the lewis a. connor memorial lecture the physiology...

The Lewis A. Connor Memorial Lecture

The Physiology of the Cardiac Output

By WV. F. HAMILTON, PH.1).

T HE PRIMARY FUNCTION of theheart is to supply an adequate streamof oxygenated blood to the body. Trans-

portationi of other nutrients and wastes is aneasy task compared to the transportation ofoxygen. Thus, even in the resting state, onefourth of the blood's oxygen is depleted as theblood passes through the body and goes backto the lutngs; whereas it picks up only oneeighth of its content of carbon dioxide on thesame trip. The nutrients and wastes such asblood sugar and urea have an even smallerarteriovenous difference in proportion to bloodcontent.Thus it would seem that oxygen transport is

the strategic function of the circulation and,from that assumption and from many otherfacts, it can be argued unequivocally that thehandicaps resulting from the sudden insuffi-ciency of the circulation in syncope and shockstem directly from failure of oxygen supply.More equivocally, but with some degree ofprobability, it can be argued that failure ofadequate oxygen transport is an essentialfactor in activating the renal and hormonalmechanisms which cause the kidney to con-serve water and salt, and which lead to theedema and plethora of congestive failure of thecirculation .'The circulation fails not necessarily because

of a weak heart but also because even a nor-mal heart cannot meet the oxygen demand as aresult of some maladjustment other than thatof the valves or the myocardium. In thyro-toxicosis the oxygen demand is increased;in certain pulmonary diseases and anemia theblood cannot take up its fair load of oxygen2;and in certain cases of beriberi there is a subtlephysiologic interference with the utilization

From the Department of Physiology, MedicalCollege of Georgia, Augusta, Ga.

527

of oxygen. In all of these conditions there maybe failure of oxygen supply and consequentcongestive failure while the heart is laboringstrongly and doing twice the normal pumpingjob. For this reason it might be well to thinkof the syndrome in general as congestive failureof the circulation rather than congestive heartfailure.The circulation rate, or cardiac output,

thus does not have simple and uncomplicatedrelation to the development of heart diseasesymptoms. In order to unravel the complica-tions of the regulation of the normal circula-tion and its disturbances in disease it is bestto review the methods and their adequacy formeasuring the output of the heart.

William Harvey3 based his argument thatthe blood did circulate upon the arrangementof the valves of the heart to permit only flowfrom veins to arteries. As a first instance of thequantitative method in physiology he suggestedthat the left ventricle contains two or threeounces of blood and, on contracting, ejects allor part of it into the arteries. He was not im-pelled by the necessities of his thesis to arguefor a two to three ounce stroke volume be-cause a single dram per beat would defeat theGalenic tradition and accumulate in the arter-ies to burst them.Among the pioneers of the study of the

circulation we should also pay our respects toStephen Hales4 who made casts of the leftventricular cavity and, assuming that eachstroke emptied it, calculated to four figures thecardiac output, the velocity of the blood flowin the aorta and in its branches by dividingthe output by the aggregate cross area of thearterial tree at various levels. He located theperipheral resistance-to use modern jargon-in the minute vessels and worked out an ex-planation for dropsy that needs little extra-polation to seem very modern.

Circulation, Volume VIII, October. 19.53

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PHYSIO5YOGY OF CARDIAC OUTPUT

These earliest workers based their estimatesupon anatomic considerations. They couldbetter be called speculations rather thanmeasurements. The first lead to a quantitativemeasurement that could be applied to anormally functioning animal or man was abrief note by A. Fick5 who, in 1870, first calledattention to the fact that were we to know theoxygen consumption and the arteriovenousoxygen difference as it obtained in the heart,the bloodflow could be readily calculated.History has played a sardonic trick on thisestimable and learned gentleman by scatteringthe dust of obscurity over the monumentaltreatises to which he gave his life, and attach-ing his name, in the minds of nearly everymedical student, to an evanescent idea thathe barely took time to put on paper and towhich he never returned.The subject must have beei introduced well

ahead of its time because contributions to thefield were few and far between for 50 years.The first was an exasperatingly brief note inthe Comptes Rendus6 ill 1886 indicating, butnot describing adequately, measurements ofthe cardiac output of dogs. This was followedin 1898 by the classic and meticulous studyof the cardiac output of horses by Zuntz andHagemann.7 Taking advantage of the factthat the blood of this creature is slow to clot,a catheter was introduced via the jugular veindown to the vicinity of the right auricle.Mixed venous samples were taken duringrest, digestion and exercise. The contribu-tions of these workers were of such great meritthat Yandell Henderson felt that we shouldrefer to the method of Zuntz and Hagemannrather than the method of Fick.

This was the only study of the cardiac out-put in the intact animal by direct measure-ment which attempted to follow physiologicresponse to changed conditions from 1870,when Fick wrote his famed paragraph, untilthe 1920's when there was a revival of interestin the control of cardiac output. It was hopedthat a key, such as blood pH, would be foundto regulate the circulation just as it was thoughtto regulate the respiration. Search for such akey was naive because the cardiac output seemsto be regulated as the summation of the de-

mands for blood by the several organs of thebody, each in control, so to speak, of its ownblood supply. Much interesting work was donein this period by workers who followed changesin blood flow of animals resulting from drugs,9arteriovenous fistulas,'0 hemorrhage, trauma,'and pneumonia,'2 to instance a few of the nu-merous studies.At the turn of the century no one had the

temerity to puncture the human heart or tocatheterize its cavities. Credit is due Loewiand von Schrotter'3 for thinking of using thelungs as an aerotonometer to measure the gastensions of the mixed venous blood and, hence,its gas content. Not only were these authorsthe first to use the lungs in this manner, butalso they were the only ones to use the prin-ciple in a nearly impeccable manner. Theyblocked off a small part of one lung and allowedtime for complete equilibrium of the air inthat part with the returning venous blood.Others to follow',4 15 attempted to arrive atequilibrium between the pulmonary air andthe venous blood before recirculation and afterblocking fresh air away from both luiigs.The results reported by these authors varied

between 4 and 8 liters per minute, and it wasnot clear why they were so erratic. During thetwenties and thirties of the present centurythe computation of the cardiac output fromrespiratory data became stylized about theprocedure of Grollmanl5 who promulgated thedoctrine that the human circulation time was25 to 30 seconds (correct figure 10 to 18 seconds)and hence that a respiratory mixture could beleft in the lungs for that length of time with-out exposure to recirculated blood. The figurefor cardiac output, had by this method, was2.2 liters per square meter per minute abouttwo-thirds the correct figure. It is perhapsfortunate that the procedure overwhelminglyin vogue pin-pointed a figure that was sodramatically in error.'6 Had this not been thecase the proponents of respiratory methodswould not have given up so easily and theliterature would have been stultified with con-troversy.

It is hardly necessary here, except for com-pleteness' sake, to discuss the brilliant anddramatic story of cardiac catheterization. It

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was introduced iln.1929 by the intrepid Forss-man'7 who, using an ordinary varnish catheter,catheterized his own heart several times. Thenext year Kleinl' drew mixed venous bloodfrom such a catheter and calculated the cardiacoutput. Cardiac catheterization was appliedduring the next decade to the visualization ofradiopaque substances injected into the cardiaccavities. Another significant advance was

made in that a nonwettable plastic catheterwas developed that minimized the danger ofintravascular clotting. The time was ripe in1941 for Cournand and his co-workers to open

up a new book'9: the study of the cardiac out-put in man, the unraveling of the pressure andflow relationships in the cardiac chambers andthe great vessels of the pulmonary and systemiccirculations. With the work of groups led byStead, Bing, Dexter, \IcMichael and others,as well as with the continued work of theBellevue group working with Cournand, thepages of the new book have been filled withaccounts of circulatory dynamics in normalman, in shock, in congenital heart disease,under the influence of drugs and in cardiacand pulmonary failure." 2, 20-26

Attention has recently been called27 to a

source of error which is inherent in the Fickprocedure and in all other "dilution" pro-

cedures when the subject is not in an ab-solutely steady state. It is easily imaginablethat cyclic changes in a heart with a congenitalanomaly or sudden vasomotor changes wouldresult in a change in the oxygen content of a

venous sample so that the arteriovenous differ-ence would change from 40 to 80 cc. per liter.The sample might be a mixture of the twobloods in equal proportion and would indicatean average arteriovenous difference of 60 cc. per

liter. Assuming an oxygen consumptioii of 240cc. per minute this average arteriovenous dif-ference would correspond to a bloodflow of4 liters per minute. This conclusion is basedon the false implied assumption that the flows,when the arteriovenous difference was highand when it was low, can be taken as equal toeach other and hence averaged together. As a

matter of fact the flow during one period was atthe rate of 6 liters per minute and, during theother period, at the rate of 3 liters per minute,

and the volume average, as distinguished fromthe time average, is 4.5 liters per minute in-stead of 4.

This error in the Fick calculation tends tobe minimized by two things. First, the timeaverage tends to follow the direction of changein the volume average, clinging more closelythan it should to the lower of the two figures.Second, any mixing of blood in the cardiac,venous, or arterial stream would tend to makethe sample a true volume average. Thus, incalculating the pulmonary bloodflow in caseof a shunt from left to right, cyclic changes inoxygen contcentratioln of blood would be lessin pulmonary artery samples if the shunt werein the auricle than if it were in the ventricle,and less in this case than if a patent ductuswere involved.

Since this source of error is involved in alldilution methods, it cannot be used to explainthe fact that one dilution method gives an up-ward trend and another a downward trend.28To evaluate this error in practical terms it isnecessary to compare results with a volumetricmethod. This has been done and the two agreeunder the limited conditions tested.29' 30

Another and more serious source of errorresults from the storage in, or liberation of,gas from the body, including the lutngs. Acase of congenital heart disease with cyanoticepisodes has been described3l in which lower-ing of the systemic resistance caused a cessa-tion of lung blood flow and of oxygen uptake.The patient lived during this episode on herblood oxygen and by means of anaerobicmetabolism. By the Fick calculation she wouldhave no cardiac output and yet her heart waspumping strongly. As the organism goes intoor comes out of an anoxic state the Fick cal-culation is dubiously related to the cardiacoutput.The vagaries of cardiac output calculations

from carbon dioxide production and venous-arterial card)oI dioxide difference are such thatthe measurement is commonly ignored. Theunreliability of the Fick method when carbondioxide is used may be related to the fact thatsmall changes in ventilation strongly influencecarbon dioxide storage by the body and a steadystate is hard to reach.

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3PHYSIOLOGY OF CARDIAC OUTPUT

In order to trace the growth of our subjectin a logical fashion it is best to give an accountof another method for measuring the cardiacoutput and cognate quantities. I refer to theinjection method which, like the Fick method,is a dilution procedure. It was introduced intothe literature by Stew-art in 1897,32 and hasbeen used by various authors since.33" 3 35

The substance by whose dilution the blood-flow is gaged is injected into the blood streaminstead of being added to it or taken from itby physiologic process. An example will il-lustrate. Twelve milligrams of a substance suchas a blood-volume dye, which remains in thevascular system, is injected into a vein. Aseries of samples is taken from an artery whosedye concentration after the lapse of a fewseconds begins to increase, to reach a peakand then to descend exponentially36 until itrises again as a result of recirculation. Fromthe nature of the exponential fall of concentra-tion it is simple to plot the time concentrationcurve of dye on its first circulation. If the dyeconcentration curve persists over a period of30 seconds and its average height is 4 mg. per

liter, the 12 mg. injected has been diluted by3 liters of blood in 30 seconds or by a cardiacoutput of 6 liters per minute (fig. 1).

This method has been checked againstmeasured flow inl models,37 and agyainist the Fickmethod both in dog38 and in man (fig. 2).39 40, 41

Its errors in measuring the cardiac output are

probably no greater than those of the Fickmethod and, in addition, the volume of bloodin the heart, lungs, and great vessels (from thepoint of injection to the point of sampling) can

be calculated from the dye concentration curve

by multiplying the mean circulation time bythe flow (fig. 1).36The accuracy of this volume calculation has

also been checked by numerous experimentsin models.37 There are large variations in thecentral volume which can be produced ex-

perimentally42 and are seen in disease.35 Ourearlier idea was that the most distensible partof this vascular bed was that of the lungs.On this basis it was assumed that the huge in-

crease in central volume seen in congestivefailure, or after large doses of epinephrinie in

dogs, was the result of pulmonary congestion.

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FIG. 2. Plot of simultaneous measurement of thecardiac output in liters per minute by the direct Fickmethod and by the dye injection method.38

Recent quantitative x-ray measuremelnts43 havemade it seem that enlargement of the heartby very large increases ill residual blood wvill

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W. F. HAMILTON

account for all, or nearly all, of the changes inthe central volume. Indeed, the heart of a dogwho has received an overwhelming dose ofepinephrine will contain 13 cc. per kilogram ofbody weight or 37 per cent of its lethal bleed-ing volume. The fact that increased pulmonaryintravascular pressure does not necessarilyresult in increased pulmonary blood volumeis borne out by measurements on man.44 4An unfortunate misconception has gotten

into the literature44 relative to the calculation of

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Details of the calculation are shown in thepaper referred to in reference 36.

If the central blood volume or some definitepart of it were simultaneously and homogene-ously mixed with the injected substance, onecould calculate the magnitude of this volumefrom the slope of the downstroke or washout

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the mean circulation time. Ebert and his col-laborators would have it that the planimetri-cally measured median circulation time can beused to calculate the capacity of the streambed. This is true only if the dye concentrationcurve is symmetric. In a series of dye curves

from dogs, use of the median circulation timeto calculate central volume was in error by50 per cent.* The mean circulation time, or theaverage time it takes all the dye to pass is

* Dow, P. Personal communication.

of the dye concentration curve.44 We havenever felt that the initial assumption wassatisfied in the animal and have shown thatin ordinary conditions of flow in models thevolume which determines the slope is ratherremotely related to the total volume.36 Wetherefore have little faith in the calculationof physiologic volumes from the washoutslopes of dye concentration curves.

This is even more to be emphasized by thefact that pulmonary flow is in all probabilityentirely different from flow through a chamber

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5PHYSIOLOGY OF CARDIAC OUTPJUT

where dye and blood are completely or evenincompletely mixed. In the perfused lungsthere is a long wait after injection for the dyeto appear; in the mixing chamber it appearsinstantly. AMoreover tubular flow does notgive a simple exponential washout type ofcurve45 and the curve from lung perfusion ex-periments resembles that from tubular flowrather than that from chamber washout (un-published work). The exponential washoutcurve obtains, however, wheti heart and lungsare perfused in series.The laborious measurement of dye concen-

tration in many samples has contributed atechnical hazard that has served to make themethod relatively unpopular. There are inprocess of development several procedures formeasuring the concentration curve of dye illthe arterial stream by means of a photoelec-tric cell and a recording galvanometer. Theblood is put in front of the photoelectric celleither in a heated ear pinna or in a translucenttube connected to the artery by a punctureneedle.47' 48, 49 The dye concentration readfrom a curve made in this manner is hard toquantitate, but the method promises to be avery useful one. A similar labor saving ap-proach is to attach a radioactive atom to aninjectable substance which remains intra-vascular. 0

Besides the dilution methods for measuringthe circulation rate we have methods in whichthe aortic stream may be metered volumetri-cally by the cardiometer,5' rotameter,25' 30 orelectromagnetically.52 To use these methodsit has been necessary to open the thorax andto make the measurements of an abnormalcirculation. Nevertheless, a great many im-portant advances have been made by thesemethods.The methods considered so far are best called

primary methods in that, if reasonable as-sumptions are granted, they are direct meas-ures of the cardiac output. Contrasted to theseare methods which are best referred to asempiric methods, methods which achieve theirvalidity from constants derived by comparisonwith a primary method. Among these areballistocardiography,53 x-ray kymography,54electrokymography,55 and the calculation of

the cardiac output from the pulse pressurecurve. Time will permit the discussion only ofthe last of these methods.

Evaluation of the stroke volume from thepressure pulse was first suggested by Erlangerand Hooker.56 Quantitative adjustments weremade against the ethyl iodide method in afew subjects by Bazett and his co-workers57and against the nitrous oxide method byLiljestrand and Zander.55 A few years agocareful measurements were made of the vol-

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ume and distensibility of 48 human aortastaken from many age groups and from patientswith various diseases (fig. 4).59 These aortasshowed twofold variation in actual volumewhich could not be predicted from age orhistory. OIi the other hand, the increase involume with increased pressure was much moreconstant from group to group and individualto individual. Since pulse wave velocity changeswith distensibility relative to the size of theaorta rather than the more constant disten-sibility in actual volume, it was thought best

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W. F. HAMILTON

to avoid the complications of a pulse wavevelocity correction, such as used by Bazett'7and by Broemser60 and others, and simplyrelate pulse pressure to stroke volume. Thiswas done for a series of patients from the di-rect Fick measurements made in Cournand'slaboratory and a smaller series from theGeorgia laboratory (fig. 5).59 By a strangecoincidence it was found that the best fit wasgiven when 1 cc. of stroke index was madeequivalent to 1 mm. Hg of pulse pressure.Thus if the arterial pressure is 120/80 theaverage stroke index would be predicted to be40 cc. These values hold only at ordinary pres-

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FIG. 5. Relation between stroke index as calcu-lated from the corrected pulse pressure and as deter-mined by the direct Fick method.5' C = cases ofcongestive failure.

sure levels. The prediction of the stroke vol-ume is of about the same order of accuracy as

that made by the ballistocardiograph. Itcould no doubt be made more accurate if, atthe beginning of an experimental procedure,an actual output measurement (for example,dye curve) were made to "calibrate" the dis-tensibility of the subject's arteries.6' After sucha calibration the stroke volume could be fol-lowed from beat to beat during an experimentalprocedure.

Since dogs die young and their arteriesrarely show the effects of aging and disease, a

potent cause for the random variation in therelation between stroke volume and pulse

pressure is not seen in these creatures. Carefulmeasurement has shown that all aortas of deaddogs are very much alike as to their size inrelation to the size of the body and as to theirdistensibility."

This fact justified the attempt to measure indetail the amount of blood required to expandthe arterial tree as the pulse wave passes outover the arteries (fig. 6).63 This is necessarybecause the contour of the pulse wave differsvery greatly in various experimental con-ditions. In some cases the pressure at themoment of aortic valve closure is very highand the aortic arch greatly expanded. Inother cases the pressure in the arch has goneback to the diastolic level when the valvesclose; and the pulse volume is stored in theaorta and its branches farther down.

These considerations caused us to measurethe distensibility of the four main subdivisionsof the arterial tree (arch, head, viscera, legs)and find what part of the pulse wave hasarrived at each of the subdivisions at the timethe aortic valve has closed. This gives us theeffective pulse pressure in each part of thearterial tree. Knowing the distensibility ofthese parts and the effective pressure changebrought about by the pulse wave, the totaluptake of the aorta and its branches (correctedfor body size) could be summated.The arterial uptake is only a part, but a

significant part, of the stroke volume (strokeindex). In addition, there is the blood whichdrains out through the arterioles duringsystole. Arteriolar outflow follows quite closelythe law of Poiseuille, that is, it is the productof pressure and time if the arterioles remain thesame. Since the uptake is known and mustdrain out the arterioles during diastole, it ispossible to calculate the arteriolar drainage incubic centimeters per millisecond per milli-meter of mercury from the diastolic part of thecurve and apply it to the systolic part of thecurve. This systolic drainage plus the uptakeis the stroke volume (stroke index).

This formidable calculation has been stylizedby means of tables and graphs so that it maybe accomplished in 15 minutes or so. Whendogs are under the influence of drugs, hemor-rhage, neurogenic or renal hypertension, or

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PHYSIOLOGY OF CARDIAC OUTPUT

traumatic shock, the pulse pressure methodgives results which compare closely with thoseof the Fick procedure or the dye injectionmethod (fig. 7). This has been confirmed bythe Baylor group (fig. 8). 64, 65 It was checkedagainst the rotameter in dogs by Longino andGregg and found to give rather close agree-

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velocity indicates the change in aorticrigidity.62' 67

It has been rather a disappointment to findthat the pulse contour method will not cal-culate the cardiac output under all con-ditions,67' 68 even though it will under mostconditions.69 Every bafflement is a stimulus to

UPTAKE OF ARTERIAL SUBDIVISIONS CC

FIG. 6. Diagram of two pulse curves and of the distensibility of four divisions of the arterial tree.The vertical lines referred to the ordinate scale indicate the pulse pressure in millimeters of mercurydistending the different parts of the arterial tree at the time of aortic valve closure. These pulsepressures are laid off on the proper distensibility curve and the uptake of the parts summated tomake the total uptake as read on the lower scale in cubic centimeters per square meter body surface.The upper pulse wave, with its greater pulse wave velocity, distends all four arterial divisions. Thelower pulse curve, with its shorter duration and slower pulse wave transmission, distends only twoparts when the valve closes. For calculation of stroke index from uptake see text.63 67 68 69

ment when the rotameter was placed in thepulmonary artery (fig. 9). 66When, however, the rotameter is placed in

the right auricle and vena cava the pulsecontour calculations become too large. Thearterial uptake under this and other severeconditions is much less than it is normallywith the same pulse pressure. The aorta hassuddenly become less distensible, has gone intorigor. Unfortunately no change in pulse wave

further work and, I hope, greater insight willresult. Why is it that the arteries lose theirdistensibility, go into rigor? Is it a reversiblephenomenon? What is its fundamental cause?Why is the change always a decrease, never anincrease, in distensibility? I hope that thesequestions will be answered before long.

After having spent so much time evaluatingthe methods of measuring the cardiac outputwe are justified in raising questions relative to

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our insight into fundamental mechanisms bymeans of which the cardiac output is regulated.That there is such regulation, that it is adaptiveand serves the ends of the organism is beyond

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FIG. 7. Relation of stroke volume as measured bydirect Fick method or dye injection method to asimultaneous calculation from the pulse contour.Intact dogs under various experimental conditionsincluding shock, hemorrhage, hypertension, and drugaction.63

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FIG. 8. Relation of measurements of stroke volumeby Fick and pulse contour method (Huggins andassociates64).

dispute. The cardiac output can change from aresting figure of 6 liters per minute to a value of15 in mild exercise,70' 71 and probably muchmore with heavy exercise. The increase isbrought about by an increase in stroke volume

as well as by an increase in rate. The increasein stroke volume is minor, as was long held byY. Henderson.51 Under conditions of cir-culatory handicap, such as hemorrhage, thecardiac output may be reduced to half theresting figure or even less. Thus the circulationrate may be varied sixfold or more but regu-lation is such that the driving force, that is, themean blood pressure, varies comparativelylittle (10 to 50 per cent).The fact that there is a relatively constant

blood pressure in the face of large changes inflow implies a regulation of the cardiac outputto match the peripheral resistance or viceversa. It can be shown, I think, that the cir-culationi rate is governed primarily by theperipheral resistance and that the output of

FIG. 9. Consecutive comparison of rotameter andpulse contour measurements of stroke volume (Lon-gino and Gregg66).

the heart is secondarily regulated so as tomaintain a relatively constant arterial pressure.The peripheral demand for blood expresses

two needs: the need for oxygen by active tissuesand the need to dissipate heat. Both of thesedemands are satisfied by local dilation, underlocal or specific control. When muscles, glandsor viscera become active their arterioles dilateand their blood supply increases. This ismainly in response to local chemical influencesand is dependent, to little or no degree, uponreflex adjustment of vascular tone. When webecome overheated, hypothalamic reflexes areactivated which cause cutaneous dilation andheat is dissipated. Both of these vasodilatormechanisms are prepotent, that is will hold

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vessels open in spite of vasoconstrictor outflowfrom the medulla.The effect of these local dilations, mediated

by mechanisms which have no relation to thecontrol of the heart beat, is to lower theperipheral resistance and, hence, the arterialpressure, and to set in action reflexes origi-nating in the aortic arch and carotid sinus whichaccelerate the heart and restore the arterialpressure, but with an increased output.Peripheral constrictor mechanisms such ascold, abatement of activity, and vasocon-strictor drugs bring about the opposite re-

ArterialReservoir

CONTROL

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FIG. 10. Schema to illustrate the theory that theprimary control of the output of the cardiac pump

rests in the variable resistance controlled at the levelof the peripheral organs and that cardiac regulationis secondary to pressure changes in the arterialreservoir.

sponse by the peripheral resistance and, hence,secondarily by the heart. The pressure risesbut is reflexly restored toward normal bycardiac slowing and a reduced cardiac output.

It must be recognized that these relation-ships are often hidden by other things goingon at the same time. Thus in exercise theperipheral resistance is half that ili rest; in a

study of the effects of exercise the arterialpressure increased 50 per cent, and the cardiacoutput more than doubled while the oxygenconsumption increased about sixfold.7" Thefact that the heart rate doubled cannot be dueto a lowered peripheral resistance because the

arterial pressure has just increased. Nervousand hormonal stimulation of the heart, arisingdirectly from the excitement of the effort, seemto have played a prepotent role over the reflexslowing which usually accompanies a rise inpressure.

Moreover, the nervous tensions of anxietyand other emotional states alter the peripheralresistance, and this alteration, acting throughthe secretion of epinephrine and the directaction of the sympathetic system, is differentin different species. Thus, in man, anxiety andemotional disturbances dilate blood vesselsin the muscles and reduce the peripheralresistance as does the injection of epinieph-rine.72-76 On the other hand it is difficult todemonstrate a primary reduction of resistanceupon the injection of epinephrine into dogs.

In addition to this psychogenic anticipatorypressor pattern there is another response which,acting at the same time, tends further tocomplicate the simple relation between increaseor decrease in peripheral demand and increaseor decrease in cardiac pumping. This is thepattern of arterial pressure regulation throughchanges in the peripheral resistance as well asthrough changes in cardiac pumping. Thus thearterial stretch receptors are connected re-flexly to produce vasoconstriction when thearterial pressure is low and to produce vaso-dilation when the arterial pressure is high. Ifthere should be a local demand for blood(oxygen) at the same time that general bloodpressure regulation demands vasoconstriction,there is a contest for prepotence between thetwo tendencies. This contest is decided before-hand by the vasculature of the brain and heart.These blood vessels cannot constrict so as todeprive the vital organs of a steady oxygensupply as can the blood vessels of the leg and toa lesser extent those of the viscera. Even in thevascular beds that are best able to constrict wecan well think of a constant conflict betweenthe effect of anoxic chemical changes producingvasodilation (provided the arterial pressure ishigh enough to prevent the elastic closure ofminute blood vessels) and the tendency forconstriction under central blood pressureregulation.The conflict between the effects of local

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demand and of general regulation can beillustrated by the following. When one liesrecumbent, gravity returns blood to the heartmore easily, filling it better, and mechanicallyincreasing its pumping action. At once the heartis reflexly slowed and vasoconstrictor tone islessened because more impulses are beinggenerated by the arterial stretch receptors inresponse to a small and aborted rise in arterialpressure. This pattern of response results in alowered peripheral resistance and an increasedcardiac output in spite of the fact that themetabolic demand for blood is lessened.

Conversely the results of trauma or hemor-rhage handicap the venous return and lessenthe pumping action of the heart. In response tolowered arterial pressure the heart acceleratesand the arterioles constrict. This happens inspite of the fact that a very low venous oxygentension indicates that the tissues are greatly inneed of oxygen. This response may not be in

to a rise in pressure that escapes noti(e-is inreality the same stimulus that seems logically toproduce the slowing, a few seconds later, whenthe pressure rise is appreciable.

This principle of accurate physiologic ad-justment is illustrated in the control of blood-flow through the Goldblatt kidney. The clamp,when it is first applied to the renal artery, mustin the nature of things reduce the bloodflow tothe kidney. Soon, by hormonal mechanisms, theblood pressure rises and, when a steady state isreached, the renal bloodflow is back withinnormal limits. Is it not reasonable to believethat physiologic compensations are accurateand delicate enough to bring the renal blood-flow back to a figure that, to our crudemeasures, seems normal? What other com-pensatory function would the hypertensionhave?Thus we might assume as a working hy-

pothesis, that whatever variable is held most

FIG. 11. The effect of small (lose of epinephrine in prodlucing a slowing of the heart before any1

conspicuous increase in pressure has occurred.

the best interests of survival, as witnessed bythe fact that when the vasoconstrictor re-sponse is aborted by Dibenamine the animalendures the hypotension of shock better thanwithout the drug.77 78Not only do adjuvant mechanisms compli-

cate responses but the responses themselves areof extraordinary accuracy and delicacy. OoIinjecting a small dose of epinephrine, or otherconstrictor drug, the heart often appears toslow before there is any visible rise in pressure.In interpreting this it has been suggested thatthe reflex slowing is teleologic and anticipatory.To quote a statement which has become"classic" in our discussions around the labo-ratory, "The decreased cardiac output . . . isattributed to reflex adjustments initiated bythe threatened (sic.) increase in blood pressurewhich would result from constriction ofcutaneous vessels."79 In contrast to this wemay assume that the reflex slowing has a verydelicate threshold and that the response is due

constant is the key to natural physiologicregulation. The wisdom of the body is such thatby the time a steady state is reached, under newdemands, the important variable, the one withsurvival value, is regulated within physiologiclimits. Thus in looking at the regulation ofrespiration we would hunt, not for somethingthat is abnormal when the respiration is in-creased or decreased, but rather for somethingwhich has been returned to normal by thechanged respiration. The answer on this hy-pothesis of accurate regulation would be thehydrogen ion concentration of the blood forrespiration, kidney blood flow for renal hyper-tension, and arterial pressure for the regulationof the circulation.

In discussing the control of cardiac output,the classic experiments of Starling and hiscollaborators must be taken prominently intoaccount."0 81 Starling's experiments were madeon the heart-lung preparation, a preparation inwhich the heart could respond only by means

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of its intrinsic myocardial mechanism. Hisevidence showed conclusively that when theheart is deprived of the natural reflex mecha-nisms, when its rate is held constant andhormonal stimuli are not acting, an increase inthe aortic pressure or in the venous returnbrings about an increase in diastolic cardiacsize. He showed moreover that within physi-ologic limits, this increase in diastolic size wasself limiting because it also brought about anincrease in the effectiveness of cardiac pump-ing and an increase in oxygen consumption bythe heart.

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` 600b-

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that are of theoretic importance in relation tothe diastolic size of the heart and Starling'slaw. In exploring in the normal animal suchaspects of cardiac action as stroke volume,cardiac work, systolic and diastolic pressure,and heart rate, it was found that only heartrate clearly and uniquely correlated withdiastolic size as computed from x-ray silhou-ettes.43 82 When the heart accelerates-pumpsmore blood it becomes smaller and when itslows it fills more and becomes larger. Changesin rate then work against any application of theStarling law in the intact animal.

x

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NET HEART SIZE CC/M2

FIG. 12. Left: The relation of cardiac blood volume to filling time. The various symbols indicateexperimental procedures such as buffer nerve section, epinephrine infusion, vagus stimulation, andothers. These procedures do not indicate significantlyr different trends or slopes.82

Right: Relation of net heart size to venous pressure. The group indicated by the lower arrow areslowly beating hearts which become large with low venous pressure; those indicated by the upperarrow are rapidly beating hearts that remain small in spite of high venous pressures.82

It is not the purpose of the following para-graphs to cast doubt upon the fundamentaltruth of the insight into cardiodynamics whichis embodied in "Starling's Law of the Heart,"but rather to inquire into the manner in whichthe reflex adjustments available to the intactanimal enable him to safeguard his heart fromstresses which illustrate Starling's law.

In making adjustments to changes in flowand in aortic pressure the most obviousphysiologic change is in heart rate. It has beenknown for more than a century. It is in responseto pressure changes in the aorta and carotidsinus, and brings about changes in heart size

These same physiologic reflexes which controlthe rate of the heart also control its strength ofbeat. Sympathetic stimuli which accelerate theheart augment its strength of beat and make itempty more completely and become smaller.Under sympathetic stimulation, then, the heartis smaller, not only because it is faster, but alsobecause it is stronrer.An opposite effect results from parasympa-

thetic stimulation. Vagus beats in man 82 ifnot in the dog, are weaker than normal beatsand the heart under parasympathetic influenceis larger, not only because it is slower and fillsmore, but also because it is weaker and empties

Us

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less. Changes due to sympathetic and para-sympathetic stimulation thus guard the heartagainst the stresses implied in the applicationof Starling's law.

Caution must be urged against gagingdiastolic heart size from the venous pressure.In the first place there are two venous pres-sures, right and left, and if we are to measureheart size at all we must measure that of thetwo hearts together. In the second place whenthe heart rate is rapid the venous pressure mayrise to great heights and the heart still remainsmall.81 It seems that the process of myo-cardial relaxation prevents cardiac filling uii-less there is plenty of diastolic time for therelaxation to take place. Thus large, slowhearts are seen with low venous pressure, andrapid, small hearts are seen with high venouspressure (fig. 12).The myocardium is a contractile engine

whose elastic properties enable it to do workagainst pressure. The amount of work which itdoes and, more importantly, the amount ofblood which it ejects is dependent upon thepressure against which it works. Thus if theaorta is pressed shut the stroke volume andoften the work per beat diminish with thenext beat and before any reflex adjustmentscan have taken place. Similarly there is animmediate increase in stroke volume and oftenin work per beat when the occlusion is re-leased.84 The same immediate mechanicalcontrol of the stroke volume obtains when anarteriovenous fistula or surgical arteriovenousshunt is occluded or opened,84' 85, 86 or when amassive vascular area is shut off until, throughthe process of reactive hyperemia, there islocal vasodilation.86 Release of such occlusionresults in an immediate iticrease in strokevolume even though cardiodynamics are notmuch changed by the occlusion itself.The fact that the stroke volume will change

twofold or more under these conditions neces-sitates the belief that there is a residualvolume of blood in the heart ready for instantmobilization, and further reserve waiting inthe venous reservoir. As the aortic pressure islessened, the residual blood is evacuated, theheart becomes smaller, the stroke volumelarger and the work increased. These changes

all occur in reverse when the aortic pressurerises. These mechanisms, even though they areintrinsically myocardial in nature, also militateagainst a clear application of the Starling law.

It seems from the considerations above thatthe reflex influences to which the normal heartin the intact animal is subject cause the heart toaccelerate and hence to decrease in diastolicsize when there is a peripheral demand for anincreased bloodflow, and to increase in sizewhen the peripheral demand is lessened. Thus

H R /min.

Heart Size(inspection)

SPVccQ

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-3

250

B

200 B P,mm.Hg.

150

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HR 1m in

140 _ <

90_

40

20 t A

500 -PO -Jc30 I

FIG. 13. Circulatory changes resulting from occlu-sion and release of the aorta. 4

the normal heart is protected against, and doesnot react to, the stresses imposed upon it inStarling's experiments.80' 81What then is the role of Starling's law?

We can say, as some have, that it operateswhen, consequent upon respiratory fluctu-ations in venous return and resulting fluctu-ations in filling pressure, there are parallelfluctuations in stroke volume.87 While this istechnically an example of Starling's law thesituation does not fulfill the implications of his

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thesis. To my mind Starling's thesis is that theincreased force of contraction and metabolismconsequent upon myocardial stretching canenable the heart to overcome a real stress.

It was well known in Starling's time thatsympathetic influences, hormonal and reflex,increase the heart beat and that parasympa-thetic influences decrease it. By means of hisheart-lung preparation he ruled out these in-fluences and held everything constant exceptincreased diastolic size and its cardiodynamicconsequences. When heart size, and heart sizealone, was varied the conclusion was ines-capable that the strength of the contractionvaried accordingly. It increased as heart sizeincreased up to a certain limit and then fell off.

In cases of heart disease the reflex reserveshave been exhausted. The sympathetic in-fluences which tend to keep the heart smallhave worked at their maximum but have notsufficed. The heart has fallen back upon theStarling mechanism and, by increased diastolicsize, has compensated the weakness, or hasbeen overloaded and given out.The evolution of the intricate adjustments

outlined in so cursory a fashion is very puzzling.It seems best to regard them as having beendeveloped as responses to a stress or emer-gency that can be answered by musculareffort. Thus the need for conservation of waterthat leads to the oliguria of exercise leads also,in the continued and desperate effort to main-tain life under the handicap of heart disease, tothe inundation of the tissues in cardiac dropsy.Similarly the hyperpnea of exercise leads to thedyspnea of heart disease, and the excitation ofthe sympathetic system in exercise is linkedwith generalized vasoconstriction of traumaticshock.

These responses have evolved as usefulstratagems in their original setting as emer-gency mechanisms, but they hare no survivalvalue as compensation for chronic degenerativeconditions. This results from the fact thatnature is indifferent to the survival value ofthings that develop after reproductive life isover. Neither an adaptation nor a handicap isrelevant to the process of evolution if itdevelops late in life. For this reason viciouscycles are often the aftermath of degenerative

disease. Thus it is customary for the physicianto allay the dyspnea of heart disease with asedative, though its analog, the hyperpnea ofexercise, is regarded as a useful response.The dyspnea of heart disease is a vicious cycle,and the welfare of the patient demands that itbe aborted. Similarly we abort the oliguria ofheart disease with diuretics but not theoliguria of exercise. The former is a viciouscycle, a response that has not been culled fromthe stream of inheritance by the rigorousprocess of evolution.

It may well be that, as medicine turns moreand more toward geriatrics, vicious cyclesresulting from late degenerative disease willconfront the physician more often. It will betruly a test of the intelligence of the physicianand his fundamental background for him to tellthe vicious cycle from the useful response, forhim to learn to interfere with the one and helpthe other.

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29 HUGGINS, R. A., SMITH, E. L., AND SINCLAIR,M. A.: Comparison between cardiac inputmeasured with rotameter and output deter-mined by direct Fick method in open-chestdogs. Am. J. Physiol. 160: 183, 1950.

3 SEELY, R. D., NERLICH, Mr. E., AND GREGG,D. E.: Comparison of cardiac output deter-mined by the Fick procedure and a directmethod using the rotameter. Circulation 1:1261, 1950.

31 HAMILTON, WY. F., WINSLOW, J. A., AND HAMILTON,W. F., JR.: Notes on a case of congenital heartdisease with cyanotic episodes. J. Clin. In-vestigation 24: 20, 1950.

32 STEWART, G. N.: Researches on the circulationtime and on the influences which affect it. IV.The output of the heart. J. Physiol. 22: 159,1897.

33 HENRIQUES, V.: uber die Verteiling des IBlutesvom linken Herzen zwischen dem Herzen unddem ubrigen Organismus. Biochem. Ztschr.56: 230, 1913.

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36 HAMILTON, XV. F., MOORE, J. XV., KINSMAN, J.MI., AND SPURLING, R. G.: Studies on thecirculation. IV. Further analysis of the injectionmethod, and of changes in hemodynamics underphysiological and pathological conditions. Am.J. Physiol. 99: 534, 1932.

37 KINSMAN, J. MI., MIOORE, J. XV., AND HAMILTON,XV. F.: Studies on the Circulation. I. Injectionmethod. Physical and mathematical considera-tions. Am. J. Physiol. 89: 322, 1929.

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19 HAMILTON, W. F., RILEY, R. L., ATTYAH, A. M.,COURNAND, A., FOWELL, D. M., HIMMELSTEIN,A., NOBLE, R. P., REMINGTON, J. W., RICHARDS,D. W., JR., WHEELER, N. C., AND WITHAM,A. C.: Comparison of Fick and dye injectionmethods of measuring cardiac output in man.Am. J. Physiol. 153: 309, 1948.

40 WERKO, L., LAGERLOFF, H., BUCH, H., WEHLE,B., AND HOLMGREN, A.: Comparison of theFick and Hamilton methods for the determina-tion of the cardiac output in man. Scandinav.J. Clin. & Lab. Investigation 1: 109, 1949.

41 DOYLE, J. T., WILSON, J. S., LUPINE, C., ANDWARREN, J. V.: An evaluation of the measure-ment of the cardiac output and of the so-calledpulmonary blood volume by the dye dilutionmethod. J. Lab. & Clin. Med. 41: 29, 1953.

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7 BARCROFT, H., EDHOLM, 0. G., \IC-MICHAE,, J.,SHARPEY-SHAFER, E. P.: Posthemorrhagic faint-ing. A study on the cardiac output and forearmflow. Lancet 1: 489, 1944.

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7 BARCROFT, H., AND EDHOLM, 0. G.: On the vaso-

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W. F. HAMILTONThe Lewis A. Connor Memorial Lecture: The Physiology of the Cardiac Output

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