Editorial III

Xenon—cardiovascularly inert?

B. Preckel* and W. Schlack

Klinik für Anaesthesiologie, Universitätsklinikum Düsseldorf, Postfach 10 10 07, D040001 Düsseldorf, Germany

*Corresponding author: E-mail: preckel{at}med.uniduesseldorf.de

Xenon{dagger} is called a ‘rare’, ‘noble’ or ‘inert’ gas, all synonyms used for the eighth group of the periodic table of the elements. Of this group, xenon is the only gas with significant anaesthetic properties, which have been recognized for more than five decades.1 Its rarity—xenon represents only 0.0875 p.p.m. of the atmosphere— combined with the inability to synthesize the gas rendered xenon noble, and the resulting high cost prohibited its routine use as an inhalational anaesthetic. Thus, xenon is a rare and a noble gas, but is it also inert? There is increasing evidence from experimental data that, although chemically inert, xenon may cause several physiological changes. These biological side-effects could mediate organ protection and the use of xenon might therefore be beneficial in certain clinical situations.

Sanders and colleagues2 published an excellent review in this journal in 2003, summarizing the advantages of xenon anaesthesia in comparison with the commonly used anaesthetic agents. They highlighted one of the areas in which xenon might become clinically important in the future: xenon is an inhibitor of the glutamatergic N-methyl-D-aspartate (NMDA) receptor,3 which can initiate neuronal injury if stimulated. Xenon may therefore serve as a neuroprotective agent. These neuroprotective properties of xenon have been investigated in several recent studies.2

A second use of xenon during anaesthesia might be in patients at high risk of cardiac failure and myocardial ischaemia. The haemodynamic stability during xenon anaesthesia has often been cited. However, there is a discrepancy between the increasing amount of experimental data and the lack of larger clinical studies. Most studies on the effects of xenon have been performed in small patient groups.46 Only one multicentre study included a larger number of 112 patients.7 In addition, in the clinical studies and most of the experimental investigations, data were obtained from subjects with healthy myocardium. So far, no data are available from patients with compromised myocardium or haemodynamic instability. This editorial will summarize the cardiovascular effects of xenon, addressing the question of whether investigation of the effects of xenon in ASA III and ASA IV patients may be justified.

Experimental data

In in vitro experiments, xenon had no significant effects on the myocardium; in isolated, buffer perfused rat hearts, a mixture of xenon 50%, oxygen 45% and carbon dioxide 5% had no effect on coronary perfusion pressure, heart rate or left ventricular developed pressure (calculated as left ventricular peak systolic minus end-diastolic pressure) compared with nitrogen 50% oxygen 45% and carbon dioxide 5%.8 However, in these experiments, oxygen delivery to the heart was 50% lower than in the control state, resulting itself in reduced contractility in control hearts. In isolated guinea pig hearts, xenon 40–80% did not significantly alter heart rate, artrioventricular conduction time, left ventricular pressure, coronary flow, oxygen extraction or consumption, cardiac efficiency, or flow responses to bradykinin.9 In isolated cardiomyocytes, the amplitudes of the sodium, the L-type calcium and the inward-rectifier potassium channel were not altered by xenon 80%, suggesting that the noble gas does not affect the cardiac action potential.9 These results indicate that xenon has no physiologically important effects on the guinea-pig heart. Xenon did not depress L-type calcium currents in human atrial myocytes,10 did not depress myocardial contractility and did not influence the positive inotropic stimulation of isoproterenol or the force-frequency relation in cardiac muscle bundles.11

While in vitro experiments can be performed in the absence of other anaesthetics, in vivo studies with xenon normally use supplementary baseline anaesthesia because the MAC of xenon in animals is higher than 80 vol %. In pentobarbital-anaesthetized pigs, cardiac index, central venous pressure, aortic pressure and systemic vascular resistance were not significantly altered by xenon 30–70%.12 In isoflurane-anaesthetized dogs, the coupling between oxygen consumption and cardiac output was maintained during xenon inhalation.13 The cardiovascular stability was accompanied by increased oxygen consumption, which was independent of the autonomic nervous system. In midazolam–piritramide-anaesthetized dogs, inhalation of up to xenon 70% had no effect on myocardial function.14 In contrast, regional administration of xenon 70% directly into the coronary artery reduced the indices of regional myocardial contractility measured by sonomicrometry by about 8%, indicating a small negative inotropic effect in vivo. Compared with the negative inotropic action of isoflurane, this effect was negligible.14

Clinical data

Most clinical studies investigating the cardiovascular effects of xenon compared its effects with those of another routinely used anaesthetic agent. No significant effect on arterial blood pressure could be observed in patients anaesthetized with xenon 70% in comparison with those anaesthetized with nitrous oxide. Fractional area change obtained by echocardiography was not altered by xenon 65% in healthy patients.4 The only change observed was a tendency to a decreased heart rate accompanied by increased variability of the cardiac rhythm.4 5 In addition, xenon produces analgesia, thereby suppressing haemodynamic and catecholamine responses to surgical stimulation. The interpretation of these clinical studies is limited by the small numbers of patients included. In the first randomized controlled multicentre trial, xenon provided safe and effective anaesthesia in 112 patients, and resulted in faster recovery compared with isoflurane–nitrous oxide anaesthesia.7 In the xenon group, a higher mean arterial pressure and a more pronounced decrease in heart rate from baseline was observed. The need for inotropic substances was lower in the xenon group, whereas the need for antihypertensives was greater. However, patients at high risk of undesirable cardiac events were excluded from the study.

Myocardial disease

In isoflurane-anaesthetized dogs with dilated cardiomyopathy, xenon decreased heart rate and increased the time constant of left ventricular relaxation, but had no effect on arterial or left ventricular pressures or the indices of left ventricular preload and afterload.15 In rabbits with chronically compromised left ventricular function 9 weeks after permanent coronary artery occlusion, the inhalation of xenon 70% had no effect on left ventricular function measured by echocardiography in closed-chest animals.16 With invasive measurements, a decrease in left ventricular pressure and left ventricular dP/dt of 10% was observed, indicating only a small negative inotropic effect. In the presence of regional myocardial ischaemia and reperfusion, xenon caused a small reduction in cardiac output and an increase in mean aortic pressure, resulting in an increase in systemic vascular resistance.17 Xenon also has cardioprotective effects: given during reperfusion, it reduced infarct size after regional myocardial ischaemia in rabbits in vivo.17 In addition, xenon can protect the heart against the consequences of ischaemia by pharmacological preconditioning.18 This effect is mediated by activation of the isoform {epsilon} of protein kinase C, by a translocation of protein kinase C from the cytosol to the cell membrane, and by the p38 mitogen-activated protein kinase.18

Only one study has investigated the effects of xenon in patients with pre-existing cardiac disease. Postoperative sedation with xenon–remifentanil in patients after coronary artery bypass grafting did not affect heart rate and mean aortic pressure compared with propofol sedation.6 In contrast to propofol sedation, xenon had no vasodilatory effects in patients with cardiovascular impairment and there were no negative effects on myocardial contractility, as determined by left ventricular stroke work index.6 In this investigation, only 10 patients were studied and the mean xenon concentration used for sedation was 27.4 (SD 11.8)%, much lower than the concentrations necessary for anaesthesia.

Xenon has been safely used in a patient with Eisenmenger’s syndrome, in whom the main concern was a reduction in systemic vascular resistance.19 Patients with Eisenmenger’s syndrome have lost the ability to adapt to sudden haemodynamic changes because of end-stage pulmonary vascular disease, and may benefit from the stable haemodynamics of xenon anaesthesia.

There is still limited information about the use of xenon during extracorporeal cardiopulmonary bypass. In rats, cardiopulmonary bypass-induced neurological and neurocognitive dysfunction was attenuated by xenon 60%.20 In these experiments, xenon was added to the bypass circuit after the blood had passed through the oxygenator. One major problem with the use of xenon during cardiopulmonary bypass is that the noble gas is eliminated during extracorporeal circulation through the oxygenator,21 and continuous xenon administration would be necessary to compensate for these losses, increasing substantially the cost of its use. There are no clinical data available on the use of xenon during heart surgery.

Effects on blood flow

In chronically instrumented dogs, cardiovascular stability during xenon anaesthesia was accompanied by an increase in total body oxygen consumption, probably caused by increased cell metabolism.13 In acutely instrumented dogs, xenon 70% given directly into the coronary artery had no effect on coronary blood flow.14 In pigs, regional perfusion in the brainstem, cerebral cortex, medulla oblongata and cerebellum was increased during xenon 79% inhalation.22 In these animals, no effect on liver, kidney, bowel, muscle, skin or cardiac blood flow was observed.22 The relationship between regional cerebral blood flow and cerebral glucose utilization was maintained, although reset at higher levels in rats.23 No influence on regional cerebral blood flow and carbon dioxide autoregulation by up to xenon 70% was observed in propofol-anaesthetized pigs24 or in pentobarbital-anaesthetized rabbits.25 In patients with severe head injury, xenon 33% produced an increase in intracranial pressure and decreased cerebral perfusion pressure, although no signs of cerebral ischaemia were observed,26 and the observation that inhalation of xenon 25–35% increased cerebral blood flow has raised concern that xenon inhalation may be hazardous in patients with decreased intracranial compliance.

In conclusion, current data indicate that xenon has relatively few, minor side-effects, such as a small but clinically irrelevant negative inotropic effect and an increase in cerebral blood flow, and at the same time it may have neuro- and cardioprotective properties. Xenon anaesthesia may therefore become a therapeutic option for specific indications, such as patients with neurological disease, as recently summarized by Sanders and colleagues,2 or for patients at high risk of cardiac ischaemia or with severely compromised myocardial function. However, xenon has been studied only in ASA I and II patients, and it is time to investigate whether ASA III and ASA IV patients will profit from xenon anaesthesia.

B. Preckel*

W. Schlack

Klinik für Anaesthesiologie

Universitätsklinikum Düsseldorf

Postfach 10 10 07

D-40001 Düsseldorf

Germany

*Corresponding author. E-mail: preckel{at}med.uni-duesseldorf.de

References

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