studies circulation 2 · studies of the circulation in pernicious anemia12 by haroldj. stewart,...

STUDIES OF THE CIRCULATION IN PERNICIOUS ANEMIA1 2

By HAROLDJ. STEWART,NORMANF. CRANEAND JOHNE. DEITRICK(From the New York Hospital and the Department of Medicine, Cornell University Medical

College, New York City)

(Received for publication December 23, 1936)

One of the most important functions of theblood is to furnish oxygen to the tissues inamounts sufficient for their requirements. Thehuman organism has available several compensa-tory adjustments to counteract alterations whichinterfere with the normal supply of oxygen. Ofthese compensatory mechanisms three of the mostimportant are: (1) variation in the oxygen carry-ing capacity of the blood, that is to say in thequantity of hemoglobin; (2) variation in thequantity of oxygen removed from the blood as itpasses through the capillaries; and (3) alterationin the minute-volume output of the heart. It waswith the object of studying certain responses ofthe heart to a slowly developing decrease in theoxygen capacity of the blood, such as is found inpatients suffering from pernicious anemia, thatthese observations were made. We have made,therefore, measurements of the cardiac output,the cardiac size, the venous pressure, the circula-tion time, the oxygen consumption, the vital capa-city, the heart rate, and the blood pressure infive patients suffering from pernicious anemia.These measurements were made first during theanemic state and later during a remission inducedby liver extract, when the count of the red bloodcells and the hemoglobin values had reached morenearly normal levels. Although there are studiesin the literature dealing with certain phases of thecirculation, there are none in which the severalfunctions mentioned above were observed simul-taneously.

METHODS

All observations were made in the morning while thepatients were in a basal metabolic state. Measurementsof the cardiac output were made by the acetylene method,

1 An abstract of these studies was read before the As-sociation of American Physicians, Atlantic City, May 5,1936.

2 This Paper is also Number 1 of the Series on Studiesof the Circulation published from the New York Hos-pital and the Department of Medicine, Cornell UniversityMedical College.

three samples of gas being taken as first recommendedby Grollman (1), and by Grollman, Friedman, Clarkand Harrison (2). During this measurement the pa-tients were sitting in a steamer chair (angle 135 degrees)with the legs extended. They were trained beforehandto carry out the procedures. While the patient was atrest, the radial pulse was counted at intervals of fiveminutes. At the end of one-half hour the acetylene-air-oxygen mixture was rebreathed. Three samples of gaswere taken during each rebreathing period for estimationof the arteriovenous oxygen difference. Three periodsof rebreathing were carried out on each patient. Shortlyafterward, the oxygen consumption was measured witha Benedict-Roth spirometer. After a short pause, thevital capacity was measured, and height and weight re-corded. Then the patient rested again, now lying down.In succession, sufficient time being allowed between eachprocedure for the patient to return to a basal metabolicstate, an electrocardiogram was taken, the arm to tonguecirculation time recorded, the venous pressure estimated,and the blood pressure measured; finally an x-ray photo-graph of the heart was made at a distance of two meters.

The arm to tongue circulation time was estimated bythe use of decholin: 5 cc. of a 20 per cent solution wereinjected rapidly (1 to 2 seconds) through an 18 gaugeneedle into an antecubital vein while the patient waslying quietly in the supine position. This was repeatedin one and one-half minutes after the response to thefirst test had been elicited. The time was recorded fromthe beginning of the injection until the patient perceivedthe bitter taste. The injection time was also recorded,but since the response may come with a minimal amountof the drug, the time which we have used was takenfrom the start, rather than from the conclusion of theinjection.

The venous pressure was measured by the direct method(3), using a large antecubital vein, the arm being placedon a level with the right auricle. The apparatus con-sisted of an L-tube of glass attached to a three-waystopcock, a syringe, and an 18 gauge needle. The ap-paratus was filled with a solution of sterile normalsaline, a venepuncture performed, and the direct pressurereadings recorded. Normal pressures with this apparatusrange from 4.0 to 9.0 cm. of saline. The antecubital veinof one arm was reserved for the injection of decholinand of the other arm for the measurement of venouspressure. In subsequent measurements the vein was en-tered at the site first punctured.

X-ray photographs of the heart were taken with thepatient in the standing position, in full inspiration, at

431

HAROLDJ. STEWART, NORMANF. CRANEAND JOHN E. DEITRICK

a distance of two meters.8 Measurements of the cardiacarea were carried out by the technique of Levy (4)and estimations of volume were made as recommendedby Bardeen (5). The volumes recorded in Table I havenot been multiplied by the constant which is in Bar-deen's formula. This was done in order to make ourobservations comparable to those of Starr, Collins andWood (13).

OBSERVATIONS

Case 1, a white woman 39 years of age, was admittedto the hospital on February 6, 1935. For 6 months be-fore admission she had experienced increasing weakness,dyspnea, palpitation, intermittent diarrhea, and a lossin weight of 25 kgm. Pallor and swelling of the anklestoward evening appeared during the last two months.On examination the patient was obese and quite pale.The heart was slightly enlarged (Table I). The rhythmwas normal sinus mechanism. A systolic murmur washeard at the apex. Neither cyanosis nor dyspnea wereobserved. Riles were not heard at the lung bases. Theliver and spleen were not palpable. Moderate pittingedema was present below the knees. Free hydrochloricacid was not present in the gastric contents after theadministration of histamine. The patient was anemicand a blood smear showed changes typical of perniciousanemia.

On February 9, 1935, when the count of the red bloodcells was 1,070,000, the various measurements recordedin Table I were made. On a regime of injections ofliver extract 4 intramuscularly, 10 cc. daily for one weekfollowed by biweekly injections of 10 cc. of this extract,together with reduced iron 1.5 grams by mouth, daily,the anemia became less severe, and on March 14, 1935,a second series of measurements was recorded (Table I).

Case 2, a white woman 54 years of age, was admittedto the hospital on March 2, 1935. She had first observeddyspnea and palpitation on exertion 11 years before ad-mission. For two years she had experienced severe epis-taxis and was then told for the first time that the bloodpressure was elevated. Following a recurrence of epis-taxis in December 1934, she suffered from increasedfatiguability and increasing dyspnea and palpitation onexertion, although she was still able to climb four flightsof stairs. Two, weeks before admission she becameaware of a yellowish pallor of the skin. On examinationthe patient was obese. There was a pale icteric tint ofthe skin. The tongue margin was smooth. A firm nod-ule was felt in the isthmus of the thyroid, but tremor ofthe hands was not present. The heart was slightly en-larged (Table I). Regular sinus rhythm was present.A systolic murmur was heard at the apex. The secondsound over the aortic area was louder than the second

8 The authors are deeply indebted to the X-ray Depart-ment of the New York Hospital for their cooperation inthis investigation.

4 The extract which was given to all patients wasprepared at the New York Hospital unless otherwisespecified.

pulmonic sound. The blood pressure was labile, varyingduring her stay in the hospital between 130 and 214 mm.of Hg systolic, and 80 to 126 mm. of Hg diastolic. Cya-nosis, dyspnea, and edema were not observed. A fewmoist riles were heard at the lung bases at the time ofadmission. These disappeared during the first few daysin bed. The liver and spleen were not palpable. Therewas a trace of albumin in the urine and occasional redblood cells were present in the centrifuged sediment. Theurea clearance was 63 per cent of normal. The gastriccontents did not contain free HCl after the administrationof histamine. A blood smear showed the changes typicalof pernicious anemia. The following diagnoses weremade: Pernicious anemia, arterial hypertension; normalsinus rhythm; obesity due to excess food; and non-toxicnodular goiter.

On March 8 when the count of the red blood cells was1,190,000 the first series of measurements was made (Ta-ble I). The patient then received injections of liverextract intramuscularly, 10 cc., daily for one week fol-lowed by injections of 10 cc. of the extract every thirdday, together with 12 cc. of a 50 per cent solution of ironand ammonium citrate given by mouth daily. On thisregime the count of the red blood cells rose to 3,200,000on March 27, 1935, and the second series of measurementswas recorded (Table I).

Case 3, a white male 66 years of age, was first admittedto the hospital on August 23, 1929, complaining of ano-rexia and weakness of ten weeks' duration. On examina-tion, marked pallor was present. The count of the redblood cells was 1,110,000 and the estimation of the hemo-globin was 22 per cent (14.5 grams hemoglobin equivalentto 100 per cent). The blood smear showed changes typi-cal of pernicious anemia. On a diet containing liver thepatient improved and was discharged on September 12,the count of the red blood cells then being 2,180,000 andthe estimation of the hemoglobin 41 per cent. Threemonths following discharge he stopped taking liver andfelt well until three weeks prior to his second admissionwhen he experienced weakness, diarrhea, tingling of thefingers and toes. He was readmitted to the hospital onFebruary 15, 1935. The patient was a thin, pale, elderlymale, who showed no dyspnea, cyanosis nor edema. Theheart was not enlarged (Table I). Regular sinus rhythmwas present. No murmurs were heard. Rales were notheard at the lung bases; the liver and spleen were notpalpable. Neurological changes were not present. Thegastric contents did not contain free hydrochloric acidafter the administration of histamine, and a blood smearshowed the changes typical of pernicious anemia.

On February 19 the count of the red blood cells was1,410,000, and the first series of measurements was made(Table I). On a regime of injections of liver extractintramuscularly, 10 cc. daily for one week followed by bi-weekly injections of 10 cc. of this extract, together with1.5 grams of reduced iron by mouth daily, the count of thered blood cells rose to 3,500,000 on March 9, 1935, and thesecond series of measurements was recorded (Table I)

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Case 4, a white male 49 years of age, was admitted tothe hospital on December 27, 1934. Two years prior toadmission he had noticed increasing pallor and had ex-

perienced anorexia, soreness of the tongue, weakness, un-

steadiness of gait, and numbness and tingling of the feet.For 18 months frequent attacks of vomiting and dyspneaon exertion had been present. For six months, substernal

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FIG. 1.In this figure is represented the effect of low hemo-

globin levels in the blood on cardiac output, circulationtime, oxygen consumption, cardiac rate, cardiac area, andvenous pressure, and the changes which occur with re-

turn toward normal hemoglobin, and red blood cell levels.Each symbol represents a patient: Case 1, A. N. open

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pain, vertigo and fainting were prominent symptoms.During the last two months before applying for admissionto the hospital, swelling of the legs and feet became quitemarked. There was a yellowish pallor of the skin andslight dyspnea on exertion. The tongue margins were

smooth. The heart was slightly enlarged (Table I).Regular sinus rhythm was present, and a systolic murmur

was heard at the apex. A few moist riles were heard atthe lung bases, and the liver edge was felt two fingersbreadths below the costal margin. There was markededema of the legs and moderate pitting over the sacrum.

The patient walked with a spastic gait and both the vibra-tion and position senses of the legs were impaired. TheWassermann reaction in the blood was negative. Thegastric contents did not contain free hydrochloric acidafter the administration of histamine. A blood smear

showed the changes typical of pernicious anemia.On December 29, 1934, the count of the red blood cells

was 1,350,000 and the previously described series of meas-

urements was made (Table I). On a regime of injec-tions of liver extract intramuscularly, 10 cc. daily, for one

week, followed by weekly injections of 10 cc. of extract,the count of the red blood cells rose to 3,700,000 on Jan-uary 14, 1935, and the series of measurements was re-

peated. The patient showed now only slight dyspnea,there were still occasional riles heard at the lung bases,the liver was no longer palpable, and only slight pittingedema of the ankles remained.

Case 5, a white woman 45 years of age, was admittedto the hospital first on August 27, 1934. One month be-fore admission she had experienced epigastric distress,numbness and tingling in the hands and feet. On exam-

ination the patient showed moderate pallor. The tonguemargins were smooth. Dyspnea, cyanosis and edemawere not present. The heart was not enlarged (Table I).The liver edge was palpated one finger's breadth belowthe costal margin. The tendon reflexes, vibration, andposition senses were absent in the lower extremities.Free hydrochloric acid was not present in the gastric con-

tents after the administration of histamine. The countof the red blood cells was 2,700,000, the estimation of thehemoglobin 55 per cent, and a blood smear showed thechanges typical of pernicious anemia. Treatment withliver extract was started, the patient receiving liver ex-

tract intramuscularly, 10 cc. daily for four days followedby weekly injections of 10 cc. of the extract. When on

September 18, the count of the red blood cells had risento 3,500,000 she was discharged from the hospital. Inspite of the administration of 12 cc. of a 50 per cent solu-tion of iron and ammonium citrate a day, and the weeklyinjection of 10 cc. of New York Hospital intramuscularliver extract, alternating with 9.0 cc. of Lederle's intra-muscular liver extract, on February 5, 1935, the count ofthe red blood cells had fallen to 2,300,000 and she was re-

admitted to the hospital. The physical signs were essen-

tially the same as on the previous admission.The patient was immediately given liver therapy in-

tensively. To this end she was given injections daily ofNew York Hospital intramuscular liver extract, thenLederle intramuscular liver extract and finally ventriculin,

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as well as ferrous sulphate 1.0 gram by mouth three timesdaily. On February 13, 1935, the count of the red bloodcells was 2,850,000 and the previously described series ofmeasurements was made (Table I).

In summary, it appears from the data of TableI that during the anemic state the cardiac output,the heart rate, and the oxygen consumption werein all cases elevated, and the circulation time short.As the anemia became less the cardiac output,the heart rate, and the oxygen consumption de-creased, and the circulation time increased, allapproaching more nearly normal values (Figure1 ). The venous pressure readings (except inone patient in whom it was initially slightly ele-vated) and the measurements of the cardiac areashowed no significant alterations.

DISCUSSION

Plesch (6) in 1909, demonstrated that the car-diac output increases when there is decrease inhemoglobin content of the blood. Making useof the Fick principle he found that the increasein cardiac output roughly paralleled the decreasein hemoglobin. Since that time several investi-gators (7, 8, 9, 10) have measured cardiac out-put in patients suffering from pernicious anemia.Certain of these employed the same technique thatwe have used, namely the Grollman method, andothers used the nitrous oxide method of Kroghand Lindhard, the Meakins-Davies method, andthe Field-Bock method. All reported increase inthe cardiac output in anemic patients. Therewere quantitative variations, however, due prob-ably to experimental errors inherent in all themethods employed (1).

Nielsen (11) using Grollman's acetylenemethod, made eleven observations of one patientsuffering from pernicious anemia. He foundthat the augmented values of minute-volume out-put obtained during the severe anemia graduallyfell to normal as the patient improved during aremission. In collecting samples of the gas foranalysis, however, he made only two, instead ofthree collections during each rebreathing period;since, however, his results follow a pattern similarto ours in which 3 samples were collected, it islikely that mixing was attained by his patient.Starr et al. (12, 13) using a reliable modificationof the ethyl iodide method, made single observa-tions in two cases of pernicious anemia in whichthe estimation of the hemoglobin was 58 per cent

and 45 per cent respectively, and found the car-diac output elevated in one instance, but normalin the other.

Our observations reveal an increase in minute-volume output (Figure 1 ) and in the cardiacindex (liters per square meter per minute) (Fig-ure 2), in all patients at their lowest hemoglobin

FIG. 2.In this figure is represented the effect of anemia on

the cardiac index (cardiac output in liters per squaremeter per minute) in each of the five patients studiedand the subsequent decrease in cardiac output during aremission induced by intramuscular liver extract therapy.The average value for a normal individual is given forcomparison.

values. Increase in cardiac output per minute isdue only in part to the rise in oxygen consump-tion (increase in basal metabolic rate) (Table I),as is shown by the fall in the arteriovenous dif-ference. The direction of our results is similarto that reported by Nielsen (11), although of asmaller magnitude. The arteriovenous oxygendifference (Table I) was in each instance smallerat low hemoglobin levels than after remissionoccurred. The stroke volume output is alsogreater during the anemic state even though the

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HemoglobiLn in percentFIG. 3.

In this figure all observations of cardiac output of allpatients are plotted against corresponding hemoglobinmeasurements. This discloses a correlation which ap-pears to be linear, in that as the hemoglobin decreasesthe cardiac output increases. The symbols representingeach patient are the same as those used in Figure 1.

cardiac rates are more rapid than when the redblood cells and hemoglobin have assumed morenearly normal values (Table I); the cardiac out-put decreases progressively as the hemoglobinvalues (Figure 3) and red blood cell counts rise(Figure 4) until normal values of minute-volumeoutput are finally reached at hemoglobin concen-tration of approximately 70 per cent.

Calculations of the percentage oxygen utiliza-tion (Table II) showed that it was greater during

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of all patients are plotted against the correspondingcardiac output. A correlation similar to that demon-strated in Figure 3 appears. The symbols are the sameas those in Figures 1 and 3.

the anemic state than after the amount of hemo-globin increased, an observation to which Rich-ards and Strauss (10) have already directed at-tention as one of the compensatory adjustmentsin anemia. In short, the percentage oxygen uti-lization varies inversely as the oxygen capacity(Table II) although the arteriovenous oxygendifference decreases in anemia.

TABLE II

Data relating to Percentage of oxygen utilizationin S anemic patients

O capacity* Oxygen utilizationtCase

numberBefore: After$ Before$ Aftert

volumes volumes per cent per centper cent per cent ~~ et prcn

1 5.4 15.2 83 382 8.4 13.2 65 493 7.0 14.4 61 414 9.0 11.6 49 475 12.4 15.0 40 43

* 1 per cent hemoglobin (Table I) equivalent to 0.2volume per cent oxygen capacity. This was assumed to beaccurate enough for the deduction to be made from thedata derived from the calculations.

t Percentage of oxygen utilization is the ratio betweenarteriovenous oxygen difference (Table I) and oxygencapacity.

t "Before" and "After" refer to the period of anemiaand period of increased hemoglobin respectively.

In these patients, as the cardiac output in-creased the velocity of blood flow increased, a

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Ctvculttion Ttme in SecondsFIG. 5.

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plotted against cardiac output. This reveals a linear cor-relation in that as the cardiac output decreases the cir-culation time becomes longer. The symbols are the sameas in Figure 1.

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plotted against circulation time. A linear correlationappears. As the hemoglobin increases the circulationtime becomes longer. The symbols are the same as inFigure 1.

linear relationship being maintained. The greaterthe cardiac output, the shorter the circulation time(Figure 5). Moreover, there appeared a correla-tion between circulation time and quantity ofhemoglobin; at low hemoglobin percentages thecirculation time was short, only to become longeras the hemoglobin values increased -(Figure 6).

These results are similar to those recorded inthe studies of Blumgart, Gargill and Gilligan (14)relating to velocity of pulmonary blood flow inpatients suffering from pernicious anemia. Theincrease in velocity is, however, of somewhatgreater magnitude than that reported by Tarr,Oppenheimer, and Sager (15) who, also usingdecholin, found an average arm to tongue cir-culation time of 12 seconds in their anemic pa-tients, as opposed to 13 seconds in their normalcontrol series. Since the hemoglobin levels atwhich their observations were made are not givenit is not possible to make an accurate comparisonof their observation with ours.

The venous pressure showed no significant al-terations except in the case of one patient (Case2, Table I) who showed a slightly elevated pres-

sure at the low hemoglobin levels which ap-proached a more normal value as the hemoglobinconcentration in the blood increased.

In all patients there was a rise in both the

systolic and diastolic levels of blood pressure asthe hemoglobin increased; in three instances theincrease in blood pressure was very striking. Inshort, although the heart put out an increasedquantity of blood per minute and per beat in thepresence of anemia the blood pressure was lower.The manner in which these factors contribute tothe work of the heart is discussed later.

The vital capacity of the lungs was moderatelyreduced in four of the patients during the anemicstate although no signs of congestive heart failurewere present. Weare unable to explain this sat-isfactorily but call attention to the suggestion of-fered by Blumgart, Gargill and Gilligan (14) thatit may be related to the presence of an increasedamount of blood in the lungs coincident with anincreased rate of flow.

The electrocardiograms showed no significantalterations as the hemoglobin concentration in theblood increased.

Du Bois (16) has summarized data in the lit-erature relating to the basal metabolic rate inanemia. Certain subjects with anemia show in-creased and others decreased basal metabolic rates.We have observed increased metabolic rates ineach instance at low hemoglobin levels (Table I);as the hemoglobin content of the blood increasedthe oxygen consumption decreased and ap-

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plotted against oxygen consumption. A linear relation-ship is revealed, in that as the hemoglobin increases theoxygen consumption decreases. The symbols are thesame as in Figure 1.

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proached more nearly normal values (Figure 7).This result is similar to that growing out of theobservations of Tompkins, Brittingham andDrinker (17) who approached this question inanother manner. They found that the metabolicrates of patients suffering from pernicious anemiadecreased following the transfusion of blood. Itappears clear, therefore, both from our own ob-servations and from those already recorded byothers, that the oxygen consumption, in short,the basal metabolic rate, may be increased ap-preciably in the presence of pernicious anemia.A satisfactory explanation for this phenomenonhas not yet been advanced. Our data do not per-mit us to make any positive contribution to thispuzzling observation. They indicate, however, aswill be shown later, that increased oxygen con-sumption is not a consequence of increased workof the heart, a notion which has been current upto the present.

That enlargement of the heart in anemic pa-tients occurs as a consequence of both dilatationand hypertrophy is an idea that has been held formany years (18, 19, 7). Most of the conclusionshave been based upon clinical and postmortemobservations in cases of pernicious anemia. Onepatient reported by Ball (20) is of especial in-terest since roentgenological enlargement of theheart was observed during severe secondaryanemia, and was followed by decrease in sizewhen the blood count returned to normal. Fromthese observations he concluded that enlargementwas due to dilatation rather than hypertrophy.In the case of three patients in the series nowbeing reported, the heart was moderately enlargedor at the upper limits of normal, only two beingwell within normal limits. That observationsmade after improvement failed to show significantchange in size of the heart may be due in partto the relatively short time covered by observa-tions of each patient.

The cause of cardiac enlargement found in thepresence of anemia has been subject to contro-versy. One notion (11) regards it as a conse-quence of increased activity of the heart; another(7) attributes it to lack of oxygen in the myo-cardium. Because of these notions it appearedof interest to ascertain the amount of work doneby the heart in patients suffering from pernicious

anemia. Work may be calculated by making useof the formula (21)

W-~QR+ V29V2g

in which Wequals work done per minute, orper beat; Q equals volume of blood expelled perminute, or per beat; R equals mean arterial bloodpressure in mm. of Hg X 13.6; V equals velocityof blood at aorta; w equals weight of blood; gequals acceleration due to gravity. The last part

of the formula, (W2g , has been omitted in orderto make our results comparable to those of Starret al. (13). By substituting values in this for-mula, we have calculated the work of the leftventricle both per beat and per minute. Sincethere is evidence (22) that the work of the rightventricle bears a constant relationship to that ofthe left, we have concerned ourselves only withthe latter. The work per beat done by the leftventricle was found less during the period of in-creased cardiac output at low hemoglobin levels,than later when the output was lowered and theamount of hemoglobin more nearly normal (Ta-ble I).

Taking into account the increased heart ratesfound in the anemic state, as is done in computingthe work per minute, does not reveal increasedwork in the presence of anemia. This is due forthe most part to the considerable increase in themean arterial pressure which is found at thehigher levels of hemoglobin. Since, therefore,the work of the heart appears to be within normallimits there seems to be no point in retaining thenotion which is current, that enlargement of theheart in anemia is a consequence of increasedcardiac work; on the other hand, by exclusion itlends credence to the view that myocardial anox-emia may be the stimulus which initiates enlarge-ment. Likewise, since we have failed to find thework of the heart increased in these patients, thismechanism does not account for the increasedbasal metabolic rate.

Stewart and Cohn (23) expressed the opinionthat the explanation of the increase in cardiacoutput with decrease in cardiac size as a conse-quence of giving digitalis to patients suAferingfrom congestive heart failure, was to be found inStarling's "Law of the Heart" (24). Further-

438


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CARDIAC VOLUME.The data from Table I relating to work of the left

ventricle per beat are plotted against the correspondingcardiac volumes. Line AB represents the best line, theregression of the work on the area, defined by Starr,Collins and Wood (13, Figure 2) on the basis of a

statistical treatment of data from a control group ofcases. Lines CD and EF are placed by these authors ata distance of twice the standard deviation from AB. Itappears from their observatoins that a patient fallingwithin zone CD-EF has a normal circulatory function,that is to say, the work of the heart is commensuratewith its size; on the other hand they found that thevalues relating to patients who had suffered from cardiacdecompensation, fell in a zone below CD. The valuesof the patients suffering from pernicious anemia now

being reported fall well within the zone CD-EF and, as

a matter of fact, lie quite near the best line AB. Thearrows in each instance point from the first observationduring anemia toward the second observation after thehemoglobin had increased. In 4 instances, progressionwas made toward or even above the best line, and inthe fifth remained unchanged.

appears to be a fact that the work of the leftventricle which is maintaining an adequate cir-culation, bears a linear relation to the size of theheart. From a statistical analysis of their datathey have defined a zone of normal circulatoryfunction. In a similar fashion we have plottedcardiac volume as abscissae and grammeters ofwork of the left ventricle per beat as ordinates(Figure 8). All our observations fall within thezone of normal circulatory function, between linesCDand EF, very near the best line, AB; in eachinstance, the work of the heart was commensuratewith its size. As the degree of anemia lessened,the values for four of the patients moved upwardslightly, either toward or above the "best" line(AB), indicating improved cardiac functionwhere the cardiac work is more commensuratewith the cardiac size. Thus, in spite of lowhemoglobin and red blood cell values during theanemic state, and presumably a decreased totalblood volume (23) as well, these patients all ex-hibit normal cardiac function at rest. This ismade possible, apparently, by a distribution ofthe burden that is placed on the circulatory ap-paratus as a result of the diminished oxygen ca-pacity of the blood and of the increased metabolicdemands of the tissues. A part of this deficit isabsorbed by compensatory increase in minute-volume output and in velocity of blood flow, anda part, as has been demonstrated already byRichards and Strauss (10) and now again shownby our data, by increased percentage utilizationof oxygen by the tissues. Thus, the adjustmentsresorted to by the anemic individual call for con-siderable encroachment on the reserves of thebody. In the clinic evidence of this encroachmentis revealed in dyspnea and other signs of circula-tory failure exhibited by anemic patients whenthey try to indulge in muscular exertion.

SUMMARY

1. Measurements of cardiac output, by theacetylene method, of cardiac size, and related cir-culatory functions, have been made in five casesof pernicious anemia both during the period ofanemia, and later during a remission induced bythe use of liver extract therapy, when the bloodpicture was more nearly normal.

2. At low hemoglobin levels in the blood. the

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stroke-volume and minute-volume output, thecardiac rate, and the oxygen consumption werein all cases elevated, and the arm to tongue cir-culation time decreased. Changes in the reversedirection occurred as the state of the blood ap-proached normal.

3. In four instances the vital capacities weremoderately lowered during anemia.

4. The venous pressure and electrocardiogramsshowed no significant alterations during theanemic state.

5. There was a rise in both the systolic anddiastolic levels of blood pressure in all patients asthe hemoglobin concentration increased.

6. Although the cardiac size was moderately in-creased in three instances, no significant changein size was observed as the hemoglobin ap-proached a normal level.

7. Left ventricular work, both per beat andper minute, was not increased during anemia; infact, the work per beat was less than when thehemoglobin concentration in the blood was nor-mal. It is suggested that the enlarged heartsfound in this type of anemia are due to myo-cardial anoxemia, rather than to increased cardiacwork. The elevated metabolic rates, observedin these patients during the anemic state, werenot due to increased cardiac work.

8. The amount of cardiac work done at rest,in anemia, was commensurate with the cardiacsize.

9. From these observations it appears that dur-ing the anemia of pernicious anemia, the heart iscalled upon to pump an increased amount of bloodper minute, the amount appearing to be a linearfunction of the hemoglobin concentration. Thisis accomplished in part by increasing the heartrate, and in part, by maintaining a greater outputper beat than they have at higher hemoglobinlevels. These alterations are reflected in a short-ening of the circulation time; in short, the redblood cells, although fewer in number, move atan increased velocity and, as a consequence, theyare used more frequently in their oxygen carryingcapacity. Shortening of the circulation time andincrease in cardiac output as well as decrease inhemoglobin and increase in oxygen consumptionalso appear to have linear relationships so thatan organ already working at an accelerated rate is

put to the disadvantage of having to maintain acirculation sufficient for the requirements of anincreased basal metabolic rate. With increase inthe level of hemoglobin, changes in the reversedirection occur. Nevertheless, the hearts of thesepatients, without congestive heart failure, at rest,mechanically perform the work expected of themfor their size.

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1. Grollman, A., The Cardiac Output of Man in Healthand Disease. C. C. Thomas, Springfield, Ill., 1932,p. 73.

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anemia. Am. Heart J., 1931, 6, 517.21. Starling, E. H., Principles of Human Physiology.

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pulmonary circulation. J. Physiol., 1913, 47, 286.23. Stewart, H. J., and Cohn, A. E., Studies on the effect

of the action of digitalis on the output of bloodfrom the heart. III, Part 2. The effect on theoutput of hearts in heart failure with congestion,in human beings. J. Clin. Invest., 1932, 11, 933.

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