ba-1973-0118.ch003

3 Respiratory Gas Transport in Brain under

Downloaded by UNIV OF CALIFORNIA SANTA BARBARA on March 17, 2018 | https://pubs.acs.org Publication Date: June 1, 1973 | doi: 10.1021/ba-1973-0118.ch003

Normal and Pathological Conditions J. G R O T E , H . K R E U S C H E R , H . J. R E U L E N , P. V A U P E L , and H. GÜNTHER Departments of Physiology, Anesthesiology, and Neurosurgery, University of Mainz, Mainz, West Germany

The oxygen supply conditions of cerebral tissue were studied in dogs and in patients under different physiological and pathological conditions. Under conditions of respiratory and nonrespiratory acidosis a decrease in paO2 induced an increase of CBF when the oxygen tension in cerebral venous blood fell below 35-40 mm Hg. At the same time the cerebral glucose uptake, the cerebral lactate output, and the lactate-pyruvate ratio in cerebral venous blood increased. Critical conditions occurred for the oxygen supply of the brain when cerebral venous pO2 fell below approximately 30 mm Hg. In edematous brain areas of patients, rCBF decreased with increasing brain water content. Theoretical analysis of oxygen diffusion in the brain tissue for the investigated conditions agreed with findings of regional metabolite concentrations.

'Tphe problems of oxygen transport i n the brain are investigated under **• different physiological and pathological conditions. The oxygen sup ply of an organ is determined by the relationship between the oxygen requirement of the tissue and the oxygen transport to the tissue cells by convection and diffusion. T o maintain normal aerobic metabolism, a mini mum oxygen tension of approximately 0.5-2.0 mm H g must be maintained in the cells of cerebral tissue under conditions of an adequate substrate and A D P level (1, 2, 3). When oxygen tension i n the mitochondria de creases below a critical value (0.2-3.0 mm H g ) , the oxygen activating system begins to unsaturate, and aerobic cell metabolism decreases (4, 5, 6,7). Because the concentrations of respiratory enzymes are higher than necessary for the maximal mitochondrial respiration, the actual limiting 35 Reneau; Chemical Engineering in Medicine Advances in Chemistry; American Chemical Society: Washington, DC, 1973.


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oxygen tension i n the single cell can be smaller than the critical oxygen tension of the mitochondria {4,7). The quantity of oxygen transported per unit of time by convection to the brain is determined by the blood flow rate, the oxygen capacity, the oxygen affinity of blood, and the arterial oxygen tension. Under nor mal conditions the mean overall blood flow rate i n cerebral tissue of dogs, monkeys, and humans ranges between 50 and 65 ml/100 g-min (8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18). Specific measured mean values of 80 to 110 ml/100 g-min were determined for cerebral cortex (18,19, 20, 21, 22, 23, 24, 25, 26, 27), and 15 to 25 ml/100 g-min were measured for white matter (20, 23, 26). In addition to blood flow rates, the oxygen capacity of blood is a major factor affecting the convective transport of oxygen to the brain. Oxy gen capacity is the maximum oxygen uptake capability of the blood per defined unit of volume. Under physiological conditions it depends almost entirely on the hemoglobin concentration of the blood. The extent to which the oxygen transport capacity, determined b y the blood flow rate and the oxygen capacity of the blood, can eventually be utilized is largely determined by the oxygen affinity of blood. The oxygen affinity of the blood is determined b y the relationship between the oxygen tension and the oxygen saturation of the hemoglobin. This function is represented diagrammatically by the oxygen dissociation curve of the blood. Under the oxygen tension conditions present in the lung, the shape of the oxygen dissociation curve primarily determines the degree of hemoglobin satura tion with oxygen. In tissue regions the blood oxygen affinity determines the oxygen tension decrease i n blood during capillary passage and, con sequently, the degree of oxygen exchange by diffusion between capillary blood and cerebral tissue. Besides the oxygen transport characteristics of blood, important fac tors influencing oxygen transport by diffusion between blood and tissue cells are the oxygen tension and the acid-base status of arterial blood, kinetics of the intracapillary release of oxygen from oxyhemoglobin, tissue metabolism, oxygen diffusion coefficients of blood and cerebral tissue, capillary dimensions, and the anatomical structure of the supply area of single capillaries in cerebral tissue. Provided that all these biological data are known, it is possible to analyze the oxygen exchange processes be tween capillary blood and cerebral tissue and to predict by calculation the oxygen tension i n tissue (9, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37,38). Experimental During our investigations of respiratory gas exchange i n the brain, we combined experimental studies of the different parameters affecting oxy-

Reneau; Chemical Engineering in Medicine Advances in Chemistry; American Chemical Society: Washington, DC, 1973.


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Gas Transport in Brain

gen supply of cerebral tissue and theoretical analyses of oxygen diffusion between capillary blood and tissue cells (31, 32, 33, 39, 40, 41). The present studies examined respiratory gas transport in the brain under normal conditions and under defined pathological conditions. Studies were conducted on dogs and humans. During experiments on dogs, we studied the influence of arterial hypoxia on cerebral blood flow, cerebral oxygen supply, and cerebral metabolism under normal acid—base conditions as well as under condi tions of respiratory and nonrespiratory acidosis. During investigations on patients, we studied the influence of local brain edema ( in the periphery of brain tumors or brain lesions ) on the cerebral blood flow, the oxygen supply, and the metabolite concentrations of the edematous tissue. Experiments on Dogs. The influence of reduced arterial oxygen tensions on respiratory gas transport in the brain under different a c i d base conditions were studied on 29 dogs during nitrous oxide anesthesia, muscle relaxation, and artificial ventilation. During the experiments ven tilation conditions were changed in such a manner that arterial oxygen tension decreased but arterial carbon dioxide tension remained constant. Parameter studies were made at constant arterial carbon dioxide tensions. Mean arterial blood pressure and body temperature were kept in normal ranges. After constant conditions (steady-state) in arterial blood had been attained, total cerebral blood flow was measured using the dye dilution technique (39, 42). In some cases regional cerebral blood flow of the cerebral cortex was measured, using the K r technique (20). The Po > Pco , and p H as well as the concentration of glucose, lactate, and pyruvate were determined polarographically, potentiometrically, and enzymatically (43), respectively, in simultaneously, anaerobically taken arterial (art. carotis communis) and cerebral venous (torcula) blood samples. The oxygen and glucose uptake and the lactate output of cere bral tissue were calculated. The E E G was recorded in some experiments. 8 5

2

2

Studies i n Patients. Oxygen transport in cerebral edema were stud ied in 14 artificially ventilated patients during nitrous oxide anesthesia (8), halothane, nitrous oxide anesthesia (2), and neuroleptanalgesia (4). Arterial C 0 tension as well as endexpiratory C 0 concentration were regularly monitored. Arterial blood pressure was kept in normal ranges. Following craniotomy and opening the dura, regional cerebral blood flow in brain areas bordering brain tumors or brain lesions was measured by the X e clearance method, using a bolus injection of the radioisotope into the internal carotid artery. Following r C B F measurements, one or two brain tissue specimens including gray and subcortical white matter were removed, corresponding to the location of the respective scintilla tion probe, by means of a precooled rongeur (in an area which had to be extirpated later). Samples for analysis of metabolites were immedi ately immersed in liquid nitrogen. In each sample the content of tissue water, different electrolytes, and the tissue metabolites phosphocreatine, A T P , A D P , glucose, lactate, and pyruvate were analyzed (44). The p , Pco , and p H were determined in the arterial blood immediately after r C B F measurements. Neither ρ in brain tissue nor ρ , Pco > and p H in regional venous blood could be measured during the operative procedure. To obtain information about the local oxygen supply, the oxygen tension 2

2

1 3 3

0 2

2

θ2

θ 2

2


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distribution i n the capillary blood and the brain tissue was predicted by calculation (28, 31, 32,33).


Discussion

of

Results

Previous W o r k . A s shown by the results of many experimentors, cerebral blood flow rate (under normal blood pressure conditions) is primarily determined by the C Q tension i n arterial blood (12,14, 21, 22, 45, 46). The p H value of the extracellular fluid i n brain is regarded as an essential factor for regulating vascular diameter (47, 48, 49, 50). Cere bral hypoxia causes the C0 -dependent regulation of the cerebral blood flow to change or vanish (9, 21, 25, 40, 45, 46, 51, 52). If the oxygen tension falls below approximately 60 mm H g i n arterial blood and below approximately 25-28 m m H g in cerebral venous blood, the cerebral blood flow increases. O n the basis of numerous experimental investigations, Noell and Schneider defined a reaction threshold for a cere bral venous oxygen tension of 25-28 mm H g and a critical threshold for a cerebral venous oxygen tension of 17-19 mm H g (46, 51). If the oxygen tension i n the cerebral venous blood falls below these values, an increased cerebral blood flow results i n the first case; whereas unconsciousness and distinct changes in the E E G are observed when the critical threshold is reached (25). It can be shown by theoretical and experimental investigations that, under normal acid-base conditions, hypoxia takes place in certain areas of the cerebral cortex or i n other regions of the brain with high oxygen consumption rates when an oxygen tension of 27 mm H g is reached in the cerebral venous blood. It can also be shown that anoxia occurs i n the same sections of the brain at cerebral venous oxygen tensions of 17-19 mm H g (28, 31,32,33). Experiments on Dogs. ACIDOSIS. Under respiratory and nonrespi ratory acidosis the progressive lowering of arterial oxygen tension leads to an increase of the cerebral blood flow whenever oxygen tensions i n cerebral venous blood fall below 35-40 mm H g . Critical conditions for the cerebral oxygen supply occur when the oxygen tension i n cerebral venous blood falls below 30-32 m m H g . These reaction and critical threshold values are higher than those reported for conditions of normal acid-base status i n arterial blood. RESPIRATORY ACIDOSIS. Under conditions of respiratory acidosis with carbon dioxide tensions between 50 and 60 mm H g the 0 -dependent elevation of cerebral blood flow is activated after reduction of cerebral venous oxygen tension to 35 mm H g . Critical conditions of oxygen supply result from a further reduction of arterial oxygen tension when the cere bral venous oxygen tension falls below 30 mm H g . W i t h a cerebral 2

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venous oxygen tension of 2 7 mm H g , we observed a definite blood pres sure fall and a pronounced bradycardia. Immediate elevation of the arterial oxygen tension restored the cerebral oxygen supply conditions to normal (Figure 1).

J 3.0 I

1

1

I

I

I

I

I

I

30

40

50

60

70

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90

100

110

p

ao

2

( m m H

e>

Figure 1. Effect of progressively decreasing arterial oxygen tension on cerebral blood flow and cerebral oxygen uptake under conditions of respiratory acidosis. Values in parentheses are the pertinent 0 tensions in cerebral venous blood. Values with a cross (+) indicate the cerebral blood flow rate and the cerebral oxygen uptake determined folhwing return of ventihtion conditions to normal. 2

NONRESPIRATORY ACIDOSIS. Under the combined conditions of non respiratory acidosis and arterial hypoxia, there was a large increase i n cerebral blood flow and i n the lactate-pyruvate ratio of cerebral venous blood. Also there was an increase i n glucose uptake of the cerebral tissue. This occurred as soon as oxygen tensions below 38 and 40 m m H g appeared i n cerebral venous blood. W h e n normal oxygen tensions in the arterial blood were adjusted again by changing the conditions of ventilation before reaching a cerebral venous oxygen tension of approxi mately 30 mm H g , the values for the cerebral blood flow and the oxygen and glucose uptake of the cerebral tissue quickly returned to initial values (Figure 2 ) . When—under comparable conditions—the arterial oxygen tension was lowered to such an extent that values of oxygen tension below 30 mm H g occurred in the cerebral venous blood, a decrease in arterial blood flow and i n oxygen uptake was registered, whereas the glucose uptake of the cerebral tissue and the lactate-pyruvate ratio of cerebral venous blood continued to increase. In these experiments the return to initial



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301 40

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120 130 Pa(mmM9) 0j

Figure 2. Effect of progressively decreasing arterial oxygen tension on cerebral blood flow, oxygen and glucose uptake of the brain tissue, and lactate pyruvate ratio of cerebral venous blood under conditions of nonrespiratory acidosis. Values in parentheses are the pertinent O* tensions in cerebral venous blood. Values with a cross (+) indicate data determined following return of ventilation conditions to normal. conditions d i d not lead to a complete normalization of the oxygen and glucose supply of the cerebral tissue if the cerebral venous oxygen ten sion was maintained below 30 mm H g for about 10 min (Figure 3 ) . Similar trend recordings were observed during investigations on anemic dogs, which were under conditions of nonrespiratory acidosis. The values for the cerebral blood flow, however, were distinctly higher than for normal animals. Under the conditions of cerebral edema and nonrespiratory acidosis, the cerebral blood flow rate d i d not increase as soon as the oxygen tension in cerebral venous blood decreased below the reaction threshold. During edema, a decrease of oxygen tension below the threshold value led to a slight decrease i n cerebral blood flow and cerebral oxygen uptake; however, glucose uptake of the cerebral tissue and the lactate-pyruvate ratio of the cerebral venous blood increased. W h e n arterial oxygen ten sions were returned to normal, the cerebral blood flow and the cerebral



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oxygen uptake d i d not return to initial values, and the lactate-pyruvate ratio increased further during the duration of the experiment ( Figure 4 ). Studies i n Patients. During the investigations i n patients with brain tumors or brain lesions, mean regional cerebral blood flow i n the perifocal edematous areas amounted to 20.6 ml/100 g-min. These values decreased significantly i n comparison with the mean hemispheric blood flow rate obtained with the same method i n normal patients (50-55 ml/100 g-min) (27). The largest reduction i n r C B F was encountered i n patients with metastatic tumors and glioblastomas and may be related to the wellknown tendency of these malignancies to develop brain edema. To determine whether the local tissue water content exerts an i n fluence on the blood flow rate, the r C B F values were plotted against the local tissue water content found i n the corresponding brain biopsies. F o r comparison, the mean of the individual values of the water content of cortex and subjacent white matter were used. A linear regression, with

25 30

40

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60

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80

90

Ï00

Pa tensions in cerebral venous blood. Return to arterial normoxie failed to normalize the oxygen and glucose conditions of supply.



42 C

B

F

50,

50

L

45

^

CMRQJ g min)

β

40

5

35

4

30

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25

2

20 15 30

35

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Figure 4. Effect of progressively decreasing cerebral venous oxygen tension on cerebral blood flow, oxygen and glucose uptake of the brain tissue, and lactate pyruvate ratio of cerebral venous blood under conditions of cerebral edema and nonrespiratory acidosis. Values with a cross (+) indicate data determined folfowing return of ventifotion conditions to normal. a high correlation coefficient ( r = 0.79) exists between both parameters. Regional cerebral blood flow rates decrease with increasing local brain water (Figure 5 ) . It seems, however, that the reduction of r C B F was related more to the increase i n water content of the subjacent white matter than to the increase of water content of the gray matter. The question of to what extent brain edema itself or increased intracranial pressure induced b y edema and tumor are responsible for the depression i n blood flow, is difficult to answer. The results indicate that the extent of local edema seems to be directly responsible for the reduction i n regional blood flow. The influence of intracranial pressure may be partially neglected since the dura was open during the intra operative r C B F measurements. Since the mean arterial blood pressure remained normal i n these patients, the regional cerebrovascular resist ance increased with increasing water content. It may be concluded that



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pathological water accumulation i n the tissue increases the local tissue pressure. Together with the increase i n local tissue pressure, the pressure in the venules and capillaries probably rises and w i l l consequently restrict the effective local tissue perfusion pressure and decrease the blood flow. In brain areas with pathologically increased water content, the lactate concentration is considerably higher than in areas with lower water con tent. However, no significant correlation could be found between the regional lactate concentration and the r C B F . 4035 30 2520 15

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r

>

E

Ε σ> Ο Ο

y «121.14 -1,27*79,18 r « 0.79

5

Cortex*White Matter 0 -

80

85

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Χ 40 IL Ο ο

30 2010 75

80

White Matter 85 62 65 70 75 Brain Water [ ml / 100 gm wet weight]

80

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Figure 5. Correlation between regional water content and regional cere bral bloodflowin cerebral edema adjacent to brain tumors and brain lesions Attempting to answer the question of whether the reduction of r C B F in edematous brain tissue surrounding tumors and lesions causes a de ficient oxygen supply of these areas, we predicted by calculation the mean oxygen tension decrease i n the capillaries and the mean oxygen tension distribution i n the tissue of these areas. Though the results of such a theoretical analysis of the oxygen tension distribution i n the capillary blood and the brain tissue are rough approximations, they agree with finding of regional metabolite concentrations. W e predicted tissue


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hypoxia to be present i n seven of 12 brain areas investigated. Simul taneously, metabolic changes characteristic of hypoxia alterations were obtained i n the same areas. The mean concentrations of lactate and the lactate-pyruvate ratio were higher, and the concentration of phosphocreatine was lower than in areas with sufficient oxygen supply. Brain areas with estimated normal oxygenation or mild hypoxia showed normal or less alterated metabolite concentrations (Table I ) . Table I.

Metabolite and Water Content i n Brain ° A η = 7

Glucose Lactate Pyruvate Lactate/pyruvate CrP ATP ADP Water

2.24 6.71 0.161 39.02 1.44 1.20 0.72 82.97

± zb ± zb zb ± ± zb

0.32 2.40 0.017 17.62 0.46 0.21 0.14 1.44

Β η = 5 2.07 2.18 0.169 16.2 2.07 1.21 0.85 75.87

zb 0.66 ±0.70 zb 0.08 zb 3.79 ±0.45 zb 0.07 zb 0.13 zb 1.35

° Comparison of metabolite and water content in edematour brain areas with mathematically predicted tissue hypoxia (A) and mathematically predicted sufficient oxygen supply or mild hypoxia (B). Metabolite concentrations expressed as ^moles/ gram wet weight, water content expressed as ml/100 grams wet weight.

In summarizing the results of investigations on patients with brain tumors or brain lesions, the following theory may be proposed. Increase in regional tissue water in edematous brain results in a rise in regional tissue pressure and a decrease in regional blood flow. This decrease i n r C B F influences the respiratory gas exchange in the edematous cerebral tissue and may cause tissue hypoxia and characteristic metabolic changes.

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August 4, 1972.


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