Optimization of oxygen tolerance extension in rats by intermittent exposure.

Optimization of oxygen tolerance extension by intermittent exposure was studied in groups of 20 rats exposed to systematically varied patterns of alternating oxygen and normoxic breathing periods at 4.0, 2.0, and 1.5 ATA. Oxygen periods of 20, 60, and 120 min were alternated with normoxic intervals that provided oxygen-to-normoxia ratios of 4:1, 2:1, 1:1, and 1:3. In general, median survival times had nearly linear relationships to increasing normoxic intervals with oxygen period held constant. Exceptions occurred at 4.0 and 2.0 ATA where a 5-min normoxic interval was too short for adequate recovery even with a 20-min oxygen period, and an oxygen period of 120 min was too long even with a normoxic interval of 30 min. These exceptions did not occur at 1.5 ATA. Survival time for many intermittent exposure patterns was equivalent to that for continuous exposure to an oxygen pressure definable as a time-weighted average of the alternating oxygen and normoxia periods. However, this predictive method underestimated the degree of protection achieved by several of the intermittent exposure patterns, especially those performed at 4.0 ATA. Results provided guidance for selection of intermittent exposure patterns for direct evaluation in humans breathing oxygen at 2.0 ATA. Definition of intermittent exposure patterns and conditions that produced prominent gains in oxygen tolerance can also facilitate the performance of future experiments designed to study potential mechanisms for oxygen tolerance extension by intermittent exposure. Heat shock and oxidation-specific stress proteins that are induced by exposure to oxidant injury are suggested for emphasis in such investigations.

Cerebral gas embolism absorption during hyperbaric therapy: theory.

Cerebral gas embolism is a serious consequence of diving. It is associated with decompression sickness and is assumed to cause severe neurological dysfunction. A mathematical model previously developed to calculate embolism absorption time based on in vivo bubble geometry is used in which various conditions of hyperbaric therapy are considered. Effects of varying external pressure and inert gas concentrations in the breathing mixtures, according to US Navy and Royal Navy diving treatment tables, are predicted. Recompression alone is calculated to reduce absorption times of a 50-nl bubble by up to 98% over the untreated case. Lowering the inhaled inert gas concentration from 67.5% to 50% reduces absorption time by 37% at a given pressure. Bubbles formed after diving and decompression with He are calculated to absorb up to 73% faster than bubbles created after diving and decompression with air, regardless of the recompression gas breathed. This model is a useful alternative to impractical clinical trials in assessing which initial step in hyperbaric therapy is most effective in eliminating cerebral gas embolisms should they occur.

Effects of prolonged oxygen exposure at 1.5, 2.0, or 2.5 ATA on pulmonary function in men (predictive studies V).

As part of a study of human organ O2 tolerance, lung flow-volume and spirometric measurements were performed repeatedly before, during, and after continuous O2 exposures at 1.5, 2.0, and 2.5 ATA for average durations of 17.7, 9.0, and 5.7 h, respectively (effects of O2 breathing at 3.0 ATA for 3.5 h were reported previously; J. M. Clark, R. M. Jackson, C. J. Lambertsen, R. Gelfand, W. D. B. Hiller, and M. Unger. J. Appl. Physiol. 71: 878-885, 1991). Additional measurements of pulmonary mechanical function, gas exchange, and alveolar inflammatory cells were obtained before and after O2 exposure. Rates of pulmonary symptom development and lung volume reduction increased progressively with elevation of O2 pressure. Average rates of vital capacity reduction over a useful range of O2 pressures provided a valuable general description of pulmonary O2 tolerance in humans. However, the existence of multiple pulmonary effects of O2 toxicity and the complexity of their interactions require awareness that deviations from the average relationships may occur in different individuals or under varying conditions of O2 exposure and subsequent recovery. The associated pulmonary function deficits may represent responses to a composite of direct and indirect effects of O2 poisoning, along with related consequences and subsequent reactions to those effects.

Hypoxic ventilatory sensitivity in men is not reduced by prolonged hyperoxia (Predictive Studies V and VI).

Potential adverse effects on the O2-sensing function of the carotid body when its cells are exposed to toxic O2 pressures were assessed during investigations of human organ tolerance to prolonged continuous and intermittent hyperoxia (Predictive Studies V and VI). Isocapnic hypoxic ventilatory responses (HVR) were determined at 1.0 ATA before and after severe hyperoxic exposures: 1) continuous O2 breathing at 1.5, 2.0, and 2.5 ATA for 17.7, 9.0, and 5.7 h and 2) intermittent O2 breathing at 2.0 ATA (30 min O2-30 min normoxia) for 14.3 O2 h within 30-h total time. Postexposure curvature of HVR hyperbolas was not reduced compared with preexposure controls. The hyperbolas were temporarily elevated to higher ventilations than controls due to increments in respiratory frequency that were proportional to O2 exposure time, not O2 pressure. In humans, prolonged hyperoxia does not attenuate the hypoxia-sensing function of the peripheral chemoreceptors, even after exposures that approach limits of human pulmonary and central nervous system O2 tolerance. Current applications of hyperoxia in hyperbaric O2 therapy and in subsea- and aerospace-related operations are guided by and are well within these exposure limits.

Relationship of 133Xe cerebral blood flow to middle cerebral arterial flow velocity in men at rest.

Cerebral blood flow (CBF) was measured by 133Xe clearance simultaneously with the velocity of blood flow through the left middle cerebral artery (MCA) over a wide range of arterial PCO2 in eight normal men. Average arterial PCO2, which was varied by giving 4% and 6% CO2 in O2 and by controlled hyperventilation on O2, ranged from 25.3 to 49.9 mm Hg. Corresponding average values of global CBF15 were 27.2 and 65.0 ml 100 g min-1, respectively, whereas MCA blood-flow velocity ranged from 42.8 to 94.2 cm/s. The relationship of CBF to MCA blood-flow velocity over the imposed range of arterial PCO2 was described analytically by a parabola with the equation: CBF = 22.8 - 0.17 x velocity + 0.006 x velocity2 The observed data indicate that MCA blood-flow velocity is a useful index of CBF response to change in arterial PCO2 during O2 breathing at rest. With respect to baseline values measured while breathing 100% O2 spontaneously, percent changes in velocity were significantly smaller than corresponding percent changes in CBF at increased levels of arterial PCO2 and larger than CBF changes at the lower arterial PCO2. These observed relative changes are consistent with MCA vasodilation at the site of measurement during exposure to progressive hypercapnia and also during extreme hyperventilation hypocapnia.

Human tolerance and physiological responses to exercise while breathing oxygen at 2.0 ATA.

Multiple physiological functions were monitored in ten men who performed two 30-min periods of 150-W ergometer exercise during 120-min exposures to O2 at 2.0 ATA. There were no convulsions or electroencephalographic manifestations of increased excitability. Sequential measurements of peripheral visual fields, pulmonary mechanical function, mental performance, and cardiovascular function during the resting recovery after each of the two exercise periods were not detectably altered from pre-exercise control values. Pre- and post-exposure measurements of visual acuity, accommodation, pupil diameter, visual cortical activity, and retinal electrical activity also revealed no significant differences. While CNS symptoms were absent, average arterial PCO2 rose by about 5 mm Hg during both exercise periods. This finding was confirmed in six subjects who performed four 6-min periods of continuous exercise at 50, 100, 150, and 200 W while breathing O2 at 2.0 ATA. Average arterial PCO2 rose nearly linearly from 34.3 mm Hg at rest to 44.0 mm Hg at 200 W. Arterial PCO2-related increments in brain blood flow and PO2 may explain part or all of the known detrimental influence of exercise on CNS O2 tolerance.

Pulmonary function in men after oxygen breathing at 3.0 ATA for 3.5 h.

As a pulmonary component of Predictive Studies V, designed to determine O2 tolerance of multiple organs and systems in humans at 3.0-1.5 ATA, pulmonary function was evaluated at 1.0 ATA in 13 healthy men before and after O2 exposure at 3.0 ATA for 3.5 h. Measurements included flow-volume loops, spirometry, and airway resistance (Raw) (n = 12); CO diffusing capacity (n = 11); closing volumes (n = 6); and air vs. HeO2 forced vital capacity maneuvers (n = 5). Chest discomfort, cough, and dyspnea were experienced during exposure in mild degree by most subjects. Mean forced expiratory volume in 1 s (FEV1) and forced expiratory flow at 25-75% of vital capacity (FEF25-75) were significantly reduced postexposure by 5.9 and 11.8%, respectively, whereas forced vital capacity was not significantly changed. The average difference in maximum midexpiratory flow rates at 50% vital capacity on air and HeO2 was significantly reduced postexposure by 18%. Raw and CO diffusing capacity were not changed postexposure. The relatively large change in FEF25-75 compared with FEV1, the reduction in density dependence of flow, and the normal Raw postexposure are all consistent with flow limitation in peripheral airways as a major cause of the observed reduction in expiratory flow. Postexposure pulmonary function changes in one subject who convulsed at 3.0 h of exposure are compared with corresponding average changes in 12 subjects who did not convulse.

Extension of oxygen tolerance in man: philosophy and significance.

The respiration of oxygen over a range of partial pressures higher than in the natural environment has expanding usefulness in health and disease. It provides for denitrogenation of the astronaut to prevent aerospace decompression sickness, it facilitates diving of many forms and improves safety in decompression after diving, and it is the key to therapy of diving and iatrogenic gas embolic diseases. In the continuum of general and hyperbaric medicine, it is essential for sustaining viability of damaged or diseased tissues not adequately oxygenated at natural oxygen pressures. Over the entire range of its clinical and operational usefulness, the pressure and duration of tolerable exposure to oxygen is limited by adverse effects on multiple chemical targets, cells, tissues, and organ functions. The rates of development and the qualitative expressions of these effects are different at different respired oxygen pressures. Successful extension of oxygen tolerance, as by slowing the rate of development of adverse effects, will further expand the medical and operational usefulness and safety of oxygen in normal, hypobaric, and hyperbaric environments. A prerequisite baseline for overall extension of oxygen tolerance is the quantitative investigation of early stages of toxic oxygen effects upon specific chemical and composite functions of multiple organ systems, including rates of development and rates of recovery. The practicality of limited oxygen tolerance extension by systematic interruption of oxygen exposure has been demonstrated and the procedure widely used. Broad present goals are both to establish oxygen tolerance for specific tissues and to optimize tolerance extension over the full range of useful oxygen pressures.

Regional cerebral glucose metabolic rate during thirty minutes hypoxia of 7% oxygen in adult conscious rats.

The effect of hypoxia on the regional cerebral metabolic rate for glucose (rCMRgl) was measured in 28 neuroanatomical structures of adult, conscious, unrestrained rats by the 2-[14C]deoxyglucose autoradiographic technique. Rats were cannulated in one femoral artery and vein 3 days before the experiments. The rCMRgl was measured in 15 rats during 30 min air breathing and in 13 rats during 30 min hypoxia of 7% O2 in N2. Statistically significant increases in rCMRgl in the order of 39-95% were observed in 25 of the 28 neuroanatomical structures examined. The highest increases in rCMRgl were observed in cerebral and cerebellar white matter (95% and 60%, respectively), as well as in limbic structures ranging from a 91% increase in the septal nuclei to a 55% increase in the hypothalamus. The superior olivary nucleus and inferior colliculus (auditory structures) were the only structures which did not show changes in glucose utilization. The present data are compared with previous studies during hypoxia in conscious or anesthetized animals. It is concluded that the degree of rCMRgl response to hypoxia is affected by anesthesia, age and species.

The relationship between cortical electrical activity and regional cerebral glucose metabolic rate in rats exposed to 3 atmospheres absolute oxygen.

The regional cerebral metabolic rate for glucose (rCMRgl) was autoradiographically measured in conscious rats during 180-210 min of exposure to 3 atmospheres absolute oxygen (ATA O2), 3 ATA N2-O2 normoxia and air at 1 ATA. The exposure time and oxygen pressure in the present study were purposely matched to a parallel project in human subjects. The electrocorticogram (ECoG) was continuously recorded throughout the exposure. According to the ECoG responses, the oxygen-exposed rats fell into two categories: 'resistant' ones, those without changes in ECoG throughout the exposure; and 'sensitive' rats, those with changes in EcoG before or during the rCMRgl measurements. The observed ECoG changes were increased slow wave activity in the delta range, which was in some cases followed by paroxysmal electrical discharges. No changes in rCMRgl were observed in oxygen-exposed 'resistant' rats as compared to air breathing or N2-O2 normoxic rats at 3 ATA. However, in the 'sensitive' rats there were increases in rCMRgl in 8 of the 28 neuroanatomical structures examined as compared to the air breathing and 3 ATA normoxic controls. It is concluded that the increase in rCMRgl are related to the onset of the oxygen-induced preconvulsive changes in ECoG.

Local cerebral glucose utilization rate following intermittent exposures to 2 atmosphere absolute oxygen.

Previous studies have shown significant increases in regional cerebral metabolic rate for glucose (rCMRgl) in 14 of 28 investigated brain structures in rats exposed to 1-h oxygen at 2 atmosphere absolute (ATA O2). Continuous 4-h exposure to 2 ATA O2 resulted in significant increases only in superior olivary nucleus and inferior colliculus. In the present study, the rCMRgl was autoradiographically measured by the [14C]2-deoxyglucose technique during the last 30 min of 4 intermittent 1-h exposures to either 2 ATA O2 or air at atmospheric pressure, with 3 h of breathing air outside the pressure chamber between each oxygen or air exposure. Statistically significant reductions in rCMRgl of the oxygen-exposed rats were observed in superior olivary nucleus and inferior colliculus, while no changes were observed in 26 other investigated structures. The previously observed increases in rCMRgl in a single 1- or 4-h exposure at 2 ATA O2 were reduced or reversed during the intermittent hyperbaric oxygen exposure. The relation of the observed changes in rCMRgl during single and intermittent hyperbaric oxygen exposures to the extension of tolerance to hyperbaric oxygenation is discussed.

Regional cerebral glucose utilization rates in rats during asymptomatic period of exposure to 1, 2 and 3 atmospheres absolute of oxygen.

A previous study has shown an increase in regional cerebral metabolic rate for glucose prior to the onset of central nervous system oxygen toxicity in rats exposed to 5 atmospheres absolute of oxygen. The present study was designed to measure regional cerebral glucose utilization rates at pressures used for oxygen therapy and prolonged exposures during which rats are known to be asymptomatic. The regional metabolic rate for glucose in 26 brain structures and in gray and white matter of the thoracic and lumbar spinal cord was autoradiographically measured in awake unrestrained rats using the autoradiographic [14C]2-deoxyglucose technique. Femoral artery and vein cannulae were inserted 3 days before the experiment. Rats were divided into four groups of 15: (a) air control; (b) 6 h at 1 atmosphere absolute oxygen; (c) 4 h at 2 atmospheres oxygen; and (d) 2 h at 3 atmospheres oxygen. Statistically significant increases in glucose utilization (p less than 0.05) are seen only in lateral thalamus at 3 atmospheres oxygen, in superior olivary nucleus and inferior colliculus at 2 atmospheres oxygen and in superior olivary nucleus at 1 atmosphere oxygen. The combination of our previous data at 5 atmospheres oxygen and the present results at prolonged and safe exposures to lower pressures indicated that increased glucose utilization in some neuronal structures precedes the onset of the central nervous system manifestations of oxygen toxicity.

Regional cerebral metabolic rate for glucose during hyperbaric oxygen-induced convulsions.

Hyperbaric oxygen-induced convulsions in awake unrestrained rats are preceded by electrocorticographic changes including paroxysmal electrical discharges (PED). During oxygen induced convulsions, alterations in regional cerebral metabolic rate for glucose (rCMRgl) were autoradiographically measured and compared with rCMRgl results obtained during pre-convulsive periods in an earlier study. Statistically elevated rCMRgl during oxygen-induced convulsions were found in globus pallidus, substantia nigra, limbic structures, and cerebellar cortex. Significant reductions were found largely in auditory structures and cerebral cortex. This pattern of changes in rCMRgl resembles the pattern of changes during successive PED in the absence of overt convulsions. This similarity may indicate that a common sequence of biochemical changes leads to both oxygen-induced pre-convulsive as well as convulsive electrical discharges.

Correlation of brain glucose utilization and cortical electrical activity during development of brain oxygen toxicity.

Central nervous system (CNS) oxygen toxicity in rats is characterized by the appearance of alterations in electrical cortical activity (ECoG), followed by the appearance of paroxysmal electrical discharges and finally the onset of clinical convulsions. The correlation between the changes in ECoG and the regional cerebral metabolic rate for glucose (rCMRgl) during progressive oxygen toxicity was studied. Cortical electrodes for ECoG recording and venal arterial cannula for autoradiographic measurement of rCMRgl were chronically implanted. Using [14C]2-deoxyglucose (2-DG), the rCMRgl was measured in conscious unrestrained rats during different periods of exposure to 5 atmospheres absolute oxygen as well as an equivalent normoxic high pressure, while ECoG was continuously recorded and analyzed. A statistically significant increase in rCMRgl in 13 out of 24 investigated brain structures was found during the pre-paroxysmal electrical discharge period. This increase was accompanied by an elevation in slow and a reduction in fast ECoG frequency bands. The largest increase in rCMRgl was found in cerebellar and cerebral cortices, limbic, auditory and visual structures. Following the appearance of the first paroxysmal electrical discharge (FED) some limbic structures and cerebellar cortex showed further increases in rCMRgl, while several auditory and visual structures exhibited a significant decrease. Five atmospheres normoxic pressure had no effect on rCMRgl in any of the brain structures examined. It is concluded that pre-paroxysmal electrical discharge ECoG changes and the onset of the FED during progressive oxygen toxicity are not due to inhibition of brain energy metabolism. The possible mechanisms leading to alterations in rCMRgl during hyperbaric oxygenation are discussed.

Human respiration at rest in rapid compression and at high pressures and gas densities.

Ventilation (V), end-tidal PCO2 (PACO2), and CO2 elimination rate were measured in men at rest breathing CO2-free gas over the pressure range 1-50 ATA and the gas density range 0.4-25 g/l, during slow and rapid compressions, at stable elevated ambient pressures and during slow decompressions in several phases of Predictive Studies III-1971 and Predictive Studies IV-1975. Inspired O2 was at or near natural O2 levels during compressions and at stable high pressures; it was 0.5 ATA during decompressions. Rapid compressions to high pressures did not impair respiratory homeostasis. Progressive increase in pulmonary gas flow resistance due to elevation of ambient pressure and inspired gas density to the He-O2 equivalent of 5,000 feet of seawater was not observed to progressively decrease resting V, or to progressively increase resting PACO2. Rather, a complex pattern of change in PACO2 was seen. As both ambient pressure and pulmonary gas flow resistance were progressively raised, PACO2 at first increased, went through a maximum, and then declined towards values near the 1 ATA level. It is suggested that this pattern of PACO2 change results from interaction on ventilation of 1) increase in pulmonary resistance due to elevation of gas density with 2) increase in respiratory drive postulated as due to generalized CNS excitation associated with exposure to high hydrostatic pressure. There may be a similar interaction between increased gas flow resistance and increase in respiratory drive related to nitrogen partial pressure and the narcosis resulting therefrom.

Successful therapy of cerebral air embolism with hyperbaric oxygen at 2.8 ATA.

A 60-year-old male patient suddenly developed blindness, agitation, and disorientation 36 h after coronary bypass surgery. Onset of symptoms followed efforts to clear an air-filled radial artery cannula. Seven hours after onset of symptoms, initial compression to 2.8 ATA (60 fsw), 100% oxygen (U.S. Navy Table 6), steroids, intravenous fluids, and antiplatelet drugs were used for therapy. The patient's agitation and disorientation dictated that we avoid initial compression to 6 ATA (165 fsw), contrary to conventional practice in therapy of air embolism, and instead immediately give oxygen at 2.8 ATA. After a second treatment with USN Table 6, given 6 h after the first, the patient's vision and mental state returned to normal. He subsequently had an uneventful recovery from surgery and cerebral air embolism.

Speech intelligibility at high helium-oxygen pressures.

Word-list intelligibility scores of unprocessed speech (mean of 4 subjects) were recorded in helium-oxygen atmospheres at stable pressures equivalent to 1600, 1400, 1200, 1000, 860, 690, 560, 392, and 200 fsw daring Predictive Studies IV-1975 by wide-bandwidth condenser microphones (frequency responses not degraded by increased gas density). Intelligibility scores were substantially lower in helium-oxygen a 200 fsw than in air at l ATA, but there was little difference between 200 fsw and 1600 fsw. A previously documented prominent decrease in intelligibility of speech between 200 or 600 fsw because of helium and pressure was probably due to degradation of microphone frequency response by high gas density.

Nature and treatment of decompression sickness occurring after deep excursion dives.

During Predictive Studies IV (PS IV), the fourth in a series of collaborative undersea investigations, plans were made for excursion compressions to 1200 and 1600 feet of sea water (fsw) from saturation depths of 800 and 1200 fsw, respectively. Three cases of decompression sickness (DCS) occurred in the excursion phases of PS IV; all were relieved by prompt treatment, and there were no residual effects. This paper describes the rationale and treatment regimen used for deep excursion DCS, reports the results of the treatment, and makes specific recommendations of the therapy of DCS occurring after such excursions.

Human respiratory control at high ambient pressures and inspired gas densities.

Four men, exposed to the pressure equivalent of 1,200 ft of seawater (37 ATA) for 6 days in a CO2-free, normoxic helium-oxygen environment (Predictive Studies III-1971, Aviation Space Environ. Med. 4: 843-855, 1977), had no evident respiratory distress at work, at rest, or asleep. Ventilatory responses of two men to CO2 were measured in 20-min acute exposures to mixtures of oxygen (173 Torr) with nitrogen, crude neon, and helium over a gas density range of 0.4-22 g/l and a pressure range of 1-37 ATA during stepwise compression of 37 ATA. Analysis of delta V/delta PACO2 as functions of pressure, of density, and of density-to-viscosity ratios shows that increased gas density, but not nitrogen narcosis, is associated with gross diminution of the ventilatory response to CO2. A small ventilatory response to CO2 is predicted for liquid breathing when viscosity is included as a parameter in the analysis. Other findings associated with increased gas densities and progressive elevation of inspired CO2 concentration are disruption of the normal patterns of tidal volume and frequency of breathing and reduction in the range of linear respiratory response to CO2.