Anesth Analg 2003;97:1364-1369
© 2003 International Anesthesia Research Society
ANESTHETIC PHARMACOLOGY
Minimum Anesthetic Concentration of Sevoflurane with Different Xenon Concentrations in Swine
Klaus E. Hecker, MD*,
Jan H. Baumert, MD DEAA*,
Nicola Horn, MD*,
Matthias Reyle-Hahn, MD
,
Nicole Heussen, MSc
, and
Rolf Rossaint, MD PhD*
Departments of *Anesthesiology and
Medical Statistics, Universitätsklinikum der RWTH Aachen, Aachen, Germany, and the
Department of Anesthesiology and Intensive Care, Waldkrankenhaus Berlin, Berlin, Germany.
Address correspondence and reprint requests to Klaus Hecker, Klinik für Anaesthesiologie, Klinikum der RWTH Aachen, Pauwelsstr. 30, 52074 Aachen, Germany. Address email to klaus.hecker{at}post.rwth-aachen.de
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Abstract
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In a previous study, we described a partial antagonism of xenon (Xe) in combination with isoflurane. One hypothetical explanation suggested that Xe and isoflurane probably induced anesthesia via different pathways at the neuronal level. This warranted investigating the combination of Xe with other inhaled anesthetics to examine the relationship between Xe and volatile anesthetics in general. We therefore investigated the influence of Xe on the minimum alveolar concentration (MAC) of sevoflurane. The study was performed in 10 swine (weight 30.8 kg ± 2.6, mean ± SD) ventilated with xenon 0%, 15%, 30%, 40%, 50%, and 65% in oxygen. At each Xe concentration, various concentrations of sevoflurane were administered in a stepwise design. For each a supramaximal pain stimulus (claw clamp) was applied. The appearance of a withdrawal reaction was recorded. The sevoflurane MAC was defined as the end-tidal concentration required to produce a 50% response rate. At each Xe concentration, the animals’ responses to the pain stimulus were categorized and a logistic regression model was fitted to the results to determine sevoflurane MAC. Sevoflurane MAC was decreased by inhalation of Xe in a linear manner from 2.53 with 0% Xe to 1.54 with 65% Xe. In contrast to Xe and isoflurane, the anesthetic effects of Xe and sevoflurane appear to be simply linear.
IMPLICATIONS: We investigated the influence of the anesthetic gas, xenon, on the minimum alveolar concentration (MAC) for the volatile anesthetic sevoflurane. The study was performed in 10 swine ventilated with fixed xenon and various concentrations of isoflurane. The sevoflurane MAC is decreased by inhalation of xenon in a linear relationship.
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Introduction
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There is a rapidly growing interest in the use of xenon (Xe) as an anesthetic. The first studies in animals and humans indicated, in addition to a lack of organ toxicity and rapid recovery, a high cardiovascular stability. Because of the reported favorable pharmacodynamic properties of Xe, the main field of clinical use will probably be anesthesia in patients suffering from cardiovascular diseases. However, because the minimum alveolar concentration (MAC) of Xe (63.1%–71%) is much larger than the MAC of volatile anesthetics, Xe has to be supplemented by other anesthetics.
In the existing literature, the reported relationships between the effects of different volatile anesthetics are not uniform: Two anesthetics may act linear or may show partial antagonism, e.g., as described for combinations of nitrous oxide (N2O) and other volatile anesthetics (1–5).
Cullen et al. (6) described a linear relationship between Xe and halothane in humans. Nakata et al. (7) determined the MAC of Xe at 63.1% in humans. Although they could not reject a linear relationship, they were not able to determine reliably the interaction between Xe and sevoflurane because of the small sample size. Moreover, the MAC values, obtained from probit analysis, suggested that there is a small antagonistic interaction between Xe and sevoflurane (7). In a previous study, we were able to detect a partial antagonism between Xe and isoflurane in swine (8). One hypothetical explanation was that Xe and isoflurane probably induced anesthesia via different pathways at the neuronal level. This warranted investigating the combination of Xe with other inhaled anesthetics to examine the relationship between Xe and volatile anesthetics in general.
Therefore, we investigated the interaction between Xe and sevoflurane by determining the effect of different concentrations of inhaled Xe on the sevoflurane MAC in swine.
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Methods
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The study was approved by the local Animal Care Ethics Committee and by the national Animal Care Office (Bez.-Reg. Koeln AZ 23.203.2-AC 38, 27/99) and conducted according to the Helsinki convention for the use and care of animals. Determination of MAC values was performed in 10 female German landrace pigs weighing 26.8–33.6 kg (30.8 ± 2.6 kg; mean ± SD). On admission to the local institute for animal studies, the pigs were thoroughly examined by a veterinarian. This examination included behavior and motor ability, as well as cardiopulmonary auscultation. None of the animals showed any symptoms of disease. The pigs were included in the study only after 5 days of appropriate feeding and observation without any abnormal findings.
After premedication with azaperone 4 mg/kg IM, an ear vein was cannulated with an 18- or 20-gauge Teflon cannula. Anesthesia was induced by propofol 2 mg/kg, and orotracheal intubation was performed using a 7.5-mm Woodbridge tube. While maintaining anesthesia with repeated bolus injections of propofol 20 mg, a 20-gauge femoral artery cannula was inserted via Seldinger’s technique, and a Foley bladder catheter was inserted.
The lungs of the pigs were mechanically ventilated using a Draeger PhysioFlex closed circuit ventilator (Draeger, Luebeck, Germany) with a tidal volume of 10 mL/kg, an inspiration/expiration ratio of 1:1, and 3 cm H2O of positive end-expiratory pressure. Target end-tidal CO2 values were 38–44 mm Hg. Body temperature was kept between 37.9° and 38.2°C by use of an airflow warming system (Warm Touch, Mallinckrodt Medical, St. Louis, MO). Heart rate (HR), electrocardiogram (ECG), mean arterial blood pressure, end-tidal CO2, SpO2, and esophageal temperature were monitored and recorded continuously using a Datex AS/3 anesthesia monitor (Datex-Engstrom, Helsinki, Finland). The end-tidal concentrations of oxygen, CO2, and sevoflurane were measured by the anesthesia monitor (infrared spectroscopy). We used the values from the anesthesia monitor because it performs continuous self-calibration. The inhaled concentration of Xe was measured by thermo-conductive analysis by the PhysioFlex ventilator. The PhysioFlex ventilator incorporates a blower in the breathing circuit that vigorously circulates the gas inside the circuit and thereby rapidly mixes inspiratory and expiratory gas with added fresh gas to keep preset concentrations. Because Xe consumption after the initial wash-in is <20 mL/min, inspiratory and expiratory Xe concentrations are virtually identical.
Analyses of blood gases, pH, oxygen saturation (SaO2), sodium, potassium, calcium, chloride, glucose, and lactate concentrations (Radiometer Copenhagen ABL 500/ABL 100, Copenhagen, Denmark) were performed during each experiment.
The experiments, which lasted 8–10 h, were started at least 3 h after premedication. After instrumentation and the last administration of propofol, anesthesia was maintained using a concentration of sevoflurane sufficient for the animals to tolerate controlled ventilation for a period of 
45 min. This enabled us to virtually exclude any influence of propofol on the study, as Cockshott et al. (9) have demonstrated that blood propofol concentration after an IV bolus of 2–5 mg/kg is reduced to 10% of the initial concentration after 45 min. With Xe concentrations of 0%, 15%, 30%, 40%, 50%, and 65%, sevoflurane concentration was changed in steps of 0.1 MAC between 3.8% and 1.4% volume, with an expected MAC of 2.0% for sevoflurane in oxygen. To reduce bias caused by the circadian rhythm, duration of the experiment, and premedication, 10 pigs were randomly assigned to one of two groups. Group 1 started with Xe 0% and increased concentrations of sevoflurane, whereas Group 2 started with Xe 65% and decreased concentrations of sevoflurane. After any change in Xe concentration, at least 20 min were allowed for equilibration before continuing the experiment.
A supramaximal pain stimulus was applied by use of the dew claw-clamp technique as described by Eger et al. (10). A large tube clamp was placed between the toes and was kept closed for 60 s. The presence or absence of a withdrawal reaction occurring within 45 s after releasing the clamp was recorded. A positive reaction was defined as not only withdrawal of the clamped foot but also gross movements of other legs or head. When the pigs showed signs of light anesthesia, such as spontaneous moving, during subanesthetic concentrations, no pain stimulus was applied. These situations were also defined as "withdrawal reaction after applying the supramaximal pain stimulus." To avoid the development of edema or hematoma, all four limbs were used consecutively.
For each Xe concentration, sevoflurane was either steadily increased or decreased until a change in reaction occurred, such as a withdrawal reaction when the pigs did not react at the previous concentration and vice versa. This was then confirmed by increasing or decreasing the concentration one step further, respectively. At the end of the experiments, the pigs were killed in deep anesthesia in accordance with German laws for animal studies.
To evaluate the relationship between sevoflurane and Xe we considered a multiple logistic regression model with interaction term:
where P = probability of no withdrawal reaction, X1 = end-tidal sevoflurane concentration, X2 = Xe concentration, ß0 = regression intercept, ß1 = coefficient for sevoflurane, ß2 = coefficient for Xe, and ß12 = coefficient for the interaction between sevoflurane and Xe (interaction coefficient).
As a result of our study design we were faced with correlated data. Therefore the approach used was the method of generalized estimating equations (11). Resulting estimates of the parameters in Equation 1 and their corresponding P values were surveyed to assess the interrelation between sevoflurane and Xe. Significance was assumed if P 
0.05.
When a linear relationship between sevoflurane and Xe could not be excluded—as indicated by a nonsignificant interaction term—the MAC of sevoflurane and its reduction by Xe were determined using a multiple logistic regression model without interaction term:
where P = probability of no withdrawal reaction, X1 = end-tidal sevoflurane concentration, X2 = Xe concentration, ß0 = regression intercept, ß1 = coefficient for sevoflurane, and ß2 = coefficient for Xe.
The MAC of sevoflurane for a given Xe concentration was then calculated by setting the probability of no withdrawal reaction to P = 0.5 and solving for sevoflurane concentration as a function of Xe concentration as follows:
To show stability in hemodynamics, electrolyte concentrations and gas exchange variables, mean values with corresponding 95% confidence limits (CL) were calculated. All statistical analyses were performed using SAS version 8.02 (SAS, Cary,NC).
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Results
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The logistic model was fitted to the response data of 10 pigs to each end-tidal sevoflurane and Xe concentration. Coefficient estimates for the logistic regression model are presented in Table 1, and resulting MAC values of sevoflurane calculated without interaction term are in Table 2. The MAC of sevoflurane in the absence of Xe was 2.53% (95% CL, 2.23%–2.83%), and it was reduced by increasing Xe concentration (Table 2, Fig. 1). The maximum reduction of the sevoflurane MAC was to 1.54% (95% CL, 1.24%–1.84%) with 65% Xe. The interaction coefficient (ß12) between sevoflurane and Xe was not significantly different from zero (P = 0.0898), indicating that Xe has a linear rather than a nonlinear effect on reducing sevoflurane requirements.
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Figure 1. Relationship between end-tidal xenon (Xe) and the minimum alveolar anesthetic concentration (MAC) of sevoflurane. The upper and lower curves are the 95% confidence intervals.
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All relevant physiological variables (HR, MAP, electrolytes, arterial blood gas analyses, glucose, and lactate concentration) were kept within normal limits in each animal throughout the study. All animals were in stable sinus rhythm throughout. PaO2, depending on FIO2, varied between 157 mm Hg for FIO2 0.3 and 494 mm Hg for FIO2 1.0. Tables 3 and 4 show the characteristics of relevant physiological variables.
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Discussion
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Our value of 2.53% for the MAC of sevoflurane in 100% O2 is within the range of MAC values reported for swine in other studies (12). This suggests that the current protocol is comparable to those of a number of previous studies investigating MAC in swine. The combination of sevoflurane with 15%, 30%, 40%, 50%, and 65% Xe reduced the sevoflurane MAC by 10% to 64% (i.e., 0.23% to 0.99% in end-tidal concentration) in our study. The interaction between sevoflurane and Xe was linear.
MAC studies are subject to several influencing factors. To exclude the influence of premedication, the study protocol did not start earlier than 3 hours after administration. During the instrumentation period, sevoflurane and propofol were used to maintain anesthesia. Propofol was stopped 45–60 minutes before the study protocol was started. This enabled us to virtually exclude any influence of these medications on the study, as Cockshott et al. (9) have demonstrated that plasma propofol concentration after IV bolus of 2–5 mg/kg of propofol is reduced to 10% of the initial concentration after 45 minutes. The reason for using propofol for induction of anesthesia was mainly to reduce the necessary concentration of sevoflurane and thereby to minimize the amount of sevoflurane stored in fat, which could have reduced the equilibration time during the study protocol.
To reduce bias caused by diurnal variability and duration of the experiment, the animals were randomly assigned to two arms of the protocol, one arm receiving increasing concentrations of sevoflurane, the other receiving decreasing concentrations. Other potential influences such as hyper- and hypothermia, age, application of the supramaximal pain stimulus, hypo- or hypernatremia, hypotension, abnormal perfusion-ventilation ratio or right-to-left shunt, and insufficient equilibration time could be excluded. All variables and values were within a normal range and kept stable during the whole study protocol.
The statistical evaluation shows a linear interaction between sevoflurane and Xe. A similar effect has been reported for Xe and sevoflurane in humans by Nakata et al. (7) and by Cullen et al. (6) with Xe and halothane in humans. In a previous study, we achieved contrasting results by establishing a nonlinear relationship between Xe and isoflurane in 10 swine (8).
General anesthetics are thought to act on one or more superfamilies of ligand-gated ion channels that include 
-aminobutyric acid type A (GABAA), glycine, nicotinic acetylcholine, 5-hydroxytryptamine3 (5-HT3), and glutamate receptors (13,14). For the volatile and IV anesthetics the GABAA receptor seems to be the prime target (13,14). In contrast, N2O and Xe have little effect at GABAA receptors but inhibit N-methyl-D-asparate receptors. These findings suggest that molecular mechanisms of two gaseous anesthetics are different from those of volatile and IV anesthetics (15–18). In addition, Suzuki et al. (19) reported that volatile anesthetics produce diverse effects on the 5-HT3 receptor. Isoflurane enhanced 5-HT3 receptor function in a concentration-dependent manner, but sevoflurane inhibited the 5-HT3 receptor noncompetitively, whereas N2O and Xe inhibited the 5-HT3 receptor competitively.
Furthermore, all of these neuronal receptors can also be found at the spinal level (20). This finding supports the hypothesis that the difference between the results of the present and several other studies could be caused by different effects of the anesthetics on the spinal neuronal level. In vitro studies demonstrate similarities between volatile anesthetics with respect to effects on synaptic neurotransmission but have also shown differences (21–23). For example, sevoflurane causes an open channel block of the GABAA receptor that seems different from other volatile anesthetics.
Because of similar mechanisms of action of Xe and N2O, interactions of volatile anesthetics with N2O may be of importance when interpreting the effects of Xe. A linear interaction for isoflurane and N2O has been reported by Eisele et al. (1), who found MAC reductions of 30% with 50% N2O and 42% with 66% N2O and demonstrated a linear effect of isoflurane between 50% and 66% N2O. This is similar to the results from Steffey et al. (24), who found a linear dose-response curve for the combination of halothane and N2O in cats, dogs, and monkeys.
In contrast, Cole et al. (3) reported a nonlinear dose-response curve with a second-order shape for the combination of N2O and several volatile anesthetics (enflurane, isoflurane, and halothane) in rats. They suggested an opposing neurophysiological effect of N2O and volatile anesthetics. Cole et al. (3) pointed out that the dose-response curve was only applicable for the N2O concentrations they examined (0%, 15%, and 75%). There may be species differences in the interactions of Xe as well as N2O with volatile anesthetics, as a linear interaction has been demonstrated in swine (25,26). The question as to whether N2O and other volatile anesthetics may interact in a nonlinear way has therefore not yet been sufficiently answered (4,5). Thus, there are no conclusions regarding the interaction of Xe and volatiles to be drawn from those studies.
In summary, our data show that there is a linear interaction between Xe and sevoflurane in swine. In contrast to this result, in a previous study, we found a nonlinear interaction between Xe and isoflurane (8).
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Acknowledgments
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Supported by Deutsche Forschungsgemeinschaft (Ro 2000/5–1), and Messer Griesheim, Krefeld/Germany.
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Accepted for publication May 21, 2003.
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Abstract
Introduction
