A model for influence of exercise on formation and growth of tissue bubbles during altitude decompression

In response to exercise performed before or after altitude decompression, physiological changes are suspected to affect the formation and growth of decompression bubbles. We hypothesized that the work to change the size of a bubble is done by gas pressure gradients in a macro- and microsystem of thermodynamic forces and that the number of bubbles formed through time follows a Poisson process. We modeled the influence of tissue O(2) consumption on bubble dynamics in the O(2) transport system in series against resistances, from the alveolus to the microsystem containing the bubble and its surrounding tissue shell. Realistic simulations of experimental decompression procedures typical of actual extravehicular activities were obtained. Results suggest that exercise-induced elevation of O(2) consumption at altitude leads to bubble persistence in tissues. At the same time, exercise-enhanced perfusion leads to an overall suppression of bubble growth. The total volume of bubbles would be reduced unless increased tissue motion simultaneously raises the rate of bubble formation through cavitation processes, thus maintaining or increasing total bubble volume, despite the exercise.     

Modeling the dynamics of risk of altitude decompression sickness

A probabilistic model of decompression sickness is modified by introducing corrections that determine more precisely the risk of tissue injury by gas bubbles as a function of blood supply and bubble nucleation intensity. Parameters of the “worst” virtual tissues and theoretical curves corresponding to empirical data on the cumulative probability of decompression sickness symptoms for some altitude decompression procedures are determined. The parameters are shown to depend on final pressure, physical load, and duration of preoxygenation.     

Effect of oxygen breathing on micro oxygen bubbles in nitrogen-depleted rat adipose tissue at sea level and 25 kPa altitude exposures

The standard treatment of altitude decompression sickness (aDCS) caused by nitrogen bubble formation is oxygen breathing and recompression. However, micro air bubbles (containing 79% nitrogen), injected into adipose tissue, grow and stabilize at 25 kPa regardless of continued oxygen breathing and the tissue nitrogen pressure. To quantify the contribution of oxygen to bubble growth at altitude, micro oxygen bubbles (containing 0% nitrogen) were injected into the adipose tissue of rats depleted from nitrogen by means of preoxygenation (fraction of inspired oxygen = 1.0; 100%) and the bubbles studied at 101.3 kPa (sea level) or at 25 kPa altitude exposures during continued oxygen breathing. In keeping with previous observations and bubble kinetic models, we hypothesize that oxygen breathing may contribute to oxygen bubble growth at altitude. Anesthetized rats were exposed to 3 h of oxygen prebreathing at 101.3 kPa (sea level). Micro oxygen bubbles of 500-800 nl were then injected into the exposed abdominal adipose tissue. The oxygen bubbles were studied for up to 3.5 h during continued oxygen breathing at either 101.3 or 25 kPa ambient pressures. At 101.3 kPa, all bubbles shrank consistently until they disappeared from view at a net disappearance rate (0.02 mm(2) × min(-1)) significantly faster than for similar bubbles at 25 kPa altitude (0.01 mm(2) × min(-1)). At 25 kPa, most bubbles initially grew for 2-40 min, after which they shrank and disappeared. Four bubbles did not disappear while at 25 kPa. The results support bubble kinetic models based on Fick's first law of diffusion, Boyles law, and the oxygen window effect, predicting that oxygen contributes more to bubble volume and growth during hypobaric conditions. As the effect of oxygen increases, the lower the ambient pressure. The results indicate that recompression is instrumental in the treatment of aDCS.     

MUSCULAR ACTIVITY AND BUBBLE FORMATION IN ANIMALS DECOMPRESSED TO SIMULATED ALTITUDES

1. Muscular activity during decompression causes bubble formation in the blood of intact bullfrogs. The amount of gas liberated depends on the degrees of muscular activity and supersaturation (as influenced by altitude). In decompressed dissected bullfrogs, bubbles appear in veins leading from active but not from inactive muscles. 2. Muscular activity during decompression similarly causes bubble formation in rats. Bubbles appear in veins coming from muscles, and often in the lymphatic system. Quiescent rats do not form bubbles. 3. Violent muscular activity before decompression favors bubble formation in bullfrogs during ensuing decompression, but it is less effective than exercise during decompression. The effect persists in large frogs for about an hour. 4. Pre-oxygenation for 2 to 4 hours before decompression reduces the incidence of bubble formation in decompressed bullfrogs. It thus has the same effect on bubble formation in bullfrogs as it does on the "bends" in man. The effect is presumably due to removal of nitrogen. 5. Possible mechanisms by which muscular activity causes bubble formation are discussed. The effects of mechanical agitation and of metabolic CO₂ are considered to be the dominant factors.     

Optimal oxygen pressure and time for reduced bubble formation in the N2-saturated decompressed prawn.

Bubbles that grow during decompression are believed to originate from preexisting gas micronuclei. We showed that pretreatment of prawns with 203 kPa oxygen before nitrogen loading reduced the number of bubbles that evolved on decompression, presumably owing to the alteration or elimination of gas micronuclei (Arieli Y, Arieli R, and Marx A. J Appl Physiol 92: 2596-2599, 2002). The present study examines the optimal pretreatment for this assumed crushing of gas micronuclei. Transparent prawns were subjected to various exposure times (0, 5, 10, 15, and 20 min) at an oxygen pressure of 203 kPa and to 5 min at different oxygen pressures (PO2 values of 101, 151, 203, 405, 608, and 810 kPa), before nitrogen loading at 203 kPa followed by explosive decompression. After the decompression, bubble density and total gas volume were measured with a light microscope equipped with a video camera. Five minutes at a PO2 of 405 kPa yielded maximal reduction of bubble density and total gas volume by 52 and 71%, respectively. It has been reported that 2-3 h of hyperbaric oxygen at bottom pressure was required to protect saturation divers decompressed on oxygen against decompression sickness. If there is a shorter pretreatment that is applicable to humans, this will be of great advantage in diving and escape from submarines.     

Exercise exacerbates acute mountain sickness at simulated high altitude.

We hypothesized that exercise would cause greater severity and incidence of acute mountain sickness (AMS) in the early hours of exposure to altitude. After passive ascent to simulated high altitude in a decompression chamber [barometric pressure = 429 Torr, approximately 4,800 m (J. B. West, J. Appl. Physiol. 81: 1850-1854, 1996)], seven men exercised (Ex) at 50% of their altitude-specific maximal workload four times for 30 min in the first 6 h of a 10-h exposure. On another day they completed the same protocol but were sedentary (Sed). Measurements included an AMS symptom score, resting minute ventilation (VE), pulmonary function, arterial oxygen saturation (Sa(O(2))), fluid input, and urine volume. Symptoms of AMS were worse in Ex than Sed, with peak AMS scores of 4.4 +/- 1.0 and 1.3 +/- 0.4 in Ex and Sed, respectively (P < 0.01); but resting VE and Sa(O(2)) were not different between trials. However, Sa(O(2)) during the exercise bouts in Ex was at 76.3 +/- 1.7%, lower than during either Sed or at rest in Ex (81.4 +/- 1.8 and 82.2 +/- 2.6%, respectively, P < 0.01). Fluid intake-urine volume shifted to slightly positive values in Ex at 3-6 h (P = 0.06). The mechanism(s) responsible for the rise in severity and incidence of AMS in Ex may be sought in the observed exercise-induced exaggeration of arterial hypoxemia, in the minor fluid shift, or in a combination of these factors.     

THE RELATION OF EXERCISE TO BUBBLE FORMATION IN ANIMALS DECOMPRESSED TO SEA LEVEL FROM HIGH BAROMETRIC PRESSURES

1. Bullfrogs (Rana catesbiana) and rats have been subjected to high barometric pressures and studied for bubble formation on subsequent decompression to sea level. Pressures varying from 3 to 60 pounds per square inch, in excess of atmospheric pressure, were used. 2. Muscular activity after decompression is necessary for bubble formation in bullfrogs after pressure treatment throughout the above range. Anesthetized frogs remained bubble-free following decompression. Rats compressed at 15 to 45 pounds per square inch likewise did not contain bubbles unless exercised on return to sea level. 3. Bubbles form without voluntary muscular activity in anesthetized rats previously subjected to pressure of 60 pounds per square inch. Small movements involved in breathing and other vital activities are believed sufficient to initiate bubbles in the presence of very high supersaturations of N₂. 4. Bubbles appear (with exercise) in rats previously compressed at 15 pounds per square inch, and in bullfrogs subjected to pressure at levels as low as 3 pounds per square inch above atmospheric pressure. The percentage drop in pressure necessary for bubble formation is less in compressed animals than in those decompressed from sea level to simulated altitudes. 5. The action of exercise on bubble formation in compressed frogs and rats is attributed to mechanical factors associated with muscular activity, combined with the high supersaturation of N₂. CO₂ probably is not greatly involved, since its concentration does not reach supersatuation, as it does at high altitude. 6. Anoxia following decompression from high barometric pressures has no observable facilitating effect on bubble formation.     

ADDITIONAL MECHANISMS FOR THE ORIGIN OF BUBBLES IN ANIMALS DECOMPRESSED TO SIMULATED ALTITUDES

1. A heavy ingestion of frothy emulsified fat by rats and bullfrogs does not increase susceptibility to bubble formation when the animals are decompressed 2 to 72 hours later. This indicates that gaseous films (bubble nuclei) initially present do not pass across the intestinal wall with the digested fat, and also that high fat content per se in the lymph and blood does not increase susceptibility to bubble formation. 2. Liquid caprylic acid injected into veins of bullfrogs crystallizes when the frogs are cooled. The crystallization causes bubbles to form without muscular activity on subsequent decompression. Cooling normal bullfrogs to 1–2°C. fails, however, to crystallize any substances occurring naturally in the animals that might act in a similar manner. 3. When bullfrogs are cooled (e.g. to –5° to –10°C.) until ice forms in the blood vessels, and are then warmed and decompressed, bubbles form in the absence of exercise. Crystallization of water in the body thus forms nuclei or even small bubbles that persist. If only one foot is frozen, bubbles originate in the frozen foot. In some cases visible bubbles were observed in thawed feet at sea level (i.e. without decompression). When frog''s blood is partly frozen in test tubes or in tied off sections of veins, bubbles will appear on decompression in the absence of mechanical agitation. The practical relation of this phenomenon to flight at high altitude should not be overlooked. 4. Fracturing a leg bone (tibia or femur) in a frog induces bubble formation on subsequent decompression. Bubble nuclei, which persist for ½ to 1 hour, are probably formed as a result of the intense mechanical disturbance when the bone snaps. Fracturing of bone is considerably more effective than crushing muscles for producing bubbles in frogs.     

Mathematical model of gas bubble evolution in a straight tube.

Deep sea divers suffer from decompression sickness (DCS) when their rate of ascent to the surface is too rapid. When the ambient pressure drops, inert gas bubbles may form in blood vessels and tissues. The evolution of a gas bubble in a rigid tube filled with slowly moving fluid, intended to simulate a bubble in a blood vessel, is studied by solving a coupled system of fluid-flow and gas transport equations. The governing equations for the fluid motion are solved using two techniques: an analytical method appropriate for small nondeformable spherical bubbles, and the boundary element method for deformable bubbles of arbitrary size, given an applied steady flow rate. A steady convection-diffusion equation is then solved numerically to determine the concentration of gas. The bubble volume, or equivalently the gas mass inside the bubble for a constant bubble pressure, is adjusted over time according to the mass flux at the bubble surface. Using a quasi-steady approximation, the evolution of a gas bubble in a tube is obtained. Results show that convection increases the gas pressure gradient at the bubble surface, hence increasing the rate of bubble evolution. Comparing with the result for a single gas bubble in an infinite tissue, the rate of evolution in a tube is approximately twice as fast. Surface tension is also shown to have a significant effect. These findings may have important implications for our understanding of the mechanisms of inert gas bubbles in the circulation underlying decompression sickness.     

Ultrasonic monitoring of decompression procedures

p6rly detection of bubbles may provide clues to the mechanism of their formation, and a knowledge of their extent during a decompression may allow the prevention of decompression sickness. We have used ultrasound imaging to study bubble formation in peripheral tissues. The results suggest that: (a) a threshold supersaturation for bubble formation exists; (b) the earliest bubbles are intravascular; (c) before signs of decompression sickness a substantial accumulation of stationary bubbles occurs. Despite the success of Doppler methods in detecting moving bubbles after decompressions normally considered safe, recent studies have shown that the correlation between number of bubbles detected and symptoms of decompression sickness is often poor. We have used a time integral of the ultrasound images, which avoids laborious image analysis, to follow the extent of both moving and stationary bubbles. Human trials involving a wide variety of decompressions suggest that correct prediction of symptoms is possible.     

Gas bubbles in rats after heliox saturation and different decompression steps and rates.

Effects of pressure reduction, decompression rate, and repeated exposure on venous gas bubble formation were determined in five groups (GI, GII, GIII, GIV, and GV) of conscious and freely moving rats in a heliox atmosphere. Bubbles were recorded with a Doppler ultrasound probe implanted around the inferior caval vein. Rats were held for 16 h at 0.4 MPa (GI), 0.5 MPa (GII and GIII), 1.7 MPa (GIVa), or 1.9 MPa (GIV and GV), followed by decompression to 0.1 MPa in GI to GIII and to 1.1 MPa in GIV and GV. A greater decompression step, but at the same rate (GII vs. GI and GIVb vs. GIVa), resulted in significantly more bubbles (P < 0.01). A twofold decompression step resulted in equal amount of bubbles when decompressing to 1.1 MPa compared with 0.1 MPa. The faster decompression in GII and GVa (10.0 kPa/s) resulted in significantly more bubbles (P < 0.01) compared with GIII and GVb (2.2 kPa/s). No significant difference was observed in cumulative bubble score when comparing first and second exposure. With the present animal model, different decompression regimes may be evaluated.     

Bubble stimulation efficiency of dinoflagellate bioluminescence

Dinoflagellate bioluminescence , a common source of bioluminescence in coastal waters , is stimulated by flow agitation . Although bubbles are anecdotally known to be stimulatory , the process has never been experimentally investigated . This study quantified the flash response of the bioluminescent dinoflagellate Lingulodinium polyedrum to stimulation by bubbles rising through still seawater . Cells were stimulated by isolated bubbles of 0 . 3–3 mm radii rising at their terminal velocity , and also by bubble clouds containing bubbles of 0 . 06–10 mm radii for different air flow rates . Stimulation efficiency , the proportion of cells producing a flash within the volume of water swept out by a rising bubble , decreased with decreasing bubble radius for radii less than approximately 1 mm . Bubbles smaller than a critical radius in the range 0 . 275–0 . 325 mm did not stimulate a flash response . The fraction of cells stimulated by bubble clouds was proportional to the volume of air in the bubble cloud , with lower stimulation levels observed for clouds with smaller bubbles . An empirical model for bubble cloud stimulation based on the isolated bubble observations successfully reproduced the observed stimulation by bubble clouds for low air flow rates . High air flow rates stimulated more light emission than expected , presumably because of additional fluid shear stress associated with collective buoyancy effects generated by the high air fraction bubble cloud . These results are relevant to bioluminescence stimulation by bubbles in two‐phase flows , such as in ship wakes , breaking waves , and sparged bioreactors . Copyright © 2015 John Wiley & Sons, Ltd.     

CARBON DIOXIDE AS A FACILITATING AGENT IN THE INITIATION AND GROWTH OF BUBBLES IN ANIMALS DECOMPRESSED TO SIMULATED ALTITUDES

1. Rats killed in a variety of ways (broken neck, nembutal, anoxia, electrocution) may undergo extensive bubble formation when subsequently decompressed from atmospheric pressure to simulated altitudes of 50,000 feet. On autopsy at sea level, large numbers of bubbles are found throughout the vascular system in the majority of animals. These bubbles appear to originate in small vessels deep within muscular regions, later spreading widely in arterial and venous systems. Dead rabbits and frogs also bubble profusely on decompression. 2. Bubble formation in dead animals is attributed primarily to the accumulation of CO₂, derived from residual cellular respiration after death, and from anaerobic glycolysis with attendant decomposition of bicarbonates in blood and tissue fluids. If anaerobic glycolysis is inhibited by using sodium iodoacetate as a lethal agent, bubble formation is greatly reduced or lacking on subsequent decompression. 3. Experiments in vitro suggest that high concentrations of CO₂ favor bubble formation by reducing the degree of mechanical disturbance necessary. 4. Administration of CO₂ in high concentrations to living frogs lowers the minimum altitude (pressure equivalent) at which bubble formation occurs, with exercise, in untreated animals. Pre-treatment with CO₂ also reduces the degree of muscular activity necessary for bubbles to form in frogs at higher altitudes. 5. Analyses have been made of the gas content of bubbles taken directly from the large veins of decompressed frogs and rats. In living animals the figures obtained indicate rapid equilibration with gas tensions in the blood. Bubbles taken from decompressed dead rats may contain 60–80 per cent CO₂. 6. The bearing of these experiments on the mechanisms of bubble initiation and growth in normal living animals is discussed. Reasons are given for suggesting that CO₂, due largely to its high dissolved concentration in localized active regions, may be an outstanding factor in the initiation and early growth of bubbles which in later stages are expanded and maintained principally by nitrogen.     

Hyperbaric oxygen may reduce gas bubbles in decompressed prawns by eliminating gas nuclei.

It is accepted that gas bubbles grow from preexisting gas nuclei in tissue. The possibility of eliminating gas nuclei may be of benefit in preventing decompression sickness. In the present study, we examined the hypothesis that hyperbaric oxygen may replace the resident gas in the nuclei with oxygen and, because of its metabolic role, eliminate the nuclei themselves. After pretreatment with oxygen, prawns were 98% saturated with nitrogen before explosive decompression at 30 m/min. Ten transparent prawns were exposed to four experimental profiles in a crossover design: 1) 10-min compression to 203 kPa with air; 2) 10-min compression with oxygen; 3) 10-min compression with oxygen to 203 kPa followed by 12 min air at 203 kPa; and 4) 10 min in normobaric oxygen followed by compression to 203 kPa with air. Bubbles were measured after explosive decompression. We found that pretreatment with hyperbaric oxygen (profile C) significantly reduces the number of bubbles and bubble volume. We suggest that hyperbaric oxygen eliminates bubble nuclei in the prawn.     

Mammary implants, diving, and altitude exposure

Mammary implants were exposed to various simulated dive profiles followed by altitude exposures to stimulate aircraft travel and then were observed for bubble formation and volume changes. Minimal volume changes occurred after each dive. Numerous bubbles formed, however, reaching their maximum size in 3 hours. By comparison, when implants were exposed to high altitude following a dive exposure, significant volume changes occurred. This in vitro study showed that bubble formation and volume expansion occur after exposing implants to diving and altitude, but the circumstances required to produce these changes in vivo are extremely unlikely to occur normally.     

Effect of hypobaric air, oxygen, heliox (50:50), or heliox (80:20) breathing on air bubbles in adipose tissue.

The fate of bubbles formed in tissues during decompression to altitude after diving or due to accidental loss of cabin pressure during flight has only been indirectly inferred from theoretical modeling and clinical observations with noninvasive bubble-measuring techniques of intravascular bubbles. In this report we visually followed the in vivo resolution of micro-air bubbles injected into adipose tissue of anesthetized rats decompressed from 101.3 kPa to and held at 71 kPa corresponding to approximately 2.750 m above sea level, while the rats breathed air, oxygen, heliox (50:50), or heliox (80:20). During air breathing, bubbles initially grew for 30-80 min, after which they remained stable or began to shrink slowly. Oxygen breathing caused an initial growth of all bubbles for 15-85 min, after which they shrank until they disappeared from view. Bubble growth was significantly greater during breathing of oxygen compared with air and heliox breathing mixtures. During heliox (50:50) breathing, bubbles initially grew for 5-30 min, from which point they shrank until they disappeared from view. After a shift to heliox (80:20) breathing, some bubbles grew slightly for 20-30 min, then shrank until they disappeared from view. Bubble disappearance was significantly faster during breathing of oxygen and heliox mixtures compared with air. In conclusion, the present results show that oxygen breathing at 71 kPa promotes bubble growth in lipid tissue, and it is possible that breathing of heliox may be beneficial in treating decompression sickness during flight.     

A model of extravascular bubble evolution: effect of changes in breathing gas composition.

Observations of bubble evolution in rats after decompression from air dives (O. Hyldegaard and J. Madsen. Undersea Biomed. Res. 16: 185-193, 1989; O. Hyldegaard and J. Madsen. Undersea Hyperbaric Med. 21: 413-424, 1994; O. Hyldegaard, M. Moller, and J. Madsen. Undersea Biomed. Res. 18: 361-371, 1991) suggest that bubbles may resolve more safely when the breathing gas is a heliox mixture than when it is pure O(2). This is due to a transient period of bubble growth seen during switches to O(2) breathing. In an attempt to understand these experimental results, we have developed a multigas-multipressure mathematical model of bubble evolution, which consists of a bubble in a well-stirred liquid. The liquid exchanges gas with the bubble via diffusion, and the exchange between liquid and blood is described by a single-exponential time constant for each inert gas. The model indicates that bubbles resolve most rapidly in spinal tissue, in adipose tissue, and in aqueous tissues when the breathing gas is switched to O(2) after surfacing. In addition, the model suggests that switching to heliox breathing may prolong the existence of the bubble relative to breathing air for bubbles in spinal and adipose tissues. Some possible explanations for the discrepancy between model and experiment are discussed.     

Modeling dynamics of decompression disease risk under high-altitude decompression

The probabilistic model of the development of decompression disease was modified by introducing the corrections into its equation that refine the dependence of the risk of the injury of tissues by gas bubbles on their blood supply and the intensity of nucleation processes. The parameters of the "worst" virtual tissues and theoretical curves were determined that correspond to the empirical data on the cumulative probability of the development of decompression disease symptoms during some procedures of high-altitude decompression. It was shown that the parameters of these hypothetical tissues depend on the final pressure, the physical load, and the duration ofpreoxygenation. The ways of constructing a working hypothesis about the gradation of real body tissues with respect to the parameters determining the risk of their injury by bubbles and developing the method for the theoretical prognosis of the probability of development of decompression disease during any decompression procedure are discussed.     

Effect of a short-acting NO donor on bubble formation from a saturation dive in pigs.

It has previously been reported that a nitric oxide (NO) donor reduces bubble formation from an air dive and that blocking NO production increases bubble formation. The present study was initiated to see whether a short-acting NO donor (glycerol trinitrate, 5 mg/ml; Nycomed Pharma) given immediately before start of decompression would affect the amount of vascular bubbles during and after decompression from a saturation dive in pigs. A total of 14 pigs (Sus scrofa domestica of the strain Norsk landsvin) were randomly divided into an experimental (n = 7) and a control group (n = 7). The pigs were anesthetized with ketamine and alpha-chloralose and compressed in a hyperbaric chamber to 500 kPa (40 m of seawater) in 2 min, and they had 3-h bottom time while breathing nitrox (35 kPa O(2)). The pigs were all decompressed to the surface (100 kPa) at a rate of 200 kPa/h. During decompression, the inspired Po(2) of the breathing gas was kept at 100 kPa. Thirty minutes before decompression, the experimental group received a short-acting NO donor intravenously, while the control group were given equal amounts of saline. The average number of bubbles seen during the observation period decreased from 0.2 to 0.02 bubbles/cm(2) (P < 0.0001) in the experimental group compared with the controls. The present study gives further support to the role of NO in preventing vascular bubble formation after decompression.     

Experimental respiratory decompression sickness in sheep

Respiratory decompression sickness (RDCS, "the chokes") is a potentially lethal consequence of ambient pressure reduction. Lack of a clearly suitable animal model has impeded understanding of this condition. RDCS, unaccompanied by central nervous system signs, occurred in 17 of 18 unanesthetized sheep exposed to compressed air at 230 kPa (2.27 ATA) for 22 h, returned to normal pressure for approximately 40 min, and taken to simulated altitude (0.75 ATA, 570 Torr). Respiratory signs, including tachypnea, sporadic apnea, and labored breathing, were accompanied by precordial Doppler ultrasound evidence of marked venous bubble loading. Pulmonary arterial pressures exceeded 30 Torr in five catheterized sheep that died or became moribund. Hypoxemia (arterial Po2 less than 40 Torr), neutropenia, and thrombocytopenia were observed. Peribronchovascular edema was the most prominent necropsy finding. Chest radiography indicated interstitial edema in most affected sheep. High body weight and catheterization predisposed the sheep to severe RDCS. It appears that this protocol reliably provides a useful animal model for studies of RDCS and obstructive pulmonary hypertension, that the precipitating event is massive pulmonary embolization by bubbles, and that venous bubbles, detected by Doppler ultrasound, can signal impending RDCS.