Oxygen Toxicity: Central Nervous System Toxicity (The ‘Paul Bert Effect’)

In diving, CNS oxygen toxicity is more likely when closed-circuit or semi-closed-circuit rebreathing sets are used, and it is the factor limiting depth when oxygen supplementation is used. With compressed air, the effect of increased partial pressure of nitrogen (see Chapter 15) usually prevents the diver from reaching a depth and duration at which oxygen will become a problem (although occasional reports can be found). ‘Technical’ diving (see Chapter 62), in which a higher FIO2 than air is commonly used, permits CNS toxicity (Case Report 17.16). High oxygen pressures are used in therapeutic recompression for decompression sickness (DCS) and air embolism (see Chapters 6 and 13).


A 47-year-old experienced underwater cave diver with no significant medical history was diving with two tanks – one containing compressed air, the other a 50 per cent mixture of oxygen and nitrogen (nitrox). Towards the end of the 47-metre, 19-minute dive, he was seen floating head down, unresponsive, with his mouthpiece out of his mouth and ‘his fins [flippers] moving as if he was shivering’ (as reported by another diver to the Coroner). The body was carried up to 15-metre depth and then allowed to ascend freely as the other divers decompressed. Cardiopulmonary resuscitation was attempted, but abandoned after 43 minutes, as there was no response.

Examination of the subject’s diving equipment revealed that he had been breathing the 50 per cent oxygen/nitrogen mixture for most of the dive (at 47 metres, the PIO2 would have been 5.7 ATA × 0.5, or 2.85 ATA). Each tank had a separate first stage connected in an unusual fashion by a two-way switch, which the diver had had made by a local engineering shop. This allowed the diver to switch from one tank to another rapidly. This switch supplied a single second-stage mouthpiece. The two tanks were different colours; the circuit from the black (compressed-air) tank was marked with yellow tape, while the circuit from the yellow (nitrox) tank was unmarked. The regulator had a small tear and a bite mark in the mouthpiece. The diver wore a face mask and separate mouthpiece rather than a full-face mask, which covers eyes, nose and mouth.

The cause of death, as determined by the Coroner, was drowning after oxygen toxicity.

(From Lawrence CH. A diving fatality due to oxygen toxicity during a ‘technical’ dive. Medical Journal of Australia 1996;165:262–263. ©Copyright 1996.The Medical Journal of Australia; reproduced with permission.)

Clinical manifestations

A wide range of symptoms and signs has been described, the most dramatic of which is a grand mal–type convulsion. Consciousness is maintained up to the time of convulsion and there are apparently no changes in the electroencephalogram before convulsion.

In practice, there is no reliable warning of impending convulsions (but see Lambertsen’s description later), and only about half of persons affected describe any premonitory symptoms. However, the list of such manifestations is long, and any unusual symptom should be suspect. The most commonly reported signs and symptoms are nausea, vomiting, light-headedness, dizziness, tinnitus, vertigo, incoordination, sensations of impending collapse or uneasiness (dysphoria), facial pallor, sweating, bradycardia, constriction of visual fields (tunnel vision), dazzle, lip twitching, dilatation of pupils, twitching of hand, muscular twitching elsewhere, hiccups, paraesthesiae (especially fingers), dyspnoea, disturbance of special senses, hallucinations and confusion.

Facial twitching is a common objective sign in chamber exposures to oxygen greater than 2 ATA, and it signifies an imminent convulsion. Lip twitching may be seen if a mouthpiece is being used. Nausea, retching and vomiting are particularly noted after prolonged exposures between 1 and 2 ATA.

Central nervous system oxygen toxicity:

  1. Twitching (especially lips).
  2. Nausea.
  3. Dizziness.
  4. Tinnitus.
  5. Tunnel vision.
  6. Dysphoria.
  7. Convulsions.

Many of these manifestations are associated with other potential causes. Facial pallor is thought to result from the intense peripheral vasoconstriction of hyperoxia and is not necessarily a sign of cerebral toxicity. Similarly, the paraesthesiae in fingers and toes do not necessarily indicate an impending convulsion. They may persist for hours after exposure and may represent an effect of local vasoconstriction on peripheral nerves or simply a tight-fitting wetsuit.

An important aspect of toxicity is the great variation in susceptibility. As well as the wide range of tolerance among individuals, there is marked variation in one person’s tolerance from day to day7. Therefore, in any one diver, the time to onset of symptoms cannot be related to a predictable depth or time of exposure. Despite this variation, the greater the PO2 and the longer the time of exposure, the more likely is the toxicity to develop.

Factors lowering threshold to central nervous system toxicity:

  • Severe exercise.
  • Immersion in water rather than in air (e.g. a chamber).
  • Hypothermia.
  • Increased arterial carbon dioxide from any cause.

Exposure in water rather than in dry chambers markedly decreases the tolerance to oxygen. Many of the previously listed clinical features are much less apparent in the water, where convulsions are more often the first manifestation. A convulsion is much more dangerous under water because of the added complications of drowning and pulmonary barotrauma. Therefore, most authorities have set a maximum safe depth for pure oxygen diving at about 10 metres. Short dives may be safe at greater depths and prolonged ones at shallower depths (Table 17.2). Exposure in a compression chamber is considered to be less hazardous for an equivalent depth-time profile. Current decompression procedures, if performed in chambers, prescribe oxygen exposures at 18 metres (2.8 ATA), and seizure is rare.

US Navy oxygen depth time limits in water

Exercise has also been shown to hasten the onset of symptoms. Shallower maximum safe depths have been set for ‘working’ as opposed to ‘resting’ dives on oxygen. This observation is also of importance when oxygen is used to shorten decompression times in the water. Divers undergoing decompression should be at rest, e.g. supported on a stage – not battling swell, current and buoyancy to maintain constant depth. Hypothermia is likely to hasten the onset of symptoms.

CO2 build-up during exercise has been suggested as a potentiating factor in producing convulsions. Increased inspired PCO2 may develop with inadequate absorbent systems and in poorly ventilated helmets and chambers, thus rendering the diver more susceptible to oxygen convulsions.

The danger of convulsions prevents divers breathing 100 per cent oxygen deeper than 8 to 10 metres of sea water.

The role of inert gas in the exacerbation of oxygen toxicity needs to be more fully elucidated.

The frequency of presenting symptoms in ‘wet’ divers resting and working is shown in Table 17.3 from Donald’s work2,3. In all cases exposure continued until the first symptoms developed (‘end-point’).

Incidence of symptoms resulting from exposure of divers to ‘end-point’ in water

Convulsions, which may be the first manifestation of toxicity, are indistinguishable clinically from grand mal epilepsy (Case Reports 17.2, 17.3 and 17.4). A review of neurological toxicity in US Navy divers showed that convulsions were more likely to be the presenting feature in inexperienced divers breathing oxygen, compared with trained divers. It is inferred that some of the so-called premonitory symptoms may result from suggestion rather than oxygen. Of 63 divers, 25 had convulsions as the first clinical manifestation, 10 had focal twitching, and 13 more progressed to convulsions despite immediate reduction of PO2. A more recent study revealed nausea as the most common manifestation, followed by muscle twitching and dizziness.


BL, a 20-year-old trainee naval diver, was taking part in air diving training to a depth of 21 metres. He was using surface-supply breathing apparatus (SSBA), which consists of a demand valve and a hose to the surface connected to large cylinder via a pressure regulator adjusted according to the depth. After approximately 20 minutes, he was signalled with a tug on the hose to return to the surface because the cylinder was running low. He remained in the water at the surface while his hose was connected to another cylinder and then recommenced his dive. Some 12 minutes into the second dive, BL’s surface attendant noted that there were no surface bubbles. The instructor told the attendant to signal BL via the hose tug system. There were no answering tugs on the line. The standby diver was then sent into the water to check BL. He found BL floating a metre off the bottom with his demand valve out of his mouth. He was brought rapidly back to the diving boat and cardiopulmonary resuscitation was commenced using a portable oxygen resuscitator. After some time, probably about 15 minutes, the small oxygen cylinder of the resuscitator was noted to be low, so one of the group was instructed to connect the resuscitator to the emergency large oxygen cylinder. The oxygen cylinder was then found to have a line already attached to it – BL’s SSBA! BL failed to respond to intense resuscitation carried on for more than 2 hours (inspired oxygen tension at 21 metres would have been 3.1 ATA).

Diagnosis: death resulting from central nervous system oxygen toxicity (presumably convulsions).


AM and his buddy, both military divers, were practising night-time underwater ship attack while using closed-circuit 100 per cent oxygen rebreathing sets. While approaching the ship, they exceeded the maximum safe depth to avoid being spotted by lights and had to ascend to the ship’s hull (depth 9 metres). During their escape from the ship, AM had difficulty in freeing his depth gauge and, when he finally did examine it, discovered he was at 19 metres. He started to ascend and remembers ‘two to three jerkings’ of his body before losing consciousness. The buddy diver noted that AM ‘stiffened’ as he lost consciousness and then started convulsing, which continued while AM was being brought to the surface. Total time of dive was 28 minutes. At the surface, AM was pale with spasmodic respirations, and the lug on the mouthpiece had been chewed off. Artificial respiration was administered. AM was incoherent for 20 minutes and vomited once. A headache and unsteadiness in walking persisted for several hours after the incident. An electroencephalogram 3 days later was normal. (The buddy diver was exhausted on surfacing, felt nauseated and was unable to climb into the boat but recovered quickly.)

Diagnosis: near drowning secondary to central nervous system oxygen toxicity.


TL was using a semi-closed-circuit rebreathing apparatus rigged for 60 per cent nitrogen. After 17 minutes at 22 metres, he suddenly noted a ringing noise in his head. He flushed through his set, thinking his symptoms were the result of carbon dioxide toxicity. He then noted that his surroundings were brighter than usual and decided to surface.

On surfacing he was noted to be conscious but pale and panting heavily. He moved his mouthpiece and while being brought on board ‘went into a convulsion, where his whole face changed shape, his eyes rolled up into his head, his face turned a dark colour and his body began to cramp’. He recovered within 3 to 4 minutes, and 30 minutes later there was no abnormality on clinical examination.

Equipment examination revealed that the emergency oxygen cylinder was nearly empty, i.e. that he had used 64 litres of 100 per cent oxygen in addition to approximately the same amount of 60 per cent oxygen. The oxygen in his breathing bag would therefore have approximated 80 per cent and the inspired oxygen tension 2.4 ATA. The carbon dioxide absorbent was normal.

Diagnosis: central nervous system oxygen toxicity.

The following description of a typical convulsion has been given by Lambertsen8, who performed much of the original work in the United States on this subject.

Localized muscular twitching, especially about the eyes, mouth and forehead usually but not always precedes the convulsion. Small muscles of the hands may also be involved, and incoordination of diaphragm activity in respiration may occur. After they begin, these phenomena increase in severity over a period, which may vary from a few minutes to nearly an hour, with essentially clear consciousness being retained. Eventually an abrupt spread of excitation occurs and the rigid tonic phase of the convulsion begins. Respiration ceases at this point and does not begin again until the intermittent muscular contractions return. The tonic phase usually lasts for about 30 seconds and is accompanied by an abrupt loss of consciousness. It is followed by vigorous clonic contractions of the muscle groups of head and neck, trunk and limbs, which become progressively less violent over about 1 minute. As the uncoordinated motor activity stops, respiration can proceed normally. Following the convulsion, hypercapnia is marked due to accumulation of carbon dioxide concurrent with breath holding. Respiration is complicated by obstruction from the tongue and by the extensive secretions, which result from the autonomic component of the central nervous system convulsive activity. Because the diver inspired a high pressure of oxygen prior to the convulsion, a high alveolar oxygen tension persists during the apnoea. The individual remains well oxygenated throughout the convulsion. Due to the increased arterial carbon dioxide tension, brain oxygenation could increase the breath-holding period. This is in contrast to the epileptic patient who convulses while breathing air at sea level.

The latent period before the onset of toxic symptoms is inversely proportional to the PIO2. It may be prolonged by hyperventilation and interruption of exposure and shortened by exercise, immersion in water and the presence of CO2.

The ‘oxygen off-effect’ refers to the unexpected observation that the first signs of neurological toxicity may appear after a sudden reduction in PIO2. Also, existing symptoms may be exacerbated. The fall in PIO2 is usually the result of removing the mask from a subject breathing 100 per cent oxygen in a chamber. It may also occur when the chamber pressure is reduced or when the diver surfaces. It has been postulated that the sudden drop in cerebral arterial PO2 in the presence of persisting hyperoxic-induced cerebral vasoconstriction results in cerebral hypoxia in a brain already impaired by oxygen poisoning.

The risk of oxygen toxicity in the presence of a diagnosis of epilepsy is unclear. The conservative assumption that such individuals are at increased risk is widely held, and epilepsy is one of the absolute contraindications to diving. Yet although there are some reports of seizures during and after hyperbaric therapy in these patients, no formal association has been described, and many patients with epilepsy are routinely treated in hyperbaric chambers without incident.

Some animal experiments have shown that older and male animals are more susceptible to oxygen toxicity, but this has not been conclusively demonstrated in humans.

The major differential diagnoses of neurological toxicity are cerebral arterial gas embolism (CAGE) and hypoglycaemia. The timing of symptoms and signs in relation to oxygen exposure, measurement of blood glucose and the subsequent recovery from oxygen toxicity are usually enough to distinguish among these entities.

Finally, there are anecdotal reports of a syndrome of fatigue, headache, dizziness and paraesthesiae in operational divers exposed to repeated oxygen at depth on a daily basis. This has not, however, been reported in patients having daily hyperbaric oxygen therapy at 2.4 ATA for 90 minutes daily.


No pathological changes in the CNS directly attributable to oxygen toxicity have been observed in humans. Animal experiments with intermittent or continued exposure cause permanent neurological impairment with selective grey matter and neuronal necrosis (the John Bean effect)9. Changes have been reported on both light and electron microscopy in rats after exposure to 8 ATA oxygen. Lesions are found in specific areas, such as in the reticular substance of the medulla, the pericentral area of the cervical spinal grey matter, the ventral cochlear nuclei, the maxillary bodies and the inferior colliculi.

Pharmacological control of convulsions and pulmonary oedema does not alter the findings. Severe exposure eventually leads to haemorrhagic necrosis of the brain and spinal cord, but even single exposures (30 minutes at 4 ATA) produce ultrastructural changes in anterior horn grey matter.


Predictable prevention of cellular changes by administration of drugs is not yet feasible. In animal experiments, many different pharmacological agents have been shown to have a protective effect against toxic effects of oxygen. The agents include disulfiram (also described in animals to potentiate toxicity), glutathione, lithium, iso-nicotinic acid, hydrazide, GABA and sympathetic blocking agents. None of these agents is in prophylactic clinical use at present. Prevention of convulsions by anaesthetics or anticonvulsant agents removes only this overt expression of toxicity, and damage at the cellular level will continue.

The only current safe approach is to place limits on exposure. These limits depend on the PO2, the duration and the conditions of exposure (e.g. ‘wet dive’ or in a dry chamber, at exercise or rest, intermittent or continuous).

The Royal Navy and Royal Australian Navy place a limit for pure oxygen diving of 9 metres for a resting dive and 7 metres for a working dive. The US Navy relates the maximum duration of exposure to the depth (see Table 17.2).

The US Navy formerly required divers to undergo a test exposure of 30 minutes at 60 feet breathing 100 per cent oxygen to eliminate those divers who are unusually susceptible10. This does not take into account the marked variation in individuals from day to day or the marked influence of the exposure environment. Some individuals may be excessively oxygen sensitive, but the variability makes this uncertain and difficult to screen for. The oxygen tolerance test probably has no value in assessing normal dive candidates.

An awareness of levels at which toxicity is likely, and close observation for early signs such as lip twitching, should reduce the incidence of convulsions. If early signs are noted, the subject should signal his or her companion, stop excessive exertion and hyperventilate. However, premonitory symptoms or signs are unlikely in the working diver in the water.

In chamber therapy, most therapeutic tables do not prescribe 100 per cent oxygen deeper than 2.8 ATA. Periods of air breathing are used to interrupt the exposure to high levels of oxygen and thus reduce the likelihood of toxicity. Animal studies have demonstrated that interrupted exposure delays the onset of CNS toxicity by up to 100 per cent.

Electroencephalographic monitoring has not proved useful in predicting imminent convulsions.

When treating serious cases of DCS where the risks of oxygen toxicity are acceptable, drugs such as diazepam may be used to reduce the effects of toxicity. If available, most practitioners would prefer the option to use helium-oxygen mixtures to reduce the risk of toxicity.

Oxygen-breathing divers are advised to avoid the following:

  1. Exposure while febrile.
  2. Drugs that increase tissue CO2, e.g. opiates, carbonic anhydrase inhibitors.
  3. Aspirin, steroids, sympathomimetic agents.
  4. Stimulants such as caffeine (e.g. coffee).
  5. Fluorescent lights.


The initial aim of treatment is to avoid physical trauma associated with a grand mal convulsion. A padded tongue depressor to prevent tongue biting may be useful in a chamber. In contrast to epilepsy, hypoxia is not a concern, at least initially.

In the water, the traditional advice was that the diver should be brought to the surface only after the tonic phase of the convulsion ceased, but this practice has been challenged and is no longer the recommendation of the Diving Committee of the Undersea and Hyperbaric Medical Society11. The same action is often indicated in compression chambers, but with allowance made for decompression staging. If it is against the interests of the patient to ascend, it is usually a simple matter to reduce the oxygen in the breathing mixture.

Anticonvulsants may be used in exceptional circumstances. Phenytoin has been successfully used to stop convulsions in a patient with cerebral air embolism who was treated with hyperbaric oxygen. Diazepam is also very effective, as is the induction of anaesthesia with propofol.

The management of oxygen toxicity in the recompression chamber