THE BLOODFLOWIN THE BRAIN ANDTHE LEG OF MAN,AND THE CHANGESINDUCED BY ALTERATION OF

BLOODGASES'

By WILLIAM G. LENNOXAND ERNALEONHARDTGIBBS(From the Department of Neuropathology, Harvard Medical School, and the Thorndike

Laboratory of the Boston City Hospital, Boston)

(Received for publication July 5, 1932)

The solution of various neurological problems awaits an increase in ourknowledge of the circulation of blood within the brain. Much has beengained by the demonstration of Forbes (1) and his co-workers that thepial vessels of the cat are under both vasomotor and chemical control.These experiments consisted of actual inspection and measurement of pialvessels viewed through a window screwed in the skull, the pressure of thecerebrospinal fluid and of the blood being measured simultaneously. Inparticular, Wolff and Lennox (2) showed that changes in the gaseouscontent of the blood had a prompt and clear cut effect on the diameter ofpial vessels, an effect which was independent of the systemic blood pres-sure. These authors observed that an increase in the carbon dioxidecontent of the blood was attended by an extreme dilatation of pial vesselswhereas a decrease was followed by a constriction. Variations in oxygencontent resulted in relatively small changes. An increase in oxygentension produced a slight constriction and a decrease in tension a slightdilatation of the observed vessels.

There are two difficulties in the way of accepting these observations assignificant of cerebral circulatory changes in man. First, experimentswere conducted on cats under amytal anesthesia. Second, the vesselslying in the pial covering of the brain may act differently from vesselslying within the brain. Intracranial circulation is of such great impor-tance to the organism and is so modified by the closed box arrangementof the skull that there is need for specific experimentation in man.

Observations concerning blood ffow through the brain of unanes-thetized persons seemed impossible until Myerson, Halloran and Hirsch(3) demonstrated the feasibility of obtaining blood from the internaljugular vein. By means of this procedure, we have repeated the experi-mental observations of Wolff and Lennox (2), using patients and judging

I This is paper XX in the series of papers on "The Cerebral Circulation"from the Department of Neuropathology, Harvard Medical School. It is alsofrom the Thorndike Laboratory of the Boston City Hospital. Work was doneunder a grant from the Harvard Epilepsy Commission.

1155

BLOODFLOW

changes in circulation by alterations in the gaseous content of bloodentering and leaving the brain. In addition we compared the brainchanges with those taking place in the leg.

A change in the oxygen content of venous blood during an experi-mental period might be indicative of alterations either in the oxygenconsumption of the tissue traversed, or in the speed of the blood flowingthrough the tissues. The oxygen consumption of tissues is not affectedby the tension of oxygen in the blood, within limits which were notoverstepped in these experiments. Patients lay quietly throughout theperiod of observation, so that there was probably no great variation in thetotal metabolism. It is therefore believed that observed changes inarteriovenous difference were due to alterations in the speed of bloodflow. Such change in pace might be consequent on change in heart rateand blood pressure, on variations in the number of open capillaries or onalterations in the size of arterioles. The observed changes in A-V dif-ference did not parallel changes in systemic blood pressure or heart rate.Webelieve alterations in the size of the vascular bed is the correct ex-planation. This view is supported by animal experiments of Wolff andLennox (2) in which pial vessels were watched under the microscope andby those of Bronk and Gesell (4) in which the volume of blood perfusingthe head and leg was measured by means of thermopiles. Both theseexperimenters observed that blood flow through the parts studied did notdepend on blood pressure. Webelieve that decreases in A-V difference(in which venous blood becomes more arterial-like) are due in our experi-ments to a dilatation of the arteriolar bed, leading to an increased speedand volume of blood flow. Increases in A-V differences (in which venousblood becomes more venous) are due to a constriction of the arteriolarbed with a slowing of the blood stream.

MATERIAL AND METHODS

The subjects used in this study were neurological patients at the BostonCity Hospital, for the most part epileptics. None had serious cardiac orpulmonary defect. Observations were made only with those patients whoexpressed a willingness to cooperate in observations designed to increaseknowledge concerning their intracranial circulation.

Observations were made in the morning, patients having fasted since theprevious evening and having lain quietly for at least half an hour. Blood wastaken without stasis (after anesthetization of the overlying skin) under oiland was immediately chilled and analyzed in the portable Van Slyke apparatus(5). Duplicate measurements were made and differed no more than one-tenthof a volume per cent. Arterial blood was taken from a brachial, radial orfemoral artery. Blood from the internal jugular vein was secured by themethod described by Myerson and associates (3), except that a small needle(1' inch 20 gauge) was used and the head was kept in a comfortable positionin a line horizontal with the rest of the body.

In previous observations with the same procedure, such as those with his-tamine by Weiss and Lennox (6), a major difficulty had been the simultaneous

1156

WILLIAM G. LENNOXAND ERNA LEONHARDTGIBBS

taking of blood from the various vessels. In order to meet this difficulty, aswell as the objection of repeated jugular punctures, we allowed the needles toremain in situ in the internal jugular and femoral veins during the minutesintervening between the drawing of the preliminary and the experimentalbloods. A stylette was inserted in the needle to prevent leakage and clotting.Blood was drawn simultaneously from the two veins, followed by puncture ofthe artery.

For purpose of comparison with the brain, a leg rather than an arm wasused. Blood from the femoral vein has passed through a relatively large pro-portion of muscle and the circulation of the leg is not so readily affected bychanges in temperature.

In order to alter the gaseous content of the blood, variations in the composi-tion of the alveolar air were induced. The procedures used will be describedlater. Because there was considerable variation in individual cases, observa-tions of each experimental procedure were made from three to ten times.Individual measurements in each of the 50 experiments are shown in the ac-companying Table I.

RESULTS

In order to distinguish the effects due to oxygen from those due tocarbon dioxide, it was necessary to cover all the possible combinations ofthese gases. Consequently observations were separated into nine groups,with reference to whether the tension of oxygen or of carbon dioxide wasincreased, normal or decreased. A first additional condition was thenormal control. I

1. Normal carbon dioxide-normal oxygenIt is important to know the amount of variation in the concentration

of the gases in blood drawn from vessels at intervals. In the controlexperiments, 15-20 minutes elapsed between the first and second bloodsamples. The average differences between successive samples (which areslight) are shown in Figure 1.

2. Increased carbon dioxide and oxygenIn five instances, patients breathed a mixture of 90 per cent oxygen

and 10 per cent carbon dioxide. Interest attaches to these results becauseof the wide clinical use of a mixture of oxygen and carbon dioxide for thetreatment of asphyxia, carbon monoxide poisoning and pneumonia. Thegas was administered from a compressed air tank by means of a face mask.Some patients did not receive the full concentration because such violenthyperpnea was produced that dilution of the gas with air was necessary.The mixture was breathed for 5-10 minutes before blood samples weretaken.

As a result of breathing this mixture the carbon dioxide content ofarterial blood was increased by 3.7 volumes per cent, and the oxygencontent by 0.9 volume per cent (Figure 2). The increase in the oxygencontent was possible because two of the patients had an initially lowarterial oxygen saturation.

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The effect on the intracranial circulation was striking. In all cases

there was a great decrease in the A-V difference, blood leaving the brainbeing nearly arterial, as regards its oxygen content. The average A-Vdifference was decreased from 6.7 volumes per cent to 2.8 volumes per

cent, a decrease of 58 per cent. This indicated a vast acceleration ofblood flow through the brain, a result which is in agreement with theanimal experiments of Wolff and Lennox, which demonstrated a dilatationof pial vessels and an increase in spinal fluid pressure when cats breathed a

NIORMAL CO, - NORMAL0.

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FIG. 1. NORMALCONTROLGROUP, SUBJECTS BREATHINGROOMAIRIn this and all figures except the last, the columns in the left hand portion

represent the oxygen and the carbon dioxide content of arterial blood before andduring the experimental period. The curves in the right hand portion representthe alterations in the gaseous content of the blood during its passage throughthe tissues, i.e. the A-V difference before (B) and during (D) the procedure.These changes refer to both oxygen (heavy lines) and carbon dioxide (lighterlines). The A-V differences for the leg are represented by a dashed line andfor the brain by a solid line. The steepness of the slant indicates the extent ofthe change. A line slanting downward from left to right means that there was

increased A-V difference during the experimental procedure and therefore a

decreased speed of blood flow, due probably to a constriction of arterioles.An upward slant of the line represents the opposite condition. The variousfigures represent the average measurements of from three to 10 experiments.

similar mixture. There is agreement also with the human experimentsof Cobb and Fremont-Smith (7) who noted that the color of retinal veinsapproached that of arteries, when subjects breathed a mixture of oxygen

and carbon dioxide.In surprising contrast to the behavior of cerebral vessels, the average

A-V difference in the leg changed almost not at all (from 5.0 to 5.1volumes per cent), an increase of two per cent. Individual results variedwidely. This failure of the circulation in the leg to show changes similarto those in the brain is in keeping with the lack of a consistent rise or fall

CONTENT ARTERIAL A - V DIFFERENCEVOL. BLOOD

PERCENT OXYGEN CARBONDIOXIDE

17 hS-.LEMALBLOOD

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162

WILLIAM G. LENNOX ANDERNA LEONHARDTGIBBS

in blood pressure. If vessels all over the body were to dilate in responseto increased arterial carbon dioxide as strongly as do the cerebral vessels,there would be a dramatic fall of blood pressure.

3. Increased carbon dioxide-normal oxygenIn these four experiments, a Tissot tank was filled with atmospheric

air to which had been added sufficient carbon dioxide to make from four toeight per cent by volume, a concentration sufficient to induce intensehyperpnea, although as compared with the previous group of experiments,the gaseous content of the arterial blood was but little increased. Therewas an average increase of one volume per cent in the carbon dioxide and

INCR ASED CO2 - INCREASED O2.CONTENTARTERIAL A-V DiFFERENCEPERcCENT 310D

AIR ONA A 10PEN CARBONDIOXIDE

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FIG. 2. AVERAGERESULTS IN A GROUPOF FiVE PATIENTs BREATHINGAIR CONTAININGAPPROXIMATELY10 PER CENTCARBONDIOXIDE AND 90 PERCENT OXYGEN.

The speed of blood flow through the bra'in i's greatly increased and throughthe leg is not affected.

0.6 volume per cent in the oxygen content of the blood (Figure 3).Venous blood drawn after an interval of five or ten minutes showed thatthe A-V difference was decreased in the head by 31 per cent and wasincreased in the leg by 50 per cent, i.e. cerebral vessels had dilated and legvessels had constricted. In both this and the preceding group, the resultsin each experiment were more consistent for the head than for the leg.Of the nine experiments, changes in A-V difference in blood traversingthe brain were all in the same direction, whereas in the leg, three wereagainst the trend. The observed changes are in agreement with the ani-mal experiments of Bronk and Gesell (4) who measured blood flow in thecarotid and femoral arteries of dogs, and found the flow was increased inthe carotid and decreased in the femoral artery when the animal breathedair rich in carbon dioxide.

1163

BLOODFLOW

4. Increased carbon dioxide-decreased oxygen

In four instances, subjects breathed air from a Tissot tank to whichboth carbon dioxide and nitrogen had been added, to make a mixturecontaining from 4 to 6 per cent by volume of carbon dioxide and from 8to 12 per cent by volume of oxygen. The average effect was to reduce theoxygen content of the arterial blood by 2.3 volumes per cent and toincrease the carbon dioxide content by 1.4 volumes per cent (Figure 4).As in the two previous groups of experiments there was a great increasein the speed of blood flowing through the brain (a reduction in the A-Vdifference of 7.3 volumes per cent; or 45 per cent) whereas the A-V dif-ference for the leg did not change.

INCREASED CO2- NORMALO0

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FIG. 3. AVERAGERESULTS IN A GROUPOF FOURSUBJECTS BREATHINGROOMAIR TO WHICHHAD BEEN ADDEDFROMFOURTO EIGHT PER CENT BYVOLUMEOF CARBONDIOXIDE.

The speed of blood flow through the brain was greatly increased and throughthe leg decreased.

In each of the foregoing experiments thirteen in all, in which carbondioxide tension of arterial blood was increased, there was a consistent andstriking decrease in the A-V difference for the brain. The average

decrease was 21 per cent for each volume per cent increase in the carbondioxide content of arterial blood. In the individual cases, however, thedegree of dilatation of cerebral vessels (as judged by decreases in A-Vdifferences) was not proportional to the observed changes in the carbondioxide content. As regards the leg, changes in A-V differences were notconsistent. In eight instances there was an increase and in five a de-crease.

5. Normal carbon dioxide-increased oxygen

In ten experiments, subjects were attached to a Collins-Roth metab-olism apparatus and breathed pure oxygen for a period of from 10 to 15

CONTENT ARTERIAL OXYGEN A - V DIF'fERENCE CAR3ON DiOXIDEPYRCLNT BLOOD - -

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minutes. While breathing oxygen the carbon dioxide content of thearterial blood did not change appreciably but the average oxygen contentincreased by 1.2 volumes per cent (Figure 5). This was possible becausethe average arterial blood was but 92.3 per cent !aturated. This condi-tion of mild anoxemia in epileptic patients has been reported by Lennox(8). In contrast with the previous groups of experiments, changes inblood flow were slight and not consistent. For the brain, the A-V dif-ference was increased in six instances and decreased in four, the averagechange being an increase of five per cent. For the leg, the A-V differencewas increased in two instances and decreased in eight, the average changebeing a decrease of 16 per cent. The results therefore are indecisive, there

INCREASED CO - DECREASEDO.OXY6EN A - V DIFFREHNCECARBONDIOXIDE

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FIG. 4. AVERAGERESULTSIN A GROUPOF FOURSUBJECTSWHOBREATHEDAIR CONTAININGFROMFOURTOSIX PERCENTBY VOLUMEOF CARBONDIOXIDEANDFROM8 TO 12 PER CENTOF OXYGEN.

The speed of blood flow through the brain was very greatly increasedwhereas the flow through the leg was not affected.

being evidence of a slight decrease in the speed of blood flow through thebrain, and more consistent evidence of an increased flow through the leg.So many experiments were conducted because of the lack of consistencyin results and because changes in circulation due to the breathing ofoxygen have received scant attention in medical literature. In dogexperiments Bernthal, Bronk, Cordero and Gesell (9) obtained evidence ofa decreased blood flow in both the carotid and the femoral arteries. Ourresults for the circulation in the leg, therefore, are not in agreement withtheirs. The difference may be due to the fact that presumably theanesthetized animals had a greater initial anoxemia than the humansubjects.

L..

-

a

I

BLOODFLOW

6. Normal carbon dioxide-slightly decreased oxygenIn four experiments subjects breathed from a Tissot tank to which

atmospheric air and nitrogen had been added. Individuals breathing thesame gas mixture showed large differences in the degree of anoxemia.Therefore, separation of cases was based on the actual degree of anoxemiapresent in arterial blood and not on the mixture breathed. The averagereduction in arterial oxygen in the four subjects of this group was onevolume per cent making the arterial blood 87 per cent saturated. Becauseof the hyperpnea induced by the diminished oxygen supply, the averagecarbon dioxide content of the arterial blood was decreased by 1.9 volumesper cent (Figure 6). In three of the four cases there was a sharp increase

NORMALCOl - INCREASED 0OCOINTENT ARTERIAL A-V DIFFE.RENCE

PEVOL. BLOODPPCENT0 OXYGEN CARBONDIOXIDE Z

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171 L.

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FIG. 5. AVERAGERESULTS IN A GROUPOF TEN SUBJECTS WHoBREATHED

The speed of blood flow through the brain was slightly decreased, andthrough the leg slightly increased.

in the A-V difference for the brain. The average increase for the fourcases was 30 per cent. For the leg, the A-V difference was increased intwo and decreased in two experiments, the average change being anincrease of 5 per cent. The decreased speed of blood flow through thebrain, in the light of evidence from other groups of experiments, waspresumably caused by the reduction of carbon dioxide, rather than thereduction of oxygen in the arterial blood.

7. Normal carbon dioxide-greatly decreased oxygenIn these seven cases, a much greater degree of anoxemia was induced,

the average oxygen content of arterial blood being reduced by 5.9 volumesper cent (from an average saturation of 93.4 per cent to 64 per cent).In spite of this anoxemia, the average carbon dioxide content of thearterial blood fell but three volumes per cent (Figure 7).

1166

WILLIAM G. LENNOXAND ERNA LEONHARDTGIBBS

In all seven instances there was a decrease in the difference in oxygencontent between arterial and internal jugular blood, the average decreasebeing 31 per cent. In five instances there was likewise a great decrease inthe difference between arterial and femoral vein blood (the average de-crease for the seven cases being 48 per cent). Therefore, the vessels ofboth the brain and the leg underwent dilatation. This is in agreementwith observations in the dog by Gesell and his associates. If all theblood vessels of the body dilated to this extent, there would be a fall insystemic blood pressure. Wewere not able to record the pulse and theblood pressure readings in all these cases, but in those in which we did,there was an increase in heart rate and a fall in blood pressure. Accordingto Marshall (10) in conditions of anoxemia, cardiac output is increasedonly when the concentration of oxygen in the inspired air is less than 11

NORMALCOX SLIGHTLY DECREASEDO0ARTERIAL A-V DifFERENCE

VOL LQ- OXYGEN CARBONDIOXIDE Zi

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PCAGENT of

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(Group~ ~ ~~7)ihrbbyepanalintianr Tedcesdcro

5011_FIG. 6. AVERAGERESULTS IN A GROUPOF FOURSUBJECTS WHoBREATHEDAIR CONTAININGFRom6 TO 12 PER CENTBY VOLUMEOF OXYGENANDWHOSEARTERIAL OXYGENSATURATION DECREASEDFROMA PRELIMINARY VALUE OF92.3 PIER CENTTo 87 PER CENT.

There was a moderate decrease in the speed of blood flow through the brainand a very slight decrease in the leg, due probably to the diminution in thetension of carbon dioxide in arterial blood.

per cent. The fact that there was decreased cerebral blood flow withslight anoxemia (Group 6) and increased flow with extreme anoxemia(Group 7) is probably explainable in this manner: The decreased carbondioxide due to dyspnea exerted its constricting effect when anoxemia wastrivial, but an even greater carbon dioxide loss could not prevent dilata-tion when anoxemia was extreme.

8. Decreased carbon dioxide-increased oxygenIn three experiments, subjects while connected with a basal metabolism

machine and breathing pure oxygen, performed voluntary hyperpnea.Arterial blood drawn after five or ten minutes revealed an average in-crease of .5 volume per cent in oxygen content and a decrease of 10volumes per cent in carbon dioxide content (Figure 8).

1167

BLOODFLOW

In each instance there was an increase in the A-V difference for thebrain, the average increase being 47 per cent and a decrease for the leg,the average being 19 per cent. These changes indicate a decreasedspeed of blood flow through the brain and an increased flow throughthe leg.

9. Decreased carbon dioxide-normal oxygenIn this group of four experiments, the subjects performed over-

ventilation in room air, a procedure which increased the average oxygencontent of arterial blood .3 volume per cent and decreased its carbon

NORMAL Ca- GREATLY DECREASEDODONTE ARTERIAL A - V DIFFERENCEVOL BLOOD

PERCENTH&EDIWETIIGFO O8PE ETB OUEO XGN

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FIG. 7. AVERAGE RESULTS IN A GROUP OF SEVEN PATIENTS WHOBREATHEDAIR CONTAINING FRom 6 TO 8 PER CENT BY VOLUMEOF OXYGEN,ANDWHOSEARTERIAL OXYGENSATURATIONDECREASEDFROMA PRELIMINARYVALUE OF 93.4 PER CENTTo 64 PER CENT.

The flow of blood through both the brain and the leg was greatly accelerated.

dioxide content by 1 1 volumes per cent. Results were not greatly dif-ferent from those in the preceding group. The effect on blood flowwas in the same direction though more distinct. For the brain there wasan increase in the A-V difference in all cases, the average increase being58 per cent. For the leg there was a decrease in the A-V difference inthree of the four cases, the average decrease for all being 35 per cent(Figure 9). The decrease in cerebral blood flow accompanying hyperpnea(per unit change in carbon dioxide content of arterial blood) is only onesixth as great as the increase which accompanies the breathing of carbondioxide.

168

WILLIAM G. LENNOXAND ERNA LEONHARDTGIBBS

10. Decreased carbon dioxide-decreased oxygenIn three experiments, subjects breathed a mixture of air and nitrogen

(the oxygen forming from 6 to 10 per cent by volume of the mixture)from a Tissot tank, at the same time performing voluntary hyperpnea.In two experiments subjects were attached to a basal metabolism ap-paratus, the bell of which had been filled with room air. In this caseanoxemia developed more slowly.

DtCREASEDCO- INCREASED OLat At1*oL BILENT

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16

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FIG. 8. AVERAGERESULTSIN A GROUPOFTHREESUBJECTSWHOPERFORMEDHYPERPNEAWHILE BREATHING PURE OXYGEN

The speed of blood flow through the brain was greatly decreased and throughthe leg was slightly increased.

Although air mixtures were practically the same as in the experimentsunder Group 7, t4e anoxemia produced was not as great when sub-jects breathed deeply, as when they breathed naturally. The percentagesaturation of arterial blood was reduced by only 6.6 per cent, against a

reduction of 29.4 per cent when hyperpnea was not performed. Schneider(11) has stated that under conditions of reduced atmospheric pressure

subjects are more comfortable if they breathe deeply. In the five experi-ments the average decrease in the oxygen content of arterial blood was 1.5and of the carbon dioxide content 13.6 volumes per cent.

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In four instances, the A-V difference was increased both for thebrain and the leg, in one it was decreased for both. For the five experi-ments, the average increase for the brain was 33 per cent and for the leg44 per cent (Figure 10).

Although overbreathing in oxygen poor air resulted in a greaterdecrease in the carbon dioxide content of arterial blood than overbreathingin room air, the diminution in blood flow through the brain was less.Presumably this was due to the counteracting effect of the anoxemiawhich in itself would cause an increase in blood flow.

DECREASEDCo1 - NORMALO0ARTERIAL A - V DIf FERENCE

BLOOD¢MDirOXYGEN - OD BN CARBONDIOXIDE

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FIG. 9. AVERAGERESULTSIN A GROUPOF FOURSUBJECTSWHOPERFORMEDHYPERPNEAWHILE BREATHING ROOMAIR

The speed of blood flow through the brain was greatly decreased and throughthe leg it was slightly increased.

The decrease in the flow of blood through the leg is not so easy toexplain, for in Groups 7, 8 and 9, in which there had been a decrease eitherin the carbon dioxide or in the oxygen content of the arterial blood, the legflow had increased. Throughout this investigation, the blood flowthrough the leg was more variable than the flow through the brain.

A - V differences in carbon dioxide contentIn the presentation of material thus far, we have dealt only with

changes in oxygen tension of the blood. In Figures 1-10 the A-V dif-

1170

WILLIAM G. LENNOXAND ERNA LEONHARDTGIBBS

ferences in carbon dioxide content are shown in the right hand portion.One would expect that curves representing changes in oxygen and incarbon dioxide content would slope in opposite directions; e.g. the A-Vdifference for carbon dioxide should increase as that for oxygen decreases.Of the nine experimental groups the slopes are opposite in five for the legand in only one for the brain. As we have pointed out (12) the respira-tory quotient (the increase in carbon dioxide of venous blood, divided byits decrease in oxygen with reference to the arterial blood) of the brain in

FIG. 10. AVERAGERESULTS IN A GROUPOF FIVE SUBJECTS WHOPER-FORMEDHYPERPNEAWHILE BREATHINGAIR CONTAINING FROM6 TO 10 PERCENTOF OXYGEN.

The speed of blood flow through both the brain and the leg was decreased.

these unanesthetized subjects is much higher than that of the leg. Underconditions in which the composition of the alveolar air is artificiallyaltered the respiratory quotient is greatly distorted. In the low oxygenexperiments one factor in such distortion is the various degrees of ab-sorption of carbon dioxide by the tissues. In the ten experiments inwhich patients quietly breathed pure oxygen (Group 5) the average respir-atory quotients before and after the procedure were approximately thesame. In the seven experiments in which marked anoxemia was pro-duced (Group 7), the quotients during the breathing were above unity,1.32 for the brain and 1.80 for the leg, against preliminary averages of .91

1171

ILQD

-i

I-1

u

0orL.

Li

IV +

BLOODFLOW

rEM1RAL BLOOD

FIG. 11. THEAVERAGERESULTSIN SEVENGROUPSOF EXPERIMENTSWITH 50SUBJECTS

The upper portion of the figure represents the changes in the gaseous contentof arterial blood which followed alteration of the alveolar air, induced bybreathing various mixtures of carbon dioxide and oxygen. Projection of

1172

WILLIAM G. LENNOXAND ERNA LEONHARDTGIBBS

and .62 respectively. This excess of carbon dioxide in the venous bloodsuggests that under conditions of anoxemia carbon dioxide is not readilyabsorbed by the tissues, and more carbon dioxide is absorbed by thebrain than by muscle. McGinty (13) found that tissues of living frogsdo not absorb carbon dioxide as readily when the animals are kept in alow oxygen atmosphere and that the brain absorbed more than muscles.If the differences in respiratory quotient between the brain and the leghad been due to differences in the distribution of capillaries in the brainand leg (a possibility suggested by Myerson, Loman, Edwards and Dill(14) for similar respiratory quotients in their cases) one would expectdistinct differences in blood flow. On the contrary the increase in thespeed of blood flow in Group 7 was practically the same in the brain as inthe leg.

DISCUSSION

The detailed changes in blood flow which have been enumerated areconfusing. In order to contrast more clearly the average changes ineach group, we calculated the percentage change in the A-V oxygendifference for the experimental as contrasted with the control period.These results are depicted in Figure 11.

At the top of the chart is shown the average change from the pre-experimental sample as regards the gaseous content of arterial blood.The changes in the composition of blood flowing through the brain areclear cut and consistent. An increase in the carbon dioxide content ofthe arterial blood causes an increase of more than 40 per cent in bloodflow, as measured by alterations in the oxygen content of venous blood.On the other hand, a similar decrease in the carbon dioxide of arterialblood results in a decrease in blood flow only a third or a fourth as great.Wolff and Lennox observed this also when watching pial blood vessels.

The effect of oxygen is less. An increase of oxygen in arterial bloodcauses a slight decrease in cerebral flow, a well marked anoxemia anincrease. When the degree of anoxemia is not great, any change in thecarbon dioxide tension of blood overshadows it. However, anoxemiapartially neutralizes the constricting effect of diminished carbon dioxide.Also, anoxemia augments the dilator effect of carbon dioxide and excessoxygen augments the constrictor effect of decreased carbon dioxide.

These conclusions are in entire agreement with the window observa-tions of Wolff and Lennox. Dilatation of pial vessels of cats occurred

columns above or below the base line indicates that the gaseous content had beenincreased or decreased. The solid columns indicate oxygen content, the doublehatched columns carbon dioxide content. The lower portion of the figurerepresents changes which took place in the A-V difference of blood oxygen.Projection of columns above the base line indicates that the A-V differencehad decreased and the speed of blood flow had increased. Projection belowthe line indicates the opposite. The single hatched columns represent thebrain and the dotted columns the leg.

1173

BLOODFLOW

under the same circumstances that cause decrease in the difference in theblood gases entering and leaving the brain. The effect of changes inoxygen tension of arterial blood was more clear cut in the human than inthe cat experiments, due presumably to the fact that the anesthetizedanimals had a mild degree of anoxemia.

Our observations demonstrate that the changes in the diameter of pialvessels do not indicate, as Kubie and Hetler (15) suggested, merely a localchange in pial circulation, but reflect, rather, a change in circulationthroughout the brain. Likewise they contradict the contention ofNicholson (16) that the increase in cerebrospinal fluid flow which accom-panies breathing of carbon dioxide is not due to enlargement of the cere-bral vascular bed.

Concerning the effects of altering blood gases on the circulation of theleg, the evidence is less clear cut. Given a normal or better than normalarterial oxygen tension, an increased carbon dioxide tension was asso-ciated with an increased A-V difference (decrease in blood flow). Adecreased carbon dioxide tension was associated with a decreased A-Vdifference (increase in blood flow). This is the opposite to the conditionfor the brain. In the presence of a profound arterial anoxemia (thecarbon dioxide tension being only slightly affected) there is a markedlyincreased blood flow, through both leg and brain.

In general, it may be said that circulatory responses to chemicalstimuli are greater in the brain than in the leg. One reason for this is thefact, pointed out by Lennox and Leonhardt (17), that the A-V differenceis greater for the brain than for the extremities. Therefore there isgreater opportunity for a decreased A-V difference, in other words, for animprovement in the quality of the blood pouring through the brain.Cerebral circulatory responses are also more constant than those of theleg from time to time and from subject to subject.

These observations demonstrate that the body has a mechanism foraltering the speed and the composition of the blood flowing through thebrain. Either anoxemia or increase of carbon dioxide is attended by adilatation of vessels, which provides capillaries and veins with blood thatis more nearly arterial in quality. The opposite conditions result in aretardation of the blood stream. The chemical mechanism which governsthese circulatory changes is probably a complicated one. In the case ofthe carbon dioxide, the coincident alterations in the acid base relation-ships of the blood are undoubtedly important. Injection of acid sub-stances other than carbon dioxide or of alkaline substances also result indilatation and constriction of brain vessels. Presumably the increasedcerebral flow consequent on anoxemia cannot be explained on the basis ofacid base changes in the blood, for according to Koehler, Brunquist andLoevenhart (18) acidosis occurs only when the anoxemia is extreme andprolonged. Whatever the exact mechanism, these adjustments in blood

1174

WILLIAM G. LENNOXAND ERNA LEONHARDTGIBBS

flow provide brain tissue with blood which is more constant in qualitythan would otherwise be the case. Presumably this contributes to moreeffective functioning of the brain.

The fact that circulatory adjustments for the brain may be andusually are the opposite of those for the leg is of great theoretical andpractical interest. This circumstance permits alteration of blood flow inthe brain without change in the systemic blood pressure. It permits thebrain to secure preferential treatment as regards allocation of arterialblood. In these experiments the differential action is more evident afteralteration of carbon dioxide than after alteration of oxygen tension.When the carbon dioxide tension of the arterial blood was increased orreduced (and oxygen tension not reduced) the speed of blood flow in thehead and leg was affected in an opposite manner. On the other hand,when anoxemia was induced (no matter what the carbon dioxide tension)the blood flow in the brain and leg increased or decreased together.These are average, not individual results.

These experiments do not shed light on the localization of the mechan-ism of chemical control, whether in a center in the brain or in the walls ofthe blood vessels. One is perplexed to explain how the same chemicalstimulus produces such diverse vasomotor effects. Nor can one explainthe differing reactions on the basis of the closed box arrangements of theskull. Though vessels in the brain are embedded in an incompressiblemedium, the alterations in calibre, as measured by A-V differences, areeven greater in the brain than in the leg. Of course, one must take intoaccount possible differences in the area of the vascular bed in relation tothe volume of brain and leg tissues. According to the researches of Cobb(19) nervous tissue has fewer capillaries per square millimeter than hasmuscle. Again, capillaries in the two regions may respond differently tochemical stimuli, or there may be differing responses of capillaries and ofarterioles. The relative scarcity of capillaries in the brain, together withthe external resistance to capillary expansion, may hinder capillary stasisand hence, when arterioles dilate, result in a relatively speedy flow of bloodthrough the brain.

Finally our observations emphasize the contention of Wolff and Len-nox (2) that when the patient benefits from measures which alter thecomposition of alveolar air, in any assignment of credit, the accompanyingchanges in cerebral circulation must be taken into account.

SUMMARY

Fifty observations were made of changes in the speed of blood flowthrough the brain and the leg of man. These changes were in response toalteration in the composition of the alveolar air, and were judged by thealterations in the difference in the oxygen content of blood entering andleaving the brain and the leg.

77

1175

BLOODFLOW

Alteration in the composition of alveolar air was attended by a markedchange in the speed of blood flow. With an increased tension of carbondioxide in arterial blood, the speed of flow through the brain was in-creased and through the leg was decreased. With a decreased tension ofcarbon dioxide the flow through the brain was decreased and through theleg increased.

Alteration of the oxygen content of arterial blood produced less pro-nounced results. Increase in the oxygen content resulted in a slightdecrease in speed of blood flow through the brain and increase through theleg. Pronounced anoxemia resulted in increased flow in both brain andleg.

Changes in speed of flow in these experiments are believed to be due todilatation or constriction of arterioles.

An increase in the flow in the brain is more readily produced than adecrease. Alterations in the flow are more consistent in the brain than inthe leg. Conclusions are based on average, not individual, results.

In conditions of anoxemia the tissues of the brain and the leg absorbless than the usual amount of carbon dioxide.

Circulatory adjustments for the brain, in response to gaseous changesin the blood, may be the opposite for those in the leg, thereby permittingthe brain to receive preferential treatment as regards allocation ofarterial blood.

BIBLIOGRAPHY

1. Forbes, H. S. and Wolff, H. G., Arch. Neurol. and Psychiat., 1928, xix,1057. Cerebral Circulation. III. The Vasomotor Control of CerebralVessels.

2. Wolff, H. G. and Lennox, W. G., Arch. Neurol. and Psychiat., 1930, xxiii,1097. Cerebral Circulation. XII. The Effect on Pial Vessels ofVariations in the Oxygen and Carbon Dioxide Content of the Blood.

3. Myerson, A., Halloran, R. D. and Hirsch, H. L., Arch. Neurol. and Psy-chiat., 1927, xvii, 807. Technic for Obtaining Blood from the InternalJugular Vein and Internal Carotid Artery.

4. Bronk, D. W. and Gessell, R., Am. J. Physiol., 1927, lxxxii, 170. TheRegulation of Respiration. X. Effects of Carbon Dioxide, SodiumBicarbonate, and Sodium Carbonate on the Carotid and Femoral Flowof Blood.

5. Van Slyke, D. D., J. Biol. Chem. 1927, lxxiii, 121. Notes on a PortableForm of the Manometric Gas Apparatus and on Certain Points in theTechnique of Its Use.

6. Weiss, S. and Lennox, W. G., Arch. Neurol. and Psychiat., 1931, xxvi, 737.The Cerebral Circulation. XVII. Cerebral Blood Flow and the Vaso-motor Response of the Minute Vessels of the HumanBrain to Histamine.

7. Cobb, S. and Fremont-Smith, F., Arch. Neurol. and Psychiat., 1931, xxvi,731. The Cerebral Circulation. XVI. Changes in the Human RetinalCirculation and the Pressure of the Cerebrospinal Fluid during Inhala-tion of a Mixture of Carbon Dioxide and Oxygen.

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WILLIAM G. LENNOXAND ERNA LEONHARDTGIBBS

8. Lennox, W. G., Certain Chemical and Physiological Conditions Which MayInfluence Seizures. Epilepsy and the Convulsive States. ChapterXV, p. 471. Williams and Wilkins Company, Baltimore, 1931.

9. Bernthal, T. G., Bronk, D. W., Cordero, N. and Gesell, R., Am. J. Physiol.,1928, lxxxiii, 435. The Regulation of Respiration. XVII. The Effectsof Low and High Alveolar Oxygen Pressure and of Sodium Cyanide onthe Carotid and Femoral Flow of Blood as Studied with the ContinuousElectrometric Method.

10. Marshall, E. K., Jr., Medicine, 1930, ix, 175. The Cardiac Output of Man.11. Schneider, E. C. and Clarke, R. W., Am. J. Physiol., 1929, lxxxviii, 633.

Studies of Muscular Exercise under Low Barometric Pressure. IV. ThePulse Rate, Arterial Blood Pressure and Oxygen Pulse.

12. Lennox, W. G. and Leonhardt, E., Arch. Neurol. and Psychiat., 1931,xxvi, 719. The Cerebral Circulation. XIV. The Respiratory Quotientof the Brain and of the Extremities in Man.

13. McGinty, D. A., Am. J. Physiol., 1930, xciii, 528. The Regulation ofRespiration. XXXIV. The Carbon Dioxide Content of the IntactBrain of the Frog in Relation to Changes of Oxidations.

14. Myerson, A., Loman, J., Edwards, H. T., and Dill, D. B., Am. J. Physiol.,1931, xcviii, 373. The Composition of Blood in the Artery, in theInternal Jugular Vein and in the Femoral Vein during Oxygen Want.

15. Kubie, L. S. and Hetler, D. M., Arch. Neurol. and Psychiat., 1929, xx, 749.The Cerebral Circulation. IV. A Study of the Circulation in the Cortexby Means of Color Photography.-

16. Nicholson, H., Am. J. Physiol., 1932, xcix, 570. Effects of Low AlveolarOxygen and High Alveolar Carbon Dioxide on the Rate of Flow ofCerebrospinal Fluid.

17. Lennox, W. G. and Leonhardt, E., Arch. Int. Med., 1930, xlvi, 630. TheOxygen and Carbon Dioxide Content of Blood from the Internal Jugularand Other Veins.

18. Koehler, A. E., Brunquist, E. H., and Loevenhart, A. S., J. Biol. Chem.1925, lxiv, 313. The Production of Acidosis by Anoxemia.

19. Cobb, S., Arch. Surg., 1929, xviii, 1200. The Cerebral Circulation. VIII.A Quantitative Study of the Capillaries in the Hippocampus.

1177