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The greatest danger faced by divers who use oxygen-enriched gas mixtures is central nervous system oxygen toxicity (CNS-OT). CNS-OT is characterised by convulsions resembling grand-mal epileptic seizures, which may terminate in drowning and death. Elevated arterial levels of carbon dioxide (CO(2)) (hypercapnia) represent a major risk factor for CNS-OT when breathing hyperoxic gas mixtures. To reduce the risk of a diver being involved in a CNS-OT incident due to hypercapnia, candidates for combat diving are examined at our institute using a routine physiological training procedure, in which they are tested for CO(2) detection and retention. We present the case of a candidate for combat diving, who unexpectedly exhibited signs typical of CNS-OT while breathing pure oxygen under normobaric conditions with > 3 kPa inspired CO(2). Severe headache and nausea, as well as facial muscle twitching, appeared during one of these routine tests. Subsequent medical examination including neurological tests, magnetic resonance imaging and an electroencephalogram were unremarkable. To the best of our knowledge, an event such as this has never previously been published in the medical literature. We present a discussion of the case, and a review of the relevant literature regarding CO(2) as a risk factor for the development of CNS-OT

Central nervous system oxygen toxicity is a major risk in closed-circuit diving, and the risk increases with elevation of the inspired carbon dioxide (CO2). Mandatory tests for CO2 retention and detection are common practice at the Israel Naval Medical Institute, for the instruction and selection of combat divers at an advanced stage in their training. Read test is a simpler test of the ventilatory response to CO2. Positive correlation between parameters from Read and mandatory tests, enable conducting the test at an earlier stage in diving candidates. In the mandatory test, divers (n = 45) breathing various levels of CO2 in oxygen, and tested for the detection and retention of CO2 reported their sensations. In the Read test, we recorded end-tidal CO2 and ventilation in subjects as they rebreathed from rubber bag. The slope of ventilation was calculated as a function of end-tidal CO2. There was low correlation between any of the parameters from our test and the Read test. There was low insignific...

Performance and safety are impaired in employees engaged in shift work. Combat divers who use closed-circuit oxygen diving apparatus undergo part of their training during the night hours. The greatest risk involved in diving with such apparatus is the development of central nervous system oxygen toxicity (CNS-OT). We investigated whether the switch from day-to-night activity may be a risk factor for the development of CNS-OT using a diurnal animal model, the fat sand rat (Psammomys obesus). Animals were kept on a 12:12 light-dark schedule (6 a.m. to 6 p.m. at 500 lx). The study included two groups: (1) Control group: animals were kept awake and active during the day, between 09:00 and 15:00. (2) Experimental group: animals were kept awake and active during the night, between 21:00 and 03:00, when they were exposed to dim light in order to simulate the conditions prevalent during combat diver training. This continued for a period of 3 weeks, 5 days a week. On completion of this phase, 6-sulphatoxymelatonin (6-SMT) levels in urine were determined over a period of 24 h. Animals were then exposed to hyperbaric oxygen (HBO). To investigate the effect of acute melatonin administration, melatonin (50 mg/kg) or its vehicle was administered to the animals in both groups 20 min prior to HBO exposure. After the exposure, the activity of superoxide dismutase, catalase and glutathione peroxidase was measured, as were the levels of neuronal nitric oxide synthase (nNOS) and overall nitrotyrosylation in the cortex and hippocampus. Latency to CNS-OT was significantly reduced after the transition from day-to-night activity. This was associated with alterations in the level of melatonin metabolites secreted in the urine. Acute melatonin administration had no effect on latency to CNS-OT in either of the groups. Nevertheless, the activity of superoxide dismutase and catalase, as well as nitrotyrosine and nNOS levels, were altered in the hippocampus following melatonin administration. On the basis of these results, we suggest that a switch from diurnal to nocturnal activity may represent an additional risk factor for the development of CNS-OT. Utilizing a diurnal animal model may contribute to our understanding of the heightened risk of developing CNS-OT when diving with closed-circuit oxygen apparatus at night.

It is commonly accepted that hyperbaric oxygen-induced seizures, the most severe manifestation of central nervous system oxygen toxicity, are harmless. However, this hypothesis has not been investigated in depth. We used apoptotic markers to determine whether cells in the cortex and hippocampus were damaged by hyperbaric oxygen-induced seizures in mice. Experimental animals were exposed to a pressure of 6 atmospheres absolute breathing oxygen, and were randomly assigned to two groups sacrificed 1h after the appearance of seizures or 7 days later. Control groups were not exposed to hyperbaric oxygen. Caspase 9, caspase 3, and cytochrome c were used as apoptotic markers. These were measured in the cortex and the hippocampus, and compared between the groups. Levels of caspase 3, cytochrome c, and caspase 9 in the hippocampus were significantly higher in the hyperbaric oxygenexposed groups compared with the control groups 1 week after seizures (p0.01). The levels of two fragments of caspase 9 in the cortex were higher in the control group compared with the hyperbaric oxygen-exposed group 1h after seizures (p0.01). Hyperbaric oxygen-induced seizures activate apoptosis in the mouse hippocampus. The reason for the changes in the cortex is not understood. Further investigation is necessary to elucidate the mechanism underlying these findings and their significance.

Elevated arterial Pco2 (hypercapnia) has a major effect on central nervous system oxygen toxicity in diving with a closed-circuit breathing apparatus. The purpose of the present study was to follow up the ability of divers to detect CO2 and to determine the CO2 retention trait after 1 year of active oxygen diving with closed-circuit apparatus. Ventilatory and perceptual responses to variations in inspired CO2 (range: 0–5.6 kPa, 0–42 Torr) during moderate exercise were assessed in Israeli Navy combat divers on active duty. Tests were carried out on 40 divers during the novice oxygen diving phase (ND) and the experienced oxygen diving phase. No significant changes were found between the two phases for the minimal mean inspired Pco2 that could be detected. The mean (with SD in parentheses) end-tidal Pco2 during exposure to an inspired Pco2 of 5.6 kPa (42 Torr) was significantly higher in the novice diving phase than in the experienced diving phase [8.1 kPa (SD 0.7), 62 Torr (SD 5) and 7.8 kPa (SD 0.6), 59 Torr (SD 4), respectively; P ≤ 0.001]. One year of shallow oxygen diving activity with a closed-circuit apparatus does not affect the ability to detect CO2 nor does it lead to increased CO2 retention; rather, it may even bring about a decrease in this trait. This finding suggests that acquiring experience in oxygen diving with a closed-circuit apparatus at shallow depths does not place the diver at a greater risk of central nervous system oxygen toxicity due to CO2 retention.

Oxygen toxicity of the central nervous system (CNS-OT) can occur during diving with oxygen-enriched gas mixtures, or during hyperbaric medical treatment. CNS-OT is characterised by convulsions and sudden loss of consciousness, which may be fatal in diving. Heat acclimation is known to provide cross-tolerance to various forms of stress in different organs, including the brain. We hypothesised that heat acclimation may delay the onset of CNS-OT in the rat. Male Sprague–Dawley rats were acclimated to an ambient temperature of 32 °C for 4 weeks. Rats in the control group were kept at 24 °C. Both groups were exposed to oxygen at 608 kPa. EEG was recorded continuously until the appearance of the first electrical discharge preceding clinical convulsions. CO2 production was measured simultaneously with the EEG. Latency to CNS-OT was measured and brain samples were taken for evaluation of heat shock protein 72 (HSP72) levels by Western blot analysis at the end of the acclimation period and during 4 weeks of deacclimation. Latency to CNS-OT was twice as long in the heat-acclimated rat, with insignificant changes in CO2 production. This prolongation continued for 2 weeks during deacclimation. There was a significant increase in the level of HSP72 following heat acclimation, with a subsequent decrease during deacclimation. We conclude that heat acclimation prolongs latency to CNS-OT in a way that does not involve changes in metabolic rate. During deacclimation there was a linear relationship between latency to CNS oxygen toxicity and the level of HSP72. A possible beneficial effect of HSP72 is discussed.

Central nervous system oxygen toxicity (CNS-OT) can occur in humans at pressures above 2 atmospheres absolute (ATA), and above 4.5 ATA in the rat. Pulmonary oxygen toxicity appears at pressures above 0.5 ATA. We hypothesized that exposure to mild HBO following extreme exposure might provide protection against CNS, but not pulmonary oxygen toxicity. We measured the activity of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX), and nitrotyrosine and nNOS levels in the brain and lung in the following groups: (1) Sham rats, no pressure exposure (SHAM); (2) Exposure to 6 ATA oxygen for 60% of latency to CNS-OT (60%LT); (3) Exposure to 6 ATA for 60% of latency to CNS-OT, followed by 20 min at 2.5 ATA for recovery (REC); (4) Exposure to 6 ATA for 60% of latency to CNS-OT, followed by 20 min at 2.5 ATA oxygen and a subsequent increase in pressure to 6 ATA until the appearance of convulsions (CONV); (5) Control rats exposed to 6 ATA until the appearance of convulsions (C). SOD and CAT activity were reduced in both brain and lung in the REC group. GPX activity was reduced in the hippocampus in the REC group, but not in the cortex or the lung. nNOS levels were reduced in the hippocampus in the REC group. Contrary to our hypothesis, no difference was observed between the brain and the lung for the factors investigated. We suggest that at 2.5 ATA and above, CNS and pulmonary oxygen toxicity may share similar mechanisms.

We examined the hypothesis that repeated exposure to non-convulsive hyperbaric oxygen (HBO) as preconditioning provides protection against central nervous system oxygen toxicity (CNS-OT). Four groups of rats were used in the study. Rats in the control and the negative control (Ctl-) groups were kept in normobaric air. Two groups of rats were preconditioned to non-convulsive HBO at 202 kPa for 1h once every other day for a total of three sessions. Twenty-four hours after preconditioning, one of the preconditioned groups and the control rats were exposed to convulsive HBO at 608 kPa, and latency to CNS-OT was measured. Ctl- rats and the second preconditioned group (PrC-) were not subjected to convulsive HBO exposure. Tissues harvested from the hippocampus and frontal cortex were evaluated for enzymatic activity and nitrotyrosine levels. In the group exposed to convulsive oxygen at 608 kPa, latency to CNS-OT increased from 12.8 to 22.4 min following preconditioning. A significant decrease in the activity of glutathione reductase and glucose-6-phosphate dehydrogenase, and a significant increase in glutathione peroxidase activity, was observed in the hippocampus of preconditioned rats. Nitrotyrosine levels were significantly lower in the preconditioned animals, the highest level being observed in the control rats. In the cortex of the preconditioned rats, a significant increase was observed in glutathione S-transferase and glutathione peroxidase activity. Repeated exposure to non-convulsive HBO provides protection against CNS-OT. The protective mechanism involves alterations in the enzymatic activity of the antioxidant system and lower levels of peroxynitrite, mainly in the hippocampus.

We have previously determined the thresholds for CO2 detection (conscious recognition of elevated CO2) and retention in male divers, beyond which a diving candidate should not continue his diving activity due to an increased risk of CNS oxygen toxicity. The purpose of the present study was to establish whether there is a difference in end tidal PCO2 between male and female divers who use oxygen-enriched gas mixtures. Ventilatory and perceptual responses to variations in inspired CO2 (range 0-42 mm Hg) were assessed during moderate exercise in 18 males and 18 females. End tidal PCO2 was lower in the female divers when breathing oxygen with 42 mm Hg CO2 (58.2±3.0 mm Hg vs. 61.5±4.5 mm Hg, P0.03). These results suggest that female divers have a lower end tidal CO2 than males when breathing a hyperoxic gas mixture during exercise, which might imply that women are less susceptible to CNS oxygen toxicity than men.

We have previously shown that heat acclimation provides protection against central nervous system oxygen toxicity (CNS-OT). This was well correlated with increased levels of heat shock protein 72 (HSP72). We now examine other antioxidative defenses against CNS-OT that are correlated with heat acclimation. Two groups of male Sprague-Dawley rats were used. The heat-acclimated group (HA) was exposed for 4 wk to 32°C, and the control group (C) was maintained at 24°C. At the end of the acclimation period, rats were exposed to oxygen at 608 kPa. EEG was recorded continuously until appearance of the first electrical discharge. Brain samples were taken from each group after exposure to pressure. Levels of the antioxidant enzymes CuZnSOD, MnSOD, catalase, and glutathione peroxidase, as well as levels of HSP72, were quantified by Western blot. Comparative proteome analysis of the brains of HA and C rats was carried out using two-dimensional electrophoresis and mass spectrometry to define protein spot alterations. Levels of HSP72 and CuZnSOD were higher in HA rats. Levels of the other antioxidant enzymes were not affected significantly by heat acclimation. Differences in the levels of four protein spots identified as α-synuclein, valosin-containing protein, adenylate kinase 1 (AK1), and the mitochondrial H+-ATP synthase α subunit were found between HA and C rats. We conclude that elevation of HSP72, CuZnSOD, AK1, and the mitochondrial H+-ATP synthase α subunit and possible phosphorylation of α-synuclein—all proteins involved in oxidative stress or energy conservation—might contribute to the prolongation of latency to CNS-OT induced by heat acclimation.

Divers and patients lacking glucose-6-phosphate dehydrogenase (G6PD) may face a serious threat of central nervous system oxygen toxicity (CNS-OT) during exposure to hyperbaric oxygen (HBO), due to the important part played by G6PD in cellular redox balance. Our objective was to investigate G6PD deficiency as a risk factor for CNS-OT. We exposed G6PD-deficient (G6PDdef) and wild type (WT) mice to HBO at 405 kPa. Latency to CNS-OT was measured by observing the animal and monitoring the time to appearance of convulsions. Changes in glutathione peroxidase (GPx) and catalase activity were measured in red blood cells, and levels of endothelial and neuronal nitric oxide synthase (eNOS and nNOS) and 3-nitrotyrosine (NT) were measured in extracts of whole brain tissue by Western blot analysis. Unexpectedly, latency to CNS-OT was more than twice as long in G6PDdef mice compared with WT (36.9 ± 15.4 and 15.6 ± 13.2 min, respectively, P < 0.005). No significant differences were found in GPx and catalase activity or in protein levels of eNOS. However, nNOS and NT levels were lower in G6PDdef mice compared with WT (50.6%, P < 0.01 and 52.8%, P < 0.05, respectively). Our results suggest that the enhanced resistance of G6PDdef mice to HBO is due in part to a reduction in nNOS and NT levels in the brain. We conclude that G6PD deficiency at the level of the animals in the present study may not be a risk factor for developing CSN-OT, but this remains to be verified for human subjects.