Hyperbaric O2 Research Articles

Cefalea secundaria a intoxicación por monóxido de carbono

Chronic intoxication due to carbon monoxide (CO) is a condition in which the frequency is underestimated since the clinical features are nonspecific. It is important since serious neurological sequelae may result: an extrapyramidal syndrome, dementia or a vegetative state. The diagnosis is established when there are venous blood levels of carboxyhemoglobin greater than 10%. Early treatment with hyperbaric O2 rapidly improves the symptoms and avoids the development of neurological sequelae. We report the case of a 30 year old woman who was admitted to hospital for investigation into two episodes of loss of consciousness with vomiting and subsequent somnolence not accompanied by other neurological sequelae. For the previous eight months she had had daily pulsatile biparietal headaches, sometimes accompanied by a fainting feeling, nausea and vomiting. During her admission she remained asymptomatic and all neurophysiological, cardiological and neuroimaging studies were normal. The day after medical discharge she returned with the same clinical condition. A woman who lived with her and accompanied her also complained of similar symptoms. Venous gasometry showed raised levels of carboxyhemoglobin in both the patient (30.4%) and her companion (31.2%). Treatment with hyperbaric 100% O2 reverted the symptoms within a few hours. Later studies showed that the domestic gas burner was faulty. Occult CO intoxication causes headache which often requires differential diagnosis from psychiatric disorders and episodes of migraine. In patients with refractory nonspecific headache, irregular course and systemic symptoms, usually in winter, CO intoxication should be considered to be a possible cause. Diagnosis is based on finding venous blood levels of carboxyhemoglobin of over 10%. Early treatment avoids lesion of the globus pallidus and irreversible extrapyramidal sequelae.

Normobaric CO2 and hyperbaric O2 stimulate the same neurons in the solitary complex

We recently reported that neurons in the dorsocaudal chemosensitive area, the solitary complex (SC), are stimulated by reactive oxygen species (ROS) during acute hyperbaric oxygen (HBO2), suggesting that oxidative stress modulates cardiorespiratory networks [1,2]. Hyperoxia is known to have various effects on car-diorespiratory function [3,4], and it has been proposed that central hypoventilation syndromes, for example, SIDS, are due in part to increased oxidative stress of neurons after birth [5]. Thus, we have tested the hypothesis that excitability of CO2-chemosensitive neurons in the caudal SC is altered during oxidative stress at normobaric and hyperbaric pressures. Intracellular recordings were made from SC neurons in 300 μm thick medullary slices prepared from weaned and adult rats. Control medium was equilibrated with 95% O2 -5% CO2 at barometric pressure (PB) ~1 atmosphere absolute (ATA) (medium PO2 ~720 Torr, PCO2 ~38 Torr). A slice was maintained in a hyperbaric chamber and exposed to one or more of the following conditions (~37°C): 1)normobaric hypercapnia (8–20 mins 15% CO2 in O2) to test for CO2 chemosensitivity; 2)normocapnic HBO2 (10–20 mins 98.3% O2 -1.65% CO2 at PB 3.3 ATA) and 3)pro-oxidants at PB ~1ATA (8–10 mins 500 μM Chloramine-T or 1 mM N-chlorosuccinimide) to test for the effects of ROS; and 4)hypercapnic HBO2 (10–20 mins 95% O2 -5% CO2 at PB 3.2ATA) to test for the effects of hypercapnic acidosis on sensitivity to HBO2[6,7,9]. During HBO2, tissue PO2 (mean ± S.E.) at the core of the slice (150 μm depth) increased from 291 ± 20 to 1517 ± 15 Torr [6]. Focusing on the caudal SC, 62% (18/29) of the neurons tested were depolarized by normobaric hypercapnia. Of these, 78% (14/18) were stimulated by normocapnic HBO2 and pro-oxidants. When hypercapnia and HBO2 were combined (hypercapnic HBO2), the firing rate response was greater to both stimuli than to the sum of their individual responses. Most neurons (9/11) that were CO2 insensitive were also unresponsive to HBO2 and/or pro-oxidants. We conclude that acute exposure to oxidative stress, either by increased tissue PO2 at hyperbaric pressure or pro-oxidants at normobaric pressure, stimulates CO2-chemosensitive neurons in the SC, suggesting that central chemosensitivity may likewise be affected by oxidative stress. It is unclear, however, if the strong neuronal excitation observed when hypercapnic acidosis and HBO2 are combined is due to increased lipid peroxidation during intracellular acidosis [7,8,9] or to the effect of increased ROS on CO2 chemosensitivity.

Nitric oxide and cerebral blood flow responses to hyperbaric oxygen.

We have tested the hypothesis that cerebral nitric oxide (NO) production is involved in hyperbaric O(2) (HBO(2)) neurotoxicity. Regional cerebral blood flow (rCBF) and electroencephalogram (EEG) were measured in anesthetized rats during O(2) exposure to 1, 3, 4, and 5 ATA with or without administration of the NO synthase inhibitor (N(omega)-nitro-L-arginine methyl ester), L-arginine, NO donors, or the N-methyl-D-aspartate receptor inhibitor MK-801. After 30 min of O(2) exposure at 3 and 4 ATA, rCBF decreased by 26-39% and by 37-43%, respectively, and was sustained for 75 min. At 5 ATA, rCBF decreased over 30 min in the substantia nigra by one-third but, thereafter, gradually returned to preexposure levels, preceding the onset of EEG spiking activity. Rats pretreated with N(omega)-nitro-L-arginine methyl ester and exposed to HBO(2) at 5 ATA maintained a low rCBF. MK-801 did not alter the cerebrovascular responses to HBO(2) at 5 ATA but prevented the EEG spikes. NO donors increased rCBF in control rats but were ineffective during HBO(2) exposures. The data provide evidence that relative lack of NO activity contributes to decreased rCBF under HBO(2), but, as exposure time is prolonged, NO production increases and augments rCBF in anticipation of neuronal excitation.

Hemodilution, cerebral O2 delivery, and cerebral blood flow: a study using hyperbaric oxygenation.

Hemodilution reduces blood viscosity and O2 content (CaO2) and increases cerebral blood flow (CBF). Viscosity and CaO2 may contribute to increasing CBF after hemodilution. However, because hematocrit is the major contributor to blood viscosity and CaO2, it has been difficult to assess their relative importance. By varying blood viscosity without changing CaO2, prior investigation in hemodiluted animals has suggested that both factors play roughly equal roles. To further investigate the relationship of hemodilution, blood viscosity, CaO2, and CBF, we took the opposite approach in hemodiluted animals, i.e., we varied CaO2 without changing blood viscosity. Hyperbaric O2 was used to restore CaO2 to normal after hemodilution. Pentobarbital sodium-anesthetized rats underwent isovolumic hemodilution with 6% hetastarch, and forebrain CBF was measured with [3H]nicotine. One group of animals did not undergo hemodilution and served as controls (Con). In the three experimental groups, hematocrit was reduced from 44% to 17-19%. Con and hemodiluted (HDil) groups were ventilated with 40% O2 at 101 kPa (1 atmosphere absolute), which resulted in CaO2 values of 19.7 +/- 1.3 and 8.1 +/- 0.7 (SD) ml O2/dl, respectively. A second group of hemodiluted animals (HBar) was ventilated with 100% O2 at 506 kPa (5 atmospheres absolute) in a hyperbaric chamber, which restored CaO2 to an estimated 18.5 +/- 0.5 ml O2/dl by increasing dissolved O2. A fourth group of hemodiluted animals (HCon) served as hyperbaric controls and were ventilated with 10% O2 at 506 kPa, resulting in CaO2 of 9.1 +/- 0.6 ml O2/dl. CBF was 79 +/- 19 ml. 100 g-1. min-1 in the Con group and significantly increased to 123 +/- 9 ml. 100 g-1. min-1 in the HDil group. When CaO2 was restored to baseline with dissolved O2 in the HBar group, CBF decreased to 104 +/- 20 ml. 100 g-1. min-1. When normoxia was maintained during hyperbaric exposure in the HCon group, CBF was 125 +/- 18 ml. 100 g-1. min-1, a value indistinguishable from that in normobaric HDil animals. Our data demonstrate that the reduction in CaO2 after hemodilution is responsible for 40-60% of the increase in CBF.

Isocapnic hyperpnea accelerates carbon monoxide elimination.

A major impediment to the use of hyperpnea in the treatment of CO poisoning is the development of hypocapnia or discomfort of CO2 inhalation. We examined the effect of nonrebreathing isocapnic hyperpnea on the rate of decrease of carboxyhemoglobin levels (COHb) in five pentobarbital-anesthetized ventilated dogs first exposed to CO and then ventilated with room air at normocapnia (control). They were then ventilated with 100% O2 at control ventilation, and at six times control ventilation without hypocapnia ("isocapnic hyperpnea") for at least 42 min at each ventilator setting. We measured blood gases and COHb. At control ventilation, the half-time for elimination of COHb (t1/2) was 212 +/- 17 min (mean +/- SD) on room air and 42 +/- 3 min on 100% O2. The t1/2 decreased to 18 +/- 2 min (p < 0.0005) during isocapnic hyperpnea. In two similarly prepared dogs treated with hyperbaric O2, the t1/2 were 20 and 28 min. We conclude that isocapnic hyperpnea more than doubles the rate of COHb elimination induced by normal ventilation with 100% O2. Isocapnic hyperpnea could improve the efficacy of the standard treatment of CO poisoning, 100% O2 at atmospheric or increased pressures.

The effect of nitric oxide and hyperbaric O2 on regulation of post ischemic cerebral circulation: [formula omitted] Anatoly Rakier, Reymond Coleman, Ori S. Better and Moshe Feinsod. Technion, Faculty of Medicine, Dep. of Physiology and Rambam Medical Center, Haifa, Israel

The effect of nitric oxide and hyperbaric O2 on regulation of post ischemic cerebral circulation: [formula omitted] Anatoly Rakier, Reymond Coleman, Ori S. Better and Moshe Feinsod. Technion, Faculty of Medicine, Dep. of Physiology and Rambam Medical Center, Haifa, Israel

Enterococcus faecalis glutathione reductase: purification, characterization and expression under normal and hyperbaric O2 conditions.

Glutathione reductase is found ubiquitously in eukaryotes and Gram-negative bacteria, and plays a significant role in bacterial defense against oxidative stress. Glutathione reductase from the Gram-positive bacterium Enterococcus faecalis was purified to homogeneity using anion exchange, hydrophobic interaction, and affinity chromatography. The homogeneous 49-kDa enzyme contained 1 mol bound FAD per subunit. The determined N-terminal amino acid sequence of the E. faecalis enzyme displays significant identity with glutathione reductases from other Gram-negative and Gram-positive bacteria, as well as yeast and human erythrocyte reductases. The kinetic mechanism is ping-pong, and the determined kinetic parameters exhibited by the E. faecalis glutathione reductase are similar to those found for glutathione reductases from yeast, Escherichia coli, and human erythrocyte. A two-fold increased expression of glutathione reductase activity and a three-fold induction of glutathione peroxidase activity were observed under hyperbaric O2 growth conditions without a corresponding change in the total glutathione and soluble thiol content. The difference in the expression of the enzyme, and its cognate substrate's intracellular concentration, under these conditions suggest that the gene encoding glutathione reductase is responsive to oxygen concentration, but that the genes encoding the glutathione synthesizing enzymes are not linked to an oxygen-sensitive promoter.

Involvement of manganese peroxidase in the transformation of macromolecules from low-rank coal by Phanerochaete chrysosporium

Manganese peroxidase (Mn peroxidase) catalyses the oxidation of Mn(II) to Mn(III), a diffusible non-specific oxidant likely to be involved in the transformation of polyphenolic macromolecules from brown coal by the white-rot fungus Phanerochaete chrysosporium. We report here that solubilised macromolecules from Morwell brown coal were depolymerised by Mn(III) ions when incubated under hyperbaric O2. However, under N2 or air they were polymerised, suggesting that net depolymerisation by Mn(III) requires molecular oxygen to inhibit coupling of coal radicals. Coal macromolecules were also polymerised when separated by a semipermeable membrane from a culture of P. chrysosporium or from a solution of Mn peroxidase, Mn(II) and H2O2, probably by Mn(III) crossing the membrane. In oxygenated cultures in which Mn peroxidase␣was up-regulated by Mn(II), the extent of depolymerisation correlated with cumulative Mn peroxidase activity suggesting that Mn-peroxidase-generated Mn(III) has a central role in initial depolymerisation of coal molecules in vivo. However, mutant ME446-B17-1, which produces Mn peroxidase but not lignin peroxidase, polymerised coal macromolecules in oxygenated cultures. In sum, it appears Mn peroxidase can both polymerise and depolymerise brown coal macromolecules and that, in vivo, both hyperbaric O2 and lignin peroxidase are also required to force net depolymerisation to products assimilable by cells.

L-arginine-NO pathway and CNS oxygen toxicity.

The involvement of the L-arginine-nitric oxide (NO) pathway in the pathogenesis of hyperoxia-induced seizures was studied by using agents controlling NO levels. We selected two inhibitors of nitric oxide synthase, the systemic inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME) and the novel cerebral-specific inhibitor 7-nitroindazole, and two generators of NO, the NO donor S-nitroso-N-acetylpenicillamine and the physiological precursor L-arginine. Rats with chronic cortical electrodes were injected intraperitoneally with different doses of one of the agents or their vehicles before exposure to 0.5 MPa O2 and O2 with 5% CO2 at an absolute pressure of 0.5 MPa. The duration of the latent period until the onset of electrical discharges in the electroencephalogram was used as an index of central nervous system O2 toxicity. The two nitric oxide synthase inhibitors L-NAME and 7-nitroindazole significantly prolonged the latent period to the onset of seizures on exposure to both hyperbaric O2 and to the hypercapnic-hyperoxic mixture. Pretreatment with the NO donor S-nitroso-N-acetylpenicillamine significantly shortened the latent period, whereas L-arginine, the physiological precursor of NO, significantly prolonged the latent period to onset of seizures. Our results suggest that the L-arginine-NO pathway is involved in the pathophysiology of hyperoxia-induced seizures via various regulating mechanisms.

Inhibition of human neutrophil beta2-integrin-dependent adherence by hyperbaric O2.

Animal and clinical investigations have reported that exposure to hyperbaric O(2) improved the outcome of some reperfusion injuries. Animal studies have suggested that this may be due to an inhibition of leukocyte adherence to injured endothelium. This investigation tested the hypothesis that exposure to hyperbaric O(2) would inhibit beta2-integrin-dependent adherence of human neutrophils. Subjects were exposed to O(2) at partial pressures of up to 3 atmospheres absolute (ATA; 1 ATA = 0.1 MPa) for 45 min, and neutrophil binding to nylon columns and to fibrinogen-coated surfaces was measured. Exposure to O(2) at 2.8 or 3.0 ATA inhibited beta2-integrin-dependent neutrophil adherence but had no effect on the cell-surface expression of beta2-integrins, respiratory burst in response to phorbol ester, or non-beta2-integrin-dependent adherence to plastic plates coated with a fibronectin-like protein. beta2-Integrin adherence was restored by incubating blood with 8-bromoguanosine 3',5'-cyclic monophosphate (cGMP) and hyperbaric O(2) inhibited synthesis of cGMP by neutrophils stimulated with N-formyl-Met-Leu-Phe (FMLP). In studies of cell fractions, the activity of membrane guanylate cyclase was found to be increased by incubation with FMLP as well as by atrial natriuretic peptide (ANP) plus ATP. Hyperbaric O(2) had no effect on the basal activity of soluble or membrane-bound guanylate cyclase. However, hyperbaric O(2) inhibited the function of both the extracellular binding domain of membrane guanylate cyclase as well as intracellular catalytic activity. There are approximately 7,300 membrane guanylate cyclase molecules per cell, based on binding studies with ANP, with a dissociation constant of approximately 450 pM. Hyperbaric O(2) inhibits the function of human neutrophil beta2-integrins by a process linked to impaired synthesis of cGMP.

Effects of hypoxia and hypercapnia on contact lens-induced corneal acidosis.

It has been assumed that contact lens wear (CLW) may induce stromal acidosis, which is a result of corneal hypoxia and the accumulation of CO2 (hypercapnia) at the tear-lens interface. However, it has not been directly shown whether hypoxia and hypercapnia are the only causes of CL-Induced corneal acidification. In this study, we provide preliminary data about the relative contributions of hypercapnia and hypoxia to CL-induced stromal acidification by monitoring pH while the cornea was exposed to a hyperbaric oxygen atmosphere. This paradigm minimized if not eliminated the pH effects of lens-induced hypoxia on all but one subject without altering the pH effect of hypercapnia. Seven subjects were fitted with hydrogel lenses; 5 with low O2 transmissibility (Dk/LO2 = 14.0 x 10(-9) (cm/s) (ml O2/[ml x mm Hg)]), and 2 with medium O2 transmissibility (Dk/LO2 = 17.2 x 10(-9) (cm/s) (ml O2/[ml x mm Hg])) lenses. After lens insertion, modified goggles were fitted to control the corneal environment by exposing 1 eye to 20%O2 and 80%N2 (air), and the contralateral eye to 80%O2 and 20%N2 (hyperbaric O2). Corneal thickness (CT) was measured before CL insertion and over 120 min of wear. We assumed that corneal hypoxia was present if CT increased during the test period. Stromal pH was measured using a slitlamp fluorophotometer before lens insertion and at 20-min intervals for a total of 80 min. After 80 min of wearing the low Dk/L lens under hyperbaric exposure, 4 of 5 subjects showed reduced pH (mean delta pH = 0.23 +/- 0.05) and no increase in CT, suggesting that only hypercapnia was contributing to acidosis. For the same lens, but with exposure to air, 4 of 5 subjects showed a larger drop in pH (mean delta pH = 0.62 +/- 0.48) compared to hyperbaric exposure and an increase in CT, indicating that both hypoxia and hypercapnia reduced pH. Subjects wearing the medium Dk/L lens showed a small but equal drop in pH under both air and hyperbaric conditions without changes in CT, suggesting that only hypercapnia was contributing to acidosis. These preliminary results suggest that both mechanisms contribute to the pH shift accompanying CLW and that the contribution of hypercapnia is approximately 30%. Finally, the effects of hypercapnia and hypoxia are dependent on individual metabolic requirements and the transmissibility of the lens to O2 and CO2.

A Model for Predicting Central Nervous System Oxygen Toxicity from Hyperbaric Oxygen Exposures in Humans

Under certain circumstances, Navy divers breathe 100% O2 when working underwater. Serious symptoms of central nervous system (CNS) O2 toxicity can develop from hyperbaric O2 exposure; immersion and exercise are also known to exacerbate toxicity. We developed risk models for quantitative prediction of the probability of developing symptoms using a large set of human data in which occupational exposure conditions were simulated. Exposures were 5 to 265 min at PO2 levels from 20 to 50 feet of sea water (fsw) (1 fsw = 3.06 kPa). Approximately half of the exposures were to a single PO2, while the remainder were more complicated consisting of exposures to multiple levels of hyperbaric O2. In 688 trials, there were 42 exposure-stopping symptoms. We used maximum likelihood to estimate parameters, likelihood ratios to compare model fits, and chi 2 tests to judge goodness-of-fit of model predictions to observations. The modeling shows that risk has a steep PO2 dependence. A model with autocatalytic features fits the data as well as a simpler model: when PO2 is elevated beyond 34 fsw, risk accumulates rapidly without bound while accumulating toward an asymptote at lower PO2 levels. This autocatalytic feature of risk accumulation implies a testable hypothesis that substantial protection from human CNS O2 toxicity can be obtained from intermittent exposure (periodic exposure to lower PO2). The models predict that the probability of O2 toxicity is less than 7% with current Navy limits while breathing 95% O2. Probability of symptoms is < 1% if FIO2 is maintained at the United States Navy recommended level of 75%.

Oxygen transport to tissue by persistent bubbles: theory and simulations.

Persistent gas bubbles able to traverse capillaries can be prepared from a slowly permeating gas or with a mechanical structure surrounding a gas phase. If they are permeable to gases, such bubbles will carry O2 from the lungs to the tissues via the blood stream. Using a mathematical model based on physical laws, we present simulations of the behavior of bubbles stabilized by a slowly permeating gas (gas X). We show that the bubble persists longer if the tissue and venous blood contain N2 to dilute gas X and slow its outward diffusion. A 6-microns -diam bubble carries 0.11 pl of O2 during the breathing of pure O2, so 4.6 x 10(8) bubbles/ml in the blood will supply a normal arteriovenous difference. In conditions used for hyperbaric O2 therapy, a bubble carries approximately 0.26 pl of O2. Stabilized bubbles have the potential to transport O2 efficiently; they release O2 to tissue at high PO2 and require injection of only small amounts of a foreign substance.

The inactivation of dihydroxy-acid dehydratase in Escherichia coli treated with hyperbaric oxygen occurs because of the destruction of its Fe-S cluster, but the enzyme remains in the cell in a form that can be reactivated.

The enzyme dihydroxy-acid dehydratase previously has been shown to be inactivated in vivo in Escherichia coli within minutes of exposure to hyperbaric O2. In this paper, we show its inactivation is due to the destruction of its catalytically active [4Fe-4S] cluster. The inactivation is not followed by an appreciable decrease in the amount of dihydroxy-acid dehydratase protein as determined by Western blots. Thus, the protein from the inactivated enzyme remains unproteolyzed in the cells. Dihydroxy-acid dehydratase activity recovers after the cells treated with hyperbaric O2 are returned to ambient oxygen. Since this recovery in activity is not accompanied by a significant increase in dihydroxy-acid dehydratase protein and is not prevented by chloramphenicol, it appears primarily to be due to reactivation of the previously inactivated enzyme. The reactivation occurs by reconstitution of the enzyme's Fe-S cluster. These results demonstrate that this enzyme can cycle between forms in which the Fe-S cluster is either present or absent. The facile ability to cycle between these two forms would be compatible with a regulatory role in addition to a catalytic role for this enzyme.

Acute and chronic hyperbaric oxygen exposure in humans: effects on blood polyamines, adrenocorticotropin and beta-endorphin.

Plasma beta-endorphin, adrenocorticotropin (ACTH) and blood polyamine (spermidine and spermine) concentrations were evaluated in healthy adult male athletes undergoing hyperbaric oxygen exposure for 10 days (2.8 atm, 100% O2, 60 min daily). In the "acute phase", corresponding to the first day of treatment, and in the "acute in the chronic phase", corresponding to the values obtained on the 5th and 10th days after 60 min of hyperbaric O2, both ACTH and beta-endorphin levels increased significantly, whereas no variations were observed for polyamine concentrations. In the "chronic phase", corresponding to the basal values of the 5th and 10th days of treatment, we found a different pattern. In fact, the concentration of polyamines showed a remarkable enhancement, while ACTH and beta-endorphin levels remained unchanged. No significant variations were observed during hyperbarism with air. These results demonstrate different modifications of polyamines and beta-endorphin and ACTH in subjects submitted to hyperbaric oxygen exposure.

The inactivation of Fe-S cluster containing hydro-lyases by superoxide.

We report in this paper that highly purified Escherichia coli dihydroxy-acid dehydratase, fumarase A, fumarase B, and mammalian aconitase are inactivated by O2- with second order rate constants in the range of 10(6) to 10(7) M-1 s-1. Each of these enzymes belongs to the hydro-lyase class and contains catalytically active [4Fe-4S] clusters. Simultaneous with inactivation by O2- is the release of iron from their clusters. Our working hypothesis is O2- inactivates these enzymes by oxidizing their clusters to an unstable oxidation state, and cluster degradation follows. Consistent with this hypothesis is our observation that spinach dihydroxy-acid dehydratase, a member of the hydro-lyase class that has a catalytically active [2Fe-2S] cluster, is not inactivated and does not lose iron in the presence of O2-. Porcine fumarase, a member of the hydro-lyase class that does not contain an Fe-S cluster, is also not inactivated by O2-. We also report the rate constants for the inactivation of E. coli dihydroxy-acid dehydratase, fumarase A, fumarase B, and mammalian aconitase by O2 are close to 2 x 10(2) M-1 s-1, and the rate constants for the inactivation of E. coli dihydroxy-acid dehydratase and mammalian aconitase by H2O2 are about 10(3) M-1 s-1. E. coli dihydroxy-acid dehydratase has been reported previously to be inactivated in vivo when cells are grown in hyperbaric O2, presumably due to the increased O2- generated under these conditions. We report here that E. coli fumarase A, fumarase B, and aconitase are also inactivated in vivo by hyperbaric O2. Thermodynamic parameters for the oxidation of the cluster of aconitase by O2- and O2 are calculated.

Toxicology of hydrogen sulfide.

Significant progress has been made in determining the action of sulfide on the primary target organs. It is reasonably clear that sulfide causes both K(+)-channel-mediated hyperpolarization of neurons and potentiation of other inhibitory mechanisms. It is not clear whether these processes are similar to those that occur in anoxia. Changes in perinatal and adult brain neurotransmitter content and release may be related to clinical impairment of cognition. H2S exposures at concentrations below the current occupational limits cause physiological changes in pulmonary function, thus suggesting that asthmatics are at risk. Studies of fetal and neonatal brain tissue have shown an abnormal development, and the long-term consequences of these neuronal changes have not yet been assessed. Finally, new approaches to therapy are required, such as the use of agents that actively remove sulfide from its sites of action. This may prove more useful in preventing some of the long-term adverse sequelae than the use of nitrites and hyperbaric O2, although the latter should be used in cases of pulmonary edema.

Recovery of energy metabolism in rat brain after carbon monoxide hypoxia.

Carbon monoxide (CO) may inhibit mitochondrial electron transport in the brain and increase the toxic effects of the gas. This hypothesis was investigated in anesthetized rats during CO exposure and recovery at either normobaric or hyperbaric O2 concentrations. During exposure and recovery, we measured the oxidation level of cerebrocortical cytochrome c oxidase by differential spectroscopy and biochemical metabolites known to reflect aerobic energy provision in the brain. CO exposure (HbCO = 71 +/- 1%) significantly decreased blood pressure and cytochrome oxidation level. Cerebral ATP was maintained while lactate/pyruvate, glucose, and succinate rose, and phosphocreatine (PCr) fell, relative to control (P less than 0.05). Intracellular pH (pHi) calculated from the PCr equilibrium also declined during the exposures. During recovery, HbCO fell more rapidly at hyperbaric than at normobaric O2 levels, but returned to 10% or less in both groups by 45 min. Cytochrome oxidation state improved to 80% of control after 90 min at normobaric O2, but recovered completely after hyperbaric O2 (P less than 0.05). In normobaric O2, PCr and pHi continued to fall for 45 min after CO exposure and did not recover completely by 90 min. PCr and pHi in animals after hyperbaric O2 improved within 45 min, but also remained below control at 90 min. These data indicate that intracellular uptake of CO can impair cerebral energy metabolism, despite the elimination of HbCO from the blood.

Hyperbaric oxygen toxicity: role of thromboxane.

Exposing rabbits for 1 h to 100% O2 at 4 atm barometric pressure markedly increases the concentration of thromboxane B2 in alveolar lavage fluid [1,809 +/- 92 vs. 99 +/- 24 (SE) pg/ml, P less than 0.001], pulmonary arterial pressure (110 +/- 17 vs. 10 +/- 1 mmHg, P less than 0.001), lung weight gain (14.6 +/- 3.7 vs. 0.6 +/- 0.4 g/20 min, P less than 0.01), and transfer rates for aerosolized 99mTc-labeled diethylenetriamine pentaacetate (500 mol wt; 40 +/- 14 vs. 3 +/- 1 x 10(-3)/min, P less than 0.01) and fluorescein isothiocyanate-labeled dextran (7,000 mol wt; 10 +/- 3 vs. 1 +/- 1 x 10(-4)/min, P less than 0.01). Pretreatment with the antioxidant butylated hydroxyanisole (BHA) entirely prevents the pulmonary hypertension and lung injury. In addition, BHA blocks the increase in alveolar thromboxane B2 caused by hyperbaric O2 (10 and 45 pg/ml lavage fluid, n = 2). Combined therapy with polyethylene glycol- (PEG) conjugated superoxide dismutase (SOD) and PEG-catalase also completely eliminates the pulmonary hypertension, pulmonary edema, and increase in transfer rate for the aerosolized compounds. In contrast, combined treatment with unconjugated SOD and catalase does not reduce the pulmonary damage. Because of the striking increase in pulmonary arterial pressure to greater than 100 mmHg, we tested the hypothesis that thromboxane causes the hypertension and thus contributes to the lung injury. Indomethacin and UK 37,248-01 (4-[2-(1H-imidazol-1-yl)-ethoxy]benzoic acid hydrochloride, an inhibitor of thromboxane synthase, completely eliminate the pulmonary hypertension and edema.(ABSTRACT TRUNCATED AT 250 WORDS)

Oxygen and Wound Healing

Surgeons have been aware of the detrimental effect of ischemia and hypoxia on healing tissues. In order to assist repair in such circumstances, a variety of modalities including revascularization, flaps, and hyperbaric O2 have been developed. Although these are apparently successful from a clinical standpoint, only recently has experimental evidence demonstrated conclusively that oxygen is a controlling factor in wound repair. Furthermore, it is now clear that traditional expectations of repair can often be exceeded by increasing the partial pressure at which oxygen is supplied to wounds.