Anesth Analg 2008; 106:823-829
© 2008 International Anesthesia Research Society
doi: 10.1213/ane.0b013e318161534b
ANESTHETIC PHARMACOLOGY
Section Editor:
: Marcel E. Durieux Section Editor: Tony Gin
The Effective Concentration 50 (EC50) for Propofol with 70% Xenon Versus 70% Nitrous Oxide
Ahmed R. Barakat, MD, FRCA*,
Markus N. Schreiber, MD ,
Joachim Flaschar, Dipl.-Ing. (FH),
Michael Georgieff, MD, and
Stefan Schraag, MD*
From the *Department of Perioperative Medicine, Golden Jubilee National Hospital, Clydebank, UK; and Department of Anesthesiology, University of Ulm, Germany.
Address correspondence and reprint requests to Stefan Schraag, MD, PhD, Department of Perioperative Medicine, Golden Jubilee National Hospital, Clydebank G81 4HX, Scotland, UK. Address e-mail to stefanschraag{at}btinternet.com.
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Abstract
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BACKGROUND: Xenon anesthesia has many favorable properties, such as pain modulation and organ protection. However, due to its MAC of 70%, it cannot be used as a sole anesthetic. We estimated the amount of propofol required to supplement xenon to produce adequate anesthesia in 50% and 95% of patients in comparison with nitrous oxide.
METHODS: We randomized 75 premedicated female patients to receive either 70% xenon or 70% nitrous oxide in oxygen supplemented by propofol target-controlled infusion anesthesia starting with 4.5 µg/mL for the first patient in each group. Dixon's up and down method was used to determine the propofol concentration for subsequent patients. After induction of anesthesia with propofol, patients breathed 70% xenon or 70% nitrous oxide in oxygen via a facemask for 15 min. They were then observed for movement in response to skin incision for 60 s after the incision and assigned as movers or nonmovers. Probit analysis was used to estimate the effective concentration 50% and 95% (EC50 and EC95) for propofol in both groups.
RESULTS: The EC50 for propofol with 70% xenon was1.5µg/mL and the EC95 was 2.3 µg/mL. The EC50 and EC95 values for propofol with nitrous oxide were 2.2 and 8.2 µg/mL, respectively. This implies a reduction of propofol requirements between 32% (EC50) and 72% (EC95) by xenon compared with nitrous oxide. The suppression of auditory evoked potentials was more pronounced with xenon than with nitrous oxide.
CONCLUSION: Xenon seems to be clinically more potent than nitrous oxide, but still requires minimal supplement of a hypnotic anesthetic to suppress noxious stimulation during and after skin incision.
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Introduction
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Xenon is a near ideal anesthetic. It is an environmentally friendly gas that does not trigger malignant hyperthermia and lacks many of the side effects of nitrous oxide.1–3 Being an N-methyl-d-aspartate receptor antagonist, xenon has analgesic properties similar to nitrous oxide and ketamine.4,5 Xenon also has several other interesting properties, including pronounced organoprotective effects in various experimental settings against ischemia-reperfusion injury of the heart and the brain.6 It causes minimal hemodynamic depression,7 and has favorable pharmacokinetics with fast induction and recovery characteristics regardless of the duration of anesthesia due to its low blood:gas partition coefficient of 0.115 compared with 0.47 for nitrous oxide.8 However, xenon is expensive and requires special equipment for administration and monitoring. Furthermore, with a minimum alveolar concentration of 0.63 to 0.71, xenon is not potent enough to be used as a single anesthetic.9
The effective concentration of propofol to prevent movement in response to a standard surgical stimulus in 50% of patients (EC50) is the equivalent to the MAC used for volatile anesthetics.10 Adjuvant hypnotic and analgesic drugs decrease propofol requirements both for loss of response to commands and to surgical stimulus.11 The effect of nitrous oxide on the EC50 of propofol has been studied both in premedicated12 and nonpremedicated patients.13 We aimed to determine how much propofol is needed to supplement xenon anesthesia by calculating the EC50 and, more clinically relevant, the EC95 of propofol with 70% xenon, and to compare this to the propofol EC50 and EC95 when the same concentration of nitrous oxide is used. We also compared the equipotent concentrations of both drugs.
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METHODS
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After Institutional Ethics Committee Approval and written informed consent, we studied 75 ASA I–II female patients undergoing elective breast or body surface surgery in a double-blind, randomized and controlled study. Patients were randomized into one of two groups using a computer program. Patients in group X received 70% xenon in oxygen and those in group N received 70% nitrous oxide in oxygen, both supplemented by propofol by target-controlled infusion (TCI) in effect-site control. Blinding was maintained throughout the study. The investigator operating the rotameters on the anesthetic machine only became aware of the randomization group before induction of anesthesia and after the consent for the study was obtained. Exclusion criteria were patients with preexisting cardiac, pulmonary, hepatic, or renal disease as well as patients with diabetes mellitus and morbidly obese patients with Broca's index more than 30% of expected (Broca's Index: Ideal body weight (kg) = Height (cm) – 100 for men or Height (cm) – 105 for women). All patients were premedicated with 20 mg temazepam 60 min before surgery. Two IV cannulae were inserted before induction of anesthesia. An 18G cannula was inserted in one arm for the infusion of propofol and a 16G cannula was inserted in a large antecubital vein in the contralateral arm for blood sampling. Patients were then administered 100% oxygen via a facemask for 5 min before propofol infusion was started. Anesthesia was induced with propofol TCI to a preset effect-site concentration using the Marsh pharmacokinetic model.14 Stanpump software (written by and freely available from Steven Shafer, MD, Department of Anesthesia, Stanford University, Stanford) running on a laptop computer was used to drive a Graseby 3400 pump (Graseby Medical, Watford, UK).
Propofol TCI was set at a target effect-site concentration of 4.5 µg/mL for the first patient in each group. Dixon's up and down method (UDM)15 was used to determine the target propofol effect-site concentration for the subsequent patients. If a patient moved, the target propofol effect-site concentration for the next patient was increased by 0.1 µg/mL. If the patient did not move, the target propofol effect-site concentration for the next patient was decreased by 0.1 µg/mL. After the calculated propofol effect-site concentration was achieved, the patients were switched from breathing 100% oxygen to 70% xenon in oxygen in group X or 70% nitrous oxide in oxygen in group N via a tight fitting facemask for 15 min with end-tidal drug concentration monitored to ensure equilibration. The anesthesiologist was blinded to the rotameters settings on the anesthetic machine (Cicero EM-Xenon, Draeger, Lübeck, Germany), which were set by one of the investigators. Before the start of surgery, a laryngeal mask airway was inserted and a blood sample for propofol level was taken. Another blood sample was taken immediately before skin incision to assess steady-state conditions. The blood samples were immediately centrifuged and the supernatant plasma stored at 4°C for analysis using a high performance liquid chromatography assay. We only collected blood samples from the first 60 patients. The patients were closely observed for movement for the 60 s after skin incision. If a patient moved from skin incision, surgery was discontinued and anesthesia deepened before surgery was allowed to continue. The definition of movement was that used by Eger et al.10 Movement was assessed by an independent observer who was blinded to the propofol effect-site concentration and to the gas mixture used. After the end of the 60-s observation period, the experiment was terminated and all patients were given alfentanil 20 µg/mL. The gas mixture was changed to 70% nitrous oxide in oxygen for all patients and propofol TCI was adjusted to maintain adequate anesthesia for the remaining surgical procedure.
To explore any concentration-related interaction with the spontaneous or evoked electroencephalogram (EEG), both a two-channel EEG and auditory evoked response was continuously recorded in every patient. Starting in the awake patient, signals were obtained from bilateral fronto-mastoidal electrode montages with an Fpz reference. Electrode impedance was always less than 2 k (silver-silver chloride electrodes, Zipprep, Aspect Medical, Norwood). The processed EEG parameter spectral edge frequency (SEF90) was derived by 2-s epoch fast-Fourier transformation using the pEEG monitor (Draeger, Lübeck, Germany). The raw EEG was edited to remove epochs containing artifacts. Derived EEG parameter values corresponding to the clinical end-points loss of consciousness and skin incision were stored on a computer hard disk via the pEEG Win software (Draeger, Lübeck, Germany) for off-line analysis. The EEG of the auditory evoked response was simultaneously obtained from three disposable silver-silver chloride electrodes (Ziprep, Aspect Medical Systems, Norwood, MA) placed on the right mastoid (+), middle forehead (–) and Fp2 as reference. The custom-built amplifier had a 5-kV medical grade isolation, common mode rejection ratio of 170 dB with balanced source impedance, input voltage-noise of 0.3 µV and current input noise of 4 pA (0.05 Hz to 1 kHz rms). A third-order Butterworth analog band-pass filter with a bandwidth of 1–220 Hz was used. The auditory clicks were of 1 ms duration and 70 dB above hearing threshold. They were presented to both ears at a rate of 6.9 Hz. The amplified EEG was sampled at a frequency of 1778 Hz by a high accuracy, low distortion 12 bit analog to digital converter (PCM-DAS08, Computer Boards, Mansfield, MA) and processed in real-time on a microcomputer (Tecra 700 CDT, Toshiba Corp., Tokyo, Japan). Auditory evoked potentials (AEP) were generated by averaging 256 sweeps of 144 ms duration. The time required to update a full signal was 36.9 s, but a moving time average technique allowed a faster response time to any change in the signal every 3 s. The AEP index, which reflects the morphology of the AEP waveform, is a mathematical derivative and is calculated as the sum of the square root of the absolute difference between every two successive 0.56 ms segments.15a
The sample size was based on similar studies.11,12 We aimed to study 30 patients in each group. However, in the xenon group, the propofol target concentration did not plateau after 30 patients were recruited, so we decreased the target concentration by 0.5 µg/mL step from 2.0 to 1.5 µg/mL and recruited 15 more patients, until the propofol effect-site concentration reached a plateau as required by the Dixon's UDM technique.15 Continuous data were tested for normality. Parametric data were analyzed using unpaired two-tailed t-test and summarized using the mean with standard deviation (sd). We used probit regression analysis to obtain propofol EC50 and EC95 values for both xenon and nitrous oxide. Probit analysis was performed using SPSS statistical software version 12 (SPSS, Chicago, IL). We also calculated the prediction error (PE) of the TCI system to compare the predicted (calculated) and measured propofol concentration, Cp predicted and Cp measured respectively, as follows:
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Data are expressed as bias and precision. Bias (mean PE) provides an estimate of the system over or under prediction, whereas precision (mean absolute PE of the individually calculated PE) provides a measure of the scatter of data around the line of perfect prediction. We used the values from the second blood sample, collected at skin incision, to calculate precision and bias. The performance of SEF90 and AEPex in predicting loss of consciousness and movement response was calculated and expressed with the prediction probability (Pk). Pk was calculated using the PKMACRO as described by Smith et al.16 The jackknife method was used to compute the standard error of the estimate. Comparison of the Pk values was performed with the PKDMACRO.16
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RESULTS
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We studied 75 female patients, 30 patients in the propofol/nitrous oxide N group and 45 patients in the propofol/xenon X group. The groups were comparable with respect to age, height, weight, and Body Mass Index. Table 1 shows the patient characteristics for both groups. All patients in both groups were hemodynamically stable throughout the anesthetic and none of the patients required assisted or mechanical ventilation.
The target blood propofol concentration for consecutive patients and their response to skin incision are shown in Figure 1. The effective concentration 50% and 95% (EC50 and EC95) for propofol with 70% xenon and nitrous oxide from the experiment are shown in Table 2 as results of the probit analysis. The table shows the calculated EC50 and EC95 values from both predicted and measured propofol concentrations. If we consider the probit results based on measured concentrations more valid, the EC50 for propofol supplemented with xenon is 32% less than with nitrous oxide, whereas the reduction in the EC95 is 72%. It needs to be highlighted, however, that with a published MAC of 0.71% one would suggest the EC50 of propofol with xenon be closer to zero.
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Figure 1. Propofol concentrations for consecutive patients in both study groups. Patient response can be extrapolated from the propofol concentration used for the following patient.
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We compared the measured to the predicted blood propofol concentrations. Both correlated well over the range of concentrations used and overall relation could be expressed as y = 0.59 + 0.93 x, where y is the measured blood propofol concentration and x is the predicted concentration (Fig. 2). The precision and bias of the TCI system for prediction of blood propofol concentration is shown in Table 3. Precision analysis for the assay (high performance liquid chromatography) disclosed a within-day variation coefficient of 5.1%–8.5% and a between-day variation coefficient of 8.5%–10%.
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Figure 2. Relationship of measured and predicted propofol concentrations in both groups. The fitted line is the line of identity.
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Table 3. Accuracy of Target-Controlled Infusion System: Bias and Precision of Predicted Blood Propofol Concentration
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We could not demonstrate any consistent relationship between derived EEG or AEP parameters and propofol concentrations, nor was there any predictive ability to detect loss of consciousness or movement response to stimulation, mainly due to the large spread and overlap of values. These findings are summarized in Table 4 and expressed as the respective prediction probability values (Pk). Thus, we were unable to calculate a meaningful EEG-based interaction model for either xenon or nitrous oxide with propofol. However, Figure 3 illustrates that the median values and their range for the AEPs (AEPex) showed a trend towards a more suppressed signal during anesthesia and stimulation with xenon compared with nitrous oxide. This is noteworthy as similar time points in the xenon group the propofol concentrations were lower. There was no such pattern with regard to the spontaneous surface EEG parameter (SEF90).
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Table 4. Prediction Probability (Pk) of Electroencephalographic Parameters Spectral Edge Frequency (SEF 90) and Auditory Evoked Potentials (AEP)ex
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Figure 3. Electroencephalographic effects of propofol with nitrous oxide (upper panel) and propofol with xenon (lower panel): auditory evoked potentials (AEPex) versus time. Individual time points refer to baseline (–2), start propofol (–1), start nitrous oxide/xenon (0), 5 min after,1 10 min after,2 insertion of laryngeal mask,3 5 min after laryngeal mask insertion,4 and incision.5 Data are shown as box plots with median values (notches), interquartil range (boxes) and range (whiskers). Outliers are identified as individual dots.
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DISCUSSION
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We found a significant reduction in propofol requirements when xenon was used as a supplement compared to using nitrous oxide. Based on published MAC equipotency values, this reduction suggests the relative potency of xenon and nitrous oxide is between 1.5:1 (based on EC50) and 2.5:1 (based on EC95). The MAC value of xenon was determined to be 71% in the 1960s.9 More recently, Nakata et al.17 investigated the MAC of xenon and sevoflurane and found xenon to be 63.1%. They suggested a small antagonistic action between xenon and sevoflurane, as the combined MAC value in the study was consistently more than 1 MAC. The same group demonstrated that fentanyl requirements under xenon anesthesia are significantly less than those under nitrous oxide anesthesia at equi-MAC concentrations.18
There are some limitations in our study. Probit analysis requires only few binary data and, by definition, the UDM provides this information reliably. Although the EC95 is more relevant to clinical practice than the EC50, it is only obtained by the calculation of the probit analysis and not by actual measurements. This highlights the problem of sparse data in pharmacodynamic research, extrapolating to extremes, as outlined by Bailey and co-workers.19 There was also a slight, but expected, difference between the EC50/EC95 values based on predicted and actually measured propofol concentrations, without affecting the principal result. We have to realize that the UDM, together with probit analysis, gives a parametric estimator for comparison of equipontent concentrations or doses.20 The UDM does not necessarily give information about the dose-response relationship over a wider concentration range, usually reported with an Emax model, although it is still considered the most robust tool for reporting EC50/EC95 for anesthetic drugs. Furthermore, we based our calculation on clinical responses to skin incision. It may well be that the equipotency ratio between xenon and nitrous oxide will be different during surgery with more intense stimulation. Another unproven assumption in comparing MAC value is linearity. For example, our results show that the calculated EC95 for propofol with 70% nitrous oxide in premedicated patients is 8.2 µg/mL, compared with 2.3 µg/mL with 70% xenon. The difference between the groups is less pronounced when comparing the respective EC50 values (Table 2).
One also has to consider the influence of premedication. We found the EC50 of propofol with 70% nitrous oxide to be 2.2 µg/mL in premedicated patients. This is less than the previously reported 4.5 µg/mL with 67% nitrous oxide by Davidson et al.,12 although their patients had the same premedication. Their report also states a difference between the EC50 based on predicted compared with measured concentrations. However, Stuart et al.13 found the EC50 of propofol (predicted concentrations) with 67% nitrous oxide without premedication to be 4.9 µg/mL, only slightly more than the value found by Davidson et al., but significantly more than our result. Therefore, it seems that premedication does have a certain, yet not consistent, influence on the calculation of EC50 or EC95. It also highlights that variability between different patient groups and experimental settings may be more relevant.
Our study failed to disclose any consistent pattern of spontaneous EEG response to various propofol concentrations when supplemented with either xenon or nitrous oxide. Whereas nitrous oxide per se has no or even reverse impact on EEG suppression,21 Goto et al.22 demonstrated an effect on the Bispectral Index when 0.8 MAC of xenon was applied to volunteers. However, emergence and stimulus-related responses were less well represented by Bispectral Index in this study. With regards to the auditory evoked response, we found demonstrable suppression of the index during unconsciousness and stimulation in the xenon group compared with nitrous oxide, which may indicate the more pronounced antinociceptive properties of xenon. This supports previous findings that the spontaneous EEG reflects the level of sedation and unconsciousness, whereas AEPs rather reflect the presence or absence of responses to stimulation.23 However, the prediction probability value for xenon is only slightly higher than for nitrous oxide and significantly lower compared with published values for propofol or volatile anesthetics.
What is the clinical implication of our findings? The spinal cord plays a major role as a site of action of anesthetics for analgesia and immobility and xenon is a more potent analgesic than nitrous oxide in this respect.24,25 On the other hand, Petersen-Felix et al.26 could not demonstrate any difference in MAC-equivalent concentrations between xenon and nitrous oxide for analgesia evaluated by experimental pain at lower concentrations. We could show that xenon is clinically more potent than nitrous oxide but still requires at least some supplement of a hypnotic anesthetic, which in previous reports of "xenon anesthesia" has often been underreported. Previous clinical studies on patients have been conducted by supplementing xenon with either volatile anesthetics or potent opioids, such as remifentanil.27 This precludes direct comparisons with our results, but this also emphasizes the need for further information on drug interaction with xenon.
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ACKNOWLEDGMENTS
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We thank Messer-Griesheim, Krefeld, Germany, for supplying xenon and Draegerwerk, Lübeck, Germany, for providing the Cicero EM-Xenon. Statistical advice from Dr. U. Bothner is gratefully acknowledged. This study was sponsored by departmental funds.
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Footnotes
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Accepted for publication November 1, 2007.
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REFERENCES
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Abstract
Introduction
