Oxygen Toxicity: Aetiology

The precise mechanism of oxygen toxicity is unknown. Oxygen is a highly reactive element and has wide-ranging, dose-dependent effects in the body, including the regulation of blood flow, tissue oxygenation and energy metabolism in the brain. These effects are pressure dependent and are involved in the development of toxicity. There are a great many sites at which oxygen acts on metabolic pathways or on specific cellular functions. These sites may involve cell membranes, ‘active transport’, synaptic transmission, mitochondria or cell nuclei. Rather than causing an increase in metabolism, as suggested by early workers, hyperoxia has been demonstrated to depress cellular metabolism.

Many enzymes are inactivated by high PO2, particularly those containing sulphydryl groups (-SH). It is postulated that adjacent -SH groups are oxidized to form disulphide bridges (-S-S-), thus inactivating the enzyme (this may be important in the development of cataracts). Enzymes containing -SH groups, and known to be susceptible, include glyceraldehyde phosphate dehydrogenase (a key enzyme in glycolysis), the flavoprotein enzymes of the respiratory chain and the enzymes involved in oxidative phosphorylation.

The oxygen free radical theory of toxicity is widely accepted as an explanation at the molecular level. The production of a range of free radicals is a normal consequence of aerobic metabolism, and for this reason, aerobic organisms (e.g. ourselves) have developed antioxidant mechanisms to cope with molecular oxygen exposure. In the presence of hyperoxia these mechanisms may be overwhelmed, leading to the formation of excess reactive oxygen forms and direct cellular toxicity through enzyme inactivation and structural damage (e.g. lipid peroxidation). These radicals are intermediates formed in many cellular biochemical enzyme catalyzed reactions and are the result of the reduction of the oxygen molecule by electrons. Superoxide anion (O2−) is formed when oxygen accepts a single electron and hydrogen peroxide (H2O2) two electrons. The final reaction is the acceptance by oxygen of four electrons to form water or a stable hydroxyl anion. Superoxide and peroxide can react to form the hydroxyl radical OH-. All these species of oxygen, referred to as oxygen radicals, are highly oxidative.

Cells have a system of enzymes to scavenge these radicals called the tissue antioxidant system. Two of these enzymes, superoxide dismutase and catalase, are involved in maintaining adequate supplies of reduced glutathione (containing sulphydryl groups) to deal with the free radicals. Hyperoxia may cause this system to be swamped, and the excess free radicals may then produce cell damage. Examples of unwanted oxidation reactions are peroxidation of lipid in cell membranes and protein oxidation in cell membrane and cytoplasm. Both have been demonstrated in rat brain after hyperoxia4. Aerosolized (recombinant human manganese) superoxide dismutase preserves pulmonary gas exchange during hyperoxic lung injury in baboons5. Antioxidants such as glutathione have also been shown to offer some protection.

The characteristic feature of chronic pulmonary oxygen toxicity is pulmonary fibrosis (see later). In animal studies, paraquat, bleomycin and ozone have all been noted to produce pulmonary fibrosis. These agents are known to produce oxygen free radicals.

Gamma-aminobutyric acid (GABA) is a transmitter at CNS inhibitory nerve synapses. One of the demonstrated consequences of enzymatic changes induced by hyperoxia is a reduction in the endogenous output of GABA that results in the uncontrolled firing of excitatory nerves and the development of convulsions. Agents that raise brain levels of GABA appear to protect against convulsions. Lithium (useful in the treatment of bipolar disorder) has proved to be effective in inhibiting convulsions in rats. It was also shown to prevent the decrease in brain GABA that normally precedes the convulsions. In the rat lung lithium inhibits the development of oedema.

Exercise, hypoventilation and CO2 inhalation predispose to convulsions, whereas hyperventilation may be protective. CO2 may play a role in lowering seizure threshold at the cellular level, but more likely by influencing cerebral blood flow and hence the ‘dose’ of oxygen delivered to the brain.

At greater than 3 ATA PIO2, oxyhaemoglobin is not reduced on passing through capillaries and so is not available for the carriage of CO2 as carboxyhaemoglobin. Therefore, this route cannot eliminate CO2. The resultant increase in brain CO2 tension (PCO2) has proved to be small (2.5 to 6 mm Hg). An equivalent rise is caused by breathing 6 per cent FICO2 and does not cause convulsions in the presence of a normal PIO2. It does, however, appear that the slight rise in PCO2 reduces the cerebral vasoconstrictive effects of hyperoxia.

In contrast, CO2 retention is unlikely to contribute to pulmonary toxicity, although related changes in acid-base balance may modify the syndrome via neurogenic and endocrine mechanisms. Very high levels of inspired CO2 may actually protect against pulmonary damage.

Atelectasis (collapse of alveoli so they are no longer ventilated) results from absorption of oxygen during 100 per cent oxygen breathing and has been suggested as a contributory mechanism to oxygen toxicity in divers. Although atelectasis has been demonstrated, it is not an initiating factor, and toxicity also develops in the presence of inert gas. If the inert gas is at narcotic levels, it may actually enhance the onset of toxicity.

Human studies show no difference in the progression of pulmonary oxygen toxicity when comparing pure oxygen and diluted oxygen at the same PO2. Rat studies indicate that the risk of CNS toxicity is enhanced by the presence of even small amounts of inert gas in the inspired mixture.

Endocrine studies show that hypophysectomy and adrenalectomy protect against hyperoxia. Adrenocorticotropic hormone (ACTH, corticotropin) and cortisone reverse this effect and, when given in normal animals, enhance toxicity. Adrenergic-blocking drugs, some anaesthetics, GABA, lithium, magnesium and superoxide dismutase have a protective effect. Adrenaline, atropine, aspirin, amphetamine and pentobarbital are among a host of agents that augment toxicity.

Light, noise and other stressful situations also affect CNS tolerance. Thus, the general stress reaction, and more specifically adrenal hormones, may have a role in enhancing CNS (and pulmonary) toxicity. Several observations suggest a role of the autonomic nervous system in modifying the degree of toxicity. Convulsions have been shown to hasten the onset of pulmonary oxygen toxicity in some animal studies. This may be related to an activation of the sympatho-adrenal system during convulsions.

Table 17.1 contains a list of factors that increase oxygen toxicity.

Factors increasing oxygen toxicity