Anaesthesiology Clinic, Universitaetsklinikum Aachen, Germany. 1 Anaesthesia Department, Waldkrankenhaus Berlin-Spandau, Germany
* Corresponding author: Anaesthesiology Clinic, Universitaetsklinikum Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany. E-mail: jbaumert{at}ukaachen.de
Accepted for publication March 24, 2005.
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Abstract |
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Methods. Twenty pigs received anaesthesia with xenon 0.55 MAC/remifentanil 0.5 µg kg1 min1 (group X, n=10) or isoflurane 0.55 MAC/remifentanil 0.5 µg kg1min1 (group I, n=10). CO, heart rate (HR), mean arterial pressure (MAP) and left ventricular fractional area change (FAC) were measured at baseline, after 5 and 15 min of hypoventilation and after 5, 15 and 30 min of restored ventilation.
Results. CO increased by 1020% with both anaesthetics, with an equivalent rise in HR, maintaining DO2 in spite of a 20% reduction in arterial oxygen content. Decreased left ventricular (LV) afterload during hypoventilation increased FAC, and this was more marked with xenon (0.600.66, P<0.05 compared with baseline and isoflurane). This difference is attributed to negative inotropic effects of isoflurane. Increased pulmonary vascular resistance during hypoventilation was found with both anaesthetics.
Conclusion. The cardiovascular effects observed in this model of moderate hypoventilation were sufficient to maintain DO2. Although the haemodynamic response appeared more pronounced with xenon, differences were not clinically relevant. An increase in FAC with xenon is attributed to its lack of negative inotropic effects.
Keywords: anaesthetics gases, xenon ; complications, hypercarbia ; complications, hypoxaemia ; monitoring, trans-oesophageal echocardiography
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Introduction |
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The effects of isolated hypoxaemia have been studied in numerous models but data on hypercarbia and the combined effects are limited. The present study design arose from the assumption that in acute pulmonary failure without intervention there would be hypoxaemia and hypercarbia. Thus, the real physiological response to ventilatory impairment, is most likely to be produced by combined rather than isolated failure.
The respective circulatory mechanisms are inhibited by most general anaesthetics, which tend to blunt the autonomic cardiovascular reflexes and, in addition, diminish cardiac inotropy and induce vasodilation. Consequently, the increase in CO may be absent or reduced during anaesthesia, and may not maintain DO2.
A multicentre study1 suggests that xenon anaesthesia shows cardiovascular stability and appears to have less effect on autonomic reflexes than volatile anaesthetics. In vitro, it has been shown that xenon does not have the inhibitory effects on myocardial calcium channels and the contractile force of isolated muscle bundles produced by volatile anaesthetics.2 3 Experimental studies suggest that xenon had no influence on LV performance,4 5 as does the only clinical study using transoesophageal echocardiography (TOE) published so far.6 This led to the hypothesis that with xenon anaesthesia there would be larger increases in cardiac output and inotropy than with a standard anaesthetic during conditions of acute hypoventilation.
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Methods |
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Animal preparation
Following approval by the local animal care authorities (Reg. Präs. Köln), female German Landrace pigs (3035 kg) were investigated. After overnight fasting, pigs were premedicated by i.m. injection of azaperone 45 mg kg1. A 20-gauge cannula was inserted in an ear vein, and anaesthesia was induced by injection of propofol 23 mg kg1, as required for orotracheal intubation, using a 7.0 mm internal diameter cuffed tube. Neuromuscular blocking drugs were not used. Ringer's solution 6 ml kg1 h1 was infused and the urinary bladder was catheterized. Ventilation was with pure oxygen using a closed circuit (PhysioFlex; Dräger, Lübeck, Germany), a tidal volume of 10 ml kg1 and a respiratory rate sufficient to maintain an end-tidal of 4.95.7 kPa. An arterial line was inserted percutaneously into a femoral artery, and an 8.5 F introducer sheath was placed in a femoral vein. A pulmonary artery catheter was advanced, and correct position was confirmed by obtaining pulmonary artery (PAP) and occlusion pressure (PAOP) curves.
Maintenance of anaesthesia
During preparation, anaesthesia was maintained with repeated bolus injections of propofol 23 mg kg1 and continuous infusion of remifentanil 0.5 µg kg1 min1. After preparation was completed, the was reduced to 0.21. Animals were randomly allocated to groups X and I: In group X, anaesthesia was maintained by adding xenon 6568% to the respirator gas. In group I, isoflurane was added at an end-tidal concentration of 0.951.05%. As previously reported, these are equivalent to about 0.55 MAC for xenon and isoflurane in pigs.7 The animals were not restrained and none showed any spontaneous movement throughout the experiment.
Data collection
HR, MAP, PAP and PAOP were monitored using a Datex AS/3 anaesthesia monitor (Datex-Engstrom, Helsinki, Finland). Values, averaged over 30 s, were taken every 5 min and stored on a personal computer. CO was measured by thermodilution using injection of 10 ml of Ringer's solution (temperature of 8°C) into the right atrium. Mean values from three consecutive measurements were stored, and SVR and PVR were calculated. End-tidal concentrations of oxygen, carbon dioxide and isoflurane were monitored using infrared spectroscopy and recorded every 5 min. Xenon concentration was monitored by thermoconductive analysis in the inspired gas. The PhysioFlex respirator mixes expired and fresh gas at 70 litre min1. As xenon uptake after the initial wash-in is less than 30 ml min1, inspired and end-tidal xenon concentrations are virtually identical.
At each point of data collection, arterial and mixed venous blood gas analyses were performed using a Radiometer ABL 100/ABL 500 analyser (Radiometer Copenhagen, Copenhagen, Denmark). Arterial ,
, pH, arterial and mixed venous oxygen saturation, haemoglobin concentration and haematocrit were stored on a personal computer. DO2 and VO2 were calculated as follows:
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Echocardiography
Before starting the protocol, an Omniplane II TOE probe connected to a Sonos 5500 machine (Philips, Leiden, The Netherlands) was placed into the distal oesophagus. Thus, a long-axis left atrial/left ventricular (LA/LV) view was obtained and 15 cycles recorded on videotape. Without moving the probe, transmitral flow was visualized in the same long-axis view, using a continuous-wave Doppler signal, and another 15 cycles were recorded.
Videotapes were examined retrospectively by two independent anaesthetists with special TOE training who were blinded to the anaesthetic used. From early diastolic (E) and atrial (A) filling peak flows, E/A ratio was calculated as a measure of diastolic LV function. A modified fractional area change (FAC) was calculated by dividing the difference between end-diastolic (EDA) and end-systolic (ESA) LV area by EDA, using mean values of planimetry from three consecutive cycles. The long-axis view was used to avoid moving the TOE probe between the recordings. Standard (short-axis) FAC may be underestimated by doing so but relative changes over time should not be affected. EDA was taken as a measure of LV preload. For estimating afterload, the use of LV end-systolic wall stress (LVESWS) has been proposed. Because this again would have made changes in probe position necessary and wall thickness should not be important in healthy young animals, we used the closely related end-systolic pressurearea product (ESPA), as has been suggested by Greim and colleagues.8
Study protocol
The protocol was started no earlier than 60 min after target concentrations of xenon 6568% (group X) or isoflurane 0.951.05% (group I) had been reached. This was at least 3 h after premedication, and at least 1.5 h after the last administration of propofol.
To produce hypoventilation, the respiratory rate was set to about 45% of the control value, with target arterial and
values around 7.3 kPa. This setting (with
0.21, tidal volume 10 ml kg1 as before) was kept for 15 min. Our preliminary experiments with these conditions found marked hypoxaemia without progressive haemodynamic instability. After 15 min, respiratory rate was set back to baseline value. The time course of data collection points was: baseline, 10 min before hypoventilation (1), after 5 (2) and 15 (3) min of hypoventilation, and 5 (4), 15 (5) and 30 min (6) after returning to baseline respiratory rate.
Statistics
After testing for normal distribution, data were analysed using two-way repeated measures analysis of variance (ANOVA). In an explorative approach, the effect of the intervention (time variable or within-subjects effect) was investigated first. At that stage, P<0.05 indicated that, at the respective point of time, there was a significant change from baseline for all animals together. In the second step, the effect of the anaesthetic (group variable or between-subjects effect) on these changes was tested, using a post hoc contrast analysis. Again, P<0.05 for the influence of this group variable indicated a significant interaction; that is, the effect of the intervention was significantly different between the two groups (Generalized Linear Model [GLM] procedure; SAS software, Cary, NC, USA).
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Results |
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Discussion |
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Hypoxaemia and hypercarbia appear to have conflicting effects on the circulation. While tachycardia and an increase in cardiac output are attributed to both, hypoxaemia is generally accompanied by vasodilation,9 10 which increases cerebral and myocardial blood flow.11 The early circulatory response is a result of autonomic nervous system activation by vascular oxygen receptors which respond to the concentration of dissolved oxygen. Hypoxic inhibition of pig tracheal smooth muscle contraction has been demonstrated in vitro,12 but there are no data on vascular smooth muscle and the mechanism is not clear. Nevertheless, a reduction in LV afterload was demonstrated using direct echocardiography in pigs.9 A negative correlation (r=0.56) between LV end-systolic wall stress and ejection fraction area (i.e. FAC) was reported, but there was no correlation between LVESWS and SVR.
In contrast to the above findings, hypercarbia alone provoked hypertension, and thus the combined effect will be difficult to predict. It has been suggested that the circulatory effects of hypoxia are likely to be potentiated by hypercarbia,13 but there are no data available on which the relative contributions to a net effect can be based.
Isoflurane has been shown not to impair the chemosensitivity of the carotid body (0.5 MAC),14 the hypoxic relaxation of the aorta (1 MAC)10 or the hypoxic increase in hepatic blood flow.15 Surprisingly, in this latter study hypoxia alone decreased cardiac index, but this is the only available report of such an effect. Isoflurane also seems to inhibit other compensatory mechanisms during hypoxia, e.g. increases in cerebral and coronary blood flow16 as well as venous contraction andmost importantlythe increase in sympathetic outflow.17 There are no reports of xenon in this setting.
The haemodynamic effects of hypoventilation in our study are in agreement with most other reports and were similar with xenon and isoflurane anaesthesia, except for the more rapid decrease in CO with xenon after restoring ventilation. There was an increase in FAC with xenon but almost no increase with isoflurane. This may be a direct myocardial effect, where, in spite of a decrease in LV afterload, FAC could not be increased. Xenon does not inhibit myocardial function at the cellular2 or muscle fibre level.3
Xenon does not appear to affect contractility18 19 or to impair left ventricular performance, in spite of an increased SVR.4 20 Consequently, the increase in FAC is regarded as the unimpaired reaction to an acute decrease in afterload. Altogether, the changes in HR, CO and FAC induced by hypoventilation, and their reversal with normal ventilation, appear faster with xenon. This is in agreement with our hypothesis that xenon produces less inhibition of the physiological response to acute ventilatory impairment. However, the changes are minimal and probably of limited clinical relevance.
A missing feature of the response to hypoventilation was the increase in LV preload, which was unexpected, as venous constriction is reported to be one of the compensating mechanisms in hypoxia.17 Together with unchanged early and increased atrial filling peak flows, this finding indicates an alteration of diastolic LV filling. There was a consistent, significant increase of 2040% in atrial peak flow, possibly caused by the rise in HR, but which persisted after HR had returned to baseline level. Such an effect has only been described with acute myocardial ischaemia21 but not with hypoxia/hypercarbia. However, the normal value of E/A ratio in pigs is unknown, and the method is affected by various technical problems concerning the quality of the Doppler signal. Thus, it is not clear if the decrease we found is of functional relevance.
The main limitation of this study may be that the degree of hypoventilation was insufficient to reduce oxygen delivery. However, DO2 was kept stable by the increase in CO despite a 30% reduction in arterial oxygen content, and VO2 was increased. This suggests that the autonomic response to the decrease of almost 50% in arterial and the 40% increase in
is sufficient to prevent hypoxia, at this level of hypoxaemia. It would have been interesting to compare different degrees of hypoventilation, but our preliminary studies demonstrated that more pronounced hypoventilation is associated with marked haemodynamic instability. We therefore decided that our target was the circulatory effect of hypoventilation without sustained hypoxic or hypercarbic damage to the heart.
As the MAC of xenon exceeds 100% in pigs,22 it could not be used as the sole anaesthetic. We used equipotent doses of 0.55 MAC for xenon and isoflurane, supplemented with remifentanil, which, because of its known vagomimetic effects,23 24 may have influenced our results and may have resulted in different levels of anaesthesia. As there is no gold standard for measuring anaesthetic depth in pigs, we used the absence of spontaneous movement in our non-paralysed animals and took this as an indicator of adequate anaesthesia.
It is possible that 0.55 MAC may be too low a concentration to produce cardiovascular effects. However, there are reports of inhibition of hypoxic pulmonary vasoconstriction (HPV)25 and efferent sympathetic activity17 even with sub-MAC doses of isoflurane. As the concentrations of volatile (or gaseous) anaesthetics in combination with an opioid, as used in the present study, correspond to a clinical situation, we believe that this design is adequate.
In summary, hypoventilation to moderate hypoxaemia and hypercarbia produced similar circulatory effects during xenon and isoflurane anaesthesia. Although the response appeared faster with xenon, our initial hypothesis that the increase in cardiac output would be greater with this agent is not supported.
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Acknowledgments |
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References |
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