Historical Aspects1

It is easy to understand the answer to this question. One single oxygen atom (or radical) is unstable and does not exist in the natural form. The oxygen molecule (O₂) which we need and breathe, is formed of two oxygen radicals. Whenever there was an excess of 4oxygen radicals, they formed ozone (O₃) which in turn cut out the ultraviolet light from the sun. This would decrease further photo-dissociation and production of oxygen.

There are two very puzzling facts about relationship of origin of life and oxygen: one, life could initially develop only in an oxygen free atmosphere; and two, it was the presence of living organisms which resulted in an increase in oxygen in the atmosphere.

The explanation for the development of life in an oxygen-free atmosphere is attributed to the formation of organic compounds from which the living organisms subsequently developed. They are the essential components in the structure of all living things—plants and animals. The compounds could form from water, carbon dioxide and ammonia only in oxygen-free surroundings. Oxygen would have oxidized and destroyed the compounds. In the absence of oxygen, the organic compounds could accumulate and result in the formation of life. The presence of primitive cellular life encouraged an increase in oxygen concentration by permitting an increase in photo-dissociation of water.

Almost half the duration of existence of earth had passed when primitive life had surfaced in the form of a single-celled organism. It is interesting to know that the living organisms themselves were responsible for increase in the concentration of oxygen in the atmosphere. They started consuming oxygen for respiration and thereby encouraging further photo-dissociation and production of oxygen.

Algae, the most primitive form of life, appeared about a billion years after the formation of organic compounds. It is photosynthetic in its function, i.e. it synthesizes energy in the presence of sunlight. At this stage, there was a marked increase in oxygen—about ten times the previous concentration. This concentration remained fairly constant for the next 2 billion years by a process of stabili-zation known as the Pasteur effect. An increase in oxygen encoura-ged respiration, which in turn reduced the available oxygen. This caused a reversal to fermentation and dissociation to produce more oxygen. This cycle went on for the next 2 billion years when there was a dramatic increase in oxygen concentration and development of multicellular organisms. This was perhaps a major milestone in the evolution of life.

Even though the atmospheric oxygen got established at same levels as of now some 100 million years ago, it was less than 52 million years when primitive man appeared. It has been explicitly illustrated with a simple example of time clock. If the total time period of earth's formation is reduced to 24 hours, man had surfaced on the earth in the last half minute.

Talking of oxygen, it is only about 100 million years since when we have concentrations similar to those of today. This is attributed to the formation of ozone layer above the earth's atmosphere. The ozone layer formed from excess of oxygen, could screen the dangerous ultraviolet light from sun and other stars of the universe. It acts like a canopy (or a tent) under which life could evolve without the danger of death from extra terrestrial rays.

It is difficult to know as to when the importance of oxygen in sustenance of life was realized. Although the true scientific references to its role were not available until the medieval period, the ancient cultures did allude to the need of respiration and the requirement of air.

It was Sarangadhara, a 13th century physician who explicitly described the concept of respiration:

In summary, it implied that the ‘vayu’ located in the ‘hrdya’ (Chest) goes out and after drinking the ‘Ambarapiyush’ (nectar) it goes back very quickly. It touches the interior of ‘hydaya’, promotes the ‘Jatharanatha’ (life) and nourishes the entire body.

Sarangadhara had described the sequences leading to the inhalation of ambrosia, the food of gods, or a nectar like substance 6vital to life, from the outside air, its circulation through the heart to the brain and all other parts of the body. This ‘nectar like substance’ is likely to be what we now know as oxygen.

Most of the beliefs on essential role of air were based on philosophical ideas than physiological evidence. The ideas were somewhat similar to those of other cultures. But oxygen as an independent component of air was neither known nor firmly conceived.

The medieval Europe from 14th century onwards had gone through a period of renaissance which saw changes in innumerable scientific concepts. The mid eighteenth century was the period of discovery of gases such as hydrogen, nitrogen and carbon dioxide. Oxygen was isolated by Joseph Priestley in 1772 and prepared in a pure form by heating mercuric oxide. He had also demonstrated that the gas supported life of a mouse better than the air. He commented: “It might be salutary to the lungs in certain cases when the common air would not be sufficient to carry off the phlogistic putrid effluvium fast enough”. Priestley, a clergyman, teacher and librarian was the son of a weaver and a married farmer's daughter. Priestley also discovered that the gas obtained on fermenting grain (now known as CO₂) produced the drink known as seltzer when dissolved in water. He fell seriously ill from tuberculosis but got well to die at the age of seventy one in 1801. Interestingly, oxygen was independently discovered a year before Priestley by Scheele who had named oxygen as ‘fire-air’. Most of the gases were being actively investigated for their role in burning which had remained a major concern for survival of man since the very inception of life. Different materials on burning (i.e. oxidation) were supposed to loose a substance called phlogiston as per the Stahl's belief; Priestley therefore called oxygen as the dephlogisticated air.

It was later when the dephlogisticated air was labeled as “oxygen” (means “acid begetting” in Greek) by Antoine Laurent Lavoisier. He compared respiration with the process of combustion and demonstrated that animal respiration involved absorption of oxygen by the lungs from the inhaled air and elimination of carbon dioxide and water. He also demonstrated the indispensable nature of oxygen for human life and that the oxygen consumption increased with increased body activity. Lavoisier was executed during the French Revolution in 1789 since he was an aristocrat by birth.

One important development which significantly advanced our knowledge on clinical applications of oxygen related to the assessment of oxygen and carbon dioxide in the blood. Blood was first described to be slightly alkaline by Des Plantes in 1776. Oxygen and carbon dioxide were detected by Davy in 1799. Robert Boyle extracted “air” from blood. Magnus in 1837 used the vacuum 8extraction technique to measure the content of these gases in the whole blood. Several other methods were employed in the first half of this century by Van Slyke, Scholander and others. Those methods used the manometric or volumetric methods which were slow, elaborate and required careful precision. Further refinements led to the development of highly accurate and fast response analysers.

Tissue respiration was described in 1870 by Pfluger and others who identified the locus of respiration in the cells. In fact there had been a lot of debate between Ludwig, Pfluger and others about the gas exchange, in the 19th century. This had further encouraged the discovery of methods for precise blood gas assessment.

Several other discoveries ran almost parallel such as the role of hemoglobin in transport of oxygen by the blood by Hoppe-Seyler during 1860s. Dalton came up with his atomic theory of respiratory gases and Paul Bert with the oxygen dissociation curve in early 1870s. It was depicted as ‘hyperbolic’ which got changed to the sigmoid shape later by Bohr. The ‘Bohr’ effect and the ‘Haldane effect’ were reported later in the early 20th century.

Oxygen deficiency was perhaps first established as “anoxemia of high altitude” in 1878 by Bert who attributed the altitude sickness and death to lack of oxygen. Even earlier, Joseph Ch Hamel, a Russian physician had believed that the lack of oxygen was responsible for muscular weakness at altitude. On an ascent to Mont Blanc in 1820, he had planned to study the oxygen content of air and blood at the summit and the effects of oxygen administration. Unfortunately, the expedition was stopped by an avalanche which killed three of his guides shortly before the summit. It was almost half a century later that the term”anoxia” was used by Barcroft and Van Slyke. Uptake of oxygen was another issue which remained controversial between Bohr and his former assistant August Krogh and wife Marie Krogh. While Bohr supported the theory of secretion of oxygen, the Krogh team showed diffusion of gases in the lungs to explain oxygen uptake. It was Joseph Barcroft who finally demonstrated that diffusion alone was the mechanism for gas exchange.

Meanwhile, there were other developments in respiratory physiology which helped in re-establishing the role of oxygen therapy. In 1920s, it was established that oxygen deficiency resulted in serious physiological disturbances which could be corrected with supplemental oxygen. These observations were supported by firm clinical and experimental evidence. Oxygen therapy now achieved a prime role in treatments of cardiac and respiratory diseases. It was commercially produced for the first time in 1895 by Carl Von Linde using fractional distillation of liquid air.

John Haldane used oxygen to treat chlorine poisoning during First world war. He had stated that ‘hypoxia not only stops the machine but wrecks the machinery’. He had also advocated the use of oxygen for treatment of other respiratory illnesses. During this period in 1921, Meakins used oxygen therapy in the manage-ment of lobar pneumonia and reported that oxygen therapy was perhaps the most important factor in the treatment apart from the specific cure of infection. This was perhaps the major landmark in oxygen therapy in modern medicine after its initial use and subsequent disrepute. Its use became widespread in the following years.

Parallel to the discovery of oxygen use were the developments concerning its toxicity. Its toxic effects were suspected by von Liebig, Pasteur and Bent. Terms such as ‘oxygen toxicity lung’ and ‘respirator lung’ were used to describe respiratory failure caused 10by excessive oxygen use or ‘oxygen free radicals’. Devison compared the oxygen molecule to a grenade which could cause tremendous damage once the safety pin was pulled out.

The history of respiratory failure is relatively more recent. The terms ‘anoxia’ and subsequently ‘hypoxia’ were used in the 3rd and 4th decades of the twentieth century. The concept of ‘pulmonary insufficiency’ was introduced in 1940 by Cournand and Richard. More precise and meaningful terms have been used thereafter. The definition continues to be debated and refined. But the facts that the respiratory failure was directly linked to oxygen deficiency and it treatment with oxygen administration, were clearly established.

The methods and devices used for oxygen administration have also undergone a sea change. Many different kinds of pipes had been used in the past. Gas pipes were popular treatment devices in the late nineteenth and early twentieth centuries. Different types of masks, oxygen tents and cannulae were developed during the world wars. Closed circuit oxygen equipment was commonly employed in the 1930s and 1950s, for example during mountainee-ring. Tom Bourdillon and Charles Evans who had climbed to within 90 m of Mt Everest in 1953, two days before the summit was finally conquered had to abandon their effort because of the circuit's malfunction.

Once the domiciliary use was shown to be effective, refinements were introduced into the design and modes of administration. Low flow oxygen delivery with the help of nasal cannulae was shown to be effective and safe. The previously held belief that intermittent oxygen could cause greater CO₂ retention and aggravate hypoxe-mia was dispelled. A significant improvement in overall survival was shown by Neff and Petty in 1970.

Studies by the Medical Research Council (MRC) and the National Institute of Health (NIH) in 1980-81 are considered as landmark studies in the use of domiciliary oxygen. Further improvements in oxygen therapy continue to occur thereafter. But the role of oxygen as a maintenance drug was settled.