Physical, Physiological, and Biochemical Aspects of Hyperbaric

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Physical, Physiological, and Biochemical Aspects of Hyperbaric Oxygenation ."

K.K.Jaih

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This chapter presents a bask, scientific foundation detailing the important and int~resting properties of oxygen, then surveys how these realities come into play under hyPerbadcconditions. The sections involved are: Introduction Physiology of Oxygenation Hyperbaric Oxygenation : ,General Effects of HBOon the Healthy Human Body .
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Chapter 2

Introduction Oxygen is the most prevalent and most important element on earth. Acomplete and in-depth discussion of the biochemical and physiological ~pects of oxygen is available in Jain (1989b), but a brief description of how oxygen is transported and the basic physical laws governing its behavior will be useful for discussion in this book. The various terms frequently encountered Partial Partial Partial Partial Partial

pressure pressure press1fre pressure pressure

of of of of of

in relation to oxygen include:

a gas oxygen oxygen in alveoli oxygen in arterial blood oxygen in venous blood

p

paz pAOz paOz pvOz

Pressures exerted by gases dissolved in water or body fluids are certainly different from those produced in the gaseous phase. The concentration of a gas in a fluid is determined not only by the pressure, but also by the "solubility coefficient" of the gas. Henry's law formulates this as follows: concentration of a di~solved gas = (pressure) X (solubility coefficient)

The solubility coefficient varies for different fluids and it is "temperature-dependent, with solubility being inversely proportional to temperature. When concentration is e{Cpressed as volume of gas dissolved in each unit volume of water, and pressure is expressed in atmospheres, the solubility coefficients of the important respiratory gases at body temperature are as follows: Oxygen: COz:

Physical Ba~ics The atmosphere is a gas rr:ixture containing by volume 20.94% oxygen, 78.08% nitrogen, 0.04% COz, and traces of other gases. For practical purposes air is considered to be a mixture of 21 % oxygen and 79% nitrogen. The total pressure of this mixture at sea level is 760 millimeters of mercury (mmHg). Dalton's law states that in a gas mixture, each gas exerts its pressure according to its proportion of the total volume: partial pressure of a gas = (absolute pressure) x (proportion of total volume of gas)

Thus, the partial pressure of oxygen (pOz) in air is (760) x (21/100) = 160 mmHg

Nitrogen:

0.024 ml Oz/ml blood atm pOz 0.5 ml plasma/atm pCOz 0.067 ml/ml plasma/atm pNz

From this one can see that COz is, remarkably, \ more soluble than oxygen.

20 times

Physiology of Oxygenation The Oxygen Pathway The oxygen pathway is shown in Figure 2.1. It passes from the ambient air to the alveolar air and continues through the pulmonary, capillary, and venous blood to the systemic arterial and capillary blood. It then moves through the interstitial and intracellular"fluids to the microscopic points

Figure 2.1

The oxygen pathway. 1 ~\ ..

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Physical, Physiological,

and Biochemical

Aspects of Hyperbaric

Oxygenation

11

Figure 2.2

Effect of alveolar ventilation and rate on oxygen absorption the alveolar p02.

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Normal

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from the alveoli on

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I~ .'. 1'0 . "15' .<1'7 20 25 . II J "'Alv-edl~;ventilation (liters/minute)

oxygen consumptjon 'i~' the perioxomes, riculum, and mitochondria. " . ~,

endoplasmic

).l'gen is continuously absorbed into the blood which aves through the lungs, and it thereby enters the systemic ·culation. The effect of alveolar ventilation, and the rate of~O)."ygen absorption from the alveoli on the pAOz, are 6C)W~hown in Figure 2.2. ":Ata' ventilatory rate of 5 liters/min and oxygen cons umiOhcof 250 mllmin, the normal operating point is at A in ·t~re2.2. The alveplar oxygen tension is maintained at fAmmHg. During moderate exercise the rate of alveolar tilation increases fourfold to maintain this tension, and ut.1,000 ml of oxygen are absorbed per minute. Carbon dioxide is being constantly formed in the body ~ischarged into the alveoli secretion is 40 mmHg. It is .1I"\known that the partial pressure of alveolar CO2 (peOl) increases directly in proportion to the rate of CO2 ....etion, and decreases in inverse proportion to alveolar 'tilation.

he' difference

between pA02 (104 mmHg) and PV02 rllmHg), which amounts to 64 mmHg, causes oxygen diffuse into the pulmonary blood. It is then transported,

~(l}'>incombination with hemoglobin, to the tissue capes, where it is released for use by the cells. There the ..•.en reacts with various other nutrients to form CO2, :jikhenters the capillaries to be transported back to the ~. ~. During strenuous exercise, the body oxygen require..i,may be as much as 20 times normal, yet oxygenation

30

35

40

of the blood does not suffer, because the diffusion capacity for oxygen increases fourfold during exercise. This rise results in part from the increased number of capillaries participating, as well as dilatation of both the capillaries and the alveoli. Another factor here is that the blood normally stays in the lung capillaries about three times as long as is necessary to cause full oxygenation. Therefore, even during the shortened time of exposure on exercise, the blood can still become nearly fully saturated with oxygen .. Normally 97% of the oxygen transported from the lungs to the tissues is carried in chemical combination with hemoglobin of red blood cells, and the remaining 3% in a dissolved state in plasma. It turns out that one gram of hemoglobin can combine with 1.34 ml oxygen from where it is removed continuously by ventilation. The normal concentration ofhemoglobin is 15 g/100 ml blood. Thus, when hemoglQbin is 100% saturated with oxygen, 100 ri1l blood can transport about 20 (i.e., lSx 1.34) ml oxygen in combination with hemoglobin. Since the hemoglobin is usually only 97.5% saturated, the oxygen carried by 100 ml blood is actually 19.5 m!. However, in passing through tissue capillaries this amount is reduced by 14.5 ml (pa02 40 mmHg and 75% oxygen saturation) . Thus, under normal conditions,S (i.e. 19.5-14.5) ml of O2 is transported to the tissues by 100 ml blood. On strenuous exercise, which causes the interstitial fluid p02 to fall as low as 15 mmHg, only 4.5 ml oxygen remains bound witQ hemoglobin in each 100 ml blood. Thus1S (i.e. 19.5-4:5) inl oxygen is transferred by each 100 nil blood - three times the amount transferred under normal:.conditions. Since cardiac output can also increase up to six d};seven times, for instance, in well-trained marathon runners, the end result is a remarkable 20-fold (i.e., 15 x 6.6 = approx; 100; 100/5 = 20) increase in oxygen transport to the tissues. This is about the top limit that can be achieved .. Hemoglobin has a role in maintaining a constant p02 in the tissues and sets an upper limit of 40 mmHg. It usually delivers oxygen to the tissues at a rate to maintain a

12

Chapter 2

pOz of between 20 and 40mmHg. In a pressurized chamber pOz may rise tenfold, but the tissue pOz changes very little. The saturation of hemoglobin can rise by only 3%, as 97% of it is already combined with oxygen. This 3% can be achieved at P0:¥' levels of between 100 and 200 mmHg. Increasing the'inspired oxygen concentration or the total pressure of inspired oxygen does not increase the hem()globin-transported oxygen content of the blood. Thus, hemoglobin has an interesting tissue oxygen buffer function.

Shift of tl;le Oxygen-Hemoglobin Curve

Dissociation

Hemoglobin actively regulates oxygen transport through the oxygen-hemoglobin (oxyhemoglobin) dissociation curve whichdescribes the relatipn between oxygen saturation or coptent of hemoglobin ~nd oxygen tension at equilibrium. There is a progressive increase in the percentage of hemoglobin that is bound with oxygen as pOz increases. Bohr (1904) first showed that that the dissociation curve was sigmoid-shaped, leading Hill to postulate that there were multiple oxygen binding sites on the hemoglobin and to derive the following equation:

be described in the Hill coefficient and its position along the oxygen tension axis can be described by PSG which is inversely related to the binding affinity of the hemoglobin for oxygen. The PSG can be estimated by measuring the oxygen saturation of blood equilibrated to different levels of oxygen tension according to standard conditions and fitting the results to a straight line in logarithmic form to solve for PSG. The resulting standard PSG is normally 26.3 mmHg in adults at sea level. It is useful for detecting abnormalities in the affinity of hemoglobin for oxygen resulting from hemoglobin variants or from disease. PSG is increased to enhance oxygen unloading when the primary limitation to oxygen transport is peripheral, e.g., anemia. PSG is reduced to enhance loading when the primary limitation is in the lungs, e.g., lung disease. The balance between loading and unloading is regulated by allosteric control of the PSG and chemoreceptor control of ventilation which is matched to diffusing capacities of the lungs and the tissues. Optimal PSG supports the highest rate of oxygen transport in health and disease. A number of conditions can displac;ethe oxyhemoglobin dissociation curve to the right or the left, as suggested' in Figure 2.3.

Delivery of Oxygen to the Tissues (oxygenP50 tension

- oxygen saturation J = 100oxygen saturation

where PSG is the oxygen tension (in mmHg) when the binding sites are 50% saturatec ..Within the range of saturation between 15 and 95%, the sigmoid shape of the curve can

During transit from the ambient air to the cellular structures, the pOz of oxygen drops from 160 mmHg to a few mmHg in the mitochondria. This gradual drop is described as the "oxygen cascade" and is shown in Figure 2.4.

Shift to left (decreases PSG) Reduced DPG

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Decreased pC02 Hypothermia

80 100 50 70 60 40 30

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Reduced ATP Alkalosis ~ ~

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Normal arteriovenous Oxygen content difference

Shift to right (increases PSG) Increased DPG Increase pC02 Hyperthermia Increased A TP Acidosis Figure 2.3

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Shift of the oxygen~hemoglobin dissociation curve. DPG, diphosphosglycerate 60 70 80 90 100 110 120 130 140 150 Source: Jain (1989b), Oxygen in physiology and medicine, Thomas, Springfield, p02 (mm Hg) by permission.

Physical, Physiological,

Inspired

and Biochemical

Aspects of Hyperbaric

13

Figure 2.4



oxygen '~ concentratio~

Oxygenation

The oxygen cascade. -' ./

pressure Barometric

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Oxygen Alveolar ventilatio~ "'- "

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n Transfer I at the Capillary Level considerable resistance to oxygen transfer in the i~s, and this is as significant as the resistance in the ding tissues. rqvascular geometry and capillary blood flow are the portant factors responsible for regulating the oxyply to the tissues to meet the specific oxygen de<~forgans such as the heart and brain. The tissues, s'e, form the end point of the oxygen pathway. The the active transport system is to ensure an adequate illary p02 so that passive diffusion of oxygen to the ondria is maintained.

n Between the Oxygen Transport and tion tionship between the transportation of oxygen and ±ation was first described long ago by Pick (1870). ing to the Pick principle, oxygen consumption of ues (p02)is equal to the blood flow to the tissues tiltiplied by the amount of oxygen extracted by the ich is the difference between the arterial and the enous oxygen contents, C(a-v)02:

Oxygen Consumption

(VOz)' = (Q) x (C(a-v)Oz)

As the V02 of a given tissue increases, the normal response in the human body is to increase the local blood flbw to the area, to maintain thelocal (1l-V)02content difference close to the normal range. A marked increase of (a-v)02' above 4-5 vol% is observed during physical exercise, as discussed further in Chapter 5. An increase of this magnitude in nonexercising individuals usually means an impaired circulation, inadequate to meet the increased demand "of the tissues in some disease states, or it means that the oxygen content of the arterial blood is very low. The increased extraction of oxygen from the blood leads to a lower p02 compared to the normal leveLof :55-40 mmHg with O2 saturation at 75%. Naturally the regional flow throughout the body is variable, and organs such as the heart and brain extract much more oxygen from the blood than do other organs. The brain makes up' 2-~% of body weight but receives 15% of the cardiac output and 20% of the oxygen uptake of the entire body. Within the brain, cerebral blood flow and oxygen uptake vary according to the level of cerebral activity.

14

Chapter 2

Oxygen Utilization in the Cell The major site of utilization of molecular oxygen within the average cell is the mitochondria, which account for about 80%, while 20% is~sed by other subcellular organs, such as microsomes, nucleus, the plasma membrane, etc. Oxygen combines with electrons derived from various substrates to release free energy. This energy is used to pump H+ ions from the inside to the outside of the mitochondria against an electrochemical gradient. As H+ ions diffuse back, free energy is made available to phosphorylate adenosine diphosphate (ADP), and adenosine triphosphate (ATP) is generated. Only a minute amount of oxygen is required for the normal intracellular chemical reactions to take place. The respiratory enzyme system is so geared that when tissue p02 is more than 1-3 mmHg, oxygen availability is no longer a limiting factor in the rate of chemical reactions. Under normal conditions, the rate of o~gen utilization by cells is controlled by the rate of energy expenditure within the cells, i.e., by the rate at which ADP is formed from ATP. The diffusion distance from the capillary wall to the cell is rarely more than 50 /..lm,and normally oxygen can reach the cell quite readily.But, if p02 falls below the critical value of 1-3 mmHg, and if the cells are located farther away from the capillaries, the oxygen utilization is diffusion-limited and not determined by ADP. This is particularly true for cerebral white matter, which is very sensitive to hypoxia as well as hyperoxia. -

Effect of Blood Flow

bicarbonate ions to form carbonic acid which then dissociates into water and CO2, which is released from the blood into the alveoli. Thus in the presence of oxygen, much less CO2 can bind. The Haldane effect is far more important in promoting CO2 transport than the Bohr effect on the transport of oxygen. The combined Bohr-Haldane effect on oxygen transport is more important than on pH or CO2 transport. Equations have been described for predicting the limits of the rates of oxygen supply to the cells of living tissues and organs. It is possible to delineate the mechanisms by which molecular oxygen is transported from the red cells while being carried in the bloodstream longitudinally through capillaries into the moving plasma, and thence radically out and through the capillary wall into the surrounding tissues for tissue cell respiration.

Autoregulation

of the Intracellular p02

Intracellular p02 has not as yet been rheasured in humans, simply due to the lack of a suitable device for doing so. Such studies have been carried out in experimentally using microelectrodes implanted in the giant neurons of aplysia (500 /..lm-1mm), and comparing it with the extracellular p02 (Ep02)' At an Ep02 value of +20 mmHg, the Ip02 showed a stable value of between 4.5 and 8 mmHg. At between 10 to 50 mmHg Ep02, Ip02 is kept fairly constant by "autoregulation." A simple, minimally invasive method for the analysis of intracellular oxygen in live mammalian cells is available. Loading of the cells with the phosphorescent oxygen-sensing probe, , . '"" MitoXpress (Luxcel Biosciences Ltd, Cork, Ireland), is achIeved by passiye liposomal transfer or facilitated endocytosis, follQwydby m()nitoring in standard microwell plates on a time-resolved fluorescent reader (O'Riordan et ~12007). Phosphorescence lifetime measure"

Since oxygen is transported to the tissues in the bloodstream, interruption off,lood flow means that the amount of available oxygen to the cells also falls to zero. Under these conditions, the rate of ti,sue utilization of oxygen is bloodflow limited.

ments provide-,\a,<;~:ut'at~·;·r~al::"dm'~, 8.uantitative of average oxygen le~~ls.in.rbsting"~~11s ,a'ndtheir assessment alterations in respohse to stimulation. Effect of Oxygen-Hemoglobin Transport of C02

Reaction on

This response, known as the Haldane effect, results from the fact that the combination of oxygen with hemoglobin causes it to become a stronger acid. This displaces CO2 from the blood in two ways: • When there is more ,~cid,hemoglobin has less of a tendency to combine wIth C02 to form carbhemoglobin. Much of the C02 present in this form in the blood is thus displaced. • The increased acidity of the hemoglobin causes it to release an excess of H+jons and these, in turn, bind with

Hyperbaric Oxygenation Theoretical Considerations Hyperbaric oxygenation (HBO) involves the use of oxygen under pressure greater than that found on earth's surface at sea level. Units commonly used to denot~ barometric pressure include: mmHg inHg psi

millimeters of mercury inches of mercury pounds per square inch

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Physical, Physiological,

and Biochemical

Aspects of Hyperbaric

15

Oxygenation

Table,H, Ideal Alveolar Oxygen

Pr,essur~s

Total

pressures(bar) Gaugepressures Pa fsw' msw psi atm 0"

16

33 50 66 99

132

o 506 21.5 342.5 5.16 7.35 10.3214.7 15.48 21.05 20.64 29.4 30.97 44.0 41.29' 58.7

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pressure 3040 3800 422 582 1140' 1520 1900 760 ,,742,,; 102 262 342 902 4560 ?280 ATA' 'rDinHg 182 , .•

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673 1053 1433 1813 2193

0.5

1 1.5

2

3

, 02 not adminis-

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ten;d at pressures > 3 ATA

kg/cm2

bar

kilograms per square centimeter bar

fsw,msw feet or meters of sea water atm atmospheres ATA atmospheres absolute The o'nly absolute pressures are those measured by a mercury barometer. In contrast, gauge pressures are a measure of difference between the pressure in a chamber and the surrounding atmospheric pressure. To convert pressure as measured by a gauge to absolute pressure (ATA) requires addition of the barometric pressure. A guide to these conversions is shown in Table 2.1. The range of partial pressures of oxygen under HBO is shown in Table 2.2, and the ideal alveolar oxygen pressures are shown in Table 2.3. Boyle's well-known law states that if the temperature remains constant, the volume of a gas is inversely proportional to its pressure. Therefore, normal or abnormal gas-containing cavities in the body will have volume changes as HBO therapy is applied.

Density As barometric pressure rises there is an increase in the density of the gas breathed. The effect of increased density on resting ventilation is negligible within the range of the 1.5-2.5 ATA usually used in HBO. However, with'physical exertion in patients with decreasei respiratory reserves or respiratory obstruction, increasec density may cause gas flow problems.

Temperature The temperature of a gasrises duffhg compression and falls during decompression. According to Charles' law, if the volume remains constant, there is a direct relationship between absolute pressure and temperature.

1000 2000 1800 1400 2.5 ATA ATI>. ATA 1.5 23600 .
-'16

Chapter 2 1

elevation of cerebral venous pCOz is of the order of 5-6 mmHg when venous hemoglobin is 100% saturated with oxygen. COz does not continue to rise in venous blood and the tissues as long as the blood flow remains constant, and presents no major problems.

Tissue Oxygen Tension under HBO

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j Figure 2.5

Oxygen uptake curve under HBO in humans.

Effect oJPressure on Oxygen Solubility in Blood Only a limited amount of oxygen is dissolved in blood at normal atmospheric pressure. But, under hyperbaric conditions, as seen in Table 2.4, it is possible to dissolve sufficient oxygen, i.e., 6 vol% in p,Jasma,to meet the usual requirements of the body' In this case oxyhemoglobin will pass unchanged from the arterial to the venous side because the oxygen physic;ally dissolved in solution will be utilized more readily than that bound to hemoglobin. The typical arterial oxygen uptake under HBO is shown in Figure 2.5. Here the usual oxygen dissociation curve has been extended to include increases in oxygen content as a result of inspiring oxygen up to 3 ATA.The pOz simply rises linearly with rise of pressur:e.

Effect of HBO on Capillary Oxygen Pressure Drop

Various factors relating to tissue oxygen tension under HBO are:

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• Arterial pOz is the maximum pOz to which any tissue will be exposed, and plays a major part in determining the pOz diffusion.gradient driving oxygen into the tissues. Arterial pOz depends on the inspired pOz. • Arterial pOz content is the total amount of oxygen available. It depends on the inspired oxygen and the blood hemoglobin level. Tissue blood flow regulates the delivery of oxygen to the . tIssues. \

• Tissue oxygen levels vary according to utilization of the available oxygen. In a typical tissue, arteriovenous oxygen difference rises to 350 mmHg when 100% oxygen is breathed at 3 ATA.If the blood flow to the tissu~s is reduced by half, the corresponding values of capillary pOz will be 288 mmHg and 50 mmHg. But, of course, the oxygen requirement of different tissues varies. For example, the needs of cardiac muscle are ten times that of the skin.

The oxygen extraction by average tissues of 5 vol% results in a remarkable pressure drop of 60 (100 down to 40) mmHg from the arterial end to the venous end of the capillary.At 2,000 mmHg the oxygen content is approximately 25 (20+5) vol%. The extraction of 5vol% \n this case causes a pressure drop of about 1,900 mmHg. Each of the differences in pOz represents '~hesame number of oxygen molecules, in the first case carried by the hemoglobin and in the second case by the plasma. The metabolic requirement of the cells can ultimately be expressed as a certain number of molecules of oxygen per minute.

Another factor is the vasoconstricting effect of HBO, which reduces the-blood flow. Effe'ctive cellular oxygenation can be accomplished at 'very low rates of blood flow when arterial pOz is very high.

HBO and Retention of C02

The important general effects of hyperoxia on a healthy human body are listed in Table 2.5. The effectsvary according to the pressures used, the duration of exposure, and th
When HBO results in velious blood being 100% saturated with oxygen, there is a rise in blood pCOz and a shift of pH to the acid side. This is due to loss of hemoglobin available to transport COz. This affects only the 20% of the venous content of COzwhich is transported by hemoglobin. Excess mechanism, as COz is transported by the HZC03/HC03 well as by entering intcphysical solution in plasma. The

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General Effects of HBO on the Healthy Human Body

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Physical, Physiological, and Biochemical Aspects of Hyperbaric Oxygenation

17

changed. Blood flow to most organs falls in proportion to the fall of cardiac output except to the right and the left ventricles of the heart. There is no impairment of the nmction of any of these organs bec~use the raised pOz more than compensates for the reduction of the blood flow. Vasoconstriction may be viewed a~ a regulatory mechanism to protect the healthy organs from exposure to excessive pOz. Usually the vasoconstrictor response does not take place in the ,hypoxic tissues. Dermal blood flow has been shown to decrease as a response to hyperoxia; it has been measured by laser Doppler flowmetry. It was also demonstri\ted that the reduction of blood flow did not occur in the vicinity of a chronic skin ulcer and that the vasoconstrictor response was restored

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after the ulcer h'}d healed. HBO is considered to modify fibrinolytic activity in the blood. To clarify the stage of fibrinolytic activation by HBO exposure, Yamami et al (1996) examined its alterations in human during and after the HBO exposure. Eight healthy female volunteers breathed oxygen at 284 kPa (2.8 ATA). Blood samples were collected be;ore compression, shortly after compression to the pressme 284 kPa, shortly before the start of decompression, sho~tly after decompression, . and then again 3 hours after decompression. The euglobulin fibrinolytic activity (EFA) and, the activities and antigens of both tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-l (PAl-I) were estimated. The PAI-I activity and PAI-I antigen showed significant decrease after compression to a pressure 284 kPa, before the start of decompression, and after decompression. The EFA level and t-PA activity rose significantly shortly after decompression, and 3 hours later returned on baseline. These findings suggest that fibrinolytic activity is elicited after HBO rather than during HBO.

Cardiovascular System The most important study on this subject is that by Bergo (1993) which was conducted on awake rats exposed to 100% oxygen at pressures ranging from 1-5 ATA. The cardiovascular observations were made as a background to the study of the effect of HBO on cerebral blood flow. Some of the conclusions drawn were as follows: 1. Increase of systolic blood pressure with fall of diastolic pressure. Although pulse pressure was increased, the mean arterial blood pressure remained constant. 2. Decrease of heart rate and cardiac output. 3. The number of cardiac arrhythmias increased with rising oxygen pressures and exposure duration. 4. Increase of peripheral vascular resistance In human patients, HBO results in a decrease in cardiac output (CO), due to bradycardia, rather than a reduction in stroke volume. Blood pressure remains essentially un-

Respiratory System Hyperoxia suppresses the respira~ory reactivity t~ COz. After an initial depression of respiration, there is hyperventilation. HBO reversibly depresses the hypoxic ventilatory drive, most probably by a direct effect on the carotid COz chemoreceptors., Usually there are no differences betWeen forced vital capacities (FVC) and maximal eipiratory flows before and after hyperbaric oxygen exposl1re while breathing dry or humidified oxygen. However, detfeases in mean expiratory flow with steady FVC have been reported after 14 days of daily hyperbaric therapy (0.24 MPa) with although 80% of the patients were symptom free and remained so 1 year after the study (Mialon et a1200 1). This toxicity is clinically insignificant in subjects free of intlammatory lung diseases. HBO therapy, though safe, is not entirely without effect on the lungs. '

18

Chapter 2

Nervous System

genase, in contrast to a 49% increase in its activity throughout the hypoxic arterial segments.

Vasoconstriction and reduced cerebral blood flow do not produce any clinically observable effects in a healthy adult when pressures of 1.5 cO 2.5 ATAare used. Pressures higher than 3 ATAfor prolo~ed periods can lead to oxygen convulsions as a result of.oxygen toxicity. The effects of HBO are more pron'ounced" in hypoxic/ischemic states of the braix::.IiBO reduces cerebral edema and improves the function -ofneurons rendered inactive by ischemia/hypoxia. The improvement on·rain function is reflected by the improved electrical activ:~tyof the brain. The effect of HBO on cerebral blood flow is discussed in Chapter 17.

Heme oxygenase (BO). This enzyme catalyzes the ratelimiting step in the oxidative degradation of heme to biliverdin. The isoform HO-1 is inducible by a variety of agents causing oxidative stress and has been suggested to play an important role in cellular protection against oxidant-mediated cell damage. A low-level overexpression of HO-1 induced by HBO exposure provides protection against oxidative DNA damage by further exposures to HBO (Rothfuss & Speit 2002) ..

Microcirculation HBO improves the elasticity of the red blood cells and reduces platelet aggregation. This, combined with the ability of the plasma to carry dissolved oxygen to areas where RBCs cannot reach, has a be~eficial effect on the oxygenation of many hypoxic tissues in various circulatory disorders.

Tyrosine Hydroxylase. Increased oxygen saturation of this enzyme leads to increased turnover of catecholaminesooHyperoxia inhibits phenylalanine and tyrosine hydroxylase. Succinic Dehydrogenase (SDH) and Cytochrome Oxidase (CCO). These enzymes are activated byHBO. Their levels decline in the liver and kidneys of patients with intestinal obstruction. HBO after surgery led to the normalization of the levels of these enzymes. \

Biochemical Effects of HBO

Effect of HBO on Free Radical Production

Biochemical Marku of HBO

The role of hyperbaric oxygen (HBO) therapy in free radical-mediated tissue injury is not clear. HBO has been shown to enhance the antioxidative defense mechanisms in some animal studies, but HBO has also been reported to increase the production of oxygen free radicals. Hyperoxia causes an increase in nitric oxide (NO) synthesis as part of a response to oxidative stress. Mechanisms for neuronal nitric oxide synt~as~ (nNOS) activation include augmentation in the associatibn with Hsp9Q and intracellular entry of calcium (Thorn et al 2(,)02):-

Urine methylguanidim' (MG) which is known as a uremic toxin is synthesized froin creatinine. Urine MG/urine creatinine/serum creatinine ratio is used as an index of MG synthesis rate whiCh has been shown to increase during HBO therapy in human subjects and can be used as a marker of active oxygen products in vivo (Takemura et al1990). Effect of HBO on the Acid-Base Balance

Effect of HS,tdn(!erebral Metabolism Increased partial pressure of oxygen in \he blood disturbs ••. I ' \ ,\_ - I -_.,~III I - • the reduction of oxyhelllogiobin to hemoglobin. Of the alThe m<;>stimportanfmetabolic 'effed~ of HBO are on the kali that neutralizes the transported COz, 70% originates brain. Most of the investigations of this topic have been from the hemoglobin. ,Asa result of BBO and due to in, prompted by the problem of oxygen toxicity. It is believed creased solubility of COz, there is retention of COzleading that the preconvulsive period of oxygen toxicity is characto a slight rise of H+ iO:1sin the tissues. terized by alterations in several interrelated physiological HBO reduces excessJactate production in hypoxic states, functions of the brain, such as electrical activity, blood flow, as well as during exercise. This important subject is distissue pOz, and metabolic activity. The relation of these cussed extensively in Chapter 5. changes to the development of oxygen-induced convulsions has not yet been clarified. Nonetheless, several interesting observations have been- made as a result of theSe Effect of HBO on Enzymes studies which throw some light on the effect of HBO on Cyclo-Oxygenase Inactjvation. This results in decreased cerebral metabolism in the absence of clipical signs of oxproduction of prostacyclin by hyperoxic tissues. A study ygen toxicity: Most of the cerebral l11etabolicstudies are was made in human umbilical arteries by Yamaga et al now done on human patients with various CNS disorders. (1984) who showed that brief exposure of arteries to hy- Use of brain imaging in metabolic studies is described in peroxia resulted in a 30% decrease in activity of cyclo-oxy- Chapters 17, 19, and 44.

Physical, Physiological,

and Biochemical

Aspects of Hyperbaric

Oxygenation

Glucose Metabolism

Effect of HBO at Molecular level

Studies on \ regional cerebral glucose metabolic rate (rCMRgl) in rats after exposure to pressures of 1, 2, and 3 ATA.show that the degree of central nervous system effects of BBO depend upon the pressure as well as the duration of exposure. Increased utilization of glucose in some neuronal structures precedes the onset of central nervous system manifestations of orygen toxicity. Exposure of rats to 100% oxygen at 3 ATAcauses an increase in rCMRgl, and this is related to the oxygen-induced preconvulsive pattern of the electrocorticogram. In cats BBO (3 ATAfor 60 min), has a definite ~ffecton the glycerophosphate shuttle mechanisfTI following acute blood loss. HB() ·stimla1~tes· th1e~it6\chona-rial glycerol-3. 11.J:' phosphate dehydrogenase m the sensonmotor cortex and the medulla oblongata, providing glycerol-3-phosphate dehydrogenation. There is activation of the cytoplasm hydrogen delivery to the mitQ,chondrial respiratory chain. In addition, there is prevention of a rise in'glycerol-3-phosphate and NADB levels, as well as inhibition of glycerol-3-phosphate dehydrogenase, which limits lactate production. Energy metabolism has also been found to be highly sensitive to raised pressures of oxygen, which can reduce the formation of ATP molecules considerably.

Effect on DNA

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Ammonia Metabolism Following injury to the brain, the activity of glutaminase increases sharply, providing a release of ammonia from glutamine and a rise in transcapillary transfer of ammonia into the brain tissue from the blood. At the same time there is activation of glutamate formation pathways under the effect of glutamine dehydrogenase, and decrease of glutamine formation due to inhibition of glutamine synthase. This also leads to a decrease in the amount of a-ketoglutarate. HBO at 3 ATAfor 60 min prevents ammonia toxicity from increasing in the dehematized brain. The toxic effects of ammonia ions on the brain are eliminated via: • stir:nulation of the activity of the mitochondrial GDG providing glutamate formation from a-ketoglutarate • binding of ammonia with glutamate resulting in glutamine formation • a decrease of glutaminase activity inhibiting the process of deaminization of glutamine - a potential source of ammoma • transcapillary discharge of ammonia in the form of glutamine from the brain to the blood

19

Dennog et al (1996) have investig:lted the DNA-damaging effect of BBO with the alkaline version of the single cell gel test (comet assay). Oxidative DNA base modifications were determined by converting oxidized DNA bases to strand breaks using ,bacterial formamidopyrimidine-DNA glycosylase (FPG), a DNA repair enzyme, which specificallynicks DNA 'at sites of 8-oxo-guanines and formamidopyrimidines. HBO treatment under therapeutic conditions clearly and reproducibly induced DNA damage in leukocytes of all test subjects investigated. Increased DNA damage was found immediately at the end of the treatment, while 24 h later, no effect was found.'Using FPG protein the authors detected significant oxidative base damage after BBO treatment. DNA damage was detected only after the first treatment and not after further treatments under the same conditions, indicating an increase in antioxidani: defenses. DNA damage did not occur when the HBO treatment was started with a reduced treatment time which was then increased stepwise. Speit et al (1998) have shown that BBO-induced DNA strand breaks and oxidative base modifications are rapidly repaired, leading to a reduction in induced DNA effects of > 50% during the first hour. A similar decrease was found in blood taken immediately after exposure and post-incubated for 2 h at 37°C in vitro and in blo~d taken and analyzed 2 h after exposure, suggesting similar repair activities in vitro and in vivo. When the same blood samples showing increased DNA damage after HBO in the comet assay were analyzed in the micronucleus test, no indications of induced chromosomal breakage in cultivated leukocytes could be obtained. The results suggest that the HBO-inquced DNA effects observed with the com:etassay are efficientlyrepaired and are not manifested as detectable chromosome damage.

Conclusions The practical significance of many of the general effects of HBO is not clear. The study of the effects on cerebral metabolism was motivated by a search for the mechanism of oxygen-induced seizures. Bigh pressures such as 6 ATA have been used which have no cIiI1icalrdevance; the pressures for treatment of cerebral qisorders usually do not exceed 2 ATA.The optimal pre~~ue for treating patients with brain injury is 1.5 ATA.The cerebral glucose metabolism is balanced at this pressure. Raising the pressure even only to 2 ATAhas unfavorable effects. Generally HBO therapy is safe and well tolerated by humans at 1.5-2 ATA.The duration 'of exposure and the percentage of oxygen also have a bearing. No adverse effects are seen at 1.5 ATAfor exposures:up to 40-60 min.

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Physical, Physiological, and Biochemical Aspects of Hyperbaric

Physical, Physiological, and Biochemical Aspects of Hyperbaric Oxygenation ." K.K.Jaih I I " This chapter presents a bask, scientific foundation d...

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