Oxygen Toxicity: History

Oxygen was ‘discovered’ in the latter half of the eighteenth century and immediately excited interest in its possible therapeutic effects. Following a series of experiments, in 1775 Priestley was among the first to suggest that there may be adverse effects of ‘dephlogisticated air’ – that is, air that was free from ‘phlogiston’, a substance thought to be released from a burning object1. Priestley had observed the rapid burning of a candle and speculated that ‘the animal powers be too soon exhausted in this pure kind of air’. In fact, in 1772 Carl Scheele had already postulated the existence of a substance he called ‘fire air’ that supported combustion (later to be called ‘oxygen’ by Anton Lavoisier) following a similar experiment. Later, in 1789, Lavoisier and Sequin demonstrated that oxygen at 1 ATA does not alter oxidative metabolism but did note a damaging effect on the lungs.

In 1878, Paul Bert published his pioneer work La pression barometrique, in which he presented the results of years of study of the physiological effects of exposure to high and low pressures. He showed that although oxygen is essential to sustain life, it is lethal at high pressures. Larks exposed to air at 15 to 20 ATA developed convulsions. The same effect could be produced by oxygen at 5 ATA. Bert recorded similar convulsions in other species and clearly established the toxicity of oxygen on the CNS, also known as the Paul Bert effect. He did not report respiratory damage1,2.

In 1899, the pathologist J. Lorrain Smith noted fatal pneumonia in a rat after exposure to 73 per cent oxygen at atmospheric pressure. He conducted further experiments on mice and gave the first detailed description of pulmonary changes resulting from moderately high oxygen tensions (approximately 1 ATA) for prolonged periods of time. Smith was aware of the limitations that this toxicity could place on the clinical use of oxygen. He also noted that early changes are reversible and that higher pressures shortened the time of onset. Pulmonary changes are also called the Lorrain Smith effect.

Although numerous animal studies were performed, evidence of the effect of high-pressure oxygen on humans was sparse until the 1930s. In 1933, two Royal Naval Officers, Damant and Philips, breathed oxygen at 4 ATA. Convulsive symptoms were reported at 16 and 13 minutes. Behnke then reported a series of exposures to hyperbaric oxygen. Exposure at 4 ATA terminated in acute syncope after 43 minutes in one subject and convulsions at 44 minutes in the other. At 3 ATA no effects were seen after 3 hours, but at 4 hours some subjects noted nausea and a sensation of impending collapse. At that time it was believed that 30 minutes of exposure at 4 ATA and 3 hours of exposure at 3 ATA were safe for men at rest. That the dose was important was confirmed in 1941 when Haldane reported a convulsion in less than 5 minutes at 7 ATA oxygen.

Meanwhile, at lower pressures, in 1939 Becker-Freyseng and Clamann found that 65 hours of exposure to 730 mm Hg oxygen at normal atmospheric pressure produced paraesthesiae, nausea and a decrease in vital capacity (VC).

At the beginning of World War II, some unexplained episodes of unconsciousness were noted in divers using closed-circuit rebreathing oxygen sets at what were considered safe depths. This prompted Donald, in 1942, to commence a series of experiments on oxygen poisoning (Figure 17.2)3. His observations in more than 2000 exposures form the basis of current oxygen diving limits. Unfortunately, many of his experiments were performed using rebreathing equipment, without CO2 measurement. Among the more important findings were the marked variation of tolerance and the aggravating effects of exercise and underwater exposure. Donald suggested a maximum safe depth for oxygen diving of 8 metres.

In 1942 and 1943, Donald carried out extensive testing for oxygen toxicity in divers.
Figure 17.2 In 1942 and 1943, Donald carried out extensive testing for oxygen toxicity in divers. The chamber is pressurized with air to 3.7 bar. The subject in the centre is breathing 100 per cent oxygen from a mask. (From Donald KW. Oxygen poisoning in man: I, II. British Medical Journal 1947;1:667–672, 712–717.)

Research since the 1980s has been primarily directed at elucidation of the mechanism of the toxicity. Workers have looked at such factors as the role of inert gas and CO2, blockage of airways and atelectasis, changes in lung surfactant, changes in cellular metabolism, inhibition of enzyme system and the role of the endocrine system. Also, further efforts to delineate the pulmonary limits of exposure have been undertaken. This has become increasingly important with saturation diving involving prolonged stays under increased ambient pressure and the use of oxygen mixtures to shorten decompression time.