 2.0 mM, 30 degrees C, stimulation frequency 0.5 Hz). The effects of equianesthetic concentrations (0.5, 1, 1.5, 2, and 2.5 minimum alveolar concentration [MAC]) of desflurane, sevoflurane, isoflurane, and halothane on inotropic and lusitropic parameters of isometric twitches were measured. RESULTS: Isoflurane, sevoflurane, and desflurane induced a moderate concentration-dependent decrease in active isometric force, which was significantly lower than that induced by halothane. In the presence of adrenoceptor blockade, the desflurane-induced decrease in peak of the positive force derivative and time to peak force became comparable to those induced by isoflurane. Halothane induced a concentration-dependent decrease in time to half-relaxation and a contraction-relaxation coupling parameter significantly greater than those induced by isoflurane, sevoflurane and desflurane. CONCLUSIONS: In isolated human atrial myocardium, desflurane, sevoflurane, and isoflurane induced a moderate concentration-dependent negative inotropic effect. The effect of desflurane on time to peak force and peak of the positive force derivative could be related to intramyocardial catecholamine release. At clinically relevant concentrations, desflurane, sevoflurane, and isoflurane did not modify isometric relaxation.     

A second-generation blood substitute (perflubron emulsion) increases the blood solubility of modern volatile anesthetics in vitro

Perfluorocarbon-based emulsions increase the blood solubility of isoflurane, enflurane, and halothane, with a maximal effect reported for the less soluble isoflurane. Current volatile anesthetics are less soluble and may be more affected by this phenomenon. Perflubron (Oxygent(TM)) is a perfluorocarbon-based emulsion in late-stage clinical testing in surgical patients for use as a temporary oxygen carrier. We tested the hypothesis that perflubron increases the solubility of isoflurane, sevoflurane, and desflurane, as reflected by their blood/gas partition coefficient (lambda(Bl:g)). Fresh whole-blood samples were drawn from eight volunteers and mixed with perflubron to obtain concentrations of 1.2%, 1.8%, and 3.6% by volume (equivalent to in vivo doses of 1.8 to 5.4 g/kg, which represent up to twice the intended clinical dose range). By using the double-extraction method, we demonstrated increased lambda(Bl:g) for isoflurane, sevoflurane, and desflurane. However, the solubility in blood does not really change, because volatile anesthetics are actually partitioning into perflubron. Increasing the amount of emulsion in the blood consequently increases the amount of gas carried, as reflected by the measured linear correlation between the lambda(Bl:g) values of all three volatile anesthetics and perflubron doses. Even though the increase ranges from 0.9 (desflurane) to 2.6 (sevoflurane) times the normal value, the apparent lack of clinical implications in current trials with perflubron may trigger further in vivo experiments. IMPLICATIONS:Perflubron increases the in vitro solubility of volatile anesthetics when present in the blood at clinically relevant concentrations. Volatile anesthetics actually partition into the emulsion, but the solubility in the blood does not change. Further studies are needed to assess whether perflubron will affect the pharmacokinetics of volatile anesthetics in vivo.     

Preservation of the Ratio of Cerebral Blood Flow/Metabolic Rate for Oxygen during Prolonged Anesthesia with Isoflurane, Sevoflurane, and Halothane in Humans

Background: In several animal studies, an increase in cerebral blood flow (CBF) produced by volatile anesthetics has been reported to resolve over time during prolonged anesthesia. It is important to investigate whether this time-dependent change of CBF takes place in humans, especially in clinical situations where surgery is ongoing under anesthesia. In this study, to evaluate the effect of prolonged exposure to volatile anesthetics (isoflurane, sevoflurane, and halothane), the CBF equivalent (CBF divided by cerebral metabolic rate for oxygen (CMRO2)) was determined every 20 min during anesthesia lasting more than 4 h in patients.

Methods: Twenty-four surgical patients were assigned to three groups at random to receive isoflurane, sevoflurane, or halothane (8 patients each). End-tidal concentration of the selected volatile anesthetic was maintained at 0.5 and 1.0 MAC before surgery and then 1.5 MAC for the 3 h of surgical procedure. Normothermia and normocapnia were maintained. Mean arterial blood pressure was kept above 60 mmHg, using phenylephrine infusion, if necessary. CBF equivalent was calculated every 20 min as the reciprocal of arterial-jugular venous oxygen content difference.

Results: CBF equivalent at 0.5 MAC of isoflurane, halothane, and sevoflurane was 21+/-4, 20+/-3, and 21+/-5 ml blood/ml oxygen, respectively. All three examined volatile anesthetics significantly (P < 0.01) increased CBF equivalent in a dose-dependent manner (0.5, 1.0, 1.5 MAC). At 1.5 MAC, the increase of CBF equivalent with all anesthetics was maintained increased with minimal fluctuation for 3 h. The mean value of CBF equivalent at 1.5 MAC in the isoflurane group (45+/-8) was significantly (P < 0.01) greater than those in the halothane (32+/-8) and sevoflurane (31+/-8) groups. Electroencephalogram was found to be relatively unchanged during observation periods at 1.5 MAC.     

Sevoflurane inhibits contraction of uterine smooth muscle from pregnant rats similarly to halothane and isoflurane

PURPOSE: The present study was designed to clarify the direct effects of the volatile anesthetics halothane, isoflurane and sevoflurane on oxytocin-induced uterine smooth muscle contraction from pregnant rats. METHODS: Longitudinal smooth muscle layers were obtained from pregnant rats. Intracellular concentration of free Ca++ ([Ca++](i)) was measured, using a fluorescence technique, simultaneously with muscle tension. Inward Ba++ current (I(Ba)) through voltage-dependent Ca++ channels (VDCCs) was measured using a whole cell patch clamp technique. After incubation with 20 nM oxytocin, halothane, isoflurane or sevoflurane (1, 2, and 3%) was introduced into the tissue bath. RESULTS: All volatile anesthetics significantly inhibited muscle contraction concomitant with a decrease in [Ca++](i). Volatile anesthetics also inhibited the peak I(Ba). When the anesthetic concentrations were expressed as multiples of minimum alveolar concentrations, there were no differences in the inhibitory potencies of the three volatile agents tested for muscle tension and VDCC. CONCLUSIONS: Volatile anesthetics halothane, isoflurane and sevoflurane reduce the oxytocin-induced contraction of pregnant uterine smooth muscle. Inhibition of the contraction by the volatile anesthetics is due, at least in part, to the decrease in [Ca++](i), and the decrease in [Ca++](i) may be mediated by inhibition of VDCC activity.     

Minimum alveolar concentration of volatile anesthetics in rats during postnatal maturation

BACKGROUND: Although neonatal rats have become widely used as experimental laboratory animals, minimum alveolar concentration (MAC) values of volatile anesthetics in rats during postnatal maturation remain unknown. METHODS: We determined MAC values of volatile anesthetics in spontaneously breathing neonatal (2-, 9-, and 30-day-old) and adult Wistar rats exposed to increasing (in 0.1-0.2% steps) concentrations of halothane, isoflurane, or sevoflurane (n = 12-20 in each group), using the tail-clamp technique. MAC and its 95% confidence intervals were calculated using logistic regression and corrected for body temperature (37 degrees C). RESULTS: In adult rats, inspired MAC values corrected at 37 degrees C were as follows: halothane, 0.88% (confidence interval, 0.82-0.93%); isoflurane, 1.12% (1.07-1.18%); and sevoflurane, 1.97% (1.84-2.10%). In 30-day-old rats, the values were as follows: halothane, 1.14% (1.07-1.20%); isoflurane, 1.67% (1.58-1.76%); and sevoflurane, 2.95% (2.75-3.15%). In 9-day-old rats, inspired MAC values were as follows: halothane, 1.68% (1.58-1.78%); isoflurane, 2.34% (2.21-2.47%); and sevoflurane, 3.74% (3.64-3.86%). In 2-day-old rats, inspired MAC values were as follows: halothane, 1.54% (1.44-1.64%); isoflurane, 1.86% (1.72-2.01%); and sevoflurane, 3.28% (3.09-3.47%). CONCLUSION: As postnatal age increases, MAC value significantly increases, reaching the greatest value in 9-day-old rats, and decreases thereafter, and at 30 days is still greater than the adult MAC value.