changes in thebloodandcirculation with...changes in thebloodandcirculation withchanges in posture....

CHANGESIN THE BLOODANDCIRCULATION WITH CHANGESIN POSTURE. THE EFFECT OF EXERCISE

ANDVASODILATATION

BY JOHN B. YOUMANS,J. H. AKEROYD, JR., AND HELENFRANK

(From the Department of Medicine, Vanderbilt University Medical School, Nashville)

(Received for publication May 31, 1935)

In the erect posture the forces tending to filterfluid from the blood into the tissues of the de-pendent parts are much greater than in the re-cumbent position. As Krogh, Landis and Turnerhave remarked, the erect human being is alwaysclose to edema (1). In a previous study of theeffect of quiet standing (2) it was pointed outthat the primary factors concerned in limiting theloss of fluid from the blood in the standing-stillposition appear to be an increasing concentrationof plasma proteins, with a resulting rise in colloidosmotic pressure 1 and, probably, an increasingtissue pressure. However, secondary factors,changes in the circulation especially, modify thismechanism, particularly under conditions of nor-mal activity. The changes may be the direct re-sult of the change in posture, as for example thevasoconstriction which apparently accompanies thechange in position. They may be the result ofother influences such as exercise, or variations inenvironmental temperature. Under abnormal con-ditions, such as a nutritional hypoproteinemia, andparticularly in border line states of such a dis-order, variations in these factors might determinethe occurrence or non-occurrence of edema.Therefore, we have studied the effect of some ofthese secondary factors on the circulation in thelegs and on changes in the composition of theblood which occur in the erect position. Thepresent paper deals with (1) the effect of muscu-lar activity on the changes in the blood resultingfrom the erect posture, (2) changes in the cir-culation in the feet and legs in the erect posture,quiet and moving, as shown by changes in the sur-face temperature, (3) a comparison of the circula-tion time in the quiet and moving leg in the erectposture, and (4) the influence of vasodilatation

1 The increase in colloid osmotic pressure is greaterthan the increase in concentration of the proteins becauseof the increase in specific osmotic pressure, i.e., pressureper gram of protein.

on the changes in the composition of the bloodwhich occur on standing. For convenience inpresentation, the methods and data in each of thestudies will be presented separately.

I. THE EFFECT OF MUSCULARACTIVITY ON THE

CHANGESIN THE BLOODRESULTINGFROM

THE ERECT POSTURE

The influence of muscular activity was deter-mined by comparing the changes in the composi-tion of the blood and in the leg volume of an ac-tively moving leg in the erect posture with thoseof the opposite leg which was kept motionless.In addition a few observations were made of thecapillaries in the great toe of the quiet leg.

The subjects consisted of six young healthy men(students) and one man with nutritional edema.About an hour after a light lunch the subject re-clined for 60 minutes or more. During this timethe capillaries at the base of the great toe nail wereobserved with a capillary microscope. At the endof the reclining period a sample of blood wasdrawn from the arm.2 After the blood was drawnthe venous pressure was measured directly. Thevolume of each leg was then determined by meas-uring the amount of water displaced from a rigidmetal boot reaching to about the knee (48.3 cm.).The temperature of the water was adjusted to ap-proximately room temperature. After the im-mersion the leg was quickly dried without rubbing.Each measurement occupied approximately fiveminutes and the subject reclined five minutes be-tween the measurements of the first and secondlegs. After the volume of the second leg wasmeasured the subject again reclined for a periodof five to ten minutes. The subject then mounteda stationary bicycle, the left pedal of which wasremoved. The left leg was allowed to hang

2 It is assumed that during reclining, blood from thefoot has the same composition as blood from the arm (2).

739

JOHN B. YOUMANS, J. H. AKEROYD, JR., AND HELEN FRANK

perpendicularly, supported comfortably in halfthe experiments by a platform and unsupportedin the others. The subject began to pedal im-mediately with the right leg against a resistancewhich was obtained by means of an adjustablespool pressing against the partially deflated tire ofthe rear wheel. The position assumed is believedto be comparable, as far as the left (motionless)leg is concerned, to standing at an angle of 75degrees as employed in previous experiments (2).Pedalling was continued at a rate of forty to fiftyrevolutions per minute except for short interrup-tions to allow for the inspection of the capillariesin the toe of the motionless foot. When thelatter was allowed to hang unsupported, it wassupported temporarily while the capillaries wereobserved. When the right leg was not pedallingit was stopped at the mid point between the topand bottom of the stroke. Total pedalling timewas thirty minutes but the time the subject was onthe bicycle varied because of the time taken outfor capillaroscopy and the drawing of samples ofblood at the end of the period of pedalling.When the subject had pedalled for thirty minutesa sample of blood was drawn from each foot froma vein on the dorsum or, at the internal malleolus.The sample from the right (moving) foot was al-ways drawn first and the venous pressure was de-termined in the left foot. The volume of eachleg was then measured again. Because of diffi-culties sometimes encountered, the time relationof the various procedures, particularly the timeelapsing between the cessation of pedalling, theobtaining of the two samples of blood and thefinal measurement of leg volume, was not the samein all the experiments. The samples of bloodwere drawn under oil without stasis, and withheparin as an anticoagulant; specimens were re-moved for determining the concentration ofplasma proteins, the colloid osmotic pressure andthe nonprotein nitrogen. The methods of analysiswere the same as those described in a previouspaper (2).

The results of the experiments are summarizedin Table I. In four experiments the increase inthe concentration of total proteins both actual andpercentile, was greater in the " motionless " (left)leg than in the " moving " (right) leg.3 In two,

3 This is believed not to be the result of a lessenedtendency to filtration, resulting from the intermittent na-

the increase was practically the same in each leg,the differences being within the limit of error.Absence of a greater difference between the twolegs in some of the experiments may have beenthe result of such irregularities as delay in draw-ing samples of blood and fainting of thesubject.The changes in the concentration of albumin weresimilar, the one instance in which the increase inconcentration of albumin was greater in the" moving " leg than in the " quiet " leg occurringin the experiment in which the increase in totalprotein was slightly greater in the moving leg.In two instances the concentration of globulin wasgreater in the moving than in the quiet leg. Whenthe percentile increase of total protein and of thetwo fractions are compared discrepancies arefound which suggest that variable amounts ofeither albumin, globulin or both were lost throughthe vessel wall. There is no evidence, however,of any consistency in respect to the amount orkind of protein which escaped. This lack of con-sistency is in accord with the observations of Lan-dis and his associates (3).

In every experiment the increase in colloid os-motic pressure of the blood was greater in the" quiet " leg, but in Subject H the difference wasvery slight, almost within the limit of experimen-tal error. The increase in leg volume was greaterin the " quiet " leg than in the " moving" leg inall the experiments. In two experiments, theright or " moving " leg not only failed to show asgreat an increase in volume as the left but showedan actual decrease compared with its volume dur-ing the reclining period. In one of these twoexperiments the subject was the patient withedema. Although the method of measuring legvolume is not very accurate, the limit of error,which is believed to be within ten or fifteen cc.,is much less than the changes in volume of thetwo legs or than the differences in change of vol-ume between the two legs, even in those experi-ments in which a decrease in volume of the " mov-ing" leg was found.

No study was made of the quantitative changesin the capillaries in the left (quiet) foot but the

ture of the venous pressure in the moving leg, the some-what smaller hydrostatic pressure during part of thecycle of movement, or the effect on leg volume of a pos-sibly lessened filling of the blood vessels in the movingleg.

740

BLOODAND CIRCULATION WITH POSTURE

TABLE I

The concentration of pkasma proteins, colloid osmotic pressure, venous pressure, and volume of the leg in the reclining positionand in the quiet and moving legs in the erect posture

Serum proteins._________ Osmotic Leg Vepressure volume V~

Subject Position t Total Albumin Globulin nous Remarks_______ _ - - _ _ _- - ~~~~~~~~~~~pres-Re ak

IsureIn- In- In- In- In-

crease crease crease crease crease

grams prgrams prgrams pr C. e Mer e,per per per Pert cm Per H20c cm.2cent centc cnt ce t cen cen H Centcc. H cc. H H20

Reclining 6.83 4.75 2.08 34.4 R3580 11.7 Delay in drawing bloodL 3490 samples from feetB. D. R 7.64 11.9 5.32 12.0 2.32 11.5 40.5t 17.8 3595 15 Fainted

Erect L 7.88 15.4 5.36 12.8 2.52 21.1 42.0t 22.1 3590 100 112.8

Reclining 6.65 4.76 1.89 35.3 R3430 8.3 FaintedS. B. L 3490

Erect R 7.24 8.9 5.22 9.7 2.02 6.8 43.3 22.7 3433 3 VomitedL 7.31 9.9 5.36 12.6 1.95 3.2 44.0 24.6 3565 75 111.5

Reclining 6.84 4.49 2.35 34.7 R5420 7.1L 5175

J.D. ErectR 7.86 14.9 5.15 14.7 2.71 15.3 42.5 21.6 5310 -110*L 9.21 34.6 6.08 35.4 3.13 33.2 55.4 59.7 5240 65 116.1

Reclining 6.50 4.83 1.67 34.2 R3572 5.4H. G. L 3712

Erect R 7.43 14.3 5.46 13.0 1.97 17.9 42.4 24.0 3630 58L 8.16 25.5 5.90 22.2 2.26 35.3 47.0 37.4 3822 110 111.0

Reclining 6.70 4.85 1.85 36.1 R4140 10.0 Delay in drawing bloodR. H. L 4050 from right leg

Erect R 7.47 11.5 5.44 12.2 2.03 9.7 41.3 14.4 4220 80 Fainted, vomitedL 7.42 10.7 5.33 9.9 2.09 13.0 42.5 17.7 4200 150 109.4 Blood pressure, 60/40

Reclining 6.20 4.11 2.09 29.5 R4360 5.4F. I. L 4410

Erect R 7.14 15.1 4.63 12.7 2.51 20.1 36.5 23.7 4310 -50*L 7.35 18.5 5.00 21.4 2.35 12.4 38.8 31.5 4570 160 125.7

* Decrease.f R = Right leg; L = Left leg.t Calculated osmotic pressure using formula of Wells,

following qualitative changes were observed.During the reclining period the observable capil-laries were usually rather few in number; thearterial and venous limbs were of about the samediameter, rather narrow and light red in color.The blood flow through them was relatively rapid.With the subject on the bicycle the number ofvisible capillaries rapidly increased. At the sametime the diameter of the loops increased, that ofthe venous more than the arterial, with the formeroften appearing engorged with blood. The colorof the blood became much darker and the flowslower. These changes increased as time elapsed.In one subject (H. G.) the arterial limbs becamegreatly constricted toward the end of the experi-ment, and in another (R. H.) it was noted that

Youmans and Miller (J. Clin. Invest., 1933, 12, 1103).

when venipuncture was performed in that leg thecapillaries " collapsed " (became constricted?).The subject with edema had fewer visible capil-laries in the reclining position than the normalsubjects, and when he mounted the bicycle, thoughmore capillaries became visible, the cyanosis wasless and the increase in the size of the venous loopover that of the arterial was less.

SummaryIn the erect posture active muscular movements

of the leg are accompanied by less concentrationand less rise in colloid osmotic pressure of theblood in the moving leg than in the other leg keptmotionless. At the same time there is a smaller

741


increase in the volume of the moving leg, and, insome cases, an actual decrease compared with itsvolume in the reclining position. In the quietleg in the erect posture the capillaries of the toeare dilated and the number of open capillariesincreased.

II. CHANGESIN THE CIRCULATION IN THE FEET

ANDLEGS, QUIET ANDACTIVE, AS SHOWN

BY CHANGESIN THE SURFACE

TEMPERATURE

Changes in the circulation in the feet and legsunder different conditions of posture, exerciseand temperature were studied by observing thechanges in the surface temperature.

The subjects were young, healthy, men andwomen. The following general procedure wasfollowed with certain variations which will bedescribed below. The subjects reclined with thefeet and legs exposed to above the knees for anhour or so. During this period the surface tem-perature of the feet and legs, at the base of thegreat toe, over the external malleolus and over themid leg on the anterior surface, was recorded witha thermocouple.4 Room temperature, which wasmaintained as constant as possible, with a varia-tion of about one degree centigrade, was meas-ured with a mercury thermometer suspended nearthe feet and legs. After the surface temperatureof the feet and legs had become relatively constantthe subject stood as quietly erect as possible forperiods of 60 to 75 minutes, and the surface tem-peratures were recorded at frequent intervals.Contact of the feet with the floor was preventedby a blanket. After the standing period the sub-jects again reclined, and the changes in surfacetemperature were followed. In most of the ex-periments the environmental temperatures were

'The instrument used was a Tycos " Dermatherm."Freeman and Linder (Arch. Int. Med., 1934, 54, 981)have recently pointed out the relatively large errors whichmay occur in measurements of surface temperature witha tlhermocouple. We are cognizant of these possible er-rors and have controlled them as far as possible. Carewas taken that exactly the same spot was tested eachtime. Although equilibrium of the skin with the sur-rounding air may not always have been reached duringthe preliminary period, in view of the consistency andmagnitude of the changes the results are believed to besignificant.

rather high, 28 to 300 C. Some of the experi-ments were performed in a constant temperatureroom at temperatures of 19 to 240 C.

In order to compare the effect of exercise andquiet standing on the surface temperature of thefeet and legs, the following experiment was per-formed. After the initial period of reclining thesubject mounted a stationary bicycle so arrangedthat he was able to stand nearly erect and quietlyon the left leg while pedalling against an adjust-able resistance with the right. Pedalling was con-tinued for approximately one hour, except forbrief periods to determine the surface tempera-tures which were measured at intervals of aboutfive minutes in each leg. At the end of the periodon the bicycle the subject again reclined, and thechanges in the surface temperature were followedfurther.

The results are summarized in Tables II andIII, and typical examples are illustrated in theaccompanying charts. In nearly every instancethe assumption of the standing-still posture wasfollowed by a drop in the surface temperature ofthe toe (Table II) (Figure 1). As a rule, the

TABLE II

Changes in the surface temperature of the feet (toe)during quiet standing

Tem- Lowest Time to Tem-pera- tem- Maxi- reach pera-

Sub. Roomtem- ture pera- mum lowest ture at Standingject perature before ture de- tem- end of time

stand- while crease pera- stand-ing erect ture ing

° C. .C. 0.C C. minutes 0 C. minutesH. G. 28.8 to 29.3 34.0 32.0 2.0 70 32.8 75E. W. 28.7 to 29.3 31.9 32.6 61A. D. 28.8 to 29.3 32.5 31.6 0.9 47 32.2 71V. S. 28.7 to 29.3 32.0 30.1 1.9 21 30.8 73P. D. 28.8 to 29.2 32.3 29.6 2.7 61 30.0 76

V. S. 22.0 to 24.0 26.1 25.1 1.0 20 25.1 40A. D. 23.5 to 24.5 27.7 26.2 1.5 33 27.1 38P. D. 24.8 to 25.5 29.8 28.7 1.1 32** 28.7 33J. Y. 19.0 to 22.0 28.8 24.6 4.2 60 24.6 60H. F. 19.5 to 21.0 28.8 24.9 3.9 40 25.2 60M. C. 19.5 to 21.0 29.3 27.0 2.3 20 29.8 60

* Surface temperature rose** Fainted twice.

while standing.

drop began very soon after the erect posture wasassumed. In some experiments the surface tem-perature continued to fall uninterruptedly untila minimum was reached. In others the declinewas irregular, being interrupted by periods duringwhich the temperature remained constant or even

742

BLOODAND CIRCULATION WITH POSTURE 743

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FIG. 1. CHANGESIN THE SURFACETEMPERATUREOF THE FooT (TOE) DURING QUIETSTANDING

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FIG. 2. CHANGESIN THE SURFACETEMPERATUREOF THE FooT (TOE) DURING QUIET STANDING

JOHN B. YOUMANS,J. H. AKEROYD, JR., AND HELEN FRANK

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FIG. 3. CHANGESIN THE SURFACETEMPERATUREOF THE FOOT (TOE) DURING QUIET STANDINGIN A COOL ENVIRONMENT

In this chart the surface temperatures have been adjusted to a room temperature of 200 C. bythe use of Vincent's factor (Vincent, J., La Temperature Climatologique, Ceil et Terre, 2d series,1890, 5, 515).

rose more or less for a variable period (Figure2). The maximum fall in temperature variedfrom 0.9 to 4.20 C., and the time to reach thelowest point ranged from 20 to 70 minutes afterthe standing position was assumed. In one sub-ject no fall occurred on standing, the temperaturerising steadily for 26 minutes from the time shestood, following which it slowly fell until, after61 minutes of standing, it had returned nearly toits level at the beginning of the standing period.In this experiment, however, the surface tempera-ture of the toe had dropped rather abruptly justbefore the subject stood. In several experimentsit was noted that following the maximum fallthere was a greater or less return of the surfacetemperature toward the initial level (Figure 1).The surface temperatures of the ankle and leg,which are not included in the charts, showed

changes similar to those of the toe but of a smallermagnitude. No special difference was noted when

TABLE III

Changes in the surface temperature of the feet (toe)during the erect posture; comparison of the

quiet and moping leg

Tem- Lowest Time to Tem-pera- tem- Maxi- reach pera-

Sub- Roomtem- ture pera- mum lowest ture atject perature before ture de- tem- end of

stand- while crease pera- stand-ing erect ture ing

J C. 0 C. 0 C. 0 C. minutes 0 C.J. Y.

Quiet leg 24.6 to 25.1 33.4 28.8 4.6 65 28.8Moving leg 32.9 28.4 4.5 65 28.4

J. A.Quiet leg 26.0 to 26.5 32.1 29.6 2.5 50 29.9Moving leg 32.2 29.6 2.6 40 29.8

H. F.Quiet leg 24.9 to 25.6 29.1 28.5 0.6 5 30.3Moving leg 30.2 28.7 1.5 30 29.5

M. C.Quiet leg 25.2 to 26.2 31.4 29.8 1.6 25 30.4Moving leg 32.3 28.8 3.5 50 28.8

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744


the environmental temperature was lower, exceptthat a lower level of surface temperature wasreached than in the warmer environment (Fig-ure 3). In most of the experiments resumptionof the reclining position after standing was asso-ciated with a return of the surface temperaturetoward the prestanding level.

When the subject stood quietly on one leg andpedalled with the other, there was a drop in thesurface temperature of both feet (Table III)(Figure 4). The fall was sometimes greater inthe moving leg, and this leg less often showed areturn of the surface temperature toward the ini-

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tial level as the erect position was maintained. Asin the other experiments the quiet leg became cya-notic but the moving leg was lighter in color andpink. The finding of a decrease in the surfacetemperature of the moving leg was somewhat sur-prising, as there is every reason to believe thatthe total blood flow through the moving leg is notonly greater but faster than in the quiet leg. Inpart, the drop in surface temperature may havebeen due to the cooling effect of movement in theair. The appearance of the leg, however, sug-gested that in addition to any cooling effect frommotion there was an actual decrease in blood flow

tO 20 w 40 300 10 20 30 405 0 to Zu 4U

FIG. 4. COMPARISONOF THE CHANGESIN THE SURFACETEMPERATUREOF THE FOOT

(TOE) IN THE QUIET (LEFT) ANDMOVING (RIGHT) LFG IN THE ERECTPOSTURE

745


in the skin and subcutaneous tissues in contrast tothe presumably much greater flow through themuscles. Therefore, changes in surface tempera-ture are probably a poor index of total blood flowin the actively moving foot and leg.

As an incidental finding in these and certainother related experiments it was observed thatvenipuncture in either arm or leg was followed bya prompt and significant fall in the surface tem-perature of the feet (and usually of the legs).The decrease amounted to as much as 20 and per-sisted for as long as 15 to 20 minutes. False veni-puncture, i.e. piercing the skin with the needlewithout entering the vein, usually caused a muchless or insignificant effect. The drop in surfacetemperature of the legs and feet following veni-puncture is apparently a reflex phenomenon sim-ilar to that caused by other physical and mentalstimuli. Venipuncture appears, however, to be amore powerful stimulus to vasoconstriction than,for example, a similar degree of pain unaccom-panied by injury to a vein, and is a factor forwhich allowance should be made when venipunc-tures are performed in conjunction with measure-ments of surface temperature.

SummaryAssumption of the erect posture is usually

accompanied by a prompt and significant fall inthe surface temperature of the feet and legs.This drop occurs in a warm as well as in a coolenvironment, and in the muscularly active (pedal-ling) leg as well as in the quiet leg in spite ofa presumably greater and more rapid total bloodflow in the former.

III. CIRCULATION TIME IN THE QUIET AND MOV-

ING LEG IN THE ERECT POSTURE

The circulation time in the leg in the recumbentand erect positions and the differences in thequiet and moving leg in the latter position weredetermined as follows. The subjects were threehealthy young men. An attempt to include twofemale subjects failed because of difficulty inperforming venipunctures in the foot and ankleof the " moving " leg and the distress caused bythe experiment. The subject reclined with thefeet and legs exposed to above the knees for anhour or more. After this preliminary period the

circulation time in an arm and each leg was meas-ured. The subject then mounted a bicycle soarranged that he stood nearly upright on the leftleg while pedalling with the right, keeping theleft practically quiet in spite of the action of theother leg. Pedalling against resistance was con-tinued at the rate of approximately 50 cycles perminute for periods of 49 to 69 minutes, exceptfor brief interruptions to inject the test solutions.An attempt was made to measure the circulationtime in each leg at the beginning, middle andlatter part of each period of standing and in thearm at the end of this period, but was completelysuccessful in only one experiment. In two ex-periments the circulation time was determined bythe injection of sodium cyanide (4) and in oneexperiment by the injection of either sodium de-hydrocholate (5) or saccharin (6). Stop watcheswere used by two observers to register the timeof the " reaction," the average being taken. Un-less a definite reaction was obtained a secondtest was made a few minutes later. During theexperiment the surface temperatures of the feetand legs were measured at frequent intervals,but the complicating effects of venipuncture andreactions to the intravenous injections obscure therelation of the changes in surface temperature toposture and exercise.

All the subjects found the procedure a verytrying ordeal. When sodium cyanide was usedto measure the circulation time in the legs, eachinjection was accompanied by a period of faint-ness, dizziness and, in some instances, nausea.This was particularly severe in the case of the leftleg (quiet standing position) and may have beenrelated to the large doses which were necessaryin these circumstances. As Bock, Dill and Ed-wards have pointed out (7), with the great slow-ing of the circulation it is necessary to employstronger concentrations of the drugs to secure asharp end point. In one subject, not included inthis series, a slough followed the injection of asmall amount of cyanide solution (2 per cent)into the tissues of the foot outside the vein, withthe formation of an ulcer which was very slowto heal. The injection of saccharin caused severepain along the course of the vein in the leg, fol-lowed by faintness and later by a venous throm-bosis. Subjects P. D. and A. D. nearly faintedtoward the end of the experiment. These com-

746


TABLE IV

Circulaion time in arm* and each leg** while reclining and while erect with left leg motionless and right leg moving

Circulation timePosture

Subject H. G. Subject P. D. Subject A. D.

secoxds secoxds secoxdsReclining

Arm.34.6 14.6 21.0Left leg .41.1 40.0 40ARight leg .49.0 39.2 40.9

ErectLeft leg .144.0 (After 18 minutes) 150.0 (After 13 minutes) 76.6 (After 17 minutes)Right leg .37.0 (After 20 minutes) 52.3 (After 23 minutes) 57.9 (After 36 minutes)

Left leg .77.4 (After 31 minutes) 62.0 (After 32 minutes) 146.2 (After 44 minutes)Right leg .31.8 (After 40 minutes) 25.5 (After 44 minutes)

Left leg .71.0 (After 49 minutes)Right leg .33.9 (After 57 minutes)Arm.10.0 (After 65 minutes) 27.0 (After 62 minutes)

* Arm to carotid.** Leg to carotid.

plications may have caused some irregularities inthe results.

The results are summarized in Table IV. Inall three subjects the circulation in the left (quiet)leg was much slower in the erect than in the re-clining position, the maximum slowing occurringin Subject H. G., in whom the circulation timewas almost four times as long 13 minutes afterthe standing period began as it had been whilereclining. In all three subjects the circulationwhile erect was much slower in the left (quiet)leg than in the right (moving) leg. The lattershowed, in general, a faster circulation while erectand moving than when reclining and quiet. Intwo determinations the circulation time in theright moving leg was slightly longer when erectthan when reclining, but it was necessary to stopthe movement of the leg while the solution wasinjected, and some delay in this maneuver mayhave allowed the circulation to slow somewhat.In two of the subjects the circulation in the left(quiet) leg was much slower in the early thanin the later part of the standing period. In Sub-ject A. D., the circulation time in the quiet leftleg was longer in the later part of the standingperiod than near the beginning. At this time,however, he was faint and suffering considerablepain.

SummaryIn the erect posture the circulation time in the

quiet leg is much longer than in the recliningposition. On the contrary, the circulation timein the moving leg is often shorter than in thereclining position, and hence often several timesshorter than in the opposite, quiet leg.

IV. THE INFLUENCE OF VASODILATATION ON THE

CHANGESIN COMPOSITION OF THE BLOODWHICHOCCURON STANDING

In order to study the part played by vasocon-striction in the changes in the blood which ac-company the erect posture, we abolished or les-sened it, and compared the ensuing changes in theblood in the feet and legs during standing withthose which occurred when vasoconstriction waspresent.

Various methods for obtaining a vasodilatationin the feet and legs were considered, but for sev-eral reasons the one which seemed most suitableand was adopted was that of heating the handsand arms (8). This procedure will produce inmost normal subjects a considerable degree ofvasodilatation in the feet and legs, which can bemeasured by determining the surface tempera-ture.

The complete study consisted of four distinctexperiments, as follows: First, a control experi-

747


ment to determine the maximum dilatation (in-crease in surface temperature) in the feet andlegs, produced by heating the arms with the sub-ject reclining. Second, a control experiment withthe subject standing quietly, to determine whetherheating of the arms could overcome the drop insurface temperature (decreased blood flow-vasoconstriction?), which we have shown occursin the erect posture. Third, a determination ofthe degree of concentration of the blood (foot)and the change in leg volume, which occurredwhen the subject stood for a given period withoutvasodilatation. Fourth, a determination of thedegree of concentration of the blood (foot) andthe change in leg volume when the subject stoodfor a similar period with vasodilatation.

Two young healthy men served as subjects.The individual experiments were performed onseparate days at varying intervals. In all theexperiments the subjects first reclined with thefeet and legs exposed to above the knees. Thesurface temperatures at the base of the great toe,over the external malleolus and just below theknee were recorded with a thermocouple, exactlythe same location being tested each time. Theroom temperature was maintained as constant aspossible in the neighborhood of 200 C., with arange of 20 C., and was recorded by a mercurythermometer suspended near the feet and legs.The hands and arms were heated by being im-mersed to above the elbows in water at a tempera-ture of 440 C. or more. White enamel basinswith covers were used, and the temperature wasmaintained by the addition of hot water at suit-able intervals. Samples of blood were drawnwithout stasis, and those for serum protein andcolloid osmotic pressure determinations under oil.The relative cell volume (hematocrit) was meas-ured with Wintrobe hematocrit tubes (9) usingheparin as an anticoagulant. The volume of theleg was measured as previously described.

In the first control experiment the subjectsreclined until the surface temperatures were rela-tively constant. The hands and arms were thenimmersed in the hot water. Both subjects showedan increase in the surface temperature of the toesfrom a " pre-heating " level of 26.1 and 26.9 to30.5 and 30.00 C., an increase of 4.4 and 3.10 C.,respectively. The increase began 11 and 7 min-

utes after the hands and forearms were immersed,and the maximum was reached in 37 and 41minutes. In both subjects the period before thetemperature began to rise was marked by aninitial drop. An initial drop in the surface tem-perature of the toe when the hands and forearmswere first immersed in hot water, amounting toas much as 20 C. and persisting for as long as11 minutes, often occurred in these experiments.In neither subject did the surface temperature ofthe toe reach 320 C., which is considered to indi-cate complete vasodilatation (Landis). This isprobably explained by the fact that the tempera-ture,at the base of the toe was measured insteadof at the base of the toe nail, where there is aricher anastomosing circulation. The ankle andleg showed a slight rise only.

In the second control experiment, after thepreliminary reclining period, Subject W. H. stoodand immediately immersed his hands and forearmsin the hot water. Contact of the feet with thefloor was prevented by a blanket. Quiet standingwas maintained for a period of 41 minutes, duringwhich time the surface temperature of the toerose from the prestanding level of 24.8 to a maxi-mumof 30.60 C. an increase of 5.8 degrees, 27minutes after standing began. The rise started11 minutes after standing and heating the handsand forearms began, the preceding interval beingmarked by a rather sharp drop of 1.50 C. Tolessen this initial drop, the forearms and handsof the second subject (J. P.) were placed in hotwater for 38 minutes before he stood. He thenstood, keeping the forearms in hot water con-stantly for 36 minutes. While he still reclinedwith the arms in hot water, the surface tempera-ture of the toes rose from 27.10 C. to a maximumof 29.9 degrees, 30 minutes after heating theforearms began. On standing, a drop of 1.10 C.occurred over a period of 9 minutes. The tem-perature then rose to a maximum of 30.90 C., 19minutes after he stood, an increase of 3.8 degreesover the preheating period. Thus, heating theforearms and hands was able not only to over-come the drop in surface temperature which oc-curs on standing but was capable of increasingthe surface temperature significantly above thepreliminary reclining period. In this second ex-periment, in which the subject stood, the surface

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temperatures of the ankle and of the leg not onlyshowed a smaller rise than that of the toe butoften remained constant or even dropped slowlybut steadily.

In the third and fourth experiments, the effectof standing on the concentration of blood in thefeet and on the leg volume, with and without vaso-dilatation, were compared. The subjects reclineduntil the surface temperature of the exposed feetand legs was quite constant and the concentrationof blood in the upper and lower parts of the bodyhad become equalized. The venous pressure inthe arm was then measured, a specimen of bloodwas removed for the various analyses, and thevolume of the leg measured. The subject thenstood quietly for a period of 45 minutes, duringwhich the changes in surface temperature wererecorded. At the end of the standing period thevenous pressure at the ankle was measured, asecond sample of blood was drawn and the volumeof the leg measured again. In Experiment 3, thehands and forearms were not heated. In Experi-ment 4, W. H. immersed the hands and forearmsin hot water immediately on standing. With Sub-ject J. P. the forearms and hands were immersedfor 25 minutes before he stood, as well as duringthe standing period.

In these experiments the complicating effect ofvenipuncture, which causes a drop in the surfacetemperature of the feet and legs, was introduced.Because of this the surface temperatures at thetime of standing were lower than in the controlexperiments. With Subject W. H., the tempera-ture of the toe at the time of standing withoutvasodilatation was 22.00 and during the standingperiod it fell gradually to 20° C. With vasodila-tation the temperature at the beginning of stand-ing was 21.90 but it dropped irregularly to 21.20C. over a period of 18 minutes, before it rose toa maximum of 23.20 C., about 3 degrees higherthan in the experiment without vasodilatation.However, he was able to stand with the arms inhot water for a period of 30 minutes only beforesyncope stopped the experiment, and thus for onlyabout 10 minutes of the standing period was thetemperature of the toe much higher than in theexperiment without vasodilatation. With Sub-ject J. P. the surface temperature of the toe whilestanding without vasodilatation ranged from 21.5

to 22.20. On standing with the arms heated thesurface temperature of the toe rose from about230 to a maximum of 28.2° and during the entirestanding period was considerably higher thanwithout vasodilatation, the maximum differencebeing about 70 C. In both subjects the surfacetemperature of the leg fell slightly on standingin spite of heating of the arms. The ankle showeda little rise. When the arms and hands wereheated a vasodilatation was shown by a pinknessof the feet which was in sharp contrast to thecyanosis which appeared in the absence of heat-ing. This was less noticeable in Subject W. H.Both subjects sweated profusely during the vaso-dilatation and both found the experiment a verytrying ordeal.

The changes in the composition of the bloodwere exactly opposite in the two subjects (TableV). Subject W. H. showed a slightly greaterconcentration of the blood on standing with vaso-dilatation than without, as shown by the concen-tration of total protein and albumin and theincrease in colloid osmotic pressure and relativecell volume. The difference in total protein wasso slight, however, as to be of little significance.Changes in the concentration of globulin werethe reverse of those of albumin and total protein,probably the result of a difference in the loss ofthe two protein fractions through the capillarywall (2). In keeping with the greater concen-tration of the blood during vasodilatation theincrease in leg volume was greater with vasodila-tation than without. Venous pressure duringstanding was essentially the same with and with-out vasodilatation. Subject J. P., in contrast toSubject W. H., showed less concentration of theblood with vasodilatation. The difference wasconsistent and was reflected in the changes in totalprotein, albumin, globulin, colloid osmotic pres-sure and relative cell volume. There was, how-ever, little difference in the increase in volumeof the leg in the two experiments, though theslight difference noted was in keeping with thechanges in the blood. The fact that there wasnearly the same increase in leg volume, in spiteof less concentration of the blood and excessivesweating, suggests that the total filtrate wasgreater with vasodilatation. As in the case ofSubject W. H., there was no difference in venouspressure, with or without vasodilatation.

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JOHN B. YOUMANS,J. H. AKEROYD, JR., AND HELEN FRANK

TABLE VThe concentration of plasma proteins, coloid osmotic pressure, relative cell volume, venous pressure and volume of the leg in the

reclining and standing still positions, with and wathout vasodilatation.

Plasma proteinsOsmotic Leg Relative cell vol-

Po pressure volume ume (hematocrit) Ve-Sub- Experi- Total Albumin Globulin r olu u ( Ve-si

__pres-ject ent ion _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ sure

In- In- In- In- In- In- In- In- In- In- In-crease crease crease crease crease crease crease crease crease crease crease

grams grams Pent grams grams Per grams grams Per cm. cm. per cc. cc. per per cm.cent cent cent H20 H20 cent H1,0 H2,0 cent cent H1,0

With-out R 7.18 5.04 2.14 37.4 2990 45.8 13.1

vaso- S 9.07 1.89 26.3 6.42 1.38 27.4 2.65 0.51 23.8 50.7 13.3 35.6 3080 90 53.0 7.2 15.7 122.2dilata-

tionW. H.

Withvaso- R 6.94 4.87 2.07 37.9 3000 44.0 12.7

dilata- S 8.91 1.97 28.4 6.50 1.63 33.5 2.41 0.34 16.4 55. 17.6 46.4 3140 140 52.0 8.0 18.2 124.7tion

With-out R 6.48 4.50 1.98 32.7 4300 40.6 10.4

dilaatoa- S 8.62 2.14 33.0 6.03 1.53 34.0 2.59 0.61 30.7 54.4 21.7 66.4 4435 135 51.7 11.1 32.1 122.7tion

J. P.Withvaso- R 6.89 4.61 2.28 34.6 4295 39.9 10.0

dilata- S 8.77 1.88 27.3 5.95 1.34 29.1 2.82 0.54 23.7 52.9 18.3 52.9 4425 130 47.8 7.9 19.8 124.2tion

The inconsistent results in the two subjects mayhave been due, in part, to variations in the lengthof the standing period, the vasomotor effects ofvenipuncture, sweating and the influence of syn-cope. Unfortunately the rigors of the experimentprevented the performance of a larger series,which might have avoided some of these difficul-ties.

SummaryHeating of the forearms and hands was ac-

companied by a rise in the surface temperatureof the feet (toe) with the subject erect, over-coming the drop in surface temperature whichoccurs in the quiet standing posture.

Vasodilatation resulted either in a greater or alesser concentration of the blood in the feet andlegs in the erect posture than occurs withoutvasodilatation. In either case the total volume offluid filtered into the tissues of the leg appearedto be greater with vasodilatation.

DISCUSSION

The results of these four studies indicate theessential difference in the mechanisms which tend

to limit the amount of fluid which accumulates inthe dependent tissues during quiet standing andactive exercise in the erect posture, respectively.In addition they emphasize the importance of thecirculatory changes which accompany the assump-tion of the erect position. As was pointed out inthe introduction, one of the primary factors con-cerned in limiting the loss of fluid from the bloodin the standing-still position is an increase in theconcentration of the blood in the dependent parts.This is aided by a decrease in the velocity andvolume flow of blood in the feet and legs, shownby the studies of surface temperature and circu-lation time. The reduced velocity permits agreater loss of fluid per unit of blood with agreater local concentration and a higher colloidosmotic pressure, while the decreased flow limitsthe total amount of fluid filtered. On the con-trary, in the moving leg the decrease in velocitydoes not occur, and the circulation time may beeven shorter than in the reclining position. Someinability to maintain these changes in the circula-tion in the quiet standing position is indicated bythe frequent occurrence of a secondary rise in thesurface temperature as the subject continued to

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stand, as well as by the fact that two subjectsshowed a much greater slowing of the circulationin the quiet leg during the first part of the stand-ing period than later.

Bock, Dill and Edwards (7) have suggestedthat an increased circulation time in the standing-still position indicates, but does not prove, the ex-istence of a smaller blood flow, since a great in-crease in the vascular bed might compensate forthe slower circulation. Such a possibility is sug-gested by the great increase in size and number ofopen capillary loops in the erect posture. How-ever, the great drop in surface temperature of thefeet and legs in the standing-still position suggeststhat in spite of an increase in the vascular bedthere is an actual decrease in blood flow as wellas in the velocity of the circulation. The changesin the circulation represented by the drop in sur-face temperature and increased circulation timeappear to be brought about, in a large measure atleast, by a vasoconstriction, since vasodilatationprevented the drop in surface temperature whichusually occurs on standing and presumably less-ened the slowing of the circulation which occursunder the same conditions. This vasoconstrictiondoes not appear to include the capillaries, althoughthe latter seem still capable of constriction. Al-though the effect of vasodilatation on the con-centration of the blood in the legs was variable,these results are believed to be consistent with theeffect which vasodilatation might have under con-ditions of normal activity. Vasodilatation usuallycauses a more rapid blood flow. This should re-sult in a smaller loss of fluid per unit of bloodand hence less concentration of blood locally. Atthe same time, however, it causes a rise in capil-lary pressure, which tends to cause a greater fil-tration of fluid and hence a greater concentrationof the blood. It appears, therefore, that in anygiven case the net result would depend on the rela-tive importance of these two effects and mightvary depending, among other things, on the de-gree and duration of vasodilatation. It seemspossible that with maximum dilatation so muchfluid might be filtered that blood flow would besignificantly impeded by the increased viscosity, astate approaching true stasis (Landis). In thiscase the local concentration of blood would begreater than without vasodilatation. In other in-

stances, the influence of increased flow might pre-dominate and cause less concentration of blood lo-cally than occurs without vasodilatation.

As far as the total volume of fluid filtered intothe tissues is concerned, it shoulf be greater withvasodilatation (absence of vasoconstriction).Even though the more rapid blood flow in thelatter case resulted in a smaller loss of fluid perunit of blood, the greater total flow should causea larger total filtrate than occurs with vasocon-striction. Should the increased capillary pres-sure, occurring in the absence of vasoconstriction,cause a greater loss of fluid per unit of blood, thetotal filtrate would again be greater. In eithercase the conditions are similar to those existingduring exercise in the erect posture. As we shallsee, however, during exercise lymph drainage isable to remove the excessive filtrate, so that thevolume of the leg increases but little or may evendecrease. When vasodilatation occurs duringquiet standing, lymph drainage is probably lessable to remove the excess fluid, and the local ac-cumulation would be greater than in the presenceof the usual vasoconstriction.

In contrast to the standing-still position thereis less concentration of the blood in the muscu-larly active leg in the erect posture. This sug-gests that less fluid is filtered from the blood inthe erect posture when the legs are moving. Fur-thermore, the active leg showed a smaller increasein volume, which again suggests the filtration ofa smaller amount of fluid. However, neither thelesser increase in the concentration of the bloodnor the smaller increase in leg volume, in them-selves, prove that a smaller amount of fluid wasfiltered from the blood into the tissues of theactive leg. Moreover, all the evidence from othersources is to the contrary. Muscular activity isaccompanied by a hyperemia, an increased intra-capillary pressure and the production of osmoti-cally active metabolic products which greatly in-crease filtration (10). According to Landis (11)fluid leaves the blood several times more rapidlyduring muscular activity than it does at rest undera venous pressure of 80 cm. of water. Under theconditions of our experiments, muscular activityand a high environmental temperature must haveresulted in a greatly increased passage of fluidfrom the blood to the tissues. Although the

751


smaller increase in concentration of the blood inthe " moving " leg indicates a smaller loss of fluidper unit of blood, a greater total blood flow wouldcause a greater total volume of filtrate. Further-more, the smaller increase in volume of the" moving " leg, by limiting the rise in tissue pres-sure, would of itself permit a greater volume offluid to be filtered. It would seem, therefore, thatthe smaller accumulation of fluid in the movingleg must be the result of a more rapid removalof the filtrate. This rapid removal is most prob-ably accomplished by lymph drainage. It isknown that muscular activity and an increasedvenous pressure cause an increase in the flow oflymph (12). At the same time they hinder re-sorption. An increased lymphatic drainage dur-ing muscular activity has been clearly shown innormal and edematous animals (dogs) by Weech,Goettsch and Reeves (13). In their experimentsthe onset of activity (walking) was accompaniedby a greatly increased flow of lymph, whichdrained the leg of accumulated interstitial fluidand, in edematous dogs, gradually reduced orabolished the edema. Thus, with muscular ac-tivity, the excessive accumulation of fluid in thedependent parts during the erect posture is pre-vented, not so much by limitation of filtration asby the more rapid removal of an even greater vol-ume of fluid than is filtered on quiet standing.5Since the volume of fluid removed by lymphaticdrainage is presumably returned to the circulationrapidly, the reduction in total blood volume at anyone time is probably much less than when stand-ing still.

SUMMARYAND CONCLUSIONS

In summary, the exchange of fluid between theblood and tissues, primarily controlled by capil-lary and colloid osmotic pressure, is greatly influ-enced by a number of secondary factors, particu-

5 Although the vasoconstriction and circulatory changeswhich we have discussed are most evident in the standing-still position and contribute greatly to the special mecha-nism by which the loss of fluid into the dependent tissuesis limited in that position, they are undoubtedly effectiveduring active movement as well and, under pathologicconditions especially, may modify the mechanism whichcontrols the accumulation of fluid in the legs duringexercise.

larly by posture. The great tendency to edema inthe quiet erect posture is opposed by a rising col-loid osmotic pressure and by an increasing tissuepressure in the feet and legs. These forces areaided by a decrease in the volume and velocity ofthe circulation in the legs. With muscular ac-tivity an even greater volume of filtrate than oc-curs on quiet standing is prevented from accumu-lating by a more active lymphatic drainage. Vari-ations in these secondary factors will influence theexchange of fluid between the blood and the tis-sues and, in the presence of -even slight changes inthe serum proteins and capillary pressure, maydetermine the appearance or non-appearance ofedema. Due consideration must be given to theinfluence of these secondary factors in interpret-ing the effect of abnormal variations in the funda-mental forces concerned, especially under condi-tions of changing activity such as exist in ambula-tory patients. For these reasons it is inadvisableto define too strictly the critical level of the serumproteins or venous pressure in relation to thepathogenesis of certain forms of edema.

BIBLIOGRAPHY

1. Krogh, A., Landis, E. M., and Turner, A. H., Themovement of fluid through the human capillary wallin relation to venous pressure and the colloidosmotic pressure of the blood. J. Clin. Invest.,1932, 11, 63.

2. Youmans, J. B., Wells, H. S., Donley, D., Miller, D.,and Frank, H., The effect of posture (standing)on the serum protein concentration and colloidosmotic pressure of the blood from the foot in re-lation to the formation of edema. J. Clin. Invest.,1934, 13, 447.

3. Landis, E. M., Jonas, L., Angevine, M., and Erb, W.,The passage of fluid and protein through the hu-man capillary wall during venous congestion. J.Clin. Invest., 1932, 11, 717.

4. Robb, G. P., and Weiss, Soma, A method for themeasurement of the velocity of the pulmonary andperipheral venous blood flow in man. Am. HeartJ., 1933, 8, 650.

5. Tarr, L., Oppenheimer, B. S., and Sager, R. V.,Circulation time in various clinical conditions de-termined by the use of sodium dehydrocholate.Am. Heart J., 1933, 8, 766.

6. Fishberg, A. M., Hitzig, W. M., and King, F. H.,Measurement of circulation time with saccharin.Proc. Soc. Exper. Biol. and Med., 1933, 30, 651.

7. Bock, A. V., Dill, D. B., and Edwards, H. T., Rela-tion of changes in velocity and volume flow tochanges in posture. J. Clin. Invest., 1930, 8, 533.

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8. Landis, E. M., Vasodilatation in the lower extremitiesin response to immersing the forearms in warm

water. J. Clin. Invest., 1932, 11, 1019.9. Wintrobe, M. M., A simple and accurate hematocrit.

J. Lab. and Clin. Med., 1929, 15, 287.10. Barcroft, Joseph, and Kato, T., Effects of functional

activity in striated muscle and the submaxillarygland. Phil. Trans. Roy. Soc., London, 1915-16,207, 149.

11. Landis, E. M., Capillary pressure and capillary per-

meability. Physiol. Rev., 1934, 14, 404.

12. White, J. C., Field, M. E., and Drinker, C. K., Onthe protein content and normal flow of lymph fromthe foot of the dog. Am. J. Physiol., 1933, 103, 34.

13. Weech, A. A., Goettsch, E., and Reeves, E. B., Theflow and composition of lymph in relation to theformation of edema. J. Exper. Med., 1934, 60, 63.

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