History of Xenon Anaesthesia
Marine divers reported first descriptions of the anaesthetic properties of xenon in 1938. They reported fatigue and dizziness below depths of 40 metres during their dive. Ramsey and Travers discovered xenon in 1898. Xenon belongs to the group of noble gases in the periodic system of elements. Its atomic number is 54. All noble gases are found in very small concentrations in the ambient air. While argon is the most common noble gas with a relative concentration of about 95%, xenon is rather rare. Its concentration in ambient air is 0.0000087 Vol%. Xenon is available for anaesthetic purposes in Germany since 2005 as well in different European countries since 2007. Xenon is manufactured from liquid air by rectification. Most industrially produced xenon is used in lamps, in nuclear research and for diagnostic purposes in computer tomography. One of the radioactive isotopes (133Xe) is used in nuclear medicine to measure organ circulation. It is frequently claimed that xenon is an ideal anaesthetic agent as it is inflammable, with low toxicity, and devoid of teratogenic effects. Furthermore, the velocity of anaesthetic introduction is determined by the specific characteristics of the anaesthetic gas. The properties of xenon provide at present the fastest increase in the effect compartment according to its low blood/gas coefficient of 0.14. The biological effect of xenon is correlated to the inspiratory gas concentration. Accumulation is not seen in humans. Pure xenon („Xenon pro anaesthesia“, LenoXe? 100%) with a bottle concentration of 99.9 Vol% is used for general anaesthesia under the terms of the specification. The determination of MAC is one of the themes most discussed in clinical anaesthesia. The main problem in determination is to compare quantified motor and hemodynamic reactions to various painful stimuli. Hemodynamic reaction showed a broad interindividual and intraindividual variability. Cullen et al. first determined the anaesthetic properties in humans in 1951 together with additional observations on krypton. He also reported the minimal-alveolar concentration (MAC) of xenon and determined the MAC on 71Vol% of a gas oxygen/xenon-gas mixture. Goto et al. recently reported on the MAC of xenon in the elderly. The authors concluded that the MAC of xenon was 69.3% in men and 51.1% in women. Another pharmacological aspect is the combination of xenon with other volatile anaesthetics. Nakata et al. demonstrated the ability of the combination of xenon with sevoflurane in human. Combinations of xenon with isoflurane, sevoflurane or halothane have been tested in animal at present.
 

Mode of action

Focusing on the mode of action, Franks and Lieb reviewed the molecular and cellular mechanisms of general anaesthesia in 1994. They demonstrated that at high concentrations general anaesthetics can act non-specifically on a wide variety of neuronal sides. At clinical concentrations the volatile anaesthetics are much more selective and probably exert their primary effects on a relatively small number of targets.. In more recent works Franks et al. explained that xenon itself has an effect on the NMDA receptor. The work of de Sousa and colleagues postulates that xenon, as a glutamate antagonist, binds to the NMDA receptor in a similar way to ketamine. This can explain the increased analgesic potency of xenon. The mode of action at the GABAA receptor is still unknown.

 

Cardiac and hemodynamic stability

The depressive influence of general anaesthesia on vital signs is well known during anaesthesia. Anaesthetics may cause blood pressure depression as well as bradycardia. Reactions may be so intensive that medical intervention is indicated. Lachmann et al. firstly described the outstanding hemodynamic stability of the patients during xenon anaesthesia in greater collective of 40 patients in 1990. This led to an increasing interest in xenon for anaesthesia. Multicentric studies showed the same results.

Another multicentric study reported that the decrease in the fractional area change (FAC) as a parameter of left-ventricular systolic function, measured by echocardiography, is significantly more pronounced in patients treated with isoflurane as compared to the xenon group. The left-ventricular end-diastolic wall-stress (LVESWS) and the heart rate corrected velocity of circumferential fiber shortening (Vcfc) were virtually unchanged during xenon while a significant decrease was found with isoflurane. (Anesthesiology 2007; 106: 463-71) Even in the presence of compromised myocardium, xenon anaesthesia is remarkable stable. In a study of 20 patients undergoing elective coronary artery bypass grafting, xenon decreased indices of cardiac function significantly less than nitrous oxide. Heart rate did not change significantly although it tended to decrease, and the cardiac output and sympathetic tone were maintained in these patients with limited cardiovascular reserve.

Brain Cerebral injury, representing a spectrum from subtile neurocognitive dysfunction to overt stroke, continues to complicate present day cardiac surgery. Stroke, the incidence of which varies considerably depending upon both patient and surgical factors, occurs in approximately 2-5% of patients. In the early postoperative period after cardiac surgery, the incidence is as high as 80-90%; thereafter. It decreases over the ensuing months to approximately 30-40% at 3 months and approximately 15-25% at one year. However, recent longitudinal studies have demonstrated that up to 5 years after cardiac surgery, the incidence of cognitive decline increases again over 40%. This problem also occurs in non-cardiac surgery with a wide variance of symptoms. This is generally defined as postoperative cognitive dysfunction (POCD). Because of the pivotal role that NMDA receptors play in neuronal injury, Wilhelm et al. investigated the efficacy of xenon as a neuroprotectant.

The authors showed that xenon, when co-administered with injurious agents, exerts a concentration–dependent neuroprotective effect at concentrations below which anaesthesia-producing inhalatory concentrations in rodents occur. Ma et al. showed that the amount of dead neurons found in histology was less compared to the sham group. Moreover, neurologic function was significantly improved using a neuromotor testing protocol. David et al. showed in vivo that xenon at 50% as well as nitrous oxide at 75% reduces ischemic neuronal death in the cortex by 70% and further decrease NMDA-induced Ca++ influx by 30%. Xenon but not nitrous oxide reduced ischemic brain damage in the striatum, which is known to be resistant to neuroprotective interventions. Dingley et al. identified the neuroprotective effects of xenon as an indication in cerebral hypoxic injury in infants. This agrees with the findings of Ma et al. in previous publications. Yao et al also critically discussed the applicability for treatment of acute stroke. He reported from an animal study in conscious monkeys that inspiratory xenon concentrations of 33 Vol% increase the cerebral blood flow by about 12% but lower the cerebral oxygen consumption by about 16%. Further reports from healthy volunteers under 33Vol% xenon also showed an increase in CBF. Varying results regarding patients with acute cerebral trauma are available. The results obtained by Latchaw et al. and Darby et al. in compromised patients with head injury showed an increase in CBF .

The study by Marion and Crosby in 23 comatose patients proved to refute this assumption for lower inhalatory xenon concentrations. Since 1994 different reports have been published about the increase in CBF during inhalation of xenon. In 1994 Plougmann et al. again reported on an increase in CBF. Plougmann et al. recommended moderate hyperventilation during the diagnostic xenon application in radiology to compensate this effect in order to prevent cerebral ischemia. Luttropp et al. demonstrated an increase in CBF during xenon anaesthesia with 65Vol% xenon in combination with transcranial duplex-sonography. In contrast the newer work of Fink et al. has demonstrated that xenon, in different concentrations, has no effect on CBF and cerebral autoregulation. They suggest that xenon is an adequate adjunct for neurosurgical anaesthesia. Lockwood et al. presented in 2007 the first phase I study in volunteers undergoing coronary artery grafting on cardiopulmonary bypass and demonstrated by Doppler measurement that there was no evidence for an increase of gaseous bubbles in the patients. Conclusion Xenon has to be applied per inhalationem at an endtidal concentration of 55-70 Vol%. This dose range provides safe anaesthetic conditions with the same risk of perioperative awareness as the established volatile anaesthetics. Xenon should be applied mainly as the primary volatile anaesthetic. Xenon should be used with caution in patients with elevated oxygen consumption or the need for increased inspiratory oxygen concentrations. In order to enhance safety it is necessary that xenon should be used only in anaesthetic circuits with inspiratory oxygen measurement units and inspiratory and exspiratory xenon determination units. At present no clinical data are available on use in neonates, newborn infants, children and young adolescents. Only once more clinical data have been presented for these subpopulations should approval be granted for general anaesthesia in these age groups. The properties themselves prove to be very interesting for, until now, there has been a problem with postoperative apnoea in former neonates or newborn infants. Another interesting area could be administration to children with known neuromuscular diseases or elevated creatine kinase in combination with a family history of malignant hyperthermia.

The use of xenon during pregnancy is an interesting favour, because xenon has no teratogenic potential in animal studies. Adequate experience regarding the safe use of xenon is lacking. Xenon should only be used if the treating physician seems it is absolutely necessary. The main side effect of xenon is nausea and vomiting, called PONV, in the early postoperative period. This is well known from all other volatile anaesthetics and occurs during xenon anaesthesia at the same rate as in other volatile anaesthetics. The symptoms of these side effects are easily manageable with antiemetic drugs. All other reported side effects are common during or after general anaesthesia and can be managed by the anaesthesiologist.
 
 
 
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