Definition/Introduction

Xenon is an element with the symbol Xe and an atomic number of 54 (group 18 of the periodic table). It is an inert mono-atomic gas firstly identified in 1898 by the British chemists William Ramsay (1852-1916) and Morris Travers (1872-1961) in the residue obtained by partial evaporation of liquid air (krypton impurity).[1] The chemical element Xe is a colorless, odorless, non-pungent, nontoxic, nonexplosive, environmentally friendly, noble gas. It is found in the earth’s atmosphere in trace amounts as the concentration in the atmosphere is only 0.086 ppm. Yet, it is also found in the gases emitted by some mineral springs. Interestingly, the gas derives its name from the Greek word for “stranger” for underlining its extreme rarity. Although there are naturally 9 isotopes, the most abundant is Xe 132.

Among the physical and chemical properties of xenon, the boiling point is 166.6 K, the melting point 161.7 K, density is 5.851 g/dm2 whereas the colour spectrum is blue-green. Because the oil-gas partition coefficient of xenon is 1.9, it is among the noble gases the most soluble gas in oil (lipids).

Even if xenon does not react with any chemical element, it is always able to form quite particular compounds with water, hydroquinone, and phenol. This noble gas can be oxidized by groups that are extremely electronegative, forming salts. For instance, the compound, called xenon hexafluoplatinate, was first synthesized in 1962 by the chemist Neil Bartlett (1932-2008) and it was the first example of a noble gas chemical compound reported in the chemical literature. Other Xenon fluorides are the Xenon difluoride (XeF2), Xenon tetrafluoride (XeF4), and Xenon hexafluoride (XeF6).

Xenon can be manufactured by the fractional distillation of liquefied air. The use of xenon in the industry is limited by high costs. Among these applications, there is the xenon lamp, a particular arc lamp that uses xenon gas to produce very intense and white light similar to sunlight. There are several types of xenon lamps, all consisting of a glass or quartz tube with two tungsten electrodes at the ends and filled with xenon gas after vacuuming them. These lamps are used for street lighting, photo flashes and projectors, car headlights, and marine lighting. It is also used for lasers, and x-ray tubes as well as in the food industry for killing microorganism, and in aerospace.

Xenon in Medicine

The main role of the element concerns its use as a radioactive diagnostic agent in clinical imaging, and inhaled anesthetic in general anesthesia. Other applications regard the organ protection, ophthalmology, and in dermatology.

Clinical Imaging

Xenon is indicated for cerebral flow assessment (xenon-enhanced computed tomography), pulmonary function evaluation, and lung imaging. Xenon has also found use in nuclear medicine with computed tomography as well as single-photon emission computed tomography (SPECT), and in magnetic resonance imaging (MRI). In summary, the gas can be useful for the measurement of cerebral blood flow, whole-brain scans, and ventilation studies of the lungs through MRI (131 Xe), SPECT (133 Xe), and CT (129 Xe). 

General Anesthesia

The anesthetic proprieties of xenon were discovered in 1939 and applied in mice in 1940 (JH Lawrence) and subsequently in two humans volunteers (Cullen and Gross), in 1951.[2] It is indicated in selected patients due to its cardiovascular stability, cerebral protection, and favorable pharmacokinetics including low solubility, and lack of metabolism. Moreover, its use is not associated with environmental impact.[3] 

Organ Protection

An important field of study concerns the xenon-induced organ protection. For example, xenon use has been proposed for preventing ischemia/reperfusion damage after Stanford Type-A acute aortic dissection surgery.[4] Again, several preclinical investigations conducted on different models subjected to preconditioning, real-time conditioning, and postconditioning have demonstrated that this gas may present important neuroprotective (in a dose-dependent manner) and cardioprotective effects by interfering with the glutamatergic transmission (glutamate receptors are implicated in both anesthesia and acute neurological injury through the apoptotic process) and by inhibiting the inflammatory cascade[5][6]. The combination of xenon with hypothermia is a fascinating hypothesis. Of note, because xenon seems to have neuroprotective properties already in sub-anaesthetic concentrations, these effects can be achieved independently from the anaesthetic effect.[7] Regardless the precise mechanism, potential clinical applications of xenon for organ protection could be manifold. For instance, Jia et al. showed that intermittent exposure to xenon is protective against gentamicin-induced nephrotoxicity.[8] This renal protection is of fundamental importance in kidney transplantation, preventing ischemia/reperfusion damages, and delaying rejection and chronic nephropathy.[9] Xenon has had promising results with neurobehavioral dysfunction caused by brain insult [10], cardiac arrest induced cerebral ischemia [11], and even against neonatal hypoxia-ischemia.[12] 

Other Clinical Uses

Apart from this research, there have been studies with the gas for pathologies including dementia, epilepsy, Alzheimer's disease, and obsessive-compulsive disorders.[13][14][15][16] Moreover, xenon is used in ophthalmology for laser therapy, and in dermatology for removal of skin lesion. Despite all these potential applications, the biggest limitation is the high cost of use. For example, the market price in anesthesia is of approximately 6-12£ per liter. 

Issues of Concern

Clinical Imaging

In clinical imaging, as per the manufacturer’s labeling, there are no adverse reactions or contraindications to the use of Xe-133 gas. There are none known metabolism effects. There are no known significant drug-drug interactions. The drug is listed as pregnancy risk factor C in which animal reproduction studies have demonstrated an adverse effect on the fetus; however there are no adequate and well-controlled trials in humans, but the potential benefits may indicate the use of the drug in pregnant women in spite of potential risks. While the Xe-133 gas excretion in breast milk is not known, the manufacturer does recommend the substitution of formula feedings due to the potential for adverse reactions to breastfeeding infants.

General Anesthesia

When used for anesthetic purposes, xenon is associated with many advantages although disadvantages must be also reported.

Advantages

Xenon anesthesia seems to be associated with:[17]

• a more stable intraoperative blood pressure, and lower heart rate through both the preservation of sympathetic tone and modulation of the autonomic heart balance. The result is an important cardioprotective effect due to an overall improvement of the myocardial oxygen supply-demand ratio [18]
• neuroprotective properties under normal surgical conditions and also when brain tissue is injured and during ischemia and hemorrhage [19] as well as favorable effects on regional cerebral glucose metabolism and regional cerebral blood flow
• renal protection as xenon preconditioning protects against renal ischemic-reperfusion damage via hypoxia-inducible factor 1α (HIF-1alpha) activation and via miR-21 target signaling pathway[20]
• no effects on coagulation, platelet function, or the immune system
• no effects on hepatic function
• a safety profile in individuals with susceptibility for malignant hyperthermia [21]
• fast anesthesia induction
• faster emergence from anesthesia than volatile agents. Of note, early studies suggested that there is no positive correlation between the anesthesia lasting and the emergence times [22] Nevertheless, data are uncertain about the superiority of xenon on intravenous agents. Compared to propofol anesthesia, indeed, xenon did not speed up recovery times [23]
• no teratogenic or toxic effects to the fetus[24]
• no detrimental ecological effects

Disadvantages

• The hypnotic effect of xenon requires a mixture with 30-37% oxygen.
• Xenon can provoke a higher incidence of postoperative nausea and vomiting (up to 45% of cases).
• Poor efficacy in preventing postoperative delirium.[25]
• Diffusion into closed spaces (caution in those with pneumothorax, or ileus).
• Increased pulmonary resistance (the gas in oxygen composes a high-density mixture increasing Reynold’s number), although the clinical consequences in those with chronic obstructive pulmonary disease, or morbid obesity is uncertain.[26]
• High costs. probably, the development of newer ventilators that operates in a closed-circuit, rebreathing mode to minimize the loss of xenon can reduce costs favoring, in turn, the diffusion of the technique.

Clinical Significance

Xenon imaging

Xenon, Xe-133 gas can serve as a contrast agent in nuclear medicine and modern laser technology. It is a beta emitter with a physical half-life of 5.2 days, a photopeak of 81 keV, and beta-decay.[27] The mechanism of action of Xe-133 gas is that it passes through cell membranes and freely exchanges between blood and tissue. It enters the alveolar wall and the pulmonary venous circulation via the capillaries. The gas entering the circulation from one single breath returns to the lungs and gets exhaled following a single pass through the peripheral circulation. In the concentrations used for diagnostic purposes, the drug is physiologically inactive. The drug is administered by inhalation from spirometers or closed respiratory systems to ensure that the delivery system is leak proof. The gas should not stand in respirator containers or tubing. The dosing should be measured by a radioactivity calibration system promptly before administration. Waterproof gloves and radiation shielding are recommended handling precautions.

Xenon Anesthesia

Pharmacokinetics

Xenon is absorbed by the pulmonary alveoli. The percentage of xenon flow into the brain correlates with the concentration available in the inspired air and with the patient's ventilation. Since the blood-gas solubility coefficient of xenon is the lowest of all inhaled anesthetics (xenon 0.115; other inhalation anesthetics 0.115-1.14), induction of anesthesia is very rapid. The minimum alveolar concentration (MAC) is a measurement of anesthetic potency corresponding to the concentration of the inhaled anesthetic in the alveoli that is needed to prevent motor response in 50% of subjects in response to surgical painful stimuli. For xenon, the MAC is very high as it is approximately 63% in adults (previously indicated as 71%) [28] and 92% for children at the age of 1 year.[29] As a consequence, xenon must be used with an inspiratory oxygen concentration of at least 30% for avoiding hypoxia. The MAC-awake (the concentration at which a patient opens the eyes to verbal command) for xenon is 33%.

The saturation concentration at the effector site (brain) is reached in a few minutes whereas the washout phase at the end of anesthesia is very fast. As a consequence, during emergence from general anesthesia, eye-opening, orientation, and reaction on-demand account for about 4 minutes.[30] Thus, recovery from xenon anesthesia is faster than other inhalation and intravenous anesthesia (twice as fast as desflurane).[31] The maximum elimination half-lives in the different organs, detected with 133-xenon as a tracer, are close to about 100 minutes. The speed of uptake is faster in highly vascularized organs, and also more consistent in adipose tissue, due to the lipophilic characteristics of xenon. Again, the permanence of the xenon was found to be maximum in the intestine.

Xenon is an inert gas, so no metabolism occurs under normal conditions and it does not interfere with renal or hepatic systems. Therefore, it is eliminated unchanged from the lungs. Regarding the elimination half-life, due to the reduced solubility coefficient of xenon, the elimination of the anesthetic begins already during its administration.

Pharmacodynamics

The glutamatergic presynaptic responses are the major target of anesthesia-induced neuronal responses. In particular, xenon decreases glutamate (Glu) N-methyl-D-aspartate (NMDA) receptor-mediated whole-cell currents through noncompetitive inhibition. Probably, xenon binds to the glycine binding site on the NMDA receptor reducing the glutamate affinity.[32] It has minimal effect on non-NMDA glutamatergic receptors including alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainate (KA). Furthermore, GABAergic (GABAA receptor-mediated currents) responses limitedly contribute to xenon anesthesia.[33] Inhibition of the calcium ATPase pump on the cell membrane of synapses, and neuronalnicotinic acetylcholine (nACh) receptors, and involvement of the channels and TREK-1 potassium channels were also demonstrated.[34]

Interestingly, the commonly used anesthetic agents work by enhancing the inhibitory transmission via the GABAA receptors and have no or nonessential effects on the glutamatergic NMDA-mediated activity. This aspect explains the greater neuroprotective effect of xenon and a potential reduced impact on memory and learning processes during anesthesia.[35] All these effects are linked to glutamatergic transmission.

The glutamatergic effect of xenon, due to the inhibition of NMDA receptors in the dorsal horn of the spinal cord, is responsible for analgesia that is about one and a half times higher than that of nitrous oxide.[36] Thus, the antinociceptive propriety of xenon is not related to the opioids receptors [37] and, clinically, may induce a favorable intraoperative opioid-sparing effect.