circulatory effects of acute expansion of blood...

Circulatory Effects ofAcute Expansion of Blood Volume:

STUDIES DURING MAXIMAL EXERCISE AND AT REST

By Brian F. Robinson, M.B., M.R.C.P., Stephen E. Epstein, M.D.,

Richard L. Kahler, M.D., and Eugene Braunwald, M.D.

ABSTRACTThe maximum cardiac output that can be achieved during exercise might

be limited either by extracardiac factors influencing ventricular filling, or bythe heart itself. In order to investigate this problem, the effect on the cardiacresponse to maximum exertion of an acute expansion of blood volume wasstudied in six men with essentially normal cardiovascular systems. Aug-mentation of blood volume produced by infusion of 1000 to 1200 ml of thesubject's own blood resulted in a small increase in central venous pressureat rest (avg = + 1.9 mm Hg) and a substantial increase in cardiac output(avg= + 1.47 liters/min). During exercise, however, the expansion of bloodvolume caused a large increase in central venous pressure (avg = +7.4 mmHg), but no significant increase in cardiac output or maximum O2 uptake.This finding suggests that the maximum cardiac output is not restricted by ex-tracardiac factors and that the upper limit must therefore be determined by theheart itself.

ADDITIONAL KEY WORDS maximum cardiac output cardiac ratecontrol of cardiac output blood volume hypervolemiacentral venous pressure oxygen consumption man

• The factors which limit the maximumcardiac output achieved during exercise areof considerable interest, since their identifica-tion would lead to an improved understand-ing of circulatory regulation. The problemcan be reduced to a consideration of twofundamental possibilities; either extracardiacfactors set a limit to ventricular filling at atime when the ventricles are still capable ofaugmenting their performance, or alternative-ly, the function of the heart itself may reacha maximum level in which case further in-crements in filling pressure would not aug-ment cardiac performance.

Previous investigators have suggested thatthe maximum circulatory response to exerciseis dependent on total blood volume, but muchof the evidence is indirect. Taylor et al.1-2

demonstrated that prolonged bed rest was

From the Cardiology Branch, National Heart Insti-tute, Bethesda, Maryland.

Dr. Robinson is a Nuffield Medical Fellow.Accepted for publication January 3, 1966.

associated with reductions in both the maxi-mum O2 uptake and blood volume, but acausal connection between these findings wasneither established nor claimed. Subsequently,Danzinger and Cumming8 studied the effectof a deliberate reduction of blood volumeinduced with chlorothiazide; they found thatthe maximum O2 uptake was consistentlylowered and that this change could be re-versed with intravenous dextran. Conflictingresults were obtained by Saltin4 who observedthe effect of a reduction of blood volumeinduced by thermal dehydration; he foundno decrease in maximum O2 uptake or cardiacoutput, but he did observe that the maximumtime during which work could be continuedwas markedly reduced. Kjellberg et al.s ob-served a strongly positive correlation betweenblood volume and the capacity for exerciseon a bicycle ergometer in a group of subjectswidi normal cardiovascular systems. In subse-quent studies, it was shown that tibe improve-ment in physical working capacity, following

26 CirailJmon Rejeuch. VoL XIX, July 1966

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BLOOD VOLUME AND CARDIAC RESPONSE TO EXERCISE 27

a period of training, was associated with anincrease in total blood volume and it wasinferred that this relationship was causal.6

The effects of deliberately augmenting theblood volume were studied by Gullbring et al.7

who infused a quantity of the subjects'own blood; they found that the heart ratewas lower at any given rate of work, fromwhich they concluded that the working capac-ity was increased, but they made no measure-ments of cardiac output or maximum O2uptake. It has also been shown that at agiven submaximal O2 uptake the cardiac out-put is higher when the exercise is done inthe supine rather than in the erect position,8"10

suggesting that the improvement in ventricu-lar filling provided by the supine positionaugments cardiac performance during exercise.

A review of previous studies thus suggeststhat the total blood volume and other factorsinfluencing ventricular filling normally limitmaximum cardiac performance. However, theeffect of acute expansion of blood volumeon the cardiac output during maximum exer-tion has not been determined, and thisexperiment, which might be considered crucialin resolving the question, forms the subjectof this investigation.

MethodsSix men ranging in age from 19 to 36 years

were studied. Five subjects had systolic heartmurmurs, but following full investigation it wasconcluded that no cardiac abnormality was pres-ent. The sixth had had an atrial septal defectrepaired several months previously, and had re-covered completely from the effects of operationat the time of study. The techniques employedin the present investigation were identical tothose used in a previous study.11 Exercise wasperformed at varying speeds and grades on amotor-driven treadmill. O2 uptake was recordedby means of a continuous flow system using aparamagnetic O2 analyzer, the details of whichhave previously been described.12 Cardiac outputwas measured by the dye dilution technique us-ing indocyanine green. The indicator was in-jected through a polyethylene catheter which hadbeen introduced percutaneously into a forearmvein and advanced to the superior vena cava.Brachial arterial blood was sampled through aTeflon catheter previously introduced by a modi-fied Seldinger technique. Systemic arterial and

Grcolition Research, Vol. XIX July 1966

central venous pressures were recorded by meansof Statham pressure transducers with the baseline set at the level of the mid right atrium. Theelectrocardiogram, mean arterial and central ve-nous pressures, and indicator dilution curveswere recorded with a photographic recorder. TheO2 demands of exercise were calculated by divid-ing the total excess O2 consumed during and af-ter running by the duration of the bout, andadding the O2 demand per minute so obtainedto the basal uptake. The O2 debt was calculatedas the quantity of O2 above basal levels con-sumed after cessation of exercise. The O2 uptake(VO2 in table 1) was the level determined justprior to the cessation of exercise; this level wasalways the maximum achieved during that par-ticular bout of exercise.

All studies were performed in the postabsorp-tive state, and the subjects were completelyfamiliarized with running on the treadmill beforeany definitive observations were made. Duringthe preliminary studies each subject was exer-cised by running at increasing grades until therewas no further rise in VO2 when the grade wasincreased by 2.5%. This level of VO2 was re-garded as the maximum and the rate of workwhichrhad been required to produce it was thatused in the subsequent investigation. When thesepreliminary studies had been completed, 1000 to1200 ml blood were removed by venesection overa period of two days and the subjects were sub-sequently given oral iron to help restore theirhemoglobin levels.

Approximately two weeks after the blood hadbeen withdrawn the definitive study was per-formed. The cardiac output was determined induplicate with the subject standing at rest on thetreadmill. The values shown for this variable intable 1 are the mean of the two determinations;the second of the paired measurements differedfrom the first by an average of 10.4%. The sub-ject then ran at the predetermined level and thecardiac output was determined at the third,fourth, and fifth minutes of exercise. VO2 was re-corded continuously during exercise and meanarterial and venous pressures were recorded ex-cept when the cardiac output was being de-termined. Following completion of the controlstudy, the previously withdrawn blood (1000 to1200 ml) was reinfused over a period of onehour. All measurements were then repeated bothat rest and during performance of a second boutof exercise at the same level as before.

ResultsI. PRE-INFUSION STUDIES

At rest in the upright position, the cardiacindex ranged from 2.06 to 3.60 liters/min/m2.



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28 ROBINSON, EPSTEIN, KAHLER, BRAUNWALD

Circulatory Effects of Augmentation of Blood Volume at Rest and During Maximum ExerciseTABLE 1

Subject

Heart riteB.S.A.(age) Diagnosis

E3 min

E4 min

E5 min

Cardiac outputR E

3 minE

4 minE

5 min

V.L.

H.T.

H.C*

L.G.

M.P.

J.O'R

m'(yr)1.80(25)1.88(26)1.80(19)1.90(31)2.00(20)1.92(36)

FM

FM

FM

FM

FM

Postop.A.S.D.

CICICI

cIcIcI

beat i/min

50 15257 15081811117888

175168186172170

7991787281

158186178164159

156154179170188176174163182178

beati/mln

160158180172188180179165183184

Uten/min4.14 16.725.17 17.035.087.026.367.763.915.607.208.49

25.2625.6320.6721.6218.4617.8228.3125.58

lltert/min

17.52 17.9317.12 19.7224.8825.3121.8422.4218.6717.8925.4021.80

23.4425.1324.5224.4817.1918.5425.2024.13

Mean*

I'

CI

8475N.S.

174165<.O2

176168<.O2

178173<.O5

5.346.81

<.01

21.4821.54N.S.

21.6620.91N.S.

21.6622.40N.S.

B.S.A.: body surface area in m2; FM: functional murmur; Postop. A.S.D.: postoperative atrial septal defect; C: con-trol study; I: post infusion study; R: rest; E: exercise; VOO: oxygen consumption; N.S.: not significant ( P > 0 . 0 5 ) .

•Excluding J.O'R.tExcluding H.C. and M.P.^Cardiac output data obtained under the same exercise conditions but on a different day from O2 and pressure data.

l50r

E£

Mtan B.A. i AMm

100

50

I -5WH

1START EXERCISE "•»

FIGURE 1

Response of mean brachial arterial (B.A.) and right atrial (R.A.) pressures to commencementof treadmill exercise.

It was below the lower limit of normal forthe supine position (2.5 liters/min/m2) intwo subjects, but was within the normal rangein the other three (table 1). Immediatelyfollowing the commencement of exercise, thecentral venous pressure showed a suddenrise following which it either remained steadyor declined slightly to reach a steady levelby the end of the second minute of exercise(fig. 1); the change in central venous pressurewith exercise averaged +1.2 mm Hg. The

cardiac output increased from an averagevalue of 5.34 liters/min at rest to 21.60 liters/min during exercise; heart rate rose from84 beats/min to 176 beats/min and strokevolume from 65 ml to 123 ml. The maximalO2 consumption averaged 3180 ml/min. Inevery subject the O2 uptake was significantlyless than the calculated O2 demand and largeO2 debts, averaging 7083 ml, accrued.

I I . POSTINFUSION STUDIES

A comparison of measurements at rest, be-Grcularion Research. Vol. XIX, July 1966



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Stroke volume Mean pressureR £

3 minE

4 minE

5 minCentral venous Arterial VOs

E

Osdemand

EOs

debtHemato-

crit

ml

839163875799447179109

ml

110114144153111127109113141144

ml

112111139149116127107110140122

ml

11212513014613013696112138131

mm Hg mm Hg

— 1+2-1.5— 1

2+0.5+0.5+1+4+7

0+3

+3+ 10- 5+0.5—4+2.5+2

+10.5+10+19.5+5+ 14

8082111118107118104107117114

9394119123

122122127

132

ml/min

274127773038308332873314298129113851403525132429

ml/min

29693042327233733712377533873293551253813274

ml

4764523951475875642571316415633112666124834993

40.040.542.544.543.045.543.045.040.043.042.044.0

6591<.01

123130<.O5

123124N.S.

122130N.S.

0+ 1.9<.O5

+ 1.2+8.6<.01

104108N.S.

lilt115f—

31803224N.S.

37703773N.S.

70837412N.S.

41.743.7<.01

fore and after infusion of 1000 to 1200 mlof the subject's blood, showed that significantincreases occurred in central venous pressure( + 1 . 9 mm Hg) , cardiac output ( + 1 . 4 7liters /min) (fig. 2), and stroke volume ( + 2 6ml). The hematocrit rose slightly in all sub-jects, the average value increasing from 42%to 44$.

With the commencement of exercise, therewas a large increase in central venous pressurein all studies and the level finally achieved

mm Ho

FIGURE 2

Changes in central venous pressure and cardiac outputat rest in the upright position following infusion ofblood (increase in central venous pressure P < 0.05;increase in cardiac output P < 0.01). Bars = Meanvalues.

Circulation Research, Vol XIX, July 1966

was an average of 7.4 mm Hg higher (P < 0.01) than during the control exercise period.The cardiac output, however, reached almostexactly the same level during each of thethree measurements made during exercise asit had before the infusion. The averageheart rate during exercise was slightly butsignificantly lower following infusion (8 beats/min). In all except one subject the strokevolume was slightly larger after infusion. TheO2 uptake during exercise, the O2 require-ments of exercise, and the O2 debt were notaltered significantly by the infusion (figs. 3and 4).

Discussion

While the augmentation of blood volumeproduced a substantial increase of cardiac out-put in the upright position at rest, it did notelevate the output during maximum exercise,despite a considerably higher central venouspressure. The possibility that these findingswere influenced by repetition of the studycan be excluded, since in an earlier investiga-tion utilising identical techniques, no signifi-cant changes in any of the variables wereobserved between two bouts of maximalexercise done one hour apart.11 The absenceof any significant rise in the maximum O2uptake following blood infusion confirms the



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CO.L/min

20

• PRE-INFUSIONo POST-INFUSION

C.V.P.mm Hg

—115

• n j _0 I 2 J 4 5

MINUTES

FIGURE 3

Cardiac output (CO.) and central venous pressure(C.V.P.) at rest and during exercise in subject L.G.before and after blood infusion.

finding of an unchanged cardiac outputduring exercise; the small increases in O2uptake observed in some subjects can beexplained by the slight rise in hematocritfollowing transfusion. The possibility that thework load after infusion might be of insuffi-cient magnitude to evoke a maximum cardiacoutput response can also be excluded, sincein each subject the OL> demand during exer-cise exceeded the O2 uptake achieved and alarge O2 debt accumulated. After infusion thelatter was comparable to, and in fact tendedto be slightly larger than, the O2 debt whichaccumulated prior to infusion. Thus, the car-diac output failed to achieve higher levelsduring exercise after expansion of the bloodvolume despite the fact that the level ofoutput was inadequate to meet the metabolicrequirements.

Although expansion of the blood volumeresulted in only a small increase in centralvenous pressure when the subjects were atrest, it nevertheless produced a substantialelevation both in the resting cardiac outputand stroke volume. These observations madewith the subjects in the upright positiondiffer from those in which the effects of acutehypervolemia were determined in the supineposition, when no consistent changes in car-diac output were observed.18 This difference

in response is probably accounted for by thefact that the stroke volume and cardiac out-put fall on assumption of the upright positionas a result of a reduction in central venouspressure;14'15 augmentation of the total bloodvolume restores the level of the central venouspressure and thus raises the level of the car-diac output. At rest in the upright position,the heart of intact conscious subjects thusresponds to an increase in blood volume andof central venous pressure in accordance withthe operation of the Frank-Starling mecha-nism.

When exercise was performed after theblood infusion, the central venous pressurewas significantly and substantially higherthan during the control period of exercise.Despite elevation of central venous pressure,however, the cardiac output did not rise anyfurther. From this it appears that the extra-cardiac mechanisms controlling central venouspressure are not normally the factors whichlimit ventricular filling and cardiac outputduring maximal exercise. These findings placethe limitation of the cardiac output duringmaximum exercise on the heart itself.

A number of specific mechanisms may beresponsible for the inability of the heart toaugment its performance during exercise inspite of an elevation of central venous pres-sure. First, it is possible that the rightventricle is operating at the peak or on a

MAXIMAL EXERCISEL/min

PRE- POST— UFUSW INFUSION

PRE- POSTIHFU90N INFUSKN

PRE- POSTKFU90N ItfUSMW

FIGURE 4

Changes in central venous pressure, cardiac output,and v"O, during maximal exercise before and after in-fusion of blood (increase in central venous pressuresignificant P < 0.01; changes in cardiac output andmaximal v"O, not significant). Bars — mean values.

Grculatioo Roorch, VoL XIX, July 1966



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flat portion of its function curve, in whichcase a rise in central venous pressure, al-though associated with an increased enddiastolic fiber length, would not further aug-ment cardiac output. Secondly, it is possiblethat the elevation of central venous pressureis not associated with an increase in enddiastolic fiber length during maximum exer-cise. The duration of diastole is very briefat the rapid heart rates achieved during maxi-mum exertion and it has been shown thatthe abbreviation of diastole during tachy-cardia may result in insufficient time for theventricle to relax completely.16 Under thesecircumstances it might be expected that theend diastolic fiber length would be littleaffected by an increase in filling pressure.The observation of Kjellberg et al.8 that heartsize appears to diminish with levels of exer-cise which elevate heart rate beyond 140 to160/min is consistent with this hypothesis.Thirdly, it is possible that cardiac filling islimited by the pericardium during maximumexertion, in which case an increase in centralvenous pressure would not be associated witha greater effective ventricular filling pressureor end diastolic fiber length. A mechanism ofthis sort would provide an automatic safe-guard against the development of pulmonaryedema during severe exertion in normalsubjects, since any increase in the filling pres-sure and volume of the left heart wouldnecessarily cause a reduction in the filling,and consequently the output, of the rightventricle.

Whatever the precise mechanism or combi-nation of mechanisms by which maximumcardiac performance is regulated, the resultsof this study suggest that it is the right sideof the heart which normally sets the upperlimit. This inference is based on the obser-vation that the "central blood volume," calcu-lated by the mean transit time method,17 wasessentially the same in the two exercise peri-ods, averaging 2.70 liters prior to infusion and2.65 liters afterwards. It is appreciated thatthis evidence is indirect since "central bloodvolume" includes not only the volume ofblood between the injection and sampling

GrcuUdon Rae»rch, Vol. XIX. July 1966

sites, but also that contained in all temporallyequidistant pathways, and can therefore beinfluenced profoundly by redistribution of car-diac output.18 Since the cardiac output, level ofexercise, and O2 uptake were essentially thesame during the two bouts of exercise, itseems improbable that substantial alterationsof distribution of cardiac output occurred.The absence of change in the calculated"central blood volume" thus suggests that thetrue central blood volume was essentially thesame during both exercise periods, whichimplies that all of the infused blood wasaccommodated in the systemic venous reser-voir. Had the function of the left heart beena limiting factor, it would have been expectedthat at least some of the infused blood wouldhave accumulated in the pulmonary vascularbed, and that the "central blood volume"during exercise would therefore have beenhigher during the postinfusion study.

The main finding of this investigation isthat an acute increase in blood volume andcentral venous pressure does not result in anyincrease in the response of cardiac output tomaximum exertion; from this it may be con-cluded that the blood volume and centralvenous pressure are not the factors which limitthe cardiac response to exercise in normal sub-jects.

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KEYS, A.: Effects of bed rest on cardiovas-cular function and work performance. J. Appl.Physiol. 2: 223, 1949.

2. TAYLOR, H. L., ERICKSON, L., HENSCHEL, A.,

AND KEYS, A.: The effect of bed rest on theblood volume of normal young men. Am. J.Physiol. 144: 227, 1945.

3. DANZINCEH, R. G., AND CUMMINC, G. R.: Effectsof chJorothiazide on working capacity of nor-mal subjects. J. Appl. Physiol. 19: 636, 1964.

4. SALTTN, B.: Circulatory response to submaximaland maximal exercise after thermal dehydra-tion. J. Appl. Physiol. 19: 1125, 1964.

5. KjELLBERC, S. R., RUDHE, U. , AND SjOSTRAND,T.: The amount of hemoglobin (blood vol-ume) in relation to the pulse rate and heartvolume during work. Acta Physiol. Scand.19: 152, 1949.

6. HOLMGREN, A., MOSSFELDT, F., SJOSTRAND, T.,

AND STROM, G.: Effect of training on work



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GuLLBRINC, B., HOLMGREN, A., SjOSTRAND, T.,

AND STRANDELL, T.: The effect of blood vol-ume variations on the pulse rate in supine andupright positions and during exercise. ActaPhysiol. Scand. 50: 62, 1960.

ASMUSSEN, E., AND CHBISTENSEN, E. H.: Ein-fluss der Blutverteilung auf den Kreislauf beikorperlicher Arbeit Skand. Arch. Physiol.82: 185, 1939.

MCGREGOR, M., ADAM, W., AND SEJCELJ, P.: In-fluence of posture on cardiac output and min-ute ventilation during exercise. CirculationRes. 9: 1089, 1961.

BEVEGARD, S., HOLMGREN, A., AND JONSSON, B.:Circulatory studies in well-trained athletes atrest and during heavy exercise, with specialreference to stroke volume and the influenceof body position. Acta Physiol. Scand. 57: 26,1963.

EPSTEIN, S. E., ROBINSON, B. F., KAHLER,R. L., AND BRAUNWALD, E.: Effects of beta-adrenergic blockade and the cardiac responseto maximal and submaximal exercise in man.J. Clin. Invest. 44: 1745, 1965.

KAHLER, R. L., THOMPSON, R. H., BUSKTRK,E. R., FRYE, R. L., AND BRAUNWALD, E.:Studies on digitalis. VI. Reduction of the oxy-gen debt after exercise with digoxin in cardiac

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AND BRANNON, E. S.: The cardiac output inmale subjects as measured by the technique ofright atrial catheterization. Normal values withobservations on the effect of anxiety and tilt-ing. J. Clin. Invest. 24: 326, 1945.

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J. T.: Components of the "central" blood vol-ume in the dog. Circulation Res. 8: 93, 1960.

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BRAUNWALDBRIAN F. ROBINSON, STEPHEN E. EPSTEIN, RICHARD L. KAHLER and EUGENE

and at RestCirculatory Effects of Acute Expansion of Blood Volume:: Studies During Maximal Exercise

Print ISSN: 0009-7330. Online ISSN: 1524-4571 Copyright © 1996 American Heart Association, Inc. All rights reserved.is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation Research

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