Hypoxia and Anaesthesia : Refs Head Injury : Penicillin and Oxygen : Amazon Book Review

Evidence that hypoxia induced in cortical neurons is the mechanism of general anaesthesia

Despite much research the mode of action of gaseous anaesthetic agents has proven elusive since the first, ether, was used in 1842. As anaesthetic gas mixtures contain at least 21% oxygen and the minimum alveolar concentration of an anaesthetic agent producing an effect does not change over a wide range of inspired oxygen concentrations,1 it appears unlikely that hypoxia is involved. However, a significant reduction in the respired oxygen concentration always causes loss of consciousness.

The intrepid balloonists James Glaisher and Henry Coxwell first discovered this on their ascent to the height of Everest over Wolverhampton in 1862: details were published in the Lancet the following year. Normal levels of oxygen in blood cannot ensure adequate oxygen tensions in cells and intracellular oxygen concentrations cannot be measured. However, the discovery of the Hypoxia-inducible transcription factor 1 (HIF-1) provides a unique marker for cellular hypoxia.2 HIF-1 is a heterodimer of alpha and beta components, with the level of HIF-1α controlled by its destruction by the Von Hippel Lindau protein (VHL). A fall in cellular oxygen tension reduces the production of VHL,allowing HIF-1α to persist, which binds to HIF-1β to produce the transcription factor HIF-1.

Anaesthesia can be produced by xenon and oxygen mixtures3 and evidence that xenon produces cellular hypoxia has come from use of the gas by athletes in performance enhancement. HIF-1 and the effector hormone, erythropoietin, are up-regulated by the inhalation of xenon/oxygen mixtures with sufficient oxygen to sustain consciousness4 and the effect lasts many hours longer than a hypoxia exposure induced by breathing a low oxygen partial pressure. As xenon is inert with no known compounds, it would seem unlikely that its action is to lower VHL production as can be achieved chemically, for example, by using cobalt compounds. Cortical neurons are exquisitely sensitive to hypoxia and their activity is abolished at oxygen levels well above that associated with irreversible cell damage.5 Xenon may induce a reversible change in cellular and/or mitochondrial membranes impairing oxygen transport and ATP production.

The loss of consciousness induced by gaseous anaesthetic agents that have a high water/lipid solubility ratio like xenon may, therefore, be due to hypoxia of cortical neurons. This can be tested by determining if HIF-1 is up-regulated in other forms of gaseous anaesthesia and it may be possible to investigate if conformational changes of cell membranes occur and the mechanism by using a physical model.

Philip B. James
Emeritus Professor of Medicine
The University of Dundee
Dundee DD1 4HN


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Submitted to the Lancet 16th September 2015



Chapter 19: Head Injuries – the Curse of Life in the Fast Lane

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Abstracts from the book review by Dr. Jane Orient M.D in the Journal of the American Association of Physicians and Surgeons, Summer 2017. Posted on Amazon.

Physicians learn something about oxygen transport in physiology class and have been using oxygen with patients since the earliest days of their clinical rotations. They may think that they already know everything they need to know about this essential gas, but they would be wrong. This book challenges some of the basic dogma that most of us were taught during our residencies. It also offers the prospect of path-breaking advances in the treatment of otherwise hopeless conditions. Many of these possibilities were discovered decades ago and then forgotten.

A key purpose of the book is to promote hyperbaric oxygenation therapy (HBOT) as a treatment for conditions going beyond the well-accepted ones for decompression sickness and wound healing. One barrier is the insistence on randomized double-blind controlled trials (RCTs) for new indications. James argues that RCTs are not only inappropriate, but often actually unethical for HBOT. Oxygen is, after all, a necessity, not an “adjunct.”

The book is extensively and brilliantly illustrated. The many historical photographs include John Scott Haldane, whose work in the field was seminal, testing his breathing apparatus in a coal mine. Photomicrographs, gross pathology specimens, retinal photographs, and the latest in neuro-imaging studies (pre- and post-treatment) help make a convincing case for James’s unifying theory on the pathophysiology of many neurologic conditions.

James not only reviews the history and the science of HBOT but has been making history himself with his pioneering work. His disruptive ideas could make billions of dollars of research based on the wrong theories obsolete, posing a serious threat to lucrative drug therapies. In short, this book is revolutionary.

The medical use of oxygen in treatment has a long history and the comments below by Dr SM Birch about using oxygen treatment are just as relevant today as when they were written - in 1857.

Demanding evidence from "controlled trials" is the defensive position adopted by many medical practitioners and derives from the need to test drugs of unknown value. The value of oxygen is not open to question and evidence from just one patient is valid.

Science is about measurement and oxygen levels can be measured in our tissues. Lack of oxygen identified by the presence of lactic acid in tissues can be assessed in the brain by Magnetic Resonance Spectroscopy.

Evidence of a deficiency of oxygen? There is a duty of care to correct it - by increasing the concentration a patient is breathing above the level obtained from breathing air.

The term "hyperbaric oxygen" is grammatically incorrect and is taken by some to imply that the oxygen somehow differs from the oxygen in the air. It is just the same: Our cells cannot know where an oxygen molecule came from: the correct term is hyperbaric oxygenation.

The power of the body to heal is miraculous but only possible when critical substances are present, oxygen being the most important.





                                               by S.B. Birch, M.D.

                                                   The Lancet

                                                 August 1, 1857


The therapeutic use of this gas, either alone or as an adjunct, in various intractable diseases, is a subject of vast importance. 


This gas, although so well known in its physiological relations, has been practically little better than a “secret” in its therapeutic bearings.


the patient needs plenty of pure air, more air  (in other words more oxygen)  than he can possibly obtain under many circumstances and in many diseased states from the atmosphere.


It would not be too difficult to show cause why the use of this remedy has been neglected. It involves some trouble and loss of time to the practitioner.


...... the very want of practical knowledge still existing may be justly attributed to the neglect to carry out fair trials on a sufficient scale in practice.


The profession has been led to overlook or ignore  oxygen as a medicine even though chemical science tells us decidedly that it ought to be a most valuable remedial agent


A single trial, or several trials on several patients, are no evidence, if they fail, against its value; they are only proof either that it was not suited to the case, or that it was not properly exhibited.