Subcutaneous oxygen therapy

Cover photo. Dr R Bayeux’s precision oxygenator, manufactured by Jules Richard, 25 Rue Mélingue, Paris. Courtesy of private collection, Dr Jean-Bernard Cazalaà.

Oxygen is the sovereign remedy for symptoms of anoxemia and, in my opinion, the subcutaneous route of giving it is the most efficacious as well as the most economical.

Oliver Simon, 1934 ¹

During the late 18th century, Lazzaro Spallanzani, Professor of Natural History at the University of Pavia, began to investigate the circulation of the blood, and the physiology of respiration.^2,3 Among his many observations, Spallanzani noted that a variety of animals were able to undertake cutaneous gas exchange, independent of their lungs or gills, and readily absorbed oxygen when it was injected beneath the skin, turning the blood bright red.

In 1787, William Maxwell published the results of more extensive experiments undertaken at the University of Edinburgh. Using a compressible bladder connected to a rigid tube, four pints of oxygen were forced into the subcutaneous tissues of a dog. Within 24 hours the subcutaneous emphysema had begun to subside, and by the tenth day, the gas had been completely absorbed. After further experimentation, Maxwell concluded that oxygen was more rapidly absorbed from the subcutaneous tissues than atmospheric air, and recorded that once accustomed to the gaseous distension, the dogs ‘ran hither and thither widely and cheerfully, and did not suffer any pain, but enjoyed complete health’. ⁴

Despite these findings, it would be almost 70 years before further research was undertaken in this field. In September 1856, Charles Leconte, Associate Professor at the Faculty of Medicine of Paris, and Jean Demarquay, surgeon to the city’s Municipal Hospital, embarked on a study which aimed to elucidate the chemical and physiological action of gases injected into the subcutaneous tissues of rabbits. Pure oxygen was found to produce no harmful effects, and ‘about 2.5 hours after the injection, but very faint traces… could be recovered’. ⁵

In 1862, the pair published a paper describing the influence of various gases on the healing of leporine tendons following surgical division. After performing subcutaneous tenotomy of the Achilles tendon, Demarquay and Leconte closed the external wound with collodion (a solution of nitrocellulose in ether and alcohol). The subcutaneous tissues surrounding the tendon were then distended with gas, via a rubber bladder attached to a small trocar. Interestingly, oxygen appeared to possess an ‘overly energetic stimulating action’ which ‘greatly delayed wound healing’, and five days after the operation, ‘tendon repair was less advanced … and the veins seriously congested’. ⁶ Nevertheless, in his Essay on Medical Pneumatology, published four years later, Demarquay reiterated that ‘oxygen may be injected into the cellular tissue … with perfect impunity’, and reported one case in which it ‘effected a cure of hydrocele’. In addition, he applied oxygen to the exterior of gangrenous wounds and ulcers, by means of a hermetically sealed India rubber boot ‘through which a constant current of oxygen was passed’. ⁷

Interest in subcutaneous oxygen therapy was renewed in 1900 by José Dómine, in Valencia,^8,9 and William Ewart in London. ¹⁰ Both were engaged in the management of typhoid fever. Dómine discovered the technique by chance, when his assistant accidentally injected air, instead of saline, into the subcutaneous tissues of a patient. The resulting effects (which included reduction of fever, cessation of vomiting, and stabilisation of the pulse) were ‘so surprising’ that they led the pair to repeat, ‘in this case and in several others, the injection, not of air, but of oxygen, supposing that the good result … was due to the activity of this gas’. ⁹

Ewart, meanwhile, set out to test the hypothesis that oxygen, ‘might … be serviceable when administered under the skin’ in severe typhoid pneumonia. After unsuccessfully trialling injections of a hydrogen peroxide solution in five cases, he encountered a patient in a ‘desperate condition’, and ‘determined to supply the oxygen yet more directly and in greater abundance by injecting the gas with due precautions immediately under the skin’. Having ascertained that the procedure was ‘painless and apparently free from danger’ by self-experimentation, a long needle was introduced into the subcutaneous tissue of the patient’s thigh, carefully avoiding any veins. Oxygen was supplied from a cylinder, and ‘judging from the bulk of the limb’, more than one pint was injected. Despite these efforts, the patient died, and Ewart abandoned his use of subcutaneous oxygen. However, he retained the hope that the ‘future observations of others may furnish more light than can be gathered from the cases in which it has been tried, and which were ill adapted to serve as fair tests’. ¹⁰

Around the same time at the University of Brussels, Jules Thiriar, Professor of Surgery, began applying oxygen directly to wounds, including those of cutaneous anthrax. Thiriar believed that the gas ‘attenuated the virulence of the bacteria and oxidised their toxins’, and obtained particularly striking results when a continuous stream of gas was directed into the opening of boils and carbuncles, as well as the surrounding tissue. ¹¹ It proved similarly beneficial ‘in hundreds of cases of diffuse phlegmons, gangrenous erysipelas, suppurating complicated fractures and arthritis’. ¹²

Encouraged by Thiriar’s findings and assisted by José Chabás and Francisco Moliner, Dómine continued to advance the practice of subcutaneous oxygen therapy in Spain during the early 1900s, reporting ‘remarkable cures’ in infectious diseases such as tuberculosis, colibacillosis and meningitis, and the rapid relief of pain in sciatica and other neuralgias.^8,9

The use of subcutaneous oxygen was subsequently adopted by several French physicians, including Félix Ramond, who, in September 1910 was among the first to recommend its employment in cases of asphyxia due to mechanical obstruction, endogenous toxaemias or exogenous poisons.^13,14 In a thesis published one year later, Armand Béraud recorded the use of hypodermic oxygen in 17 cases of dyspnoea and asphyxia managed by seven separate clinicians. In several instances, the injections apparently brought about a ‘veritable resurrection’ of the patient. ¹⁴

While the majority of these practitioners used simple apparatus, consisting of an oxygen balloon connected to a Pravaz hypodermic needle via a length of rubber tubing, it proved difficult to control the flow of gas accurately with such equipment. As a result, a number of more sophisticated devices were developed, including the ‘precision oxygenator’ designed by Raoul Bayeux. ¹⁵ Manufactured by the Parisian instrument maker Jules Richard, this was intended for use in research as well as clinical practice, and from 1912 to 1921, Bayeux utilised his apparatus to investigate the effects of subcutaneous oxygen on the symptoms of altitude sickness. His experiments were conducted at the Vallot Observatory, Mont Blanc, as well as the hypobaric chamber at Saint-Cyr Aeronautical Station. The results were deemed sufficiently promising that he went on to recommended the prophylactic administration of subcutaneous oxygen to pilots and passengers embarking on flights.^16–20

Concomitantly, reports endorsing the therapeutic employment of subcutaneous oxygen emerged from doctors in Canada,^21,22 Great Britain,^23–25 and the Netherlands. ²⁶ However during the late 1920s and early 1930s physiologists began to question the mechanisms underlying its purported benefits in anoxaemia.^27–30 In 1927, H. Whitridge Davies and colleagues established that massive injections of subcutaneous oxygen were associated with little or no increase in the arterial oxygen saturation of dogs which had been rendered hypoxaemic by pulmonary emboli, ²⁸ and five years later at the University of Rangoon, Indeyit Singh demonstrated that the rate of absorption of oxygen from the subcutaneous tissues was very slow, varying from 0.6 to 1.2 ml per minute. ²⁹

Unperturbed, a handful of enthusiasts, including Oliver Simon and John Evans, continued to promote the therapy in North America during the 1930s and 1940s,^1,31–33 erroneously predicting that the subcutaneous administration of oxygen was ‘destined to supplant the inhalation method in a few years’. ³¹