Despite much research the mode of action of gaseous anesthetic agents has proven elusive since the use of ether was first reported by Morton and Parkman in 1847.As anesthetic gas mixtures contain at least 20% oxygen and the minimum alveolar concentration of an anesthetic agent producing an immobilizing effect does not change over a wide range of inspired oxygen concentrations,it would appear unlikely that hypoxia is involved.However,normal levels of oxygen in blood cannot ensure adequate oxygen tensions within cells and intracellular oxygen concentrations cannot be measured.

The progression and reversibility of neurological deficits due to hypoxia,from leg immobility to unconsciousness,were published in theLancetin 1862 by James Glaisher1after a balloon ascent to an altitude equivalent to the height of Everest.Aware of these exploits,Claude Bernard in 1875 suggested hypoxia may be involved in anesthesia produced by volatile agents,as did Verworn in 1912 but were unable to produce evidence.At the turn of the century,Meyer2and Overton3observed that gaseous anesthetics have a high lipid to water solubility ratio but,although this has been confirmed,it has been found that molecules that have similarly high lipid solubility are not anesthetics.They are now classified as “non-immobilizers.”

The discovery of the protein hypoxia-inducible factor 1,the subject of the award of the 2019 Nobel Prize for Physiology or Medicine,has provided a unique marker of intracellular hypoxia.Hypoxia-inducible factor 1 has been detected when a sub-anesthetic concentration of xenon and oxygen is breathed to simulate the hypoxia induced at high-altitude.Hypoxia-inducible factor 1 and the effector hormone,erythropoietin,are up-regulated by hypoxia and the effect lasts many hours longer than an exposure induced by breathing a low oxygen partial pressure.4

In 1961,Linus Pauling5published “A Molecular Theory of General Anesthesia” observing that gaseous anesthetic agents are,firstly,non-hydrogen bonding and,secondly,they form clathrates - lattices of water molecules in membranes,which trap gas molecules by van der Waals forces.His paper discusses xenon,which is inert under biological conditions,but an excellent anesthetic.Figure 1 shows the diagram of the lattice from his paper representing xenon.

Other inert gases,for example,argon,also produce anesthesia at the higher concentrations possible by increasing ambient pressure,as does nitrogen.As no chemical reaction is involved,this suggests a physical basis as the mechanism of anesthesia.Pauling suggested that hydrates may “decrease the rate of chemical reactions by entrapping reactant molecules,” but did not discuss oxygen,the most critical agent in the maintenance of consciousness,despite having invented the paramagnetic oxygen analyzer.Oxygen is poorly soluble in water and hydrates by causing perturbations of cell membranes6may impede oxygen transport into neurons and reduce mitochondrial production of adenosine triphosphate.

Neurons are certainly sensitive to hypoxia:respiring a gas not containing oxygen causes immediate loss of consciousness.7However,the concept of the “idling” neuron in which minimal levels of blood flow and,therefore,oxygen delivery can maintain cell viability without functional capability is now well-accepted.8The many effects relevant to general anesthesia observed in studies of xenon may follow reductions in oxidative phosphorylation induced by hypoxia in the many regions of the nervous system.9It remains to be seen if hypoxia-inducible factor 1 is detectable with other gaseous anesthetic agents.

Figure 1:The structure of the 12-Å hydrate crystals of small molecules,such as xenon.

The author is pleased to acknowledge helpful discussions withfriend and colleague Duncan Black PhD FRCS.