cardiac, duringinduced peripheraldm5migu4zj3pb.cloudfront.net/manuscripts/103000/103834/... ·...

CARDIAC, HEMODYNAMICANDRENALFUNCTIONSIN CONGESTIVEHEARTFAILURE DURINGINDUCEDPERIPHERALVASODILA-

TATION; RELATIONSHIP TO STARLING'S LAWOFTHE HEARTIN MAN* t

BY BRUCEJ. SOBOL, RICHARD H. KESSLER, BERTHARADERANDLUDWIGW. EICHNA

(From the Department of Medicine, New York University College of Medicine and the Third[New York University] Medical Division, Bellevue Hospital,

New York, N. Y.)

(Submitted for publication June 30, 1958; accepted September 11, 1958)

The present study of the hemodynamic effectsof induced peripheral vasodilatation had two pur-poses: one, to determine what changes are pro-duced in cardiac, hemodynamic and renal func-tion's of man in congestive heart failure when vas-cular pressures are lowered by noncardiac means,and two, to determine whether Starling's law ofthe heart applies in intact man, especially in con-gestive heart failure.

Expanding on the observations of Frank (1)on the frog heart, Starling, with Patterson andPiper (2, 3), determined in the isolated heart-lung preparation of the dog that cardiac outputincreased progressively as ventricular filling pres-sure (2) and ventricular diastolic volume (3)increased (ascending limb of curve); however,beyond a point considered to indicate a failingmyocardium, cardiac output decreased with fur-ther increments in ventricular filling pressure ordiastolic volume (descending limb of curve). Thefinal generalization derived from these observedrelationships Starling (4) then expressed as thelaw of the heart: "The energy of contraction,however measured, is a function of the length ofthe muscle fiber." Starling's law has been ex-trapolated to the intact, humorally and neuro-genically homeostatic animal, including man, andhas come to dominate present concepts of bothnormal and abnormal cardiac function. Such ex-trapolation requires validation.

The applicability of Starling's law to the moreintact animal has been investigated by Sarnoff

* Presented in part at the Sixty-Ninth Annual Meet-ing of the Association of American Physicians, AtlanticCity, N. J., May 1, 1956.

t This work has been supported by grants-in-aid fromthe Life Insurance Medical Research Fund and the NewYork Heart Association, Inc.

and his collaborators, Berglund, Isaacs, Case andSarnoff (5-8), in the anaesthetized, open-chesteddog with the heart in situ and its nerve supplyintact but its circulation completely isolated andsubjected to measurement. In large measure, therelationships between cardiac work and ventricu-lar filling pressure were similar to the results ob-tained by Starling. Two modifications evolved:one, ventricular function did not follow a singlestroke work-filling pressure curve but rather a seriesor family of similar curves, each curve determinedby the circulatory state at the time (anemia, aorticconstriction, coronary artery constriction, inducedepinephrinemia); two, a descending limb on theventricular work-filling pressure curve did not oc-cur in the "normal" satisfactory preparation but ap-peared when the myocardium was "compromised,"as by severe anemia, severe coronary artery con-striction or shock. Several features of these ex-periments, especially the large changes in bloodvolume required to alter the filling pressures andthe relatively short periods during which thealtered pressure-flow relationships were deter-mined, still raise the question whether the ob-served results are applicable to man with normal,and especially failing, circulations in a steady statefor long periods.

Several studies suggest that Starling's law mayapply in man. McMichael, with Sharpey-Schaferand Howarth (9, 10), and Judson, Hollander,Hatcher, Halperin and Friedman (11), observedan increase in cardiac output (hence cardiac worksince arterial pressure did not change) when theelevated intracardiac pressures of subjects in con-gestive heart failure were lowered by phlebotomyor by inducing venous stasis in the limbs. Theseobservations have the disadvantage that phle-

557

SOBOL, KESSLER, RADERAND EICHNA

botomy reduces blood volume and the cuffs in-ducing venous stasis can be maintained for periodswhich may be too short to permit attainment ofcirculatory equilibrium.

The advent of vasodilator drugs suggested thepossibility of lowering ventricular filling pressureby noncardiac means for sufficiently long periodsto attain circulatory equilibrium at a lowered pres-sure level and, thereby, to permit testing of theapplicability of Starling's law to man. The pres-ent experiments were designed to lower ventricu-lar filling pressure by producing primary pe-ripheral vasodilatation, then observing whethercardiac function altered as predicted by the law ofthe heart: an increase in cardiac work when theelevated ventricular filling pressure in congestiveheart failure was lowered, and a decrease incardiac work when normal filling pressure wasreduced.

PROCEDURES,METHODSANDSUBJECTS

General. The plan of study was to measure allfunctions simultaneously during a control state, duringinduced and maintained vasodilatation and again on re-turn of the control state. The drug Arfonad®, a thi-ophanium derivative [d-3,4(1',3'-dibenzyl-2'-ketoimidazo-lido)-1,2-trimethylene thiophanium d-camphor sulfonate],was chosen to produce vasodilatation and lower vascularpressures because this drug has no known direct myo-cardial or cardiac action. Its effects are produced byblocking sympathetic and parasympathetic ganglia andperhaps also by direct peripheral vascular dilatation (12,13).

Cardiac output was determined by the direct Fick (14)method. Intracardiac and systemic vascular pressureswere obtained directly and recorded with strain gages andelectronic recorder. Renal hemodynamic functions weremeasured by clearance techniques (15) and electrolyteconcentrations by flame photometer. Standard methodswere used to determine the following: oxygen and car-bon dioxide in blood (16), room air (17) and exhaled air(17); the concentrations of inulin (18), para-aminohip-purate (19) and sodium and potassium (flame photom-eter) in blood and urine; the plasma and blood volumes(20). Determinations were made in successive periodsof 15 to 20 minutes duration, with cardiovascular dy-namic measurements made at the midpoint of the pe-riods and renal hemodynamic functions and water andelectrolyte excretions measured over the entire period.The nature, timing and sequence of the necessary proce-dures have been described previously in detail (21, 22).Renal hemodynamics and urinary excretions were de-termined in only one-half of the experiments.

Procedures. The observations were made in the morn-ing on supine subjects without breakfast. A control elec-

trocardiogram was taken and the urinary bladder wascatheterized. The intravenous infusion of inulin andpara-aminohippurate was delivered continuously at 1 ml.per minute by a Bowman pump. A double lumen intra-cardiac catheter was placed with the distal opening in thepulmonary artery and the proximal opening in the rightventricle. A systemic artery was cannulated. A slowintravenous infusion of 5 per cent dextrose in water wasbegun and the system was provided with a three-waystopcock to permit switching from dextrose infusion toArfonad® infusion without the subject's knowledge.

After three periods of control measurements the in-travenous infusion of Arfonad®, 1 mg. per ml. in 5 percent dextrose in water, was begun and delivered continu-ously by an infusion pump. The ArfonadO infusion wasstarted at 0.5 mg. per minute and adjusted at 5 to 10minute intervals until the desired degree of vasodilatation,as determined by the level of arterial pressure, was ob-tained. This level was maintained for one hour, duringwhich three periods of determinations were made, withtheir midpoints 15, 30 and 60 minutes after attaining thedesired level of vasodilatation. The infusion of Arfonad®was then discontinued and after the vascular pressureshad returned to control levels, or as close as it appearedthey would return, the final period of determinations wasmade. While awaiting return of the control state, bloodvolume was determined by the Evans blue dye (T-1824)method (20).

When possible, pulmonary "capillary" or "wedge" pres-sure was obtained during the third control, the third vaso-dilatation and the one postvasodilatation periods. Rightatrial pressure was recorded during vasodilatation onlyon those occasions when the catheter could not be placedin the pulmonary artery. Right atrial pressure wasroutinely recorded during removal of the catheter at theclose of the observations. Arterial hematocrits were ob-tained during the control period and again during thepostvasodilatation period. Blood oxygen capacity wasdetermined twice, once on samples pooled from the con-trol periods and the second time on samples pooled fromthe later vasodilatation periods. The corresponding val-ues were used to calculate arterial oxygen saturation forthe individual periods.

Even though Arfonad® was infused in small doses,ventricular filling pressure could not be lowered with-out a concomitant reduction in systemic arterial pres-sure. Therefore, the dose of the drug was carefullyregulated and the fall in systemic arterial pressure wasalways controlled. In hypertensive patients arterialpressure was lowered to normal, or slightly higher,levels; in normotensive subjects systolic arterial pres-sure was lowered to 100 to 110 mm. Hg. These pres-sures served as criteria for the desired degree of vaso-dilatation and were maintained for one hour. Circula-tory collapse and severe hypotension were specificallyavoided.

Calculations. Standard calculations were used, attimes modified as required by substitutions and assump-tions which led to the actual formulations used. Surface

558

VASODILATATION IN CONGESTIVE HEART FAILURE

area was always based on edema-free weight. Whenmeasured right atrial pressure was not available, its valuewas taken to be the corresponding right ventricular enddiastolic pressure minus the difference observed betweenright ventricular end diastolic pressure and right atrialpressure measured when the catheter was removed at theend of the observations. In occasional instances an avail-able right atrial pressure was substituted for an unavail-able right ventricular diastolic pressure. In calculationsrequiring pulmonary "wedge" pressure (pulmonary vascu-lar resistance and left ventricular minute and stroke work)the following substitutions were made in those periodswhere this measurement was not available: The singlevalue obtained during vasodilatation was used in calcula-tions for both the maximum vasodilatation period and theaverage of the vasodilatation periods; values obtained dur-ing the control period or the postvasodilatation periodwere substituted for each other when one of the measure-ments was not available.

The formulae used were: systemic vascular resistance=(SAm- RAm) . C.O.; pulmonary vascular resistance= (PAm- PCm) * C.O.; renal vascular resistance = (SAm- RAm)+ RBF. Vascular resistances are expressed asmm. Hg per L. per minute, since nothing is gained bythe more elaborate calculation into fundamental units.

Left ventricular minute work index = (SAm- PCm) XC.I. X 14.4 . 1,000; right ventricular minute work index= (PAm- RVd) X C.I. X 14.4 *. 1,000; stroke work in-dex = minute work index of corresponding ventricleX 1,000 V.R. Minute work index is expressed as Kg.M. per M.' per minute and stroke work index as Gm. M.per M.' per beat.

The symbols are defined as follows: SAm= mean sys-temic arterial pressure, mm. Hg; RAm= mean rightatrial pressure, mm. Hg; PAm= mean pulmonary arterialpressure, mm. Hg; PCm= mean pulmonary "wedge"pressure, mm. Hg; RVd = right ventricular end diastolicpressure, mm. Hg.

C.O. = cardiac output, L. per minute; C.I. = cardiacindex, L. per M.' per minute; RBF=renal blood flowin L. per minute = renal plasma flow + (1-Hct), whereHct = hematocrit, expressed as a decimal; V. R. = ven-tricular rate, per minute.

RESULTS

Subjects. Table I presents clinical informationregarding the 17 patients on whom 21 experi-ments were performed. The subjects have beendivided into four groups: Group I, congestiveheart failure-five normotensive and five hyper-tensive cardiac patients with typical clincial con-gestive heart failure indicated by low cardiacindices and high A-V oxygen differences; GroupII, partial cardiac compensation-two normoten-sive and two hypertensive cardiac patients clini-cally recovered from congestive heart failure by

appropriate therapy and without signs or symp-toms of heart failure but with below normalcardiac indices and A-V oxygen differences above6 volumes per cent; Group III, noncardiac andcardiac compensation-two noncardiac subjectsconvalescing from pneumonia and alcoholism,respectively, and three cardiac patients, onenormotensive and two hypertensive, fully com-pensated from congestive heart failure, receiv-ing maintenance doses of digitalis, without signsand symptoms of heart failure and with nor-mal cardiac indices and A-V oxygen differ-ences; Group IV, "normal output" congestivefailure- two subjects, one normotensive and onehypertensive, with signs and symptoms of con-gestive heart failure but with normal cardiacindices and normal arterial-mixed venous oxygendifferences. The four subjects, B.K., L.R., S.T.and E. S., who were studied twice, once duringcongestive heart failure and again after recoveryof compensation, appear in two groups accord-ing to their cardiovascular status on each occasion.

General response. There were no apparentdifferences between the subjects with congestiveheart failure and the compensated cardiac andcontrol subjects with respect to the amount ofArfonad® required to maintain vasodilatation, thespeed with which vasodilatation occurred and therapidity of return to the control state after stop-ping the drug (Table I). The dosage range was0.35 mg. to 1.25 mg. per minute with the usualdose between 0.5 mg. to 1.0 mg. per minute.Two subjects (J.H. and J.M.), both of GroupIII, required much larger amounts, 3.0 and 2.0mg. per minute, respectively. The rate of infu-sion of the drug was often increased by 0.25 mg.to 0.5 mg. per minute during the last half hour ofvasodilatation in order to prevent the blood pres-sure from rising above the desired level. Thetime required to reach the desired level of vasodila-tation varied considerably but averaged 25 to 30minutes. The control state was reached on anaverage of 30 minutes after stopping the infusion.

During the vasodilatation the subjects with con-gestive heart failure seemed somewhat improved.They were quieter, less restless and less complain-ing. Cerebration seemed less active and they evendozed. Respirations were often more shallowand irregular. Yawning occurred infrequently.

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When ventricular premature contractions werepreviously present they became less frequent.Similar reactions occurred in subjects withoutcongestive heart failure and, in addition, restless-ness, tension and "inside nervousness" were en-countered. After stopping the infusion of thedrug, the initial condition of the patient rapidlyreturned.

Presentation of data. The primary and deriveddata are too voluminous to be presented for allsubjects. The data presented are tabulated foreach group of subjects and give the following in-formation for each subject in a group: a) theaverage data of the control periods, b) the dataof the period of maximum change during vaso-dilatation, c) the average data of the vasodilata-tion periods, d) the data of the postvasodilata-tion period, then the average data for all subjectsof the group in the four categories above. Theaverage data of the control (a) and vasodilatation(c) periods are the averages of three periods ex-cept occasionally when experimental difficultiesreduced the number to two and once to one. Theperiod of maximum change during vasodilatationwas usually the first vasodilatation period andonly once later than the second. The differencebetween the average data of the three vasodilata-tion periods (c) and the data of the period ofmaximum change (b) indicates the failure of theinitial changes to be maintained throughout theperiod of vasodilatation. The shortcomings of thecomparison of individual data with average dataare recognized. However, the presentation per-mits comparison of average data from controlperiods with average data during vasodilatationand comparison of the single "maximum change"period with the single postdilatation period, per-mitting, thereby, several ways of examiningthe effects produced by vasodilatation. Theseabridged data present with validity the changesindicated by the complete data.

Vascular pressures, vascular resistances, ventricu-lar rate (Tables II to VII, Figures 1 and 2)

In all subjects of all four groups the blood pres-sure during Arfonad® infusion fell in the sys-temic circuit, the pulmonic circuit and right heart;remained at the lowered level, or rose slightly,during the hour of vasodilatation; and returned

FIG. 1. TYPICAL SERIAL DETERMINATIONSOF VASCU-LAR PRESSURESIN A REPRESENTATIVE SUBJECT (L.R.)WITH CONGESTIVEHEART FAILURE

Rate of intravenous infusion of Arfonad®, 0.8 mg. perminute. FA designates femoral artery pressure; VR,ventricular rate; PA, pulmonary artery pressure; "PC,"pulmonary "wedge" or "capillary" pressure; RVd, rightventricular end diastolic pressure.

to, or well toward, the control levels after stoppingthe infusion. Although the actual decreases inthe various systemic and pulmonic pressures weregreater when the control pressures were elevated,the percentile decreases were of the same orderof magnitude, usually between 20 and 30 per cent(Table VII), in both the greater and lesser circu-lations. An exception was the 60 per cent de-crease in pulmonary "capillary" pressure inGroups II, III and IV. Although the elevatedpressures due to congestive heart failure (rightatrial, right ventricular, pulmonary arterial andpulmonary "capillary") were lowered decidedly,they did not fall to the normal range. Qualita-tively and quantitatively the same degree of changein vascular pressures occurred in all four groupsof subjects, and within each group normotensiveand hypertensive subjects responded similarly.

Systemic vascular resistance decreased in allgroups of subjects by about 30 per cent duringvasodilatation and returned to control levels afterthe drug was discontinued. Exceptions were a10 per cent decrease in systemic vascular resis-tance in the noncardiac and compensated sub-jects (Group III). Pulmonic vascular resis-tance, on the other hand, decreased, again byabout 30 per cent, only in the the congestive heart

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FIG. 2. EFFECT OF INTRAVENOUS INFUSION OF AR-FONAD® ON VASCULARPRESSURESIN CONGESTIVEHEARTFAILURE AND IN CARDIAC COMPENSATION

The data are the average data for all subjects in eachgroup. For any line the first point is the average of thecontrol periods, the second point is the period of maxi-mumeffect during vasodilatation, the third point is theaverage of the vasodilatation periods, the fourth pointis the postvasodilatation period. In each panel the twohorizontal lines indicate the range of normal values.

failure group and increased in each of the otherthree groups.

Ventricular rate decreased during the vasodilata-tion by 5 to 10 per cent in all subjects except inGroup III where the rate tended to increaseslightly, by 5 per cent. Unlike the vascular pres-sures and resistances, ventricular rate tended to

remain below the control level after stopping theArfonad® infusion.

The data indicate a generally similar decreasein vascular pressures and resistances in all groupsof subjects, except for the changes in oppositedirection in pulmonary vascular resistance.

Respiration and metabolism (Tables II to VII,Figure 3)During vasodilatation the rhythm of respira-

tion frequently became irregular but in all fourgroups of subjects the respiratory rate remainedessentially unaltered. The minute volume of re-spiration showed inconsistent changes, tending todecrease slightly, 6 per cent, in subjects withheart failure (Group I) or partial compensation(Group II) and to increase by a comparableamount in noncardiac and compensated subjects(Group III). Except for lack of change in thetwo subjects with "normal output" failure (GroupIV), the metabolic rate decreased slightly, 6 to12 per cent, but consistently and significantly(p = < 0.01) in the other subjects during vaso-dilatation and returned to the initial level upondiscontinuing the vasodilator drug.

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FIG. 3. TYPICAL SERIAL DETERMINATIONS OF BLOODOXYGENCONTENTAND CARDIAC OUTPUT IN A REPRE-SENTATIVE SUBJECT (L.R.) WITH CONGESTIVE HEARTFAILURE

Rate of intravenous infusion of Arfonad®, 0.8 mg. per

minute. 02 Cons. designates oxygen consumption; Art.Sat., arterial oxygen saturation; C.I., cardiac index. Inthe third panel from the top are indicated the oxygencontent of blood of artery, top line; of mixed venous blood,lower line; and A-V oxygen difference, vertical con-necting lines.

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Cardiac output and blood oxygen contents (TablesII to VII, Figures 3 and 4)

During the fall in vascular pressures, cardiacoutput increased slightly, 15 per cent, but never-theless definitely and consistently (8 of 10 sub-jects) in both the normotensive and hypertensivesubjects in congestive heart failure (Group I). Theincrease appears significant: p value for the 10 sub-jects lies between 0.05 and 0.02. The increasesdid not, however, bring the cardiac outputs to nor-mal values. In contrast, cardiac output fell in fourof the five noncardiac and compensated cardiacsubjects (Group III) and remained unchanged inone. Statistically, the average fall of 18 per centappears significant: p value between 0.05 and0.02. The validity of these changes in cardiacoutput is indicated by the opposite, and againcontrasting, changes in arterial-mixed venous oxy-gen difference, a better index of cardiac functionthan cardiac output in that the A-V oxygen dif-ference relates the blood supply (cardiac output)to the need for it (oxygen consumption). Thus,in congestive heart failure (Group I), the A-Voxygen difference decreased by 22 per cent (pvalue significant, less than 0.01); but again thefinal values were not in the normal range. Incontrast, A-V oxygen difference in the compen-sated cardiac and noncardiac subjects (GroupIII) changed variably (rose in three, decreasedin one, unaltered in one) to give an average 5per cent increase (p value a not significant 0.3).Furthermore, the decrease in A-V oxygen dif-ference in congestive heart failure was associatedwith an average 5 to 10 per cent increase (p valuebetween 0.1 and 0.05) in oxygen content of mixedvenous blood. In contrast, an average 4 per centdecrease (p value between 0.1 and 0.05) in mixedvenous oxygen content occurred in the noncardiacand compensated subjects. The changes in A-Voxygen difference were similar in normotensiveand hypertensive subjects within a group.

As the period of vasodilatation progressed, thechanges in cardiac output, A-V oxygen differenceand oxygen content of mixed venous blood tendedto lessen and revert toward control values in thesubjects with congestive heart failure (Tables IIand III) but were better maintained at their alteredlevels in the compensated cardiac and noncardiac

L/M2/NUN

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8

VOL6

4

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0

A-V OXYGENDIFFERENCE

CHF IPARr.COMp COMP. a NON- CARD

3 1 vflNORMOTENSIVE

-- HYPERTENSIVE

FIG. 4. EFFECT OF INTRAVENOUS INFUSION OF AR-FONADOON CARDIAC OUTPUTAND A-V OXYGENDIF-FERENCEIN CONGESTIVEHEARTFAILURE AND IN CARDLACCOMPENSATION

Details of plotting are the same as those in Figure 2.

subjects (Table V). After withdrawal of Arfo-nad® these functions returned to control values inthe subjects with congestive failure but tended toremain at their altered values in the compensatedcardiac and noncardiac subjects.

In the partially compensated subjects (GroupII) the two hypertensive patients manifestedchanges similar to those in congestive heart fail-ure; the two normotensive subjects developedno changes, nor did the two patients with "normaloutput" heart failure (Group IV).

In all subjects and at all levels of arterial oxy-

gen content and arterial oxygen saturation, thereoccurred during vasodilatation a consistent fall(p value less than 0.01) in arterial oxygen con-

tent and oxygen saturation, amounting to 3 to 4per cent in the noncardiac and compensated sub-jects and 6 to 8 per cent in the other three groups.

These values returned well toward control levelsafter discontinuing the infusion of Arfonad®.

CARDIAC OUTPUT ({PEx)

565

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--NORMOTENSIVE ---OHYPERTEI

FIG. 5. EFFECT OF INTRAVENOUS INFUSFONADOON CARDIAC WORKIN CONGESTIVEURE AND CARDIAC COMPENSATION

Details of plotting are the same as in I

cept that the horizontal line separates thetwo ventricles and not the range of normalnumbers indicate subjects averaged for the a

greater in hypertensive than in normotensive sub-jects. Because of the small numbers of subjects

P. in the several groups, statistical analysis of thedata on cardiac work did not prove helpful.

LEFT In the one subject (hypertensive) with partialVENTRICLE compensation (Group II) vasodilatation resulted

in increases in minute work index (15 per cent)and stroke work index (25 per cent) of the leftventricle and decreases in both minute work in-

RIHT dex (15 per cent) and stroke work index (5 perVENTRICLE cent) of the right ventricle (Table IV). The

one (hypertensive) subject with "normal output"congestive failure (Group IV) developed markeddecreases in both minute work and stroke workindices of the left (30 per cent) and right (45

LENT per cent) ventricles (Table VI), a decided con-

trast with the results in low-output congestiveheart failure.

RIGHT Renal functions and water and electrolyte excre-VENTRICLE tions (Tables VIII to X, Figure 6)

NSIVE The changes in renal hemodynamic functionsSION OF AR- during vasodilatation were relatively small andHEARTFAIL- variable. Glomerular filtration rate altered slightly

and inconsistently in all groups, with decreasesFigure 2, ex- perhaps more frequent than increases. In sub-data for the jects with congestive heart failure (Group I)values. The renal plasma flow tended to increase (20 perLdjacent lines.

Cardiac work (Tables II to VII, Figure 5)

In the patients with congestive heart failure(Group I) minute work index and stroke workindex of both the left and right ventricle remainedessentially unchanged, or perhaps decreasedslightly, during the fall in vascular pressures andrise in cardiac output which accompanied vaso-

dilatation (Tables II, III and VII). The lowervalues tended to persist in the postvasodilatationperiod. In contrast, in the compensated cardiacand noncardiac subjects (Group III) both left andright ventricular minute work index and strokework index decreased, by 30 to 40 per cent, duringthe vasodilatation and tended to return to controlvalues in the postvasodilatation period (TablesV and VII). Hypertensive and normotensivesubjects in congestive heart failure had largelysimilar and equal responses (Figure 5). In thecompensated cardiac and noncardiac subjects, thedecreases in both cardiac work indices were

FIG. 6. TYPICAL SERIAL DETERMINATIONS OF RENALHEMODYNAMICSAND SODIUM AND WATEREXcRETIONSIN A REPRESENTATIVESUBJECT (L.R.) WITH CONGESTIVEHEARTFAILURE

Rate of intravenous infusion of Arfonad®, 0.8 mg. perminute. RPF designates renal plasma flow; GFR, glo-merular filtration rate; FF, filtration fraction.

z

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570


TABLE VIII

Effects of Arfonad ( on renal hemodynamics and urinary excretions: Congestive heart failure

Glomer- Renal Renalular Renal Filtra- Renal fraction vascular Urinary Urinary

filtration plasma tion blood of cardiac resist- Urine sodium potassiumPatient* rate flow fraction flow output ance output excretion excretion

ml./mis. mi./min. % ml./min. % mm. Hg ml./min. ;&Eq./min. pEq./min.L./min.

G. L. Avg. Cont.(1) Max. Vasod.

Avg. Vasod.Post Vasod.

B. K. Avg. Cont.(1) Max. Vasod.


L. R. Avg. Cont.(2) Max. Vasod.


R. H. Avg. Cont.(2) Max. Vasod.


B. K. Avg. Cont.(1) Max. Vasod.


S. T. Avg. Cont.(2) Max. Vasod.


165214156203

Normotensive patients262 9.9340 11.5248 10.3322 15.4

54 162 33 337 11.951 180 28 375 9.553 184 28 384 11.7

Hypertensive patients71 156 4651 162 3276 200 37

264381328254

60 125 46 223 8.676 157 48 280 14.474 138 54 247 11.769 131 52 234 9.1

376 0.4 <0.2 26176 0.7 <0.2 34284 0.5 <0.2 26273 0.6 <0.2 38

289 0.9 5 53200 0.6 1 46207 0.8 2 54

73375045

1.4 1870.3 <100.7 300.6 29

1.1 1011.1 1440.8 1150.8 102

430 0.9 is 5243 0.8 7 5320 0.9 4 5355 0.9 8 5

17 59 29 77 1.6 1,562 2.0 187 2814 53 26 72 1.2 1,194 1.1 83 2613 54 23 74 1.3 1,228 1.1 85 3020 60 34 82 2.0 1,366 1.7 134 44

1.1 82 37(5)

0.8 41 30(60.8 46 33(5)0.9(6) 73(5) 33(4)

B. 0. Avg. Cont.(1) Max. Vasod.


"Normal output" congestive heart failure56 162 34 249 6.1 410 5.6 867 <3035 138 25 212 4.7 259 0.4 65 1640 162 25 248 5.3 236 0.7 106 2650 165 30 254 8.6 295 3.0 514 48

* For each subject the data are: first row, average of all control periods; second row, period of maximum effect; thirdrow, average of all vasodilatation periods; fourth row, postvasodilatation period. Number under initials of patientsindicates period of maximum effect of Arfonad

t Averages are for six patients except as otherwise indicated by superscript numbers in parentheses.

cent) and similar, if slightly less marked, risesoccurred in renal blood flow and in the renalfraction (Tables VIII and X). No similarchanges occurred in the other three groups of sub-jects, where decreases in these three renal hemo-dynamic functions were more common thanincreases. However, consistent decreases in filtra-tion fraction, 10 to 15 per cent, and in renal vascu-

lar resistance, 15 to 30 per cent, occurred in allfour groups of subjects and to approximately the

same extent. In the few patients studied no dif-ference was noted between the normotensive andhypertensive subjects.

In all four groups the renal excretion of waterand sodium, and less markedly and regularly ofpotassium, decreased during the period of vaso-

dilatation, usually by about 30 per cent, but byas much as 80 to 90 per cent for water and so-

dium when their initial excretions were large.The decrease in urine volume was usually associ-

Avg.6

Pts.t

Avg. Cont.Max. Vasod.Avg. Vasod.Post Vasod.

50(4) 15548(4) 19154(4) 17745(2) 162(4)

38 (4) 225(4)33(4) 267(4)36(4) 238(4)43(2) 213(3

8.0(4) 664(4)9.2(4) 453(4)8.8(4) 510(4)8.9(3) 664(3)

571


ated with a decrease in glomerular filtration butfalls in electrolyte excretion occurred without ap-

preciable changes in glomeruluar filtration. Thewater and electrolyte excretions remained de-creased, at least to some degree, during the post-vasodilatation period, when cardiovascular dy-namics had already returned to, or well toward,control values.

DISCUSSION

On the whole the patients, even with severe

congestive heart failure, tolerated surprisinglywell the irksome and long procedures imposedby this study. The complexity of the procedures,the variations in circulatory state between pa-

tients even of the same group, and the difficultyof obtaining a similar circulatory state or changeof state during vasodilatation probably contributedto the variability of the data obtained. This var-

iability and the relatively few subjects studied donot permit strict quantitative relationships to bedrawn between the various functions. Neverthe-less, the qualitative changes which emerged ap-

pear valid.

Nature of the cardiovascular and renal responses-during vasodilatation

The present observations substantiate previ--ously reported studies, usually of individual or-few functions, which indicate that primary vaso-

dilatation, induced by various vasodilating agents,.produces changes similar to those here observed:decreases in pressure in all parts of the compen-

sated circulatory system in both normal and hy-pertensive circulations (23-26) and in congestiveheart failure (23-25, 27-29), a rise in cardiac out-put in congestive heart failure (23-25, 27) buta fall in output in the normal circulations (23,25, 26) and a decrease in water and electrolyteexcretions, associated with inconsistent changesin renal hemodynamics, in all circulatory states-(23, 25, 26, 30, 31). Through repeated, inte-grated and simultaneous determinations of mul-tiple functions, the present observations permita more direct correlation of the changes in the-several functions.

One question in the present study was to ex-amine whether differences in vascular tonus be-tween normal and congested circulations mightbe disclosed by the need for different amounts of

ILE IX

Effects of Arfonad® on renal hemodynamics and urinary excretions: Noncardiac subjects andpartially compensated cardiac patients


filtration plasma tion blood of cardiac resist- Urine sodium potassiumPatient* rate flow fraction flow output ance output excretion excretion

ml./min. ml./min. % ml./min. % mm. Hgl ml./min. Eq./min. gI&.min..L./min.

Noncardiac control subjectL. K. Avg. Cont. 102 539 19 842 16.1 124 0.5 134 41(1) Max. Vasod. 100 584 17 885 21.2 106 0.4 60 46

Avg. Vasod. 104 571 18 866 18.4 99 0.4 64 45Post Vasod. 113 581 19 881 18.1 111 0.6 30 33

Normotensive partially compensated cardiac patientJ. J. Avg. Cont. 67 209 32 362 13.5 299 1.2 83 61(1) Max. Vasod. 61 196 31 356 12.6 275 1.0 73 51

Avg. Vasod. 66 214 31 390 14.2 252 1.1 76 56Post Vasod.

Hypertensive partially compensated cardiac patientL. R. Avg. Cont. 101 251 41 6.3 619 79(1) Max. Vasod. 56 157 36 0.4 28 43

Avg. Vasod. 70 211 34 0.4 19 56Post Vasod. 1.1 74 80

* For each subject the data are: first row, average of all control periods; second row, period of maximum effect; thirdrow, average of all vasodilatation periods; fourth row, postvasodilatation period. Number under initials of patients-indicates period of maximum effect of Arfonad®.

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TABLE X

Renal hemodynamic and urinary effects of Arfonad®0: Percentage changes from average control values *


filtration plasma tion blood of cardiac resist- Urine sodium potassiumPeriodst rate flow fraction flow output ance output excretion excretion

ml./min. ml./min. % ml./min. % mm. Hg/ ml./min. pEq./min. sEq./min.L./min.

Group I. Congestive heart failure (6 patients)Avg. Cont.-Max. Vasod. - 4 +23 -13 +19 +15 -32 -31 -50 -19Avg. Cont.-Avg. Vasod. + 8 +1 - 5 + 6 +10 -23 -32 -44 -11Avg. Cont.-Post-Vasod. -10 + 4 +13 - 5 +11 0 -20 -11 -11

Group II. Partial compensation (2 patients)Avg. Cont.-Max. Vasod. -30 -23 - 6 - 2 - 7 - 8 -81 -86 -33Avg. Cont.-Avg. Vasod. -19 - 8 -11 + 8 + 5 -16 -80 -86 -20Avg. Cont.-Post-Vasod. -71 -79 +14

Group III. Noncardiac control and compensation (1 patient)Avg. Cont.-Max. Vasod. - 2 + 8 -10 + 5 +32 -14 -30 -55 +12Avg. Cont.-Avg. Vasod. + 4 + 6 - 5 + 3 +14 -20 -26 -52 +10Avg. Cont.-Post-Vasod. +13 + 8 0 + 5 +12 -10 +13 -78 -19

Group IV. "Normal output" congestive heart failure (1 patient)Avg. Cont.-Max. Vasod. -38 -15 -26 -15 -23 -37 -93 -92Avg. Cont.-Avg. Vasod. -29 0 -26 0 -13 -42 -88 -88Avg. Cont.-Post-Vasod. -11 + 2 -12 + 2 +41 -28 -47 -41

* The data are averaged data for the patients in each group and are percentage values to the nearest whole number.t The analysis represents, for each group, the percentage change from the average of the control values (avg. cont.)

as follows: first row, period of maximum effect (max. vasod.); second row, average of all vasodilatation periods (avg.vasod.); third row, postvasodilatation period (post-vasod.).

vasodilator agent in the two states. The data donot provide an answer. The two noncardiac sub-

jects required the largest amounts of ArfonadDused. The same amount of Arfonad@ appearedto produce larger actual falls in vascular pressures

in congestive heart failure but the percentilechanges in pressure were as great, and even

greater, in the normal circulations, particularly inregard to residual or filling pressures.

The fall in systemic and renal vascular resis-tances during both rising and falling cardiac out-puts and in both the normal circulation and incongestive heart failure indicates that Arfonad@produced primary vasodilatation of the systemicvascular circuit. A similar fall in pulmonaryvascular resistance in congestive heart failure sug-

gests a primary dilatation of the pulmonary vascu-

lature and not solely a redistribution of blood fromthe pulmonary vascular bed into the concomitantlydilating systemic vessels (32). ArfonadD isconsidered to be primarily a ganglionic blockingagent and the decreases in vascular resistancesmay, at first, be taken as evidence that the vaso-

dilatations are of neurogenic origin. However, a

direct dilator action of Arfonad® on blood ves-sels has been reported (13). The data cannot,therefore, resolve the question of the existence ofsympathetic innervation of the pulmonary ves-sels. This is particularly so since pulmonaryvascular resistance actually rose in the more nor-mal circulations (Group III), presumably in re-sponse to the distribution of blood away from thelung into the systemic vascular bed.

No explanation is apparent for the unexpectedfall in oxygen consumption during vasodilatation,unless the drug actually lowers the metabolic rate.It is also possible that tissue metabolic rate didnot change and that the observed low pulmonaryuptake of oxygen was supplemented by additionaland unaccounted oxygen from other sources. Nosuch sources are apparent.

The consistently lowered arterial oxygen con-tent during vasodilatation was associated with nosignificant change in respiratory rate or minutevolume of respiration. Accordingly, it is unlikelythat impaired alveolar ventilation with decreasedalveolar oxygen tension was responsible for thearterial unsaturation. An intriguing possible ex-

573


planation might be the opening up during vaso-dilatation of communications between pulmonaryarterial and pulmonary venous channels, by pass-ing the alveoli and permitting a greater degree ofvenous admixture.

Since hypoxia has been shown to induce hemo-dynamic effects, the fall in arterial oxygen satu-ration during vasodilatation introduces a compli-cating factor in the analysis of the results obtained.In noncardiac subjects, arterial oxygen satura-tion down to 80 or 82 per cent is tolerated withoutchange in cardiac output, while hypoxia of greaterdegree causes an increase in cardiac output(33-35). In the present 21 observations arterialoxygen saturation during vasodilatation fell to 82per cent or below only six times; 12 times thesaturation remained above 85 per cent and threetimes above 90 per cent. It appears unlikely thatthis degree of hypoxia influenced the cardiac out-put in the noncardiac and compensated cardiacsubjects. Two further points support this con-clusion: The change in cardiac output during thehypoxia was opposite (a fall) to the expected in-creases induced by significant hypoxia and the de-gree of change in cardiac output was not related tothe extent of fall in arterial oxygen saturation.Data indicating the effect of hypoxia on cardiacfunction of patients with congestive heart failurewere not located. In the present study the in-crease in cardiac output during vasodilatation incongestive failure patients is considered to be un-affected by the associated hypoxia, largely for thereason already cited, but particularly because theinduced hypoxia was rarely down to 80 per centarterial oxygen saturation and because the changesin cardiac output were much the same whetherarterial oxygen saturation fell considerably (to82 per cent) or only minimally (to 88 per cent).

Comparison of effects produced by vasodilatationwith effects produced by digitalis

In congestive heart failure, some of the effectsproduced by intravenously administered Arfo-nad® were strikingly similar to the effects whichfollowed intravenous administration of digitalisglycosides (9, 21). In each instance there oc-curred: rapid onset of effect, fall in intracardiacpressures, decrease in vascular resistances, somedecrease in heart rate, increase in cardiac output,

decrease in A-V oxygen difference, slight de-crease in oxygen consumption and slight de-crease in arterial oxygen content and saturation.Single therapeutic doses of the glycosides gener-ally produced more marked effects than those hereevoked by primary vasodilatation, but in individualinstances ArfonadD produced just as marked re-sults as digoxin. There were, however, im-portant differences in the results produced by thetwo drugs. The hemodynamic effects producedby the digitalis glycoside were sustained, whereasthe responses induced by the vasodilator drug didnot outlast its infusion and even tended to de-crease toward the later part of the infusion.Digoxin did not lower systemic arterial pres-sure and usually increased it slightly. Accord-ingly, during the action of digoxin the lower-ing of intracardiac filling pressures was associatedwith increased cardiac minute and stroke work,in contrast to the unchanged cardiac work notedduring the vasodilator action of Arfonad@. Thehemodynamic effects produced by digitalis gly-cosides were, therefore, consistent with Starling'slaw; the effects produced by Arfonad® were per-haps not. The differences in cardiac work pro-duced by the two drugs permit speculation re-garding a possible difference in primary action ofthe drugs in congested failing circulations: theglycosides affecting heart muscle directly to in-crease myocardial action and produce greater work,the vasodilator agent apparently having no directmyocardial effect but permitting the unalteredheart muscle to eject more blood against thelowered vascular resistance.

The renal effects of the two drugs were instriking contrast: A diuresis of water and electro-lytes followed administration of digoxin, whereasArfonad® produced a reduction in water andelectrolyte excretion. This difference in urinaryexcretions occurred even though both drugs in-duced similar slight, but inconsistent, alterationsin renal hemodynamic functions. In view of thereported decreased urinary excretion of water andelectrolytes when renal venous pressure is raised(36-38), a reduction of elevated renal venouspressure, such as probably was produced by Arfo-nad®s, would be expected to produce an increasedrenal excretion of water and electrolytes-as wasthe case with digoxin. The falls in systemicarterial pressure were not so great as to jeopar-

574


dize glomerular filtration pressure. Further-more, in animal experiments, diureses have beenreported following removal of sympathetic in-nervation of the kidney (39). In view of theserelated findings the absence of a diuresis followingArfonad® is contrary to expectation and remainsunexplained.

Cardiovascular changes during vasodilatation andStarling's law

Although the circulation, as measured by cardiacoutput and A-V oxygen difference, improvedwhen the high intracardiac filling pressures in con-gestive heart failure were lowered, and becameimpaired, in the majority of instances, when thenormal ventricular filling pressures of noncardiacand compensated cardiac subjects were decreased,these changes are not evidence that Starling'slaw was fulfilled (40). Moreover, there was adiscordant observation: Often in congestive heartfailure the increase in cardiac output, which oc-curred when the elevated filling pressures werefirst lowered, tended not to persist and cardiacoutput gradually decreased even though ventricu-lar filling pressures remained at their loweredlevels.

When Starling's law is considered in its cor-rect terms of cardiac work, it appears that cardiacwork did not increase when the elevated intra-cardiac filling pressures of congestive heart failurewere lowered. In both normotensive and hyper-tensive patients with congestive heart failure, min-ute work index and stroke work index of both theleft and right ventricles remained essentially un-changed as ventricular filling pressures fell. Inthe normotensive and hypertensive compensatedcardiac patients and the noncardiac subjects thefall in intracardiac filling pressures was ac-companied by the expected decreases in minutework index and stroke work index of both theleft and right ventricles.

The interpretation of these changes in heartwork in reference to Starling's law is rendereddifficult, perhaps impossible, by the occurrence inthe present observations of the fall in arterialpressures, both systemic and pulmonic. Sincecardiac work is a function of both cardiac outputand the arterial pressure against which the outputis ejected, a reduction in arterial pressures repre-

sents an influence toward decreased cardiac work.Thus, in the patients with congestive heart fail-ure, the tendency for cardiac work to increase asa result of the greater cardiac output was offsetby the lowering of arterial pressures and cardiacwork remained essentially unchanged. In thecompensated cardiac and noncardiac subjects thelowered arterial pressures had a greater influencein reducing the cardiac work than the observedsmall decreases in cardiac output.

Since the present experimental procedureslowered the pressures on both sides of the ven-tricles, it was not possible to determine the effectof changes in intracardiac filling pressures alone,as a test of Starling's law requires. However,if one accepts the work equation as a correct rep-resentation of the work performed by the heartand accordingly accepts the basic concept thatwork as calculated is equivalent irrespective ofthe differences in the individual components enter-ing into work, then the present conditions of con-comitantly lowered arterial pressures offer no barto the application of a general principle, and henceof Starling's law. This argument would also ac-cept as no bar the consideration that for the samecalculated work, the heart tolerates (i.e., lower myo-cardial oxygen consumption and energy expendi-ture for the same amount of external work) flowwork better than pressure work. Accepting thesebasic concepts, then the present observations sug-gest that Starling's law applies when ventricularfilling pressures are normal but not when ven-tricular filling pressures are elevated. An alterna-tive interpretation would stress the decidedly dif-ferent changes in cardiac work in the twocirculatory states, in relation to each other. Thus,the unchanged cardiac work during the loweringof the elevated filling pressures in congestiveheart failure represents a better cardiac perform-ance (a relative increase in work) than the de-creased cardiac work associated with the fall inthe normal ventricular filling pressures of the nor-mal circulation. Such an interpretation suggeststhat Starling's law applies in the failing as wellas in the nonfailing circulations. However, thisintepretation requires that the measurements inthe patients with congestive heart failure weremade at the flat portion of the cardiac work-fill-ing pressure curve, where no change in work oc-

575


curs upon lowering of the filling pressure. Italso requires that all 10 patients with congestiveheart failure had cardiac functions of similar de-grees of insufficiency-even when the degrees ofcongestive failure, as clinically evaluated, variedfrom relatively mild to very severe. Finally,this interpretation is not entirely consistent withthe observed increase in cardiac output and workwhich occurs when patients with congestive heartfailure recover compensation (22).

It is apparent that the observations in both thefailing and nonfailing circulation can be inter-preted as consistent with Starling's law, but in thefailing circulations only if certain assumptionsare made regarding the state of the congestive fail-ure in the clinical material. It is apparent, too,that the whole issue requires observations madeunder conditions of unchanging arterial pressures.

"Beneficial" effect of peripheral vasodilatation incongestive heart failureThe observation that primary vasodilatation in

congestive heart failure results in an increasedblood flow (cardiac output) without an increasein cardiac work suggests clinical and therapeuticapplications (41). Presumably lowering the pres-sure against which the heart must eject blood per-mits an impaired myocardium to circulate moreblood without an intrinsic improvement in its con-tractile activity. Such a result can be consideredof advantage to the circulation in that the supplyof blood to the various organs can be increased,even when the failing myocardium is not capableof improvement and greater work. However, thepresent observations deal with short periods oftime (one hour) and in some instances the in-creased cardiac output was not sustained for theentire interval of lowered vascular pressures. Ac-cordingly, no extrapolation of the acute effectshere observed to chronic vasodilatation in conges-tive heart failure is intended. Furthermore, shouldthe acute decrease in urinary excretions, here pro-duced by Arfonad@, persist during chronic vaso-dilatation, the long term effect of this vasodilatoragent could be undesirable.

SUMMARY

1) Primary peripheral vasodilatation for onehour was produced by the intravenous infusion of

the ganglionic blocking agent Arfonad@ in 12cardiac subjects during congestive heart failure, inseven cardiac subjects after recovery of compensa-tion and in two noncardiac subjects.

2) In all subjects vascular and intracardiac pres-sures were lowered, by 20 to 30 per cent, in boththe systemic and pulmonic circulations.

3) In 8 of 10 subjects with low output conges-tive heart failure the lowering of vascular pressureswas associated with an increase in cardiac outputof approximately 15 per cent. Since the oxygencontent of mixed venous blood rose and A-V oxy-gen difference fell, the increase in cardiac outputwas considered a valid one.

4) In four of five noncardiac and compensatedcardiac subjects the lowering of vascular pres-sures resulted in a decrease in cardiac output(approximately 15 per cent), a fall in oxygencontent of mixed venous blood and a small risein A-V oxygen difference.

5) In all groups of subjects peripheral vaso-dilatation was accompanied by consistent de-creases in the excretion of water and sodium,while renal hemodynamic functions changed vari-ably and slightly.

6) The effects were similar in hypertensive andnormotensive subjects.

7) Because of the fall in arterial pressuresagainst which the heart ejected blood, the in-crease in cardiac output during vasodilatation inthe patients in congestive heart failure was achievedwithout increase in cardiac minute or stroke work.In the noncardiac and compensated cardiac sub-jects minute and stroke work of the heart de-creased during vasodilatation and this decreasewas due more to the fall in arterial pressure thanto the decrease in cardiac output.

8) The fall in arterial pressures in the presentobservations makes it difficult, if not impossible, todetermine whether Starling's law of the heart ap-plies to the hemodynamic effects produced byperipheral vasodilatation. If one accepts the con-dition of altered arterial pressures, then Starling'slaw may be considered to have held in the non-cardiac and compensated cardiac circulations butnot in congestive heart failure, unless one as-sumes that cardiac function in all of these pa-tients was on the flat portion of the cardiac work-filling pressure curve.

9) ArfonadD given intravenously in congestive

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heart failure produced effects similar to digitalisglycosides with respect to decreased intracardiacpressures, increased cardiac output and decreasedA-V oxygen difference. However, following di-goxin, cardiac work increased and a diuresis ofwater and electrolytes was produced, whereasafter Arfonad®, cardiac work remained unalteredand water and electrolyte excretions decreased.

10) It is not clear whether the increase in bloodflow without increase in cardiac work, which fol-lows peripheral vasodilatation by Arfonad®, isof benefit to the circulation in those states wherethe heart is so impaired that myocardial activitycannot be intrinsically improved.

ACKNOWLEDGMENTS

The authors wish to thank Mrs. Lydia Tucker, Mrs.Edna Weinick, Miss Shirilyn Shulman, Miss EileenMaticka and Mr. Flavio Amerio for their careful tech-nical assistance, without which these observations couldnot have been made.

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