EDEMAAND DECREASEDRENALBLOODFLOWIN PATIENTSWITH CHRONICCONGESTIVEHEARTFAILURE: EVIDENCE

OF "FORWARDFAILURE" AS THE PRIMARYCAUSEOF EDEMA1

By A. J. MERRILL

(From the Medical Sertice of Grady Hospital and the Department of Medicine, EmoryUniversity School of Medicine, Atlanta)

(Received for publication November 14, 1945)

During the course of chronic congestive heartfailure it is known that patients retain salt andwater. It seems evident that this is not due toforcing of fluid into the tissues by an increasedhydrostatic pressure, since such a mechanismwould result in hemoconcentration, whereaschronic heart failure produces hemodilution (1,2). Furthermore, Warren and Stead haveshown that in chronic congestive failure the weightgain and blood volume increase precede the risein venous pressure (3). This fact points to arenal factor in heart failure, and the results of aninvestigation of this factor by some of the newertechniques (4) is the subject of this paper.

Patients were chosen with chronic congestivefailure requiring mercurial diuretics at frequentintervals to maintain compensation. This groupwas selected because they tended to become edem-atous at bed rest when diuretics were withheldand, therefore, would be expected to show at bedrest whatever abnormality was responsible fortheir edema. Many patients with heart diseasewho have become decomnpensated when active showno abnormality of the circulation at rest. Suchpatients would therefore not be expected to showany disturbance in function leading to a retentionof salt and water unless observations were madeduring exertion.

METHODS

Patients with hypertension or obvious renal disease areexcluded from the discussion in the text but a few hyper-tensive individuals are included in Table I and Figures 1,2 and 3 for comparison.

Because of orthopnea most patients required a 10 to 20degree elevation at the head of the bed, and to rule out

1 The work described in this paper was done under acontract, recommended by the Committee on MedicalResearch, between the Office of Scientific Research andDevelopment and the Emory University School of Medi-cine, Atlanta.

this factor two subjects with failure were studied flat andat an elevation of 60 degrees. The renal blood flow andfiltration rate, instead of falling as in a normal individual(5), remained the same.

The renal plasma flow and filtration rate were studiedwith sodium para-amino hippurate2 and inulin as de-scribed by Smith et al. (4). Observations were madeafter a 6- to 8-hour fast. Each patient was given 2glasses of water 30 minutes before, and phenobarbital 0.03grams an hour before, the test. Priming doses of inulinand hippurate, calculated to give extracellular fluid andblood levels of approximately 2 mgm. per cent hippurateand 50 mgm. per cent inulin were administered. A sus-taining venoclysis, which contained sufficient inulin andhippurate to maintain constant blood levels, was deliveredat the rate of 4 ml. a minute. Forty minutes were al-lowed for equilibrium to be established between plasmaand extracellular fluid. The bladder was then emptiedthrough a catheter (4-hole when possible) by injectionof 10 ml. of air and aspiration with a 50 ml. syringe. Theair was reinjected, and urine and air expressed with pres-sure over the bladder. Then 20 ml. of distilled waterfollowed by 30 ml. of air were introduced and aspirated.Finally, the air was reinjected and all possible residueexpressed with bladder pressure alone. This entire ma-neuver occupied a period of one and a half minutes.Three or four 15-minute samples of urine were obtainedand venous blood specimens were drawn at the mid-point.This blood was collected using metycaine as. a local anes-thetic since novocaine gives the same color reaction ashippurate with the coupling reagent. It was found thatintroducing a needle through a novocaine wheal yieldedanswers 4 or 5 times the true values. Patients receivingany sulfonamide preparation were excluded from thestudy because these drugs also contain the para-aminoradical. The cells were separated from the plasma bycentrifugation within an hour after collection of the blood.In man, we have not found it necessary to separate andprecipitate the plasma immediately between collection pe-riods, though Smith advises this in dogs because para-amino hippurate enters their red blood cells. Two ml.portions of plasma were precipitated by the cadmiumsulfate-sodium hydroxide method and the plasma para-amino-hippuric acid level determined by a modification ofthe Bratton-Marshall technique for sulfonamides (6).

2 Para-amino hippurate was supplied through the cour-tesy of Dr. John Henderson of Sharpe and Dohme.

389

A. J. MERRILL

One ml. portions were precipitated with acid zinc sulfate,and inulin determinations were made by the method ofCorcoran and Page (7). Urine was diluted in volumetricflasks to a urine to plasma ratio of approximately one.This was done in 2 steps, the first dilution being used forinulin determinations and the second for hippurate, start-ing with 5 to 10 ml. of urine measured from an accuratepipette. Standards for inulin and hippurate were madeup from dilutions of the original ampules and were treatedin the same manner as the unknowns. Standards were notmade up from dried free acid and from dried inulin, sinceit is the urine to plasma ratio which determines the clear-ance, and exact quantitation is not necessary. All urineand blood specimens were run in duplicate and usuallyagreed within 2 per cent, with occasional variations of 4per cent.

The gravimetric uranyl zinc acetate method as de-scribed by Butler and Tuthill (8) was used to determinethe blood sodium. Each determination was run in dupli-cate and all duplicates at variance more than 2 m.eq.were discarded.

The cardiac output was determined in some of thepatients usually within a few days of, and sometimes simul-taneously with, the renal studies. The direct Fick prin-ciple was employed, utilizing a radiopaque ureteral cathe-ter passed from the cubital vein to the right atrium underfluoroscopic control (9). Arterial blood was obtainedfrom an inlying needle with a stylette in the femoral ar-tery. The oxygen consumption was measured by theanalysis of a 2-minute sample of expired air collectedin a Douglas bag.

Venous pressures were estimated with a No. 19 needleconnected to a glass manometer filled with normal saline,using a point 5 cm. below the 4th right costochondraljunction for a base-line, and atrial pressures were meas-ured from the same point. Measuring from the backwas not feasible on our bed (10).

RESULTS

All results were corrected to a body surfacearea of 1.73 square meters to make them compar-able. Thirty-nine studies on thirty-five normal in-dividuals without evidence of renal di*ease or hy-pertension gave average figures of 626 ml. perminute per 1.73 square meters for the renal plasmaflow, 123 ml. per minute for filtration rate, and20.6 per cent for the filtration fraction. The meanvalue for renal plasma flow was 626 ± 165 ml.per minute per 1.73 square meters; for filtrationrate, 129 ± 40 ml. per minute per 1.73 squaremeters excluding three patients who were far outof line. We did not find the filtration fraction(RPF/FR) so constant as did Goldring and Chas-sis (11), the mean being 20.6 + 5.6 per cent.Eight patients had filtration fractions outside of20 per cent + 5. Two of the latter were studied

a second time with essentially the same results.It is possible that some of our patients were ab-normal as many came from the older age groups.The wide variation of the renal plasma flow andfiltration rate is partially accounted for by thefact that both males and females are included.The means of Goldring and Chassis were 697 ±135.9 ml. per minute per 1.73 square meters renalplasma flow for males, and 594 ±+102.4 ml. perminute for females; 131+ 21.5 ml. per minute per1.73 square meters filtration rate for males, and117 ±+15.6 ml. per minute per 1.73 square metersfor females. The mean filtration fraction was 20

- 0.03 per cent (11).In the patients with chronic failure the renal

plasma flow was reduced to one-third to one-fifthnormal. The filtration rate was one-half to one-third normal, giving filtration fractions rangingfrom 30 to 50 per cent (Table I). The filtrationfraction is obtained by dividing the filtration rateby the renal plasma flow. It represents the per-centage of the renal plasma flow which is filtered.High values indicate a high filtration pressure,probably most frequently due to efferent arteriolarconstriction (12).

Figure 1 shows the results of renal studies incardiac failure on the same and different subjectsat various venous pressures. There is no signi-ficant correlation between venous pressure levelsand inulin and hippurate clearances. In many pa-tients these studies were repeated after the venouspressure was lowered by mercurial diuretics. Therenal blood flow remained low despite the changein venous pressure. An increase in renal bloodflow in some patients was observed when digitaliswas given, or. when .the cardiac output increasedduring the period of observation. For this reasona decrease in venous pressure was at times as-sociated with a rise in renal plasma flow. Two pa-tients with acute failure had a normal cardiac out-put at rest and a normal renal plasma flow despitea high venous pressure. These patients made arapid recovery. The lack of correlation betweenthe venous pressure and the renal blood flow iseven more evident in these patients with acutefailure.

Figure 2 shows the correlation between the re-nal plasma flow and the cardiac index. The car-diac index is the cardiac output per square meterof body surface area, and the normal range in our

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FIG. 1. RENAL PLASMA FLOW AT VARIOUS VENOUSPRESSURELEVELS IN PATIENTS WITH CONGESTIVEHEARTFAILURE

Correlation coefficient r = - 0.1750. Pr is greater than 0.10, indicating no significant correlation.

laboratory is 2.3 to 4.1, with an average of 3.3liters per square meter per minute (13). In gen-

eral the renal plasma flow tended to fall as thecardiac index decreased. Two patients, G. H. andN. G., had a normal cardiac index with a low renalblood flow. It is possible that they had renal di-sease although this was not investigated.

From Figure 2 it is obvious that in many of thepatients the absolute figure for the cardiac indexis within the normal range. As pointed out pre-

viously there is no absolute level of the cardiacindex below which patients develop cardiac fail-ure (14). The cardiac index must be consideredin relation to the metabolic needs of the subject.Thus patients with thyrotoxicosis may have car-

diac failure with an output that is far above thenormal resting level, but one which is inadequatefor the increased metabolism. In many patientswith cardiac failure and dyspnea the metabolicrate is increased. In these subjects the cardiacindex may be in or above the normal range forresting subjects and heart failure still be present.

That the circulation was not optimum for theneeds of our patients is shown by the increasedarteriovenous oxygen differences. Figure 3 showsthe renal blood flow plotted against the arterio-venous oxygen difference. In the great majorityof the patients studied the arteriovenous differ-ence was increased beyond the average normalvalue of 4 volumes per cent found in this labora-tory (13), and that of 4.5 volumes per cent foundin another laboratory (15).

The amount of sodium filtered was calculatedfrom the product of the filtration rate times theblood sodium level. The amount of sodium ex-

creted was calculated directly from the urine so-

dium, and the difference represents the amountresorbed. Twelve normals were studied and theyshowed an average value of 18.09 m. eq. sodiumfiltered per minute, 0.22 m. eq. excreted, and 1.23per cent of filtered sodium excreted. In the pa-

tients with heart failure, one may see there was a

definite decrease in the amount of sodium filtered,due to the low filtration rate (Table II). The

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FIG. 2. RENAL PLASMA FLOW CORRELATEDWITH CARDIAC INDEX IN PATIENTS WITH CONGESTIVE FAILURECorrelation coefficient r = 0.6393. Pr is less than 0.10, indicating a high degree of correlation.

amount of sodium excreted per minute is also di-minished. The percentage of the filtered sodiumexcreted is related to some interesting factorswhich bear upon the control of sodium excretionin normal individuals. Experiments clarifyingthese relationships have been done and will be re-

ported in a separate communication.

DISCUSSION

The reduction in renal blood flow in patientswith chronic heart failure is so marked that thequestion immediately arises as to whether or notthe method is valid in heart failure. The methodis dependent upon the almost complete removal ofhippurate in a single passage through the kidney.To see if this occurred in heart failure, blood was

obtained by passing a catheter into the renal veinof cardiac patients in whom the renal blood flowwas being measured by the hippurate technique(16). The hippurate concentration in this bloodwas compared with that of the arterial blood col-lected simultaneously. The results in Table I in-

dicate a normal clearance even in patients withsevere heart failure. The calculations for the renalplasma flow were corrected to the average clear-ance figure of 88 per cent in the two cases inwhich the clearance was distinctly below normal.One of these, L. H., had severe pyelonephritisin addition to his heart failure. The other, J. C.,died of multiple pulmonary infarctions. Autopsyshowed only severe renal congestion and edema.As may be seen, two of the most severe cases offailure, M. R. and S. H., cleared normally. Sey-mour et al. (2) found normal renal tubular con-

centrating ability in patients with failure. VanSlyke et at. (17) showed that in shock the renalblood flow could be reduced to as low as 3 per centwithout decreasing the percentage extraction ofhippurate by the kidneys. They also demonstrated(17) that the kidney differs from muscles, brainand other tissues in that the arteriovenous oxygen

difference does not rise proportionately as the re-

nal blood flow falls. A reduction to 20 per centof normal in the renal blood flow produces no

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significant correlation.

change in the amount of oxygen removed by thekidney. The renal blood flow of dogs in shockwas reduced far out of proportion to the reduc-tion in cardiac output, and they interpreted thisas a saving mechanism to tissues more susceptibleto anoxemia, such as the brain. The same mech-anism seems to operate in patients with chroniccongestive heart failure with a low cardiac output.In many of our patients the renal arteriovenousoxygen difference was increased. This is furtherevidence that the renal blood flow is actually mark-edly decreased, and that the low values are not theresult of experimental error.

Our results are incompatible with the "back-ward failure" concept of edema formation inchronic heart failure, and point instead to a "for-ward failure" pathogenesis. In chronic congestiveheart failure the low renal blood flow has no re-

lationship to the height of the venous pressure

OXYGENDIFFERENCEthan 0.02, indicating a

either in the same or different individuals. Itcan be correlated with an inadequate cardiac out-put. The cardiac output is rarely reduced belowone-half the normal resting value, while the renalblood flow is frequently reduced to approximatelyone-fifth normal. This indicates a specific di-version of blood away from the kidneys, organs

which with the subject at rest normally receiveabout 20 per cent of the cardiac output. The factthat the filtration rate remains relatively normaluntil the renal blood flow is markedly reduced sug-

gests a high intraglomerular pressure from efferentarteriolar constriction (12). It is well known thatrenin, the renal pressor substance, causes efferentarteriolar constriction (18). By a technique pre-viously described we have obtained blood directlyfrom the renal vein in unanesthetized patients withchronic congestive failure (17). Preliminary bio-assays (19) of this blood show a considerable

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396

EDEMAIN CHRONIC CONGESTIVEHEART FAILURE

TABLE II

Excretion of sodium in patients with chronic heart disease

F.R./ SodiumRenal Filtra- R.P.F. Ex_____

Date Patient Diagnosis plasma tion trFiatAi cretion Diureticsflow rate trto mountAnuncrtoDieis

frac- fil- ex-tion) tered creted

per 1.73 sq. m. per m. eq. per mix. permi. per mix. cent cent

3-145 M.W. Rheumatic heart disease 187 80 43.0 10.7 .153 1.4 Salyrgan 48 hrs. before

1-1045 A.H. Syphilitic aortic insufficiency 200 60 30.0 8.22 .08 .975 Salyrgan 1 week before

10-5-44 L.F. Syphilitic aortic insufficiency 291 56 19.1 Salyrgan 1 week before10-12-44 348 51 14.7 6.93 .05 .72 Salyrgan 4 days before10-19-44 206 48 23.1 6.24 .02 .317 Salyrgan 11 days before

5-29-45 248 57 23.0 7.46 .10 1.34 Salyrgan 24 hrs. before

5-1445 L.H. Rheumatic heart disease 148 60 40.5 8.3 .0033 .039

8-10-45 J.G. Rheumatic heart disease 151 91 60.5 11.9 .0013 .011

amount of renin (20). Increase in renin associ-ated with a low cardiac output has been describedin shock (21). A decrease in the amount of bloodavailable to the kidney is supposed to be the fun-damental cause of the increase in renin (22).

Weattribute the salt retention, which in chroniccongestive heart failure results in edema, to a lowfiltration rate which is caused by a marked reduc-tion in renal blood flow. The data reported heredemonstrate that the tubules continue to reabsorbsalt at a fairly normal rate. The reason for thisis not known, 'but it is probably related to theirfundamental sodium-conserving mechanism. Thedecreased amount of sodium filtered- in the pres-ence of normal or slightly decreased -reabsorptionaccounts for the fact that edema in cardiac failuredevelops with the quantity of sodium present inthe average diet. Sodium retention will occur innormal subjects if the intake of sodium is greatlyincreased. Lyons showed that salt and water re-tention can produce a rise in venous pressure byadminstering large quantities of salt solution tonormal people (23). Venous pressures as high as170 mm. were observed. La Due found elevatedvenous pressures in some patients with acuteglomerulonephritis without other evidence of heartfailure (24). This was probably due to the lowfiltration rate produced by disease of Bowman'scapsule (25).

Seymour et al. (2) found that the renal bloodflow and filtration rate were decreased in patientswith failure from hypertensive heart disease.

After digitalization and compensation of the pa-tient, the renal blood flow rose while the filtrationrate was relatively unchanged. They believedthat the low renal blood flow and relatively highfiltration rate during failure were due to the highvenous pressure, because as compensation was re-stored the venous pressure fell and the renal bloodflow increased out of proportion to the change infiltration rate. However, in each case which theyreport, a rise in cardiac output was present aftercompensation was restored by the use of digitalis,and it is to this that we attribute the rise in renalblood flow. The relatively high filtration rateswere probably caused by efferent arteriolar con-striction.

The evidence against "backward failure" or in-creased venous hydrostatic pressure as the causeof chronic cardiac edema is strong. It has beensuggested that a slight rise of venous pressurewhich does not at first exceed the limits of normalproduces the early edema in chronic heart failure.The fact that the gain in weight and the increasein blood volume precede a measurable rise in ve-nous pressure indicates that a rise in capillaryand venous pressures does not occur initially. Aprimary increase in venous and capillary pressureswould cause hemoconcentration rather than he-modilution such as is found in chronic congestivefailure.

Patients with acute heart failure associated witha sudden decrease in cardiac output may have arise in venous pressure due to redistribution of

397

A. J. MERRILL

blood in the venous system produced by veno-

constriction (26). The patients of Reichsman andGrant who had auricular fibrillation and were per-

mitted to go into failure by omitting digitalisshowed an initial rise in venous pressure followedby a gain in weight (27). They probably have a

similar mechanism for their rise in venous pres-

sure. Such subjects are not suitable for determina-tion of the mechanism of sodium retention in heartfailure, because a decrease in cardiac output and a

rise in venous pressure occur simultaneously, andthere is no means of telling which factor is re-

sponsible.The low renal blood flow of patients with

chronic heart failure might have resulted frompressure on the arterioles and veins from greatlyswollen kidneys constricted by a tight capsule.In several patients with failure the venous pres-

sure was reduced to normal with mercurial di-uretics and kept at a normal value for severaldays. The renal blood flow remained essentiallythe same, demonstrating that a swollen kidneydid not cause a reduction in renal blood flow.

Futcher and Schroeder (28) demonstrated theinability of the kidney to excrete salt properly incongestive failure by measuring the rate of ex-

cretion of salt in the urine after a venoclysis ofconcentrated salt solution. They found that car-

diac subjects eliminated this salt much more slowlythan normal controls. They attributed this to in-creased reabsorption of salt by the tubules. Ourdata on sodium excretion and reabsorption indi-cate that tubular reabsorption is not increased, andthat the decreased output of sodium results froma decrease in the amount of sodium filtered, ratherthan an increase in the amount reabsorbed. Thesestudies will be reported in detail elsewhere.

Several objections to the thesis that cardiacedema is caused by a reduction in renal blood flowarise. Many patients who are compensatable bybed rest alone, and who fail only with exertion,have a normal cardiac output and renal blood flowat rest (29). It is believed that these patients willbe found to have an inadequate cardiac output anda low renal blood flow if they are studied underthe conditions during which they developed thesigns of heart failure; namely, during exertion or

in the presence of infection. Studies on this prob-lem are under way. A somewhat similar situationis found in patients with thyrotoxicosis, anemia

and beri-beri, who at rest may have failure withsupernormal cardiac outputs. When the require-ments for blood rise, as in anemia and thyro-toxicosis, the cardiac output may become inade-quate for the increased demand for blood, eventhough the resting cardiac output still exceeds thevalue found in normal subjects. Whenthe cardiacoutput is inadequate for the body needs, the kid-neys, through a humoral or reflex mechanism,direct part of their blood supply elsewhere.Practically every patient with severe anemia has adecrease in renal blood flow, despite a markedrise in cardiac output (30, 31). In three patientswith heart failure, two with anemia and one withthyrotoxicosis, a marked reduction in renal bloodflow was found (28). In the thyrotoxic patientthe renal blood flow rose to a supernormal valueas the venous pressure fell and the edema disap-peared. One of the anemia patients had a nor-mal renal blood flow after recovery. The otherdid not, and was found to have renal disease.

Hypertensive patients who may have low filtra-tion rates without edema are able to respond toexercise with an increase in cardiac output, and theshunting mechanism suggested above is notbrought into play.

Patients with renal disease which has progressedto the point of uremia all have low filtration rates,many lower than any of our cardiac patients. Mostof these individuals seen in this hospital during thepast two years have had edema and/or an elevatedvenous pressure. iThose without edema or ele-vated venous pressure have had nausea and vomit-ing and were unable to take salt and water. Hy-dration with salt and water intravenously promptlybrought edema and elevated venous pressure.

Individual; with shock have very low filtrationrates and yet rarely develop edema. The dura-tion of shock is usually too short for the accumula-tion of salt and water. However, in prolongedshock edema may develop without other evidenceof congestive heart failure (32).

The demonstration that salt and water are re-tained in patients with chronic cardiac decompen-sation on the basis of "forward failure" in no wayinvalidates the "backward failure" theory of pul-monary congestion. All of the phenomena ob-served on the ward are in accord with the conceptthat the left ventricle usually fails before the right.The assumption that this causes a rise in venous

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EDEMAIN CHRONIC CONGESTIVEHEART FAILURE

pressure in the lungs seems acceptable. This risein venous pressure may be responsible for the factthat fluid not excreted by the kidneys because of"forward failure" is deposited so early and ex-tensively in the lungs. During the day the highcapillary and venous pressures produced in partsof the body lying below the heart cause fluid to beforced into the tissues in the dependent portionsof the body. It is believed that, when the patientslie down, this fluid is mobilized and is redepositedin the lungs because of the abnormally high capil-lary pressure from failure of the left ventricle. Areduction in renal blood flow is the primary causeof the retention of salt and water, but local changesin venous and capillary pressures produced bygravity and left ventricular failure determine wherethe retained fluid is deposited.

SUMMARYAND CONCLUSIONS

1. Patients with chronic congestive heart failurewithout evidence of hypertension or renal diseasewere studied to determine the r6le of the kidneyin the formation of cardiac edema. These pa-tients tended to have an inadequate cardiac out-put by the catheter method utilizing the directFick principle, and a low renal blood flow by thepara-amino hippurate method.

2. The filtration rate by the inulin technique wasreduced only about half as much as the renalplasma flow, frequently giving filtration fractionshigher than those reported in any other condition.This indicates a high intraglomerular pressure,which was probably caused by efferent arteriolarconstriction.

3. Studies of sodium filtration, excretion andreabsorption show that the retention of salt re-sulting in edema is caused by the low filtrationrate, and is not due to increased reabsorption ofsalt.

4. The renal blood flow was reduced to aboutone-fifth normal, when the cardiac output was ap-proximately half normal, indicating a specific di-version of blood away from the kidney.

5. It is suggested that a similar shunting of bloodfrom the kidneys may be important in those pa-tients who have a normal renal blood flow andnormal cardiac output at rest, but who developevidence of heart failure and edema on exertion.When the cardiac output becomes inadequate to

meet the demands of exercise, blood may be di-verted from the kidneys to other parts of the bodywhose metabolic needs are greater.

6. The reduction in renal blood flow had no re-lation to the venous pressure, but was correlatedwith the reduction in cardiac output, indicatingthat it is a "forward failure" phenomenon and notdue to "backward failure" or increased hydro-static pressure in the veins.

This work was done with the technical assistance ofMiss Georgia Coleman, Miss Marguerite Acuff, MissEloise Cavin, Miss Lois Jackson and Mrs. Dorothy HallGraham. Statistical analyses were by Mrs. CharlesStone, Jr.

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