1 Department of Anaesthesiology and 2 Department of Medical Statistics, Klinikum der RWTH Aachen, Pauwelsstr. 30, D-52074 Aachen, Germany. 3 Department of Anaesthesiology and Intensive Care, Waldkrankenhaus Berlin, Germany
*Corresponding author. E-mail: klaus.hecker@post.rwth-aachen.de
Accepted for publication: September 26, 2003
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Abstract |
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Methods. The study was performed using ten swine (weight 27.835.4 kg) anaesthetized with halothane and Xe 0, 15, 30, 40, 50 and 65% in oxygen. With each Xe concentration, various concentrations of halothane were administered in a step-by-step design. For each combination, a supramaximal pain stimulus (claw clamp) was applied and the appearance of a withdrawal reaction was recorded. The MACXe with halothane was calculated using a logistic regression model.
Results. During stable ventilation, haemodynamics and temperature, MACXe value was determined as 119 vol. % (95% confidence limits 103135).
Conclusion. MACXe in swine was calculated by extrapolation of a logistic regression model. Its theoretical value is 119 vol. %.
Br J Anaesth 2004; 92: 4214
Keywords: anaesthesia, closed circuit; anaesthetics volatile; pharmacology
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Introduction |
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Reduction of the MAC of one volatile anaesthetic by administration of another permits extrapolation of an unknown MAC. Thus, we are able to determine a MAC that exceeds 100% and cannot be reached under normobaric conditions. This method has been used to determine the MAC of nitrous oxide in swine.3 The aim of this study was to determine MACXe in swine from the ability of Xe to reduce the MAC of halothane (MAChalo).
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Methods and results |
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After premedication with azaperone 4 mg kg1 i.m., an ear vein was cannulated. Anaesthesia was induced with propofol 2 mg kg1 and orotracheal intubation was performed using a 7.5 mm woodbridge tube. Thereafter, anaesthesia was maintained with repeated boluses of propofol.
Animals were mechanically ventilated using a Draeger PhysioFlex closed system ventilator (Draeger, Luebeck, Germany). Target end-tidal carbon dioxide values were 3845 mmHg. Body temperature was maintained between 37.5 and 39.0°C by use of an airflow warming system (Warm Touch, Mallinckrodt Medical, Ireland). Heart rate, mean arterial pressure, end-tidal carbon dioxide and temperature were monitored and recorded continuously using a Datex AS/3 anaesthesia monitor (Datex-Engstrom, Helsinki, Finland). Inspiratory and end-tidal concentrations of oxygen, carbon dioxide and halothane were monitored using Datex AS/3 infrared spectroscopy. The inhaled concentration of Xe was measured via thermoconductive analysis using the PhysioFlex ventilator. Because Xe consumption after the initial wash-in is less than 20 ml min1, inspiratory and expiratory Xe concentrations are virtually identical.
At the end of instrumentation, anaesthesia was maintained with halothane 1.3 MAC in 100% oxygen until the effect of propofol was no longer likely to influence the study protocol. The experimental protocol started at least 3 h after premedication, and at a mean of 45 min after the last propofol administration.
In the presence of Xe concentrations of 0, 15, 30, 40, 50 and 65%, the halothane concentration was changed in 0.1 vol. % steps, with an expected MAC of 1.0 vol. % for halothane in oxygen. Ten animals were randomly assigned to one of two arms of the protocol. Arm 1 started with Xe 0% and received increasing doses of halothane; arm 2 started with Xe 65% and received decreasing doses of halothane. After any change in gas concentrations, we allowed a minimum of 20 min for equilibration before continuing the experiment.
A supramaximal pain stimulus was applied using the dew claw clamp technique as previously described.4 For each concentration of Xe, halothane was either steadily increased or decreased until a change in reaction occurred: a withdrawal reaction when the individual had been asleep and vice versa. This was then confirmed by increasing or decreasing the concentration one step further, respectively. At the end of the experiments, the animals were killed according to German laws for animal studies.
Statistics
MAC determination
To evaluate the relationship between halothane and Xe, we considered a multiple logistic regression model with an interaction term:
logit (p) = ß0 + ß1X1 + ß2X2 + ß12X1X2(1)
where p=probability of no withdrawal reaction, X1=end-tidal halothane concentration, X2=Xe concentration, ß0=regression intercept, ß1=coefficient for halothane, ß2=coefficient for Xe and ß12=coefficient for the product of halothane 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.5 Resulting estimates of equation (1) and their corresponding P values are presented in Table 1.
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logit (p) = ß0 + ß1X1 + ß2X2(1b)
The hypothetical MACXe without an additional anaesthetic was determined by setting the response probability p in equation (1) to 0.5 and solving the equation for Xe with a halothane concentration of 0% as follows:
The MACXe determined by the logistic regression without interaction term was extrapolated to 119 vol. % (95% confidence limits 103135).
All statistical analyses were performed using SAS V8.02 Software (SAS Institute Inc., Cary, NC, USA).
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Comment |
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Our value of 1.0% for MAChalo is within the range of MAC values from other studies involving swine.7 8 This suggests that the current protocol is comparable to those of a number of previous studies investigating MAC in swine. Our results show that the interaction between Xe and halothane in swine is likely to be linear. MAC studies are subject to several influencing factors. To exclude the influence of premedication, the study protocol did not start until at least 3 h after administration. During the instrumentation period, halothane and propofol were used to maintain anaesthesia. Propofol was stopped 4560 min before the study protocol was started. This enabled us to virtually exclude any influence of these medications on the study. Indeed, Cockshott and colleagues9 have demonstrated that the plasma propofol concentration after i.v. boluses of 25 mg kg1 is reduced to 10% of the initial concentration after 45 min. The reason for using propofol for induction of anaesthesia was mainly to reduce the required concentration of halothane and thereby minimize the amount stored in fat, which could have reduced the equilibration time during the study protocol, as described above. To reduce bias caused by diurnal variability and duration of the experiment, the animals were randomly assigned to two arms of the protocol.
Other potential influences like hyper- and hypothermia, age, application of the supramaximal pain stimulus, hypo- or hypernatraemia, hypotension, abnormal perfusionventilation ratio, right-to-left shunt or insufficient equilibration time could be excluded. All parameters and values were within a normal range and maintained stable during the entire study protocol.
The main limitation of our study is that we did not directly measure MACXe but estimated it from data obtained in combination with halothane. It is difficult to administer more than 70% Xe to determine MAC because it would put the animals at risk of hypoxia. Therefore, we used Xe 65% as the highest concentration to keep the study design comparable in the two groups. Thus, we determined the MAC for the combination of Xe and halothane and we regard this method of extrapolating MACXe to be appropriate.
One may be concerned about a potential error resulting from extrapolation beyond the range of data. In contrast to Nakata and colleagues,1 we did not find a small antagonistic interaction between Xe and halothane. Therefore we used the assumptions of additivity of MAC between Xe and halothane and calculated MAC from the logistic regression model and excluded an interaction coefficient.
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References |
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