Departments of 1Anaesthesiology and 2Physiology, Heinrich-Heine-University, Moorenstrasse 5, D-40225 Düsseldorf, Germany*Corresponding author
Accepted for publication: November 11, 2001
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Abstract |
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Methods. We studied the relationship between V·O2 (indirect calorimetry) and CO (ultrasound flowmetry) by adding xenon to isoflurane anaesthesia in five chronically instrumented dogs. Different mixtures of xenon (70% and 50%) and isoflurane (01.4%) were compared with isoflurane alone (1.4% and 2.8%). In addition, the autonomic nervous system was blocked (using hexamethonium) to study its influence on V·O2 and CO during xenon anaesthesia.
Results. Mean (SEM) V·O2 increased from 3.4 (0.1) ml kg1 min1 during 1.4% isoflurane to 3.7 (0.2) and 4.0 (0.1) ml kg1 min1 after addition of 70% and 50% xenon, respectively (P<0.05), whereas CO and arterial pressure remained essentially unchanged. In contrast, 2.8% isoflurane reduced both, V·O2 [from 3.4 (0.1) to 3.1 (0.1) ml kg1 min1] and CO [from 96 (5) to 70 (3) ml kg1 min1] (P<0.05). V·O2 and CO correlated closely during isoflurane anaesthesia alone and also in the presence of xenon (r2=0.94 and 0.97, respectively), but the regression lines relating CO to V·O2 differed significantly between conditions, with the line in the presence of xenon showing a 0.30.6 ml kg1 min1 greater V·O2 for any given CO. Following ganglionic blockade, 50% and 70% xenon elicited a similar increase in V·O2, while CO and blood pressure were unchanged.
Conclusions. Metabolic regulation of blood flow is maintained during xenon anaesthesia, but cardiovascular stability is accompanied by increased V·O2. The increase in V·O2 is independent of the autonomic nervous system and is probably caused by direct stimulation of the cellular metabolic rate.
Br J Anaesth 2002; 88: 54654
Keywords: anaesthetic techniques, inhalation; anaesthetics gases, xenon; heart, cardiac output; metabolism, oxygen consumption
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Introduction |
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Recently, the noble gas xenon has been the subject of widespread interest because it has minimal effects on the cardiovascular system, leading to haemodynamic stability.4 This cardiovascular stability has been explained by the fact that xenon does not alter myocardial function in humans5 and animals6 or in isolated hearts.7 This haemodynamic stability with an unchanged CO despite an increase in anaesthetic depth is in contrast to findings with other volatile anaesthetics, which reduce V·O2 and CO in parallel.3
We therefore questioned whether, and to what extent, xenon alters V·O2 and whether metabolic regulation of blood flow is maintained during xenon anaesthesia. To test this, we studied the relationship between CO and V·O2 during different levels of xenon anaesthesia added to an isoflurane baseline in chronically instrumented dogs and compared the effects of xenon with those elicited by isoflurane.
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Methods |
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Surgery
Several weeks before the experiments, the dogs were operated on under general anaesthesia (enflurane/nitrous oxide + fentanyl) and aseptic conditions. For blood pressure recording and blood sampling, both carotid arteries were exteriorized in skin loops.8 Ultrasound transit-time flow transducers were implanted around the pulmonary artery through a left-sided thoracotomy for continuous recording of CO.
Measurements
Cardiac output
Blood flow through the pulmonary artery was measured continuously with an ultrasound transit-time system (T101, Transonic Systems, Ithaca, NY, USA). Each flow transducer (2024 mm S-series with silicone shielded U-reflector; Transonic Systems) was calibrated in vitro before implantation and in vivo at least 3 weeks after implantation, using the Fick principle from V·O2 and the arterial-to-mixed venous oxygen content difference (C(a)O2) measured with a galvanic cell (Lex-O2-Con-TL®, Lexington Instruments, Waltham, USA), resulting in high precision, as described previously.9
Oxygen uptake (V·O2)
V·O2 (at standard temperature [273 K], pressure [760 mmHg] and dry PH2O 0 mm Hg]) was measured continuously by indirect calorimetry with a Deltatrac II® Metabolic Monitor (Datex-Engstrom Division, Instrumentarium Corp., Helsinki, Finland). Before each experiment, the gas sensors were calibrated with air and a gas mixture containing 95.0 (0.05)% O2 and 5.0 (0.03)% CO2, and the measurement of V·O2 was calibrated by burning 5 ml pure ethanol (alcohol burning test kit, Datex-Engstrom, Helsinki, Finland).
Burning of alcohol was also repeated in the presence of 50 and 70% xenon to ensure that the high density of xenon did not alter the flow constant of the built-in flow generator. In addition, baseline stability of the gas sensors was tested by feeding xenon to the mixing chamber of the Deltatrac II to check if xenon alters O2 and CO2 measurements.
During spontaneous breathing in awake dogs, V·O2 was measured with a flow-through technique (canopy mode), as described previously,10 which calculated V·O2 from the difference of inspired and expired oxygen concentration and the constant gas flow through the built-in flow generator. For this purpose, a transparent plastic canopy was fixed above the dogs head and upper trunk, allowing room air to enter at the edges as air was sucked continuously through the Deltatrac II for analysis. A canopy volume of approximately 70 litres and a flow generator rate of about 40 litre min1 resulted in a system time constant of 1.75 min.
During anaesthesia and controlled ventilation V·O2 was measured directly from the respiratory gases. The expired air was collected and fed to the mixing chamber of the Deltatrac II (respiration mode, a collection technique with a time constant of 1 min). As a cross-check of the Deltatrac II measurements, we also intermittently measured V·O2 from the product of CO and C(a)O2 (pulmonary artery catheter). In agreement with others,11 12 the precision of this device was 3.5% (average coefficient of variation) and the accuracy was 0.1 ml min1, with 95% confidence intervals of 4.8 to 5.0 ml min1.
Arterial pressure
Arterial pressure was measured electromanometrically (Statham P-23ID, Elk Grove, USA) through a catheter in the carotid artery. The electromanometer was calibrated with a mercury manometer and referenced to the processus spinosus of the 7th vertebra while the dogs were lying on its right side. Mean arterial pressure (MAP) was measured by integration from the original pressure signal.
Heart rate and RR intervals
HR and RR were determined from a standard ECG (surface electrodes) used for triggering a rate meter, which provided a continuous recording of the heart periods (RR intervals).
All variables were recorded continuously on an eight-channel polygraph (model RS 3800, Gould Inc., Cleveland, OH, USA) and simultaneously stored on the hard disk of a conventional personal computer for further analysis after analog-to-digital conversion with a rate of 400 Hz. During anaesthesia, respiratory gases and vapour concentrations were measured continuously at the endotracheal tube orifice by infrared spectroscopy (Capnomac® Ultima SV, Datex-Engstrom, Helsinki, Finland). We also intermittently determined arterial blood gas tensions, oxygen saturation, and pH (ABL3®, Radiometer, Copenhagen, Denmark).
Derived variables
Heart rate variability
HR variability (HRV), an indicator of the activity of the autonomic nervous system, was studied as recommended.13 For this purpose, the original ECG signal, free of aberrant ECG complexes and artefacts, was analysed during the last 5 min of each intervention (CHART®, ADInstruments, Castle Hill, Australia). HRV was analysed in the frequency domain and calculated as activity in the high frequency (HF: 0.150.5 Hz) and low frequency (LF: 0.040.15 Hz) range, the former showing predominantly vagal activity and the latter mainly sympathetic activity.13 Autonomic balance was assessed by calculating the quotient of power in the high frequency (nuHF) and low frequency (nuLF) range, respectively, divided by total power (sum of HF and LF power).13
Experimental protocol
All experiments were carried out with awake dogs in the basal metabolic state (food withheld for 12 h with free access to water) and under standardized experimental conditions (lightly dimmed laboratory at thermoneutral temperature for dogs of 24°C).14 To ensure complete elimination of the inhalation anaesthetic, successive experiments were performed at least 1 week apart.
After instrumentation and connecting the animal to the recording system, we waited for 30 min until all variables had reached steady state. The experiments started with baseline measurements for a further 30 min while the animal breathed spontaneously. Following the insertion of the endotracheal tube (intravenous injection of propofol 3 mg kg1), the animals lungs were ventilated with 25% oxygen in nitrogen (tidal volume about 10 ml kg1 and a rate of 14 bpm to maintain normocarbia). Isoflurane was added and adjusted to an end-tidal concentration of 1.4% (1 MAC).15 We then waited 30 min, in order to minimize interaction with propofol. During this equilibration period, a pulmonary artery catheter was advanced from the animals hind limb to obtain mixed venous blood samples. Thereafter, the following experiments were performed.
Oxygen uptake during xenon anaesthesia (n=5)
To evaluate whether xenon alters oxygen uptake, the following three mixtures were administered to each dog, but in a sequence which was randomized for each dog: FE'iso = 1.4% + FIxe = 50%, FE'iso = 1.4% + FIxe = 70%, FE'iso = 2.8%. The randomization resulted in two of the six possible sequences being used in two dogs each and one in another dog. Each gas mixture was maintained for 20 min to reach steady state. Before the end of the experiment, the animal was ventilated again with isoflurane 1.4% (1 MAC) in air to check whether V·O2 and CO returned to control values.
Metabolic regulation of CO during xenon anaesthesia (n=5)
In a second series of experiments on the same animals, the interventions of group 1 were repeated (with randomization leading to one of the six possible sequences being used in three dogs and one in two dogs) and extended by two additional mixtures: FE'iso = 0.7% + FIxe = 50%, and FIxe = 70%, always in that sequence. The total of five different mixtures was again administered between two periods of FE'iso = 1.4%. Thus, we studied the dogs under a total of four interventions in the presence of xenon and under two different interventions with isoflurane, alone plus the awake state.
Oxygen uptake during ganglionic blockade (n=5)
After completion of groups 1 and 2, we studied the same animals again in order to see whether the increase in V·O2 is of central or peripheral origin. For this purpose, hexamethonium, a ganglionic blocking agent, 7.5 mg kg1 was injected before induction of anaesthesia, followed by continuous infusion of 7.5 mg kg1 h1. Thereafter, the following two mixtures were administered to each dog: FE'iso = 1.4% + FIxe = 50%, FE'iso = 1.4% + FIxe = 70%, with randomization leading to one sequence being used in four dogs and the other in one dog.
Data analysis and statistics
Results are given as mean (SEM) and were compared using a paired t test. The resulting P values were corrected for multiple testing according to the Bonferroni procedure. In the case of repeated experiments in one animal, the results from individual dogs were averaged. CO was regressed on V·O2 during the awake state and isoflurane anaesthesia, as well as during anaesthesia in the presence of xenon, and results were compared using an F test for differences between regression lines. The slopes of the individual relationships between V·O2 and CO are given as mean slope and confidence interval. The effects on HR, MAP, systemic vascular resistance and C(a)O2 were compared by an analysis of variance for repeated measures (ANOVA), followed by Fishers protected least significant difference test16 if appropriate. Statistical significance was assumed when P<0.05.
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Results |
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Discussion |
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Critique of methods
Attempts to compare the effects of different anaesthetics on CO and V·O2 rest primarily on the precision of the measurement methods. This question is of particular interest because V·O2 during xenon anaesthesia has not been measured before.
V·O2 was measured with the Deltatrac II at a precision of 3.5%. The precision is independent of the collection mode, flow through, or canopy,12 17 18 and is not influenced by the addition of volatile anaesthetics if a correction for the exhaled concentration of the anaesthetic is made.19 Moreover, the four times greater density of xenon4 compared with air did not alter the flow constant of the flow generator, and xenon did not influence oxygen or carbon dioxide measurements in our experiments. Accordingly, measurements of V·O2 using a Deltatrac II were sufficiently precise to evaluate V·O2 during anaesthesia with xenon in relationship to isoflurane.
CO was measured by ultrasound transit-time flow probes placed around the pulmonary artery. These probes had been calibrated in vitro by a given saline flow and, after implantation, by the Fick principle from V·O2 and C(a)O2. Implantation around the pulmonary artery was chosen to obtain the entire cardiac output, which cannot be measured with flow probes placed around the aorta because coronary flow is not detected. These probes have been shown to continuously measure CO precisely over several years.9
The accuracy of our three independent measurement methods (V·O2, CO and C(a)O2) can be cross-checked using the Fick equation. Adding 50% xenon to 1.4% isoflurane did not change CO, so that changes in V·O2 and C(a
)O2 should balance each other. In fact, V·O2 and C(a
)O2 increased by 18% and 9%, respectively, confirming that CO was an essentially unchanged (calculation would yield 108%), with only 8% difference between independent measurement (ultrasound flowmetry) and calculation. This accuracy is likewise confirmed by the mean difference between measured and calculated C(a
)O2 values, which was only 3.9 (3.1)%.
Propofol, needed for inserting the endotracheal tube, may have influenced the effects of the inhalation anaesthetics. However, the plasma concentration of propofol should have decayed to a fraction of the initial peak within 10 min because of redistribution (half-life of the -phase of about 2 min) and, thereafter, more gradually as elimination continues (half-life of the
-phase of about 4 h).20 Moreover, in pilot experiments, all dogs resumed their normal activity and behaviour within 15 min after the injection of a single dose of propofol. Accordingly, the additive anaesthetic effects of propofol should have been small, and comparable for all interventions.
The dosage of hexamethonium used in our study was appropriate to eliminate the influence of the autonomic nervous system, as indicated not only from the literature21 but also from our own experiments, in which arterial pressure and HR did not change after 45 s of bilateral carotid artery occlusion. In contrast, before hexamethonium administration, arterial pressure increased by about 40 mm Hg and HR by 20 beats min1. Thus, our methods should have been appropriate for deriving reliable measurements.
Interpretation of results
Metabolic regulation of blood flow manifests itself as a linear relationship between CO and V·O2, during both physiological conditions1 and inhalation anaesthesia.3 In this context, V·O2 is considered the independent variable and thus determines CO, and not vice versa.3 In our experiments during inhalation anaesthesia with isoflurane, CO and V·O2 decreased from the awake state (basal metabolic conditions) to 2 MAC (points AD in Fig. 2). This relationship was linear, with a slope of CO vs V·O2 of 47, confirming our previous observations.3 In that study,3 we could also show that the relationship between CO and V·O2 did not differ significantly between the five most commonly used volatile anaesthetics.3
In contrast to the effects of these volatile anaesthetics, increasing anaesthetic depth from 1 MAC isoflurane with xenon by about 0.5 MAC (MAC value of 119% in dogs22) increased V·O2 while CO remained essentially unchanged. Cardiovascular stability during xenon anaesthesia has generally been observed in healthy individuals,23 24 as well as in dogs with dilated cardiomyopathy.6 Moreover, xenon had only minimal effects on myocardial contractility in vivo5 25 and maintained cardiovascular stability during surgical stimulation.26 However, total body oxygen consumption, the main determinant of CO, has not been measured during xenon anaesthesia before.
Increases in V·O2 could be related to either an increase in efferent sympathetic activity or a direct stimulating effect on the cellular metabolic rate. To test the contribution of the autonomic nervous system, we repeated the experiments after autonomic blockade. The increase in V·O2 during xenon anaesthesia was identical after ganglionic blockade, thus excluding increased sympathetic activity and suggesting a direct effect on cellular metabolic rate. However, there are no studies of the interaction between xenon and the molecular mechanisms of metabolism, and explanations of this phenomenon are beyond the scope of our experiments. The absence of sympathetic contribution to the increase in V·O2 is confirmed by the shift towards vagal activation, as indicated from the analysis of HRV in the experiments with the intact autonomic nervous system. Similar effects of xenon on the autonomic nervous system were previously observed in humans.27 In conclusion, xenon increases V·O2 most likely by directly stimulating the cellular metabolic rate.
Only myocardial oxygen consumption has been previously studied in detail during xenon anaesthesia, but this did not change either in vivo25 or in isolated hearts.7 However, myocardial oxygen consumption contributes only 1015% to total body V·O2, and changes in myocardial oxygen consumption may not necessarily parallel changes in total body V·O2
When anaesthetic depth changed, V·O2 and CO were linearly related in the presence of xenon, much like in the presence of volatile anaesthetics. However, the regression lines for xenon with and without isoflurane, and for isoflurane alone, differed significantly (Fig. 2). At any given CO, V·O2 was greater in the presence of xenon. If, in addition, CO and V·O2 are plotted against MAC, at least one more interpretation can be obtained (Fig. 6). Over the range of anaesthetic depths studied (below 2 MAC), substituting xenon for a proportion of the isoflurane (see arrows) would lead to an increase in CO and V·O2, with the effects of xenon tending to decrease as MAC increases. However, this interpretation has to be drawn with caution since it depends on the MAC of xenon, which has only been measured once in dogs22 and, in contrast to the other inhalation anaesthetics, differed by a factor of two between dogs and humans. It is also worth noting that HR decreased slightly during xenon anaesthesia in parallel with vagal activation, a phenomenon which has likewise been shown for the volatile anaesthetics.28 Thus, changes in HR during xenon anaesthesia are most likely caused by vagal activation. This interpretation is in accordance with the absence of this effect in isolated hearts.7 Accordingly, regulation of HR during xenon anaesthesia apparently does not differ from that during isoflurane anaesthesia.
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Acknowledgements |
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