Definition/Introduction

Xenon is an element with the symbol Xe, has an atomic number 54, and belongs to group 18 of the periodic table. Xe is a monoatomic, inert gas, first discovered in 1898 by British chemists William Ramsay (1852-1916) and Morris Travers (1872-1961) in the residue left after partial evaporation of liquid air (with krypton as an impurity).[1] Xe is a colorless, odorless, non-pungent, nontoxic, nonexplosive, and environmentally friendly noble gas. Xe exists in trace amounts in the Earth's atmosphere, with a concentration of only 0.086 ppm, and is also found in gases emitted from certain mineral springs. The name Xe is derived from the Greek word for "stranger," which reflects its rarity. Of its 9 naturally occurring isotopes, Xe-132 is the most abundant.

Xe has several notable physical and chemical properties, including a boiling point of 166.6 K and a melting point of 161.7 K. The density of Xe is 5.851 g/dm², and it exhibits a blue-green color spectrum. With an oil-gas partition coefficient of 1.9, Xe is one of the noble gases and is the most soluble gas in oil (lipids). Although Xe typically does not react with most elements, it can form specific compounds with substances such as water, hydroquinone, and phenol. This noble gas can be oxidized by highly electronegative groups, resulting in the formation of salts. For example, the compound Xe-hexafluoroplatinate was first synthesized in 1962 by chemist Neil Bartlett (1932–2008). This was the first noble gas chemical compound reported in the scientific literature. Other Xe fluorides are the Xe difluoride (XeF₂), Xe tetrafluoride (XeF₄), and Xe hexafluoride (XeF₆).

Xe can be produced through the fractional distillation of liquefied air, but its high cost limits industrial use. One application is the Xe lamp—a type of arc lamp that uses Xe gas to produce an intense white light similar to sunlight. Xe lamps consist of a glass or quartz tube with 2 tungsten electrodes at the ends, filled with Xe gas after the air is evacuated. These lamps are used in street lighting, photo flashes, projectors, car headlights, and marine lighting. Xe is also used in lasers, x-ray tubes, the food industry for microorganism sterilization, and aerospace applications.

Xenon in Medicine

The primary medical use of Xe is as a radioactive diagnostic agent in clinical imaging and as an inhaled anesthetic for general anesthesia. Xe also has applications in organ protection, ophthalmology, and dermatology.

Clinical imaging: Xe is indicated for assessing cerebral blood flow via Xe-enhanced computed tomography (CT), pulmonary function evaluation, and lung imaging. Xe is also used in nuclear medicine through techniques such as CT, single-photon emission CT (SPECT), and magnetic resonance imaging (MRI). In summary, Xe can be used to measure cerebral blood flow, perform whole-brain scans, and conduct lung ventilation studies using MRI (¹³¹Xe), SPECT (¹³³Xe), and CT (¹²?Xe). 

General anesthesia: The anesthetic proprieties of Xe were discovered in 1939, with initial applications in mice by JH Lawrence in 1940, and later tested on human volunteers by Cullen and Gross in 1951.[2] In addition, it is indicated in selected patients due to its cardiovascular stability, cerebral protection, and favorable pharmacokinetics, including low solubility and lack of metabolism. Moreover, the use of Xe is environmentally friendly, as it does not have a significant environmental impact.[3] 

Organ protection: An important area of research is Xe-induced organ protection. For instance, Xe has been proposed as a means to prevent ischemia or reperfusion damage following Stanford type-A acute aortic dissection surgery.[4] Several preclinical investigations conducted on various models subjected to preconditioning, real-time conditioning, and postconditioning have demonstrated that Xe may provide significant neuroprotective and cardioprotective effects. These effects are dose-dependent and are thought to result from Xe's interference with glutamatergic transmission, as glutamate receptors are involved in both anesthesia and acute neurological injury through apoptotic processes, as well as its ability to inhibit the inflammatory cascade.[5][6]

The combination of Xe with hypothermia is a fascinating hypothesis. Xe appears to offer neuroprotective properties even at sub-anesthetic concentrations, suggesting these effects can occur independently of its anesthetic effect.[7] Regardless of the precise mechanism, the potential clinical applications of Xe for organ protection are significant. For example, Jia et al demonstrated that intermittent Xe exposure protects against gentamicin-induced nephrotoxicity.[8] This renal protection is crucial for kidney transplantation, as it helps prevent ischemia or reperfusion damage, delays rejection, and reduces the risk of chronic nephropathy.[9] Xe has also shown promise in treating neurobehavioral dysfunction from brain insults,[10] cardiac arrest-induced cerebral ischemia,[11] and neonatal hypoxia-ischemia.[12] 

Other clinical uses: In addition to this research, Xe has been studied for its potential in treating various conditions, including dementia, epilepsy, Alzheimer disease, and obsessive-compulsive disorders.[13][14][15][16] Moreover, Xe is used in ophthalmology for laser therapy and dermatology for removing skin lesions. Despite these potential uses, the high cost remains a significant limitation, with the market price for anesthesia ranging from approximately £6 to £12 per liter. 

Issues of Concern

Clinical Imaging

According to the manufacturer’s labeling, no reported adverse reactions or contraindications exist for using Xe-133 gas in clinical imaging. No known metabolic effects or significant drug-drug interactions have been identified. The drug is classified as FDA pregnancy category C by the US Food and Drug Administration (FDA), indicating that animal reproduction studies have shown adverse effects on the fetus. However, no adequate and well-controlled human trials exist, though the potential benefits may warrant its use in pregnant women despite the potential risks. Although it is unknown whether Xe-133 gas is excreted in breast milk, the manufacturer recommends using formula feedings due to the potential risk of adverse reactions in breastfeeding infants.

General Anesthesia

Xe offers many advantages when used as an anesthetic, although some disadvantages should also be noted.

Advantages: Xe anesthesia offers several benefits, as mentioned below.

• Xe anesthesia provides more stable intraoperative blood pressure and a lower heart rate by preserving sympathetic tone and modulating autonomic balance. This leads to significant cardioprotection by improving the myocardial oxygen supply-demand ratio.[17][18]

• Xe anesthesia offers neuroprotective properties both under normal surgical conditions and in cases of brain injury, ischemia, or hemorrhage.[19] This also has beneficial effects on regional cerebral glucose metabolism and blood flow.

• Xe anesthesia provides renal protection, as preconditioning with Xe helps prevent renal ischemic-reperfusion damage through the activation of hypoxia-inducible factor-1α and the microRNA-21 (miR-21)–signaling pathway.[20]

• Xe anesthesia does not affect coagulation, platelet function, the immune system, or hepatic function.

• Xe anesthesia has a favorable safety profile in individuals susceptible to malignant hyperthermia.[21]

• Xe anesthesia offers fast induction of anesthesia.

• Xe anesthesia provides faster emergence from anesthesia compared to volatile agents. Early studies indicated no positive correlation between the duration of anesthesia and emergence times.[22] Nevertheless, data on the superiority of Xe over intravenous agents remain uncertain. In fact, Xe did not accelerate recovery times compared to propofol anesthesia.[23]

• Xe anesthesia has no teratogenic or toxic effects on the fetus and does not have detrimental ecological effects.[24]

Disadvantages: The disadvantages of Xe anesthesia are mentioned below.

• The hypnotic effect of Xe anesthesia requires a mixture of 30% to 37% oxygen.

• Xe anesthesia may lead to a higher incidence of postoperative nausea and vomiting, affecting up to 45% of cases.

• Xe anesthesia has limited efficacy in preventing postoperative delirium.[25]

• Caution is required while using Xe anesthesia due to the diffusion of Xe into closed spaces, particularly in patients with pneumothorax or ileus.

• Xe anesthesia can increase pulmonary resistance, as the gas in oxygen forms a high-density mixture that raises the Reynolds number. However, the clinical consequences for patients with chronic obstructive pulmonary disease or morbid obesity remain uncertain.[26]

• Xe anesthesia is associated with high costs. However, the development of newer ventilators that operate in a closed-circuit rebreathing mode can help minimize Xe loss, potentially reducing expenses and promoting wider diffusion of the technique.

Clinical Significance

Xenon Imaging

Xe-133 gas serves as a contrast agent in nuclear medicine and modern laser technology. This is a beta emitter with a physical half-life of 5.2 days, a photopeak of 81 keV, and undergoes beta decay.[27] The mechanism of action of Xe-133 gas involves the gas passing through cell membranes and freely exchanging between blood and tissue. The gas enters the alveolar wall and pulmonary venous circulation via the capillaries. After one breath, the gas that enters the circulation returns to the lungs and is exhaled following a single pass through the peripheral circulation. In the concentrations used for diagnostic purposes, the drug is physiologically inactive. Spirometers or closed respiratory systems are used to inhale the gas, ensuring the delivery system is leakproof. The gas should not remain in respirator containers or tubing. Dosing should be measured with a radioactivity calibration system immediately before administration. Handling precautions include wearing waterproof gloves and using radiation shielding.

Xenon Anesthesia

Pharmacokinetics: Xe is absorbed by the pulmonary alveoli, and the percentage of Xe that flows into the brain correlates with its concentration in inspired air and the patient's ventilation. With the lowest blood-gas solubility coefficient among inhaled anesthetics (0.115, compared to 0.115-1.14 for others), the induction of anesthesia is very rapid. The minimum alveolar concentration (MAC) measures anesthetic potency, representing the concentration of the inhaled anesthetic in the alveoli required to prevent a motor response in 50% of subjects exposed to surgical pain stimuli. The MAC for Xe is relatively high, approximately 63% in adults (previously indicated as 71%) [28] and 92% for children aged 1.[29] Consequently, Xe must be administered with an inspiratory oxygen concentration of at least 30% to prevent hypoxia. The MAC-awake, defined as the concentration at which a patient opens their eyes in response to a verbal command, is 33% for Xe.

The saturation concentration at the effector site (the brain) is reached within a few minutes, and the washout phase at the end of anesthesia is very rapid. As a result, during emergence from general anesthesia, eye-opening, orientation, and responsiveness occur within approximately 4 minutes.[30] Thus, recovery from Xe anesthesia is faster than that from other inhalation and intravenous anesthetics, being twice as quick as desflurane.[31] The maximum elimination half-lives in various organs, detected using Xe-133 as a tracer, are nearly 100 minutes. Uptake is faster in highly vascularized organs, while it is more consistent in adipose tissue due to the lipophilic properties of Xe. Additionally, the permanence of Xe was found to be maximum in the intestine.

Xe is an inert gas, meaning it undergoes no metabolism under normal conditions and does not affect the renal or hepatic systems. Consequently, Xe is eliminated unchanged through the lungs. Due to its low solubility coefficient, the elimination of Xe starts during the administration of the anesthetic.

Pharmacodynamics: The primary target of anesthesia-induced neuronal responses is the glutamatergic presynaptic pathways. In particular, Xe decreases glutamate (Glu) N-methyl-D-aspartate (NMDA) receptor-mediated whole-cell currents through noncompetitive inhibition. Xe likely binds to the glycine-binding site on the NMDA receptor, thereby reducing the affinity of glutamate.[32] Xe has minimal effects on non-NMDA glutamatergic receptors, including alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate (KA). Furthermore, GABAergic (GABAA receptor-mediated) responses have a limited role in Xe anesthesia.[33] Inhibition of the calcium ATPase pump on synaptic cell membranes, neuronal nicotinic acetylcholine (nACh) receptors, and involvement of TREK-1 potassium channels have also been observed.[34]

Interestingly, commonly used anesthetic agents enhance inhibitory transmission via GABAA receptors and have minimal or negligible effects on glutamatergic NMDA-mediated activity. This distinction likely accounts for Xe's greater neuroprotective effect and its potentially reduced impact on memory and learning processes during anesthesia.[35] All these effects are linked to glutamatergic transmission.

The glutamatergic effect of Xe, due to the inhibition of NMDA receptors in the dorsal horn of the spinal cord, results in analgesia approximately 1.5 times more effective than nitrous oxide.[36] Thus, the antinociceptive properties of Xe are independent of opioid receptors and may clinically facilitate a favorable intraoperative opioid-sparing effect. Please see StatPearls' companion resource, "Mu Receptors," for more information.