Abstract

Background. This study was designed to examine whether the coupling between oxygen consumption (V˙o2) and cardiac output (CO) is maintained during xenon anaesthesia.

Methods. We studied the relationship between 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 (0–1.4%) 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 O2 and CO during xenon anaesthesia.

Results. Mean (sem) o2 increased from 3.4 (0.1) ml kg–1 min–1 during 1.4% isoflurane to 3.7 (0.2) and 4.0 (0.1) ml kg–1 min–1 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, o2 [from 3.4 (0.1) to 3.1 (0.1) ml kg–1 min–1] and CO [from 96 (5) to 70 (3) ml kg–1 min–1] (P<0.05). 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 O2 differed significantly between conditions, with the line in the presence of xenon showing a 0.3–0.6 ml kg–1 min–1 greater o2 for any given CO. Following ganglionic blockade, 50% and 70% xenon elicited a similar increase in 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 o2. The increase in 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: 546–54

Accepted for publication: November 11, 2001

Metabolic regulation contributes to the adjustment of the circulation in order to meet tissue oxygen demand, and manifests itself as a linear relationship between blood flow (i.e. cardiac output [CO]), and oxygen consumption (o2) during physiological conditions (e.g. physical exercise) in dogs1 and humans.2 We have recently shown that this fundamental principle is preserved during inhalation anaesthesia with the five volatile anaesthetics currently in use, unless the anaesthetic concentration exceeded 2 MAC.3 This finding implies that increasing anaesthetic depth reduces o2 and CO in parallel. We have also shown that the decrease in CO during inhalation anaesthesia is mainly a consequence of reduced metabolic rate rather than a direct side‐effect of the anaesthetic.3

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 o2 and CO in parallel.3

We therefore questioned whether, and to what extent, xenon alters o2 and whether metabolic regulation of blood flow is maintained during xenon anaesthesia. To test this, we studied the relationship between CO and 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.

Methods

The data derive from 15 experiments on five trained dogs (foxhounds of both sexes weighing 24–34 kg) studied with the approval of the District Governmental Animal Investigation Committee. Each dog was assigned to each of the three intervention groups with an interval of at least 1 week between successive experiments in the same animal, so that each dog served as its own control.

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 (20–24 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 o2 and the arterial‐to‐mixed venous oxygen content difference (C(a–v̄)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)

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 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, o2 was measured with a flow‐through technique (canopy mode), as described previously,10 which calculated 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 dog’s 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 min–1 resulted in a system time constant of 1.75 min.

During anaesthesia and controlled ventilation 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 o2 from the product of CO and C(a–v̄)O2 (pulmonary artery catheter). In agreement with others,1112 the precision of this device was 3.5% (average coefficient of variation) and the accuracy was 0.1 ml min–1, with 95% confidence intervals of –4.8 to 5.0 ml min–1.

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: 0.15–0.5 Hz) and low frequency (LF: 0.04–0.15 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 kg–1), the animal’s lungs were ventilated with 25% oxygen in nitrogen (tidal volume about 10 ml kg–1 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 animal’s 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 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 o2 is of central or peripheral origin. For this purpose, hexamethonium, a ganglionic blocking agent, 7.5 mg kg–1 was injected before induction of anaesthesia, followed by continuous infusion of 7.5 mg kg–1 h–1. 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 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 o2 and CO are given as mean slope and confidence interval. The effects on HR, MAP, systemic vascular resistance and C(a–v̄)O2 were compared by an analysis of variance for repeated measures (ANOVA), followed by Fisher’s protected least significant difference test16 if appropriate. Statistical significance was assumed when P<0.05.

Results

In general, o2 increased significantly while CO remained essentially constant when xenon was added to isoflurane baseline anaesthesia. In detail, with the addition of xenon (50% and 70%) during isoflurane anaesthesia, o2 increased from 3.4 (0.1) to 4.0 (0.1) and to 3.7 (0.2) ml kg–1 min–1 (P<0.05), respectively, whereas CO remained essentially unchanged (Fig. 1). In contrast, with the transition from awake to 1 MAC and eventually 2 MAC isoflurane alone, o2 decreased by about 25% from 4.1 (0.2) ml kg–1 min–1 (awake) to 3.1 (0.1) ml kg–1 min–1 (2 MAC isoflurane). In parallel, CO decreased by about 40% from 121 (6) ml kg–1 min–1 (awake) to 70 (3) ml kg–1 min–1 (2 MAC isoflurane).

To answer the question of whether metabolic regulation of blood flow is maintained during xenon anaesthesia, we analysed the relationship between CO and o2 in the presence and absence of xenon (Fig. 2). In both conditions, CO increased linearly with o2 (r2=0.97 and 0.94, respectively) and the regression lines differed significantly (P<0.05). For any given CO, o2 was 0.3–0.6 ml kg–1 min–1 greater in the presence of xenon. Conversely, CO is 14–21 ml kg–1 min–1 lower for a given o2 when xenon is present.

To distinguish whether the increase in o2 results from a central or peripheral effect, we analysed HRV to assess sympathovagal balance (see Fig. 3) and, in additional experiments, added xenon to the respiratory gases after ganglionic blockade (pretreatment with hexamethonium). After increasing anaesthetic depth with xenon or isoflurane, nuHF tended to increase and nuLF tended to decrease, indicating a shift towards vagal activation.

After ganglionic blockade (Fig. 4), o2 increased during the addition of 50% or 70% xenon to 1.4% isoflurane anaesthesia from 3.4 (0.2) ml kg--1 min–1 to 4.0 (0.2) and 3.7 (0.3), respectively, whereas CO remained almost unchanged. Thus, in the presence or absence of ganglionic blockade, xenon elicited similar effects on o2 and CO, albeit at a lower CO (compare with Fig. 1).

C(a–v̄)O2 tended to increase from 3.7 (0.2) ml 100 ml–1 during 1 MAC isoflurane anaesthesia to 4.1 (0.5) ml 100 ml–1 and finally 4.4 (0.5) ml 100 ml–1 with the addition of 50% and 70% xenon, respectively (Table 1). Nevertheless, C(a–v̄)O2 increased with increasing anaesthetic depth in a parallel manner in the presence and absence of xenon – except for 70% xenon alone (Fig. 5). However, the error bars show that, at any given MAC, the differences between isoflurane and xenon (with or without isoflurane) are not significant. It is worthy of note that HR (105 [5] beats min–1 during 1.4% isoflurane), decreased on the addition of xenon 50% and 70% to 95 (2) and 92 (2) beats min–1, respectively, which was in parallel with vagal activation, as indicated from the analysis of HRV (Fig. 3). Arterial pressure, however, did not change on the addition of xenon to 1.4% isoflurane anaesthesia.

Discussion

Our experiments show that, within the range of conditions studied, adding xenon to isoflurane baseline anaesthesia increases o2. This increase in o2 is independent of the autonomic nervous system and is probably caused by an increase in the cellular metabolic rate. Furthermore, metabolic regulation of blood flow is maintained during xenon anaesthesia, as shown by the linear relationship between CO and o2. Accordingly, haemodynamic stability when adding xenon to isoflurane baseline anaesthesia is accompanied by an increase in the whole body metabolic rate (o2).

Critique of methods

Attempts to compare the effects of different anaesthetics on CO and o2 rest primarily on the precision of the measurement methods. This question is of particular interest because o2 during xenon anaesthesia has not been measured before.

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,121718 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 o2 using a Deltatrac II were sufficiently precise to evaluate 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 o2 and C(a–v̄)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 (o2, CO and C(a–v̄)O2) can be cross‐checked using the Fick equation. Adding 50% xenon to 1.4% isoflurane did not change CO, so that changes in o2 and C(a–v̄)O2 should balance each other. In fact, o2 and C(a–v̄)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–v̄)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 α‐phase of about 2 min) and, thereafter, more gradually as elimination continues (half‐life of the γ‐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 min–1. 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 o2, during both physiological conditions1 and inhalation anaesthesia.3 In this context, 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 o2 decreased from the awake state (basal metabolic conditions) to 2 MAC (points A–D in Fig. 2). This relationship was linear, with a slope of CO vso2 of 47, confirming our previous observations.3 In that study,3 we could also show that the relationship between CO and 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 o2 while CO remained essentially unchanged. Cardiovascular stability during xenon anaesthesia has generally been observed in healthy individuals,2324 as well as in dogs with dilated cardiomyopathy.6 Moreover, xenon had only minimal effects on myocardial contractility in vivo525 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 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 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 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 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 10–15% to total body o2, and changes in myocardial oxygen consumption may not necessarily parallel changes in total body o2

When anaesthetic depth changed, 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, o2 was greater in the presence of xenon. If, in addition, CO and 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 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.

In summary, adding xenon to isoflurane baseline anaesthesia increases o2, while haemodynamics, including CO, are essentially unchanged. Metabolic regulation of blood flow is maintained at a higher tissue oxygen extraction rate. When xenon is substituted for a proportion of the isoflurane, both o2 and CO are increased.

Acknowledgements

Xenon was provided by Messer Griessheim, Frankfurt, Germany. The authors thank Mrs B. Berke for her skilled assistance during experimentation and data analysis.

Fig 1 Oxygen consumption (o2) and cardiac output (CO) in the awake state, during isoflurane anaesthesia 1.4% and 2.8% and after adding 50% and 70% xenon to an isoflurane baseline. Data are mean±SEM from five dogs. Note the significant increase in o2 (*P<0.05) in the presence of xenon compared with 1.4% isoflurane, whereas CO remained essentially unchanged. n.s., not significant.

Fig 1 Oxygen consumption (o2) and cardiac output (CO) in the awake state, during isoflurane anaesthesia 1.4% and 2.8% and after adding 50% and 70% xenon to an isoflurane baseline. Data are mean±SEM from five dogs. Note the significant increase in o2 (*P<0.05) in the presence of xenon compared with 1.4% isoflurane, whereas CO remained essentially unchanged. n.s., not significant.

Fig 2 Relationship between cardiac output (CO) and oxygen consumption (o2) in the awake state (A) and during isoflurane anaesthesia (1.4% [B, C] and 2.8% [D]) in comparison with xenon anaesthesia (70% and 50% xenon with 1.4% isoflurane [E, F], 50% xenon with 0.7% isoflurane [G] and 70% xenon alone [H]). Values are given as mean±SEM from five dogs. Note the close relationship between o2 and CO during the awake state and during isoflurane anaesthesia (open circles), as well as in the presence of xenon (closed circles), with different regression lines (P<0.05).

Fig 2 Relationship between cardiac output (CO) and oxygen consumption (o2) in the awake state (A) and during isoflurane anaesthesia (1.4% [B, C] and 2.8% [D]) in comparison with xenon anaesthesia (70% and 50% xenon with 1.4% isoflurane [E, F], 50% xenon with 0.7% isoflurane [G] and 70% xenon alone [H]). Values are given as mean±SEM from five dogs. Note the close relationship between o2 and CO during the awake state and during isoflurane anaesthesia (open circles), as well as in the presence of xenon (closed circles), with different regression lines (P<0.05).

Fig 3 Sympathovagal balance analysed as heart rate variability in the frequency domain and expressed as high and low frequency normalized units (nuHF [squares] and nuLF [circles], respectively) during isoflurane anaesthesia ([open symbols] 1.4% [C], 2.8% [D]) and after adding xenon (70% and 50% [closed symbols] to 1.4% isoflurane [E, F]). Values are mean±SEM from five dogs. Note the parallel shift towards vagal activation (nuHF) when the anaesthetic depth is increased by adding xenon or by increasing the isoflurane alone.

Fig 3 Sympathovagal balance analysed as heart rate variability in the frequency domain and expressed as high and low frequency normalized units (nuHF [squares] and nuLF [circles], respectively) during isoflurane anaesthesia ([open symbols] 1.4% [C], 2.8% [D]) and after adding xenon (70% and 50% [closed symbols] to 1.4% isoflurane [E, F]). Values are mean±SEM from five dogs. Note the parallel shift towards vagal activation (nuHF) when the anaesthetic depth is increased by adding xenon or by increasing the isoflurane alone.

Fig 4 Oxygen consumption (o2) and cardiac output (CO) after ganglionic blockade with hexamethonium in the awake state, during 1.4% isoflurane anaesthesia alone and after adding 50% and 70% xenon to isoflurane baseline anaesthesia. Data are mean±SEM from five dogs. Note that o2 increased (P<0.05), whereas CO remained almost unchanged (n.s., not significant), as in the absence of ganglionic blockade (compare with Fig. 1).

Fig 4 Oxygen consumption (o2) and cardiac output (CO) after ganglionic blockade with hexamethonium in the awake state, during 1.4% isoflurane anaesthesia alone and after adding 50% and 70% xenon to isoflurane baseline anaesthesia. Data are mean±SEM from five dogs. Note that o2 increased (P<0.05), whereas CO remained almost unchanged (n.s., not significant), as in the absence of ganglionic blockade (compare with Fig. 1).

Fig 5 Arterial to mixed venous oxygen content difference (C(a–v̄)O2) during isoflurane anaesthesia (1.4% [C] and 2.8% [D]) in comparison with xenon anaesthesia (70% and 50% xenon with 1.4% isoflurane [E, F], 50% xenon with 0.7% isoflurane [G] and 70% xenon alone [H]) plotted against combined MAC. Data are mean±SEM from five dogs. Note that in the range above 1 MAC, C(a–v̄)O2 tended to increase with increasing anaesthetic depth in a parallel manner in the presence and absence of xenon.

Fig 5 Arterial to mixed venous oxygen content difference (C(a–v̄)O2) during isoflurane anaesthesia (1.4% [C] and 2.8% [D]) in comparison with xenon anaesthesia (70% and 50% xenon with 1.4% isoflurane [E, F], 50% xenon with 0.7% isoflurane [G] and 70% xenon alone [H]) plotted against combined MAC. Data are mean±SEM from five dogs. Note that in the range above 1 MAC, C(a–v̄)O2 tended to increase with increasing anaesthetic depth in a parallel manner in the presence and absence of xenon.

Fig 6 Oxygen consumption (o2 [diamonds]) and cardiac output (CO [circles]) in relation to the anaesthetic depth (MAC), in the awake state (A) and during isoflurane anaesthesia (1.4% [B, C] and 2.8% [D]) in comparison with xenon anaesthesia (70% and 50% xenon with 1.4% isoflurane [E, F], 50% xenon with 0.7% isoflurane [G] and 70% xenon alone [h]). Values are means from five dogs. Both variables correlate closely in the absence (open symbols) and presence (closed symbols) of xenon. Note that substituting xenon for parts of the isoflurane (see arrows) would lead to an increase in CO and o2, with the effects of xenon tending to decrease as MAC increases.

Fig 6 Oxygen consumption (o2 [diamonds]) and cardiac output (CO [circles]) in relation to the anaesthetic depth (MAC), in the awake state (A) and during isoflurane anaesthesia (1.4% [B, C] and 2.8% [D]) in comparison with xenon anaesthesia (70% and 50% xenon with 1.4% isoflurane [E, F], 50% xenon with 0.7% isoflurane [G] and 70% xenon alone [h]). Values are means from five dogs. Both variables correlate closely in the absence (open symbols) and presence (closed symbols) of xenon. Note that substituting xenon for parts of the isoflurane (see arrows) would lead to an increase in CO and o2, with the effects of xenon tending to decrease as MAC increases.

Table 1

Haemodynamic variables and blood gas tensions in the awake state and during combinations of xenon and isoflurane anaesthesia in the intact dog and after ganglionic blockade with hexamethonium. Data are mean (sem) from 15 experiments in five dogs. *P<0.05 vs awake; P<0.05 vs 1.4% isoflurane (1st). HR, heart rate; MAP, mean arterial pressure; SVR, systemic vascular resistance; PaO2 and PaCO2, arterial oxygen and carbon dioxide gas tensions, respectively; SaO2, arterial oxygen saturation; C(a–v̄)O2, mixed venous oxygen content difference

 Isoflurane  Xenon  HR  MAP  SVR  PaO2 PaCO2 pH SaO2 C(a–v̄)O2 
 (vol %) (vol %) (beats min–1) (mm Hg) (mm Hg litre–1 min) (mm Hg) (mm Hg)  (%) (ml 100 ml–1) 
Intact autonomic nervous system Awake  82 (3) 98 (3) 25 (1) 94 (2) 37 (1) 7.35 (0.01) 95 (1)  
 1.4 (1st)  105 (5)* 63 (3)* 20 (1)* 123 (4)* 37 (1) 7.33 (0.01) 97 (1) 3.7 (0.2) 
 1.4 (2nd)  110 (4)* 71 (2)*† 21 (1)* 126 (4)* 41 (1) 7.31 (0.01) 97 (1) 3.7 (0.2) 
 2.8  102 (1)* 42 (2)*† 19 (1)* 119 (7)* 41 (1) 7.30 (0.01) 97 (1) 5.1 (0.5) 
  70 110 (4)* 115 (3*† 26 (1) 120 (2)* 44 (1) 7.29 (0.02) 97 (1) 4.1 (0.4) 
 0.7 50 107 (7)* 85 (3)*† 21 (2)* 116 (3)* 43 (1) 7.29 (0.02) 96 (1) 3.3 (0.2) 
 1.4 50 95 (2)* 63 (4)* 21 (1)* 121 (6)* 41 (1) 7.31 (0.01) 97 (1) 4.1 (0.5) 
 1.4 70 92 (2) 65 (5)* 23 (1)*† 121 (5)* 42 (1) 7.29 (0.01) 97 (1) 4.4 (0.5) 
Plus hexamethonium Awake  137 (4) 88 (3) 36 (3) 83 (4) 40 (2) 7.34 (0.01) 93 (1)  
 1.4  117 (4)* 61 (3)* 27 (1)* 124 (7)* 38 (1) 7.34 (0.01) 97 (1) 3.8 (0.4) 
 1.4 50 112 (4)* 55 (3)* 27 (3)* 117 (5)* 42 (1) 7.30 (0.01) 97 (1) 4.0 (0.4) 
 1.4 70 111 (3)*† 52 (3)*† 26 (3)* 115 (5)* 43 (2) 7.29 (0.01) 96 (1) 4.0 (0.4) 
 Isoflurane  Xenon  HR  MAP  SVR  PaO2 PaCO2 pH SaO2 C(a–v̄)O2 
 (vol %) (vol %) (beats min–1) (mm Hg) (mm Hg litre–1 min) (mm Hg) (mm Hg)  (%) (ml 100 ml–1) 
Intact autonomic nervous system Awake  82 (3) 98 (3) 25 (1) 94 (2) 37 (1) 7.35 (0.01) 95 (1)  
 1.4 (1st)  105 (5)* 63 (3)* 20 (1)* 123 (4)* 37 (1) 7.33 (0.01) 97 (1) 3.7 (0.2) 
 1.4 (2nd)  110 (4)* 71 (2)*† 21 (1)* 126 (4)* 41 (1) 7.31 (0.01) 97 (1) 3.7 (0.2) 
 2.8  102 (1)* 42 (2)*† 19 (1)* 119 (7)* 41 (1) 7.30 (0.01) 97 (1) 5.1 (0.5) 
  70 110 (4)* 115 (3*† 26 (1) 120 (2)* 44 (1) 7.29 (0.02) 97 (1) 4.1 (0.4) 
 0.7 50 107 (7)* 85 (3)*† 21 (2)* 116 (3)* 43 (1) 7.29 (0.02) 96 (1) 3.3 (0.2) 
 1.4 50 95 (2)* 63 (4)* 21 (1)* 121 (6)* 41 (1) 7.31 (0.01) 97 (1) 4.1 (0.5) 
 1.4 70 92 (2) 65 (5)* 23 (1)*† 121 (5)* 42 (1) 7.29 (0.01) 97 (1) 4.4 (0.5) 
Plus hexamethonium Awake  137 (4) 88 (3) 36 (3) 83 (4) 40 (2) 7.34 (0.01) 93 (1)  
 1.4  117 (4)* 61 (3)* 27 (1)* 124 (7)* 38 (1) 7.34 (0.01) 97 (1) 3.8 (0.4) 
 1.4 50 112 (4)* 55 (3)* 27 (3)* 117 (5)* 42 (1) 7.30 (0.01) 97 (1) 4.0 (0.4) 
 1.4 70 111 (3)*† 52 (3)*† 26 (3)* 115 (5)* 43 (2) 7.29 (0.01) 96 (1) 4.0 (0.4) 

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