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Anesth Analg 2003;96:119-124
© 2003 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

Minimum Alveolar Anesthetic Concentration of Isoflurane with Different Xenon Concentrations in Swine

Klaus E. Hecker, MD*, Matthias Reyle-Hahn, MD*, Jan H. Baumert, MD*, Nicola Horn, MD*, Nicole Heussen, MSc{dagger}, and Rolf Rossaint, MD, PhD*

Departments of *Anesthesiology and {dagger}Medical Statistics, Klinikum der RWTH Aachen, Aachen, Germany

Address correspondence and reprint requests to Klaus Hecker, Klinik für Anaesthesiologie, Klinikum der RWTH Aachen, Pauwelsstr. 30, 52074 Aachen, Germany. Address e-mail to klaus.hecker{at}post rwth-aachen.de.


   Abstract
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 Abstract
Introduction
 Methods
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 Discussion
 References
 
For patients requiring a fraction of inspired oxygen more than 0.3, the use of xenon (Xe) as the sole anesthetic is limited because of its large minimum alveolar anesthetic concentration (MAC) of 71%. This warrants investigating the combination of Xe with other inhaled anesthetics. We therefore investigated the influence of Xe on the MAC of isoflurane. The study was performed in 10 swine (weight, 28–35 kg) ventilated with Xe 0%, 15%, 30%, 40%, 50%, and 65% in oxygen. For each Xe concentration, various concentrations of isoflurane were administered in a step-wise design. For each combination, a supramaximal pain stimulus (claw-clamp) was applied, and the appearance of a withdrawal reaction was recorded. The isoflurane MAC was defined as the end-tidal concentration required to produce a 50% response rate. At each Xe concentration, the responses to the pain stimulus were categorized, and a logistic regression model was fitted to the results to determine isoflurane MAC. Isoflurane MAC was decreased by inhalation of Xe in a nonlinear manner from 1.92% (95% confidence interval, 1.70%–2.15%) with 0% Xe to 1.17% (95% confidence interval, 0.75%–1.59%) with 65% Xe. Although this indicates partial antagonism of the two anesthetics, a combination of Xe with isoflurane may prove valuable for patients requiring a fraction of inspired oxygen more than 0.3.

IMPLICATIONS: We investigated the influence of the anesthetic gas xenon on the minimum alveolar anesthetic concentration (MAC) for isoflurane (another anesthetic gas). The study was performed in 10 swine ventilated with fixed xenon and various concentrations of isoflurane. The isoflurane MAC is decreased by inhalation of xenon in a nonlinear relationship.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Increasing interest in the anesthetic use of xenon (Xe) inhalation on the one hand (1,2–4) and a limitation of worldwide Xe supplies raises questions about the best indications for Xe anesthesia (5). Because of favorable pharmacokinetics and pharmacodynamics, one of the indications for Xe will probably be anesthesia in high-risk patients (6,7). However, these patients often require a high fraction of inspired oxygen (FIO2) for adequate oxygenation during anesthesia. Because the minimum alveolar anesthetic concentration (MAC) for Xe in humans is reported to be 63.1% (8), Xe anesthesia in these patients will have to be supplemented by other anesthetics potentially interfering with the main advantages of Xe’s lack of adverse effects and rapid recovery.

We therefore investigated the interaction between Xe and isoflurane by determining the effect of different concentrations of inhaled Xe on the isoflurane MAC in swine.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The study was approved by the local Animal Care Committee as well as by the governmental 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 land-race pigs weighing 28–35 kg (32.4 ± 2.1 kg; mean ± SD). On admission to the local institute for animal studies, the pigs were thoroughly examined by a veterinarian. This examination included behavior, motor ability, and cardiopulmonary auscultation. None of the pigs showed any symptoms of disease, and body temperature was between 38.1°C and 39.2°C (mean, 38.6°C ± 0.6°C). 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 injection of propofol 2 mg/kg, and orotracheal intubation was performed without any muscle relaxant using a 7.5-mm Woodbridge endotracheal tube. While maintaining anesthesia with repeated bolus injections of propofol 20 mg, a 20-gauge femoral artery cannula was placed 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 38–45 mm Hg. Body temperature was kept between 37.5°C and 39.0°C by use of an airflow warming system (Warm Touch, Mallinckrodt Medical, Dublin, Ireland). Heart rate, 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 and CO2 were monitored by the anesthesia monitor. The end-tidal concentrations of isoflurane were monitored in duplicate by the anesthesia monitor (infrared spectroscopy) and the ventilator (infrared spectroscopy), and the mean value was used. Inhaled concentration of Xe was measured via 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 fresh gas added 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 value, oxygen saturation, sodium, potassium, calcium, chloride, glucose, and lactate concentrations (Radiometer Copenhagen ABL 500/ABL 100, 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 isoflurane sufficient for the pigs to tolerate controlled ventilation for a period of at least 45 min. This enabled us to virtually exclude any influence of propofol on the study, because Cockshott et al. (9) have demonstrated that blood propofol concentration after an IV bolus of 2–5 mg/kg of propofol is reduced to 10% of the initial concentration after 45 min.

With Xe concentrations of 0%, 15%, 30%, 40%, 50%, and 65%, isoflurane concentration was changed in 10% MAC steps between 0.96% and 2.24% volume, with an expected MAC of 1.6% for isoflurane in oxygen. To reduce bias caused by 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 doses of isoflurane, whereas Group 2 started with Xe 65% and decreased doses of isoflurane. Schedules for both groups are shown in Table 1. After any change in Xe concentrations, at least 20 min were allowed for equilibration before continuing the experiment.


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  		Table 1. Schedules for Groups 1 and 2. In Both Groups, the Isoflurane Concentration at a Given Xenon Concentration was Changed in Steps of 0.16%. All Concentrations are End-Tidal
 
A supramaximal pain stimulus was applied by use of the dew claw-clamp technique, as described by Eger et al. (10): A large clamp was placed between the toes and 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 not only as withdrawal of the clamped foot, but also as 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 extremities were used consecutively.

For each Xe concentration, isoflurane 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.

The MAC of isoflurane and its reduction by Xe was evaluated using a logistic regression model approach:

equation


where X1 is the end-tidal isoflurane concentration, X2 is the end-tidal Xe concentration, ß0 is the regression intercept, ß1 is the coefficient for isoflurane, ß2 is the coefficient for Xe, ß12 is the coefficient for the interaction between isoflurane and Xe, and p is the probability of a response.

Because our model contains repeated measurements, the generalized estimating equation approach (11) was used to estimate the coefficients for the logistic regression model. Variable estimates, 95% confidence intervals, z-scores, and P values are based on empirical SE estimates.

The isoflurane MAC for a given end-tidal Xe concentration was then determined by setting the probability of response to 0.5 and solving for isoflurane concentration as a function of end-tidal Xe concentration:

equation


Statistical analysis was performed using SAS version 8.0 software (SAS Institute Inc, Cary, NC).


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The logistic model was fitted to the response data of 10 pigs to each end-tidal isoflurane and Xe concentrations. Coefficient estimates for the logistic regression model are presented in Table 2, and resulting MAC values for isoflurane are in Table 3. The MAC of isoflurane in the absence of Xe was 1.92% (95% confidence interval, 1.70%–2.15%) and was reduced by increasing Xe concentrations (Table 3; Fig. 1). The maximum reduction of the isoflurane MAC was 0.75% with Xe 65%. The reduction in MAC by Xe was nonlinear, with the interaction coefficient between Xe and isoflurane being significantly less than zero (P < 0.0001), indicating that the reduction in MAC by Xe was smaller than would be expected from simple additivity and that Xe antagonized the effect of isoflurane in preventing the response to a supramaximal stimulus.


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  		Table 2. Coefficient Estimates for the Logistic Regression Model for the Interaction Between Xenon and Isoflurane. The Interaction Coefficient (Isoflurane x Xenon) is Significantly Less than Zero (P < 0.0001), Indicating that the Interaction Between Xenon and Isoflurane Concentrations is Nonlinear
 

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  		Table 3. MAC Values for Isoflurane (MACIso) for Different End-Tidal Xenon Concentrations
 


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  		Figure 1. Relationship between end-tidal xenon (Xe) and the minimum alveolar anesthetic concentration (MAC) of isoflurane. The upper and lower curves are the 95% confidence limits.

 
All relevant physiological variables (heart rate, mean arterial blood pressure, electrolytes, and arterial blood gas analyses) were kept stable in each pig throughout the study. PaO2, depending on FIO2, varied between 150 mm Hg for FIO2 0.3 and 577 mm Hg for FIO2 1.0. No symptoms of cardiovascular or metabolic instability were encountered. Table 4 shows the relevant physiological variables. There were no significant differences in any of these variables between the different Xe concentrations.


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  		Table 4. Effect of Xenon on Hemodynamic and Biochemical Values and Gas Exchange
 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
In our study, the combination of isoflurane with 15%, 30%, 40%, 50%, and 65% Xe reduced isoflurane MAC by 5.2% to 39% (that is 0.1% to 0.75% in end-tidal concentration). A similar effect has been reported by combining nitrous oxide (N2O) with isoflurane; Eisele et al. (12) found MAC reductions of 30% with 50% N2O and of 42% with 66% N2O, and they demonstrated a linear-additive effect of isoflurane and N2O between 50% and 66% N2O. A linear interaction for isoflurane and N2O was also found by Eger (13), with a reduction of the MAC by 0.1% end-tidal isoflurane for each 10% N2O. This is similar to the results by Steffey et al. (14) who found a linear dose-response curve for the combination of halothane and N2O in cats, dogs, and monkeys.

In contrast, Cole et al. (15) 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 effects of N2O and volatile anesthetics. In their work, Cole et al. (15) point out that the dose-response curve was only applicable for the N2O concentrations they examined (0%, 15%, and 75%). There may also be species differences in the interactions between Xe and N2O because a linear interaction has been demonstrated in swine (12,16). The question as to whether N2O and other volatile anesthetics may interact in a nonlinear way has therefore not yet been sufficiently answered (17,18). When one examines our results for Xe 50% and 65%, the interaction with isoflurane seems to be linear (Table 3), as in the experiments with N2O. However, if one examines the entire dose-response curve for Xe and isoflurane, a nonlinear relationship becomes obvious, which we have demonstrated both graphically (Fig. 1) and by fitting a logistic regression model. In general, smaller Xe concentrations were less effective in reducing the isoflurane MAC as compared with larger concentrations.

Because there are no data available on the combined use of different Xe concentrations and other volatile anesthetics, we can only speculate on the explanation for these results. One possible explanation could be provided by studies by Franks et al. (19) and de Sousa et al. (20). Franks et al. (19) reported a 60% reduction in the N-methyl-D-aspartic acid (NMDA)-activated currents in rat hippocampal cells by Xe 80%. Blockade of the receptor with a highly selective NMDA antagonist produced an almost identical effect. de Sousa et al. (20) reported a marked {gamma}-aminobutyric acid (GABA)ergic activation but very little effect on NMDA receptors by isoflurane in the same experimental model. These results support the hypothesis that Xe and isoflurane probably induce anesthesia via different pathways at the neuronal level.

The movement response to a painful stimulus is mainly mediated at the spinal cord level. As NMDA and GABA receptors are found in the spinal cord as well (21,22), it seems likely that the effects of Xe and volatile anesthetics at this site are identical to those found in the brain. Indeed, antinociceptive effects of NMDA antagonists in the spinal cord have been demonstrated (23,24).

The method used for applying the supramaximal pain stimulus is of importance in determining MAC values. In swine, Lundeen et al. (25), Eisele et al. (12), and Tranquilli et al. (16) used the original tail-clamp technique described by Eger et al. (10). When comparing this MAC to the one determined using a different painful stimulus, the dew claw-clamp, Eger et al. reported a larger MAC of 2.04% for the latter technique (10). They concluded that stimulation by clamping the tail was not supramaximal and suggested the claw-clamp as more appropriate for determining the MAC in swine. For this reason, we used this method in our study.

In conclusion, our data show that there is a nonlinear interaction between Xe and isoflurane in swine. However, the combined effect is sufficient for the anesthesiologist to supplement Xe anesthesia in a quick, simple, and inexpensive way once an increase in FIO2 becomes required. Once these results are verified in humans, indications for the use of Xe anesthesia may be extended to patients with cardiopulmonary disease and procedures in which large blood loss is expected—both situations associated with a desired FIO2 > 0.3—by using Xe in combination with volatile anesthetics.


   Acknowledgments
 
Supported, in part, by Deutsche Forschungsgemeinschaft (Ro 2000/5–1), and Messer Griesheim, Krefeld, Germany.

The authors thank Thaddeus Stopinski, Marion Weitz, and Thorsten Rinkens for their technical assistance.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication September 11, 2002.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press