SIMULTANEOUSMEASUREMENTOF EFFECTIVE RENALBLOODFLOWANDCARDIAC OUTPUTIN RESTING NORMAL

SUBJECTSANDPATIENTS WITH ESSEN-TIAL HYPERTENSION1

BY ALFRED A. BOLOMEY,2 ALEXANDERJ. MICHIE,8 CATHARINE MICHIE,'ERNESTS. BREED, GEORGEE. SCHREINER, AND HENRYD. LAUSON5

(From the Departments of Physiology', qnd Medicine, New York University College of Medicine,and the Third Medical Division\Wew York University] of Bellevue Hospital,

New York City)

(Received for publication May 14, 1948)

Unpublished data of Bradley and associates(1) indicate that about 25 to 30 per cent of thecardiac output, as measured by the ballistocardio-graph (2), perfuses the kidney of healthy adultsat rest. This figure has been reported in a reviewon renal physiology (3). Levy and Blalock (4)obtained an average value of 18.5 per cent in un-anesthetized dogs, using the catheterization tech-nique or heart puncture and the direct Fick prin-ciple for the determination of the cardiac output.When normal human values for the resting car-diac output obtained by the direct Fick procedure(5, 6) are divided into the normal human valuesfor effective renal blood flow (7), the resultingeffective renal fraction is about 19 to 20 per cent.

The present investigation was undertaken tomake these measurements simultaneously in aseries of normal subjects and in patients with es-sential hypertension, using the cardiac catheteri-zation technique (8, 9) and the direct Fick prin-ciple for the measurements of the cardiac output.

METHODS

All studies were made during the morning at least 12hours after the previous meal.

Effective renal blood flow was determined from therenal plasma clearance of p-aminohippurate or diodrastand from the hematocrit (10). At the same time, theglomerular filtration rate was measured by the renalplasma clearance of mannitol, inulin (10), or sodium

1This investigation was aided by a grant from theCommonwealth Fund.

2 Present address: Permanente Foundation Hospital,Oakland, California.

8Present address: University of Pennsylvania Hos-pital, Department of Urology, Philadelphia, Pa.

4 Present address: Department of Physiology, TempleUniversity School of Medicine, Philadelphia, Pa.

6 Present address: Hospital of the Rockefeller Institutefor Medical Research, New York City.

thiosulfate (11). In about two-thirds of the cases theeffective tubular excretory mass was determined from theexcretion at high plasma concentrations of p-aminohip-purate (TmPAHI) or of diodrast (TmD) (10, 12).Urethral catheterization with saline and air washout wasemployed routinely.

Mixed venous blood for oxygen analysis was obtainedthrough a cardiac catheter introduced into the pulmonaryartery, the right ventricle, or failing these, the right auri-cle. The exact position in the auricle was checked fluoro-scopically immediately before or after sampling to assureoptimal placement (5, 10). After insertion of the car-diac and bladder catheters and placement of the indwell-ing femoral arterial needle, a rest period of 30 minutesensued, following which the patient was familiarized withthe noseclip, mouthpiece, and with bedside procedure.Several trial collections of expired air were obtained priorto the definitive collection, in order to minimize anxietyand to prove the stability of the ventilation, respiratoryand heart rates. Arterial and mixed venous blood weredrawn simultaneously under oil during the two-minutecollection of expired air. Blood oxygen contents weredetermined in duplicate by the method of Van Slyke andNeill (13). Oxygen consumption was calculated fromgas analysis of the expired air by the Haldane method(13).

Shortly before and after the above procedure, the arte-rial pressure was recorded optically by the Hamiltonmanometer (14), or the mean pressure was read directlyfrom a calibrated aneroid manometer connected to thearterial needle through a short rubber tubing containingair which damped the pressure pulse almost completely.In the former case, the mean pressure was calculatedfrom the weight of a representative sample cut out care-fully from the photographic record. In a few subjectsthe arterial pressure was determined by cuff sphygmo-manometry, the mean pressure being estimated as Pm=PD+ 0.4 (P8 - PD). The total peripheral resistance wascalculated by dividing the mean arterial pressure by thecardiac output per 1.73 sq.m. and is expressed as dynescm. sec. (absolute unit).

The metabolic rate was calculated from the minutevolume of oxygen consumed and the assumed R.Q. of

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0.82. The observed R.Q. was not used for this purposebecause the short collection period makes the CO2 valuetoo dependent on variations in the respiratory pattern,and therefore not a reliable measure of metabolic CO,production. The values of ventilation rate and oxygenconsumption are corrected to saturation at 370 C. andprevailing barometric pressure.

CLINICAL SUBJECTS

All subjects were patients of the Third (NewYork University) Medical Division of--BellevueHospital. The normal subjects are representativeof the convalescent ward population of a large cityhospital. Most of them had had an upper respira-tory infection or acute alcoholism. There wasone each with a diagnosis of mild anxiety neu-rosis, headache of unknown cause and withoutneurological signs, central nervous system degen-erative disease, mild chronic cholecystitis, oldquiescent small lung abscess, and central nervoussystem syphilis. In addition, six patients, con-valescent from traumatic or hemorrhagic shock,who were studied 17 to 76 days after injury, areincluded in the present series by the kind per-mission of Drs. Andre Cournand, D. W. Richards,Jr., and their co-workers (15, 16). None of thenormal subjects had any evidence of cardiovascu-lar or renal disease. All had been afebrile and allbut two were ambulatory for at least a week priorto study.

Most of the patients with essential hypertensionwere admitted to Bellevue from the New YorkUniversity Hypertension and Nephritis Clinic forthe express purpose of study. None presentedevidence of cardiac insufficiency.

RESULTS

Tables I and II present the data from eachsubject. The more pertinent data are presentedin the form of frequency diagrams in Figures 1and 2.

The control and hypertensive groups are fairlycomparable with respect to distribution of hema-tocrit, metabolic rate and pulse rate. This isconsidered essential for the comparison of theother values, in so far as deviations from acceptednormal standards in these three might be ex-pected to affect cardiac output and renal function.The hypertensive group averages 7.5 years older,and contains a higher proportion of women thanthe control group. The two groups are reason-

ably comparable as regards nutritional status andgeneral health exclusive of hypertensive disease.

The cardiac output, expressed as liters perminute per square meter of body surface area,averages 4.07 in the control group as comparedto 3.97 in the hypertensive group. The differenceis not significant. This is in accord with the ob-servations of previous investigators (17, 18).

Mean arterial pressure is, of course, markedlyhigher in the patients with essential hypertension.Since the cardiac output is about the same inboth groups, the average calculated total periph-eral resistance is elevated in the hypertensivegroup to about the same extent as is the arterialpressure.

Effective renal blood flow is within the normalrange of plus or minus twice the standard devia-tion from the respective male and female means(7, 12) in 17 and below in only one of the controlsubjects. Ten of the hypertensive patients haverenal blood flow within the normal range; eightare below it, and none exceeds it. Moreover, inall but one of the hypertensive patients the valuesare less than the normal mean.

The effective renal plasma flow is within thenormal range in all of the control subjects,whereas it is below this range in eight of the 19hypertensives.

The filtration rate is below the normal rangein one control subject and above in another. Inthe rest, it is well within the normal range.Among the hypertensives, 11 fall below the rangeand none exceeds the normal mean.

Seven of the nine determinations of TmpAHmade in the control group fall in the normal rangereported by Chasis, Redish, Goldring, Ranges andSmith (12), while five of the ten determinationsin hypertensive patients lie below this range.Diodrast Tm, measured in five hypertensives, isin the normal range in four and below normalin one.

The filtration fraction (filtration rate/effectiveplasma flow) averages 0.190 in the control groupand 0.221 in the hypertensive group. The differ-ence between normal and hypertensive patients isless striking than that observed by Goldring andChasis (10).

The effective renal fraction (effective renalblood flow/cardiac output) was calculated fromthe average effective renal blood flow and from

13

A. A. BOLOMEY,A. J. MICHIE, C. MICHIE, E. S. BREED, G. E. SCHREINER, H. D. LAUSON

CONTROL

2 3 4 5 6 7 8 9

HYPERTENSIVE

CARDIAC INDEX

70 90 110 130 150 170 190 210

70 90 110 130 150 170 190 210

MEAN ARTERIAL PRESSURE,FEMORAL

5 10 15 20 25 30 35

5 10 15 20 25 30 35(X 102)PERIPHERAL RESISTANCE

FIG. 1. FREQUENCYDISTRIBUTION OF OBSERVEDPHYSIOLOGICAL VARIABLES IN CONTROLAND

HYPERTENSIVE SUBJECTSThe values shown are those obtained in connection with the first cardiac output determination.

14

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FILTRATION FRACTION RNLFRACTION

16 A. A. BOLOMEY,A. J. MICHIE, C. MICHIE, E. S. BREED, G. E. SCHREINER, H. D. LAUSON

the first cardiac output determination on eachindividual. It varies from 0.102 to 0.269, withan over-all average of 0.156 in the control group.The corresponding range for the hypertensives isfrom 0.014 to 0.207, with an average of 0.106.This average figure of course has little meaning,since the renal blood flow must necessarily de-crease with the progressive parenchymal destruc-tion known to be associated with this disease, andif the cardiac output is maintained, the effectiverenal fraction will decrease correspondingly.7

DISCUSSION

As noted in the introductory paragraph, thenormal effective renal fraction in the resting post-absorptive condition averages about 0.19 to 0.20if the normal mean effective renal blood flow re-ported by Smith (7) is divided by the normalmean cardiac output reported by Cournand, Riley,Breed, Baldwin and Richards (5) and by Steadet al. (6).

The lower average of 0.156 for the effectiverenal fraction in the present control series maybe due in part to the influence of moderate anemiaon the renal blood flow of some of the subjects.Such a possibility would be suggested from thedata of Bradley and Bradley (19). A more im-portant factor, however, is the elevation of thecardiac output. From the data in Table I andfrom those of Brannon, Merrill, Warren andStead (20) it would appear that anemia of themoderate degree encountered in these subjectsdoes not, by itself, affect the cardiac output. On

7 It should perhaps be emphasized that the term "ef-fective" renal blood flow indicates the volume per minuteof blood perfusing functioning excretory tissue (22). Onthe same basis, "effective" renal fraction is defined as thefraction of the cardiac output which perfuses the func-tioning renal excretory tissue. If the renal extraction ofp-aminohippurate is in the normal range of about 85 to100 per cent (23, 24), the "effective" renal blood flow and"effective" renal fraction represent 85 to 100 per cent ofthe "total" renal blood flow and "total" renal fraction.If the extraction is less than normal, the relationshipbetween the "effective" and "total" values will be corre-spondingly altered. Bradley (23) found that the extractionwas normal in 12 of 14 cases of essential hypertensionand was reduced only in two patients, both of whom hadadvanced renal disease with uremia. Judging from Brad-ley's data, it seems probable that the extraction is mod-erately or greatly reduced in M.Bl. Furthermore, it ispossible that the extraction may be slightly to moderatelydecreased in M.D., T.V. and M. deL. (see Table II).

the other hand, anxiety, tenseness, annoyance, etc.,which frequently complicate this type of investi-gation, would be expected to raise the cardiacoutput. This view is supported by the recentstudies of Stead et al. (6), and of Hickam, Car-gill and Golden (21).

It is believed that our control and hypertensivegroups are reasonably comparable as regards ane-mia and anxiety, in so far as may be inferred fromthe hematocrit, metabolic rate and heart rate.Since the average cardiac output is the same inboth groups, it is apparent that the decreasedaverage effective renal fraction in the hyperten-sive group is attributable to the diminished effec-tive renal blood flow known to accompany thisdisease.

SUMMARY

Results of simultaneously determined cardiacoutput by the direct Fick method and renal clear-ances are presented for 18 nonhypertensive andfor 19 hypertensive subjects in the post-absorptiveperiod at rest.

The cardiac indices of control and hypertensivesubjects are within the same range, the averagefor each group being 4.07 and 3.97 liters, re-spectively.

The average effective renal fraction of the con-trol subjects (0.156, range 0.102 to 0.269) islower than that calculated from non-simultaneousdeterminations reported in the literature. This isbelieved to be a consequence of an increase inaverage cardiac output associated with the multi-ple manipulations of simultaneous study, and, toa lesser extent, of the moderate anemia of someof the subjects which may have led to some reduc-tion in the effective renal blood flow.

An additional reduction in the effective renalfraction in the hypertensive subjects (average0.106, range 0.014. to 0.207) results from thefunctional ischemia and progressive destructionof renal parenchyma characteristic of the disease,and in advanced hypertensive disease the effectiverenal fraction may be less than 0.020.

BIBLIOGRAPHY

1. Bradley, S., Unpublished data.2. Starr, I., Rawson, A. J., Schroeder, H. A., and

Joseph, N. R., Studies on the estimation of thecardiac output in man, and of the abnormalities in

EFFECTIVE RENAL FRACTION IN ESSENTIAL HYPERTENSION

cardiac function from the heart's recoil and theblood's impacts; the ballistocardiogram. Am. J.Physiol., 1939, 127, 1.

3. Pitts, R. F., Kidney. Ann. Rev. Physiol., 1946, 8,199.

4. Levy, S. E., and Blalock, A., Fractionation of theoutput of the heart and of the oxygen consump-tion of normal unanesthetized dogs. Am. J.Physiol., 1937, 118, 368.

5. Cournand, A., Riley, R. L., Breed, E. S., Baldwin,E. de F., and Richards, D. W., Jr., Measurementof cardiac output in man using the technique ofcatheterization of the right auricle or ventricle.J. Clin. Invest., 1945, 24, 106.

6. Stead, E. A., Warren, J. V., Merrill, A. J., andBrannon, E. S., The cardiac output in male sub-jects as measured by the technique of right atrialcatheterization. Normal values with observationson the effect of anxiety and tilting. J. Clin.Invest., 1945, 24, 326.

7. Smith, H. W., Lectures on the kidney. UniversityExtension Division, Univ. of Kansas, Lawrence,Kansas, 1943, 96-97.

8. Cournand, A., and Ranges, H. A., Catheterization ofthe right auricle in man. Proc. Soc. Exper. Biol.and Med., 1941, 46, 462.

9. Cournand, A., Measurement of the cardiac output inman using the right heart catheterization. Fed-eration Proc., 1945, 4, No. 2, 207.

10. Goldring, W., and Chasis, H., Hypertension andHypertensive Disease. The Commonwealth Fund,New York, 1944.

11. Gilman, A., Philips, F. S., and Koelle, E., The renalclearance of thiosulfate with observations on itsvolume distribution. Am. J. Physiol., 1946, 146,348.

12. Chasis, H., Redish, J., Goldring, W., Ranges, H.,and Smith, H. W., The use of sodium p-amino-hippurate for the functional evaluation of thehuman kidney. J. Clin. Invest., 1945, 24, 583.

13. Peters, J. P., and Van Slyke, D. D., QuantitativeClinical Chemistry: Vol. II, Methods. The Wil-liams and Wilkins Co., Baltimore, 1932.

14. Hamilton, W. F., Brewer, G., and Brotman, I.,Pressure pulse contours in the intact animal. I.

Analytical description of a high frequency hypo-dermic manometer. Am. J. Physiol., 1934, 107,427.

15. Cournand, A., Riley, R. L., Bradley, S. E., Breed,E. S., Noble, R. P., Lauson, H. D., Gregersen,M. I., and Richards, D. W., Jr., Studies of thecirculation in clinical shock. Surgery, 1943, 13,964.

16. Lauson, H. D., Bradley, S. E., and Cournand, A.,The renal circulation in shock. J. Clin. Invest.,1944, 23, 381.

17. Steele, J. M., The circulation in hypertension. Pub-lication of the Am. Assoc. for the Advancement ofScience, 1940, 13, 289.

18. Holman, D. V., and Page, I. H., Cardiac output inarterial hypertension; the study of arterial hyper-tension produced by constricting renal arteries inunanesthetized and anesthetized (pentobarbital)dogs. Am. Heart J., 1938, 16, 321.

19. Bradley, S. E., and Bradley, G. P., Renal functionduring chronic anemia in man. Blood, 1947, 2, 192.

20. Brannon, E. S., Merrill, A. J., Warren, J. V., andStead, E. A., Jr., The cardiac output in patientswith chronic anemia as measured by the techniqueof right atrial catheterization. J. Clin. Invest.,1945, 24, 332.

21. Hickam, J. B., Cargill, W. H., and Golden, A.,Cardiovascular reactions to emotional stimuli. Ef-fect on cardiac output, arteriovenous oxygen dif-ference, arterial pressure and peripheral resistance.J. Clin. Invest., 1948, 27, 290.

22. Smith, Homer, W., Note on the interpretation ofclearance methods in the diseased kidney. J. Clin.Invest., 1941, 20, 631.

23. Bradley, S. E., The validity of the clearance tech-nique in the measurement of renal blood flow innormal man and in patients with essential hyper-tension. Transactions of the First Conference onFactors Regulating Blood Pressure, Josiah Macy,Jr. Foundation, New York, 1947, 118-124.

24. Warren, J. V., Brannon, E. S., and Merrill, A. J.,A method of obtaining renal venous blood in un-anesthetized persons, with observations on the ex-traction of oxygen and sodium para-amino hip-purate. Science, 1944, 100, 108.

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