464

Institute for Cancer Research, 7701 Burholme Avenue, FoxChase, Philadelphia, Pennsylvania 19111, U.S.A.

REFERENCES

1. Klatskin, G. in Principles of Internal Medicine (edited by T. R.Harrison, R. D. Adams, I. L. Bennett, Jr., W. H. Resnik, G. W.Thorn, and M. M. Wintrobe); p. 1670. New York, 1962.

2. Blumberg, B. S. Bull. N.Y. Acad. Med. 1964, 40, 377.3. Blumberg, B. S., Gerstley, B. J. S., Hungerford, D. A., London,

W. T., Sutnick, A. I. Ann. intern. Med. 1967, 66, 924.4. Sutnick, A. I., London, W. T., Millman, I., Coyne, V. E., Blumberg,

B. S. Med. Clins N. Am. 1970, 54, 805.5. Blumberg, B. S., London, W. T., Sutnick, A. I. Am. J. Med. 1970,

48, 1.6. Sutnick, A. I., Millman, I., London, W. T., Blumberg, B. S. Annual

Rev. Med. 1972, 23, 161.7. Blumberg, B. S., Byrne, R. J., Chanock, R. M., Cockburn, W. C.,

Kono, Y., Koza, J., McCollum, R. W., Menache, D., Penttinen,K., Purcell, R. H., Taylor, P. E., Wewalka, F. G., Zucker-man, A. J. Bull. Wld Hlth Org. 1970, 42, 957.

8. Pesendorfer, F., Krassnitzky, O., Wewalka, F. Klin. Wschr. 1970,48, 58.

9. Goeser, E., Dahlke, M. B., London, W. T., Sutnick, A. I., Blumberg,B. S. Ann. intern. Med. 1971, 74, 834.

10. Wroblewski, F., LaDue, J. S. Proc. Soc. exp. Biol. Med. 1956, 91,569.

11. Coller, J. A., Millman, I., Halbherr, T. C., Blumberg, B. S. ibid.1971, 138, 249.

12. Mann, H. B., Whitney, D. R. Ann. Math. Statistics, 1947, 18, 50.13. Lepage, Y. Biometrika, 1971, 58, 213.14. Prince, A. M. Proc. natn. Acad. Sci. U.S.A. 1968, 60, 814.15. Barker, L. F., Shulman, N. R., Murray, R., Hirschman, R. J.,

Ratner, F., Diefenbach, W. C. L., Geller, H. M. J. Am. med. Ass.1970, 211, 1509.

16. Murray, R., Oliphant, J. W., Tripp, J. T., Hampil, B., Ratner, F.,Diefenbach, W. C. L., Geller, H. ibid. 1955, 157, 8.

17. Murray, R., Ratner, F., Diefenbach, W. C. L. ibid. 1954, 155, 13.18. Allen, J. G. Archs Surg., Chicago, 1970, 100, 2.19. Krugman, S., Giles, J., Hammond, J. J. Am. med. Ass. 1967, 200, 95.20. Giles, J. P., McCollum, R. W., Berndtson, L. W., Krugman, S.

New Engl. J. Med. 1969, 281, 119.21. Gocke, D. J., Greenberg, H. B., Kavey, N. B. J. Am. med. Ass.

1970, 212, 877.22. Maccarato, R., Rizzo, A., Marubini, E. Personal communication.23. Alter, H. J., Holland, P. V., Purcell, R. H., Lander, J. J., Feinstone,

S. M., Morrow, A. G., Schmidt, P. J. Ann. intern. Med. 1972, 77,691.

LACK OF ASSOCIATION BETWEEN PLASMA-

RENIN AND HISTORY OF HEART-ATTACK

OR STROKE IN PATIENTS WITH ESSENTIALHYPERTENSION

WILLIAM J. MROCZEK FRANK A. FINNERTYKEVIN J. CATT

Georgetown University Medical Division, District ofColumbia General Hospital, Washington, D.C., andReproduction Research Branch, National Institute ofChild Health and Human Development, Bethesda,

Maryland, U.S.A.

Summary The relation between plasma-reninactivity and the occurrence of heart-

attacks and strokes was examined in 371 Black patientswith essential hypertension, who were categorisedas having low, normal, or high renin activity accordingto their 24-hour sodium excretion. The incidence ofsuch complications was found to be identical in eachof the renin subgroups. No evidence was found to

support the proposal that patients with low reninhypertension are protected against these complica-tions, or that high renin activity is vasculotoxic perse. These findings are not consistent with the viewthat plasma-renin activity is a potential risk factor inuncomplicated essential hypertension, and emphasise

the need for effective therapy in all hypertensivepatients regardless of the plasma-renin activity.

Introduction

No abnormality of the renin/angiotensin systemhas been detected in the majority of patients withuncomplicated essential hypertension, and there isno reason to believe that the genesis or course ofthe disease has any relation to renin secretion. Follow-

ing the demonstration that primary aldosteronismis accompanied by subnormal plasma-renin activityP.R.A.,1 the widespread use of plasma-renin assayas a diagnostic aid in the evaluation of hypertensivepatients revealed that " low " or

" suppressed " reninactivity was relatively common in patients with un-complicated essential hypertension.2-12 Because nor-mal subjects frequently show relatively low basalrenin activity, manoeuvres to stimulate renin secretion,such as sodium restriction and depletion, uprightposture, and induced hypotension, have been em-ployed to distinguish between patients with normalor responsive P.R.A. and those with suppressed P.R.A.which remained low despite the use of such stimuli.By such means, a substantial subgroup of the

essential-hypertension population has been classifiedas having " low-renin hypertension " and numerousstudies have been performed to determine the natureand significance of this condition. The frequency oflow-renin hypertension has varied considerably indifferent studies from 9% to as high as 43 % .6.8,9 Thisvariation is largely attributable to the proportion ofBlack patients included in the studies, since low-renin activity and low-renin hypertension are morecommon in the Black population 2·lo In patients withlow-renin hypertension, aldosterone secretion is

usually normal or low, although excessive secretionof other adrenal steroids with " niineralocorticoid "

activity has been demonstrated in a small proportionof patients 13 To date, there has been no convincingevidence that abnormal steroid secretion contributes

significantly to the hypertension or the renin sup-pression in the majority of patients with this con-dition.

Recently, plasma-renin activity has been suggestedby Laragh and his colleagues as an important riskfactor in essential hypertension.a,15 These authorshave used the hyperbolic relationship between P.R.A.and urinary sodium excretion to classify hypertensivepatients into low, normal, and high renin subgroups.By this method, the incidence of stroke and heart-attack in patients with essential hypertension wasfound to be higher in those with elevated plasma-renin, whereas patients with low-renin hypertensionhad a negligibly low incidence of such complications.It was therefore concluded that high plasma-reninactivity predisposes to serious vascular injury, andthat patients with low-renin hypertension are pro-tected from the development of heart-attack andstroke.16,17

The suggestion that low-renin hypertension is a

benign condition which may not require earlytreatment is markedly at variance with current viewsabout the necessity for early and effective therapyfor all forms of hypertension. Because of the im-

465

portant clinical implications of such a proposal ]8,]9it was important to evaluate its validity in furthergroups of patients. Low-renin hypertension is knownto be more common in Black hypertensive patients,who have a higher incidence of hypertension, developthe disease at an earlier age, and have more severe

complications of hypertension.’, 10,10,21 In order to testthe hypothesis that low-renin hypertension is a

prognostic index of myocardial infarction and cere-brovascular accidents, we undertook a retrospectivestudy of the incidence of such complications in anurban Black hypertensive population, in relation to

the plasma-renin activity and urinary sodium ex-

cretion of 371 patients.

Methods

Patients attending the hypertension clinic at the Districtof Columbia General Hospital were instructed in thecollection of a 24-hour-urine specimen which was lateranalysed for sodium, potassium, and creatinine. Noneof the patients had received any antihypertensive or

diuretic medication for at least 7 days prior to study.Upon returning to the laboratory with the 24-hour-urinecollection and after 4 hours of upright posture, blood-samples were obtained for determinations of P.R.A. andserum sodium, potassium, and creatinine. Specimens forP.R.A. were collected in chilled test-tubes containing di-sodium E.D.T.A., and immediately centrifuged at 4°C; andthe plasma was separated and frozen for later analysis.Specimens for sodium, potassium, and creatinine were

collected in 7 ml. siliconised test-tubes and centrifuged,and the serum was frozen for later analysis.Plasma-renin activity was determined by radioimmuno-

assay of angiotensin I generated during incubation of

plasma-samples for 3 hours at pH 6’0 in the presenceof 10 mM E.D.T.A., 5 mM dimercaprol, and 2-4 mM 8-hydroxyquinoline sulphate. The final plasma dilutionfor incubation was 1:2, and an aliquot of each plasma-incubation mixture was kept at 4°C for 3 hours, fordetermination of the blank of the sample. After incuba-

tion, appropriate aliquots of the incubation mixture,usually 25 and 50 ju.1., were taken in duplicate for radio-immunoassay of generated angiotensin I. Assays wereperformed in 10 X 75 mm. polystyrene tubes in a finalvolume of 1 ml. containing antiserum to angiotensin I

(1/50,000) and 8000-10,000 c.p.m. of monoiodoangio-tensin I. After incubation at 4°C for 16 hours, boundand free fractions were separated by charcoal adsorptionof the free tracer, and following centrifugation theradioactivity of the charcoal pellets was counted in an

automatic gamma-spectrometer. Assay results were cal-culated by computer programs based upon log-logit con-version of the bound tracer, with the facility to acceptdirect entry of the values for free counts adsorbed to

charcoal in each assay tube.22The mean plasma blank in, 127 samples was 0-27 ng.

per ml. per hour and the P.R.A. of normal subjects onunrestricted diet was 0’3-1’5 ng. per ml. per hour (supine)and 2’9±2’1 (s.D.)- ng. per ml. per hour (upright). TheP.R.A. response to furosemide (frusemide) administrationwas quite variable, with a mean increase to 5’1±4’3 ng.per ml. per hour. The within-assay reproducibility ofthe method over this range of P.R.A. was ±5’0%(coefficient of variation), and the between-assay repro-ducibility was ± 12%.

28 normotensive Black volunteers and 12 normotensiveWhite volunteers had 24-hour-urine collections, P.R.A.,and serum sodium, potassium, and creatinine measuredunder similar conditions. None of the volunteers had a

past history of hypertension, cardiac disease, renal disease,or cerebrovascular disease, and none had received anymedication for the 14 days prior to study; all patientsand volunteers were instructed to maintain their regulardiet. Many of the hypertensive patients ingesting low-sodium diets were in a state of moderate sodium restric-tion ; also, because of cultural dietary preferences, a sub-stantial proportion of the patients had relatively highsodium intakes. In all cases where a past history of myo-cardial infarction or cerebrovascular accident was elicited,the relevant hospital charts were extensively reviewed.Only those patients with verified hospital records wereincluded in the analysis of the association of P.R.A. withmyocardial infarctions or cerebrovascular accidents.The hypertensive patients were considered to have

essential hypertension on the basis of family history,absence of known renal disease, serum-electrolytes, andin most cases rapid-sequence intravenous pyelography.Patients were considered to be hypertensive if the averageof three determinations of arterial pressure on separatedays was greater than 90 mm. Hg diastolic. The dis-

appearance of the Korotkoff sounds was recorded as thediastolic pressure. All patients with clinical features of

malignant or accelerated hypertension were excluded fromthis study.

Results

A total of 420 determinations of P.R.A. were per-formed in 394 patients. Due to inadequate urinecollections, 23 patients were excluded from the finalanalysis. All the patients were Black and 106 weremale. The normotensive volunteers included 28Blacks and 12 Whites, all of whom were male. The

average age of the hypertensive patients was 5O ± 12

Fig. 1-Relation of plasma-renin activity to daily rate of sodiumexcretion in 40 normal subjects.

The interrupted lines bracket the normal values described byBrunner et al. 14

466

Fig. 2-Relation of plasma-renin activity to daily rate of sodiumexcretion in 371 hypertensive patients, compared with normalrange described by Brunner et al.14

years and of the volunteers was 31:t 8 years. The24-hour sodium excretion of the volunteers

ranged from 40 to 291 meq. daily, and that of thehypertensive patients from 20 to 420 meq.The P.R.A. ranged from 0-8 to 15.3 ng. per ml. per

hour in the normotensive volunteers and from zeroto 23.9 ng. per ml. per hour in the hypertensivepatients. The relation between the 24-hour urinesodium excretion and the P.R.A. is shown in fig. 1for the normotensive volunteers and in fig. 2 for thehypertensive patients. The relation between the 24-hour sodium excretion and the P.R.A. (fig. 1) is broadlysimilar to that described by Brunner et al.14 73%of our normotensive volunteers had plasma-reninactivities that fell within the normal limits of P.R.A.

Fig. 3-Relation of plasma-renin activity to daily rate of sodiumexcretion in 38 Black hypertensive patients with past historyof myocardial infarction or cerebrovascular accident.

described by Brunner et al., indicating that the renin-assay methods are comparable. Although the use ofsuch " normal limits " may not be directly applicableto other groups of patients, the relatively symmetricaldistribution of our renin-activity values around thelimits of Brunner et al. permits comparisons to bemade between the two populations. By these criteria42% (157 patients) could be categorised as havinglow P.R.A., 12% (45 patients) high P.R.A., and 46%(169 patients) normal P.R.A. in relation to the 24-hoursodium excretion (fig. 2).The clinical and laboratory characteristics of the

patients in each renin subgroup are summarised inthe accompanying table. There were no significantdifferences in the age, diastolic blood-pressure, or

serum sodium, potassium, and creatinine in the three

CLINICAL AND BIOCHEMICAL CHARACTERISTICS OF HYPERTENSIVE PATIENTS

* Standard error of mean in parentheses.T M.I. =myocardial infarction. C.V.A. = cerebrovascular accident.

467

renin subgroups. However, there was a significantdifference between the systolic blood-pressures ofthe low, normal, and high renin subgroups. Alsonotable was the increased percentage of male patientsin the high-renin subgroups, both in the total hyper-tensive population and in the patients with myo-cardial infarction and cerebrovascular accidents.There were 42 hypertensive patients with a past

history of myocardial infarction or cerebrovascular

accident; 4 of these subjects were excluded becausethe complications could not be documented by hos-pital records or physical examination. The relation-

ship of P.R.A. to 24-hour sodium excretion in the 38patients with proven myocardial infarctions or cere-brovascular accidents is shown in fig. 3. 34 patientshad strokes and 4 had myocardial infarction, 18

patients (47%) were classified as having low P.R.A.,4 (11 %) as having high P.R.A., and 16 (42%) as havingnormal P.R.A. according to the level of 24-hour sodiumexcretion. By comparison with the total hypertensivepopulation, the incidence of vascular complicationswas evenly distributed throughout the group of

patients with essential hypertension, and no signifi-cant trends were distinguishable at the higher andlower levels of plasma-renin activity.

Since the initiation of this study in April, 1972,there have been 5 cardiovascular or cerebrovascularaccidents in patients who had previous P.R.A. deter-minations.

Low-renin HypertensionCase 1.-A 59-year-old woman with a 20-year history

of hypertension had no past history of heart-attack orstroke. Without therapy her arterial pressure was 185/102 mm. Hg and the P.R.A. was undetectably low witha 24-hour urine sodium of 74 meq. After treatmentwith hydrochlorothiazide SO mg. daily for 4 months witha good blood-pressure response, the patient suddenlydeveloped right hemiplegia and was subsequently dis-

charged with a residual hemiparesis. While she was still

receiving 50 mg. hydrochlorothiazide daily, the P.R.A.

measured two weeks later was 0-26 ng. per ml. per hour.The diuretic was discontinued and another P.R.A., deter-mined a week later, was 0-06 ng. per ml. per hour witha 24-hour sodium excretion of 96 meq. This patient withsubnormal P.R.A. had a cerebrovascular accident and sub-sequently maintained very low levels of P.R.A. despite thestimulus of hydrochlorothiazide administration.

Case 2.-An 80-year-old woman with more than 30years’ history of hypertension had been treated for theprevious 3 years with a restricted sodium diet and diuretics.After 15 days without medication the P.R.A. was 2’5 ng.per ml. per hour with a 24-hour sodium excretion of42 meq. The patient sustained a cerebrovascular accidentin December, 1972, with a recurrence in January, 1973,which terminated fatally; the preceding P.R.A. level waslow in relation to the concomitant 24-hour sodiumexcretion.

Case 3.-An obese 35-year-old woman with an 11-yearhistory of hypertension had a P.R.A. of 085 ng. per ml.per hour with a 24-hour sodium excretion of 106 meq.9 months later, while receiving propranolol, 360 mg.daily, she sustained an extensive anterolateral-wall myo-cardial infarction. This patient with low P.R.A. was alsonoted to have suppressed renin after treatment with in-travenous furosemide or diazoxide.

Normal and High Renin HypertensionCase 4.-A 42-year-old man with a year’s history of

hypertension and angina pectoris was classified as havingnormal-renin hypertension. After medication had beendiscontinued for 2 weeks, the P.R.A. was 6’8 ng. per ml.per hour with a urinary sodium excretion of 44 meq. per24 hours. 7 months later, while receiving alphamethyl-dopa and hydrochlorothiazide, he sustained an anteroseptalmyocardial infarction which was followed by an uneventfulrecovery.

Case 5.-A 42-year-old woman with an 8-year hist-

ory of hypertension had a past history of myocardialinfarction in 1971. The P.R.A., determined 12 days afterdiscontinuing all medication except chlordiazepoxide 10

mg. three times daily, was 9’6 ng. per ml. per hour witha 24-hour sodium excretion of 154 meq. After resumingher therapy of alphamethyldopa, hydrochlorothiazide, andpotassium chloride, she was admitted to another hospitala month later with the clinical diagnosis of acute myo-cardial infarction, and she died soon after admission.

Discussion

The present data, derived by analysis of the valuesobtained from plasma-renin activity ard urinarysodium excretion in Black hypertensive patients, arein distinct contrast to the findings of Brunner et al.14In our series of patients, the incidence of low-reninhypertension (47%) in the patients with cerebro-vascular accidents and myocardial infarcts was similarto the incidence of low-renin hypertension in the

general hypertensive population (42%). Although theproportion of Black patients in Brunner’s New Yorkgroup was only 27%, in contrast to the 100% Blackpopulation examined in the present Washingtonstudy, it is important to note that Blacks comprised42 % of the low-renin patients in the New York study.In our study, Dr Laragh’s nomograms were utilisedas arbitrary standards because these " normal limits "included three-quarters of our normal population.However, figs. 2 and 3 reveal that the patients withvascular complications are uniformly distributed

throughout the hypertensive population, and that theapplication of any arbitrary classification will not

identify patients who are either protected from, ormore susceptible to, myocardial infarctions and cere-brovascular accidents.

Other investigators who employed different criteriafor low-renin hypertension have also noted that theplasma-renin level was not related to the develop-ment of myocardial infarction and cerebrovascularaccidents.23-25 Using intravenous furosemide as a

stimulus to renin secretion, Kem et a1.26 found nodifference between the P.R.A. responses of Black

hypertensive patients with and without a history ofmyocardial infarction or cerebrovascular accident.Amery et al.27 were also unable to detect a relationbetween the level of P.R.A. and the incidence of cere-brovascular accidents and myocardial infarction in agroup of patients studied retrospectively. However,the P.R.A. was not evaluated with reference to the

prevailing level of sodium excretion in these patients,and comparison with the New York study could notbe made conclusively as in the present study. Becauseof the inherent limitations of retrospective studies,it is particularly significant that three of the fivevascular complications that have occurred in our

patients followed prospectively were in the low-P.R.A. group. Indeed, after 5 years of follow-up,

468

Doyle et al. found no relation between renin levelsand vascular complications in 39 untreated and 116treated hypertensive patients .21The proposed vasculotoxic effect of renin has also

been the subject of an exchange of views followingthe publication of Brunner’s data.28,29 In the presentstudy, the 12 °/, incidence of high P.R.A. in the generalhypertensive population was comparable with the

11 °, incidence in patients with a past history of myo-cardial infarction or cerebrovascular accident. There-

fore, our data did not indicate that high-renin hyper-tension was associated with any increase in morbidityor mortality from these disorders, and show no

evidence of a vasculotoxic action of circulating renin.The clinical impression that " hypertension is

different in Blacks " may be extended to include the

possibility that P.R.A. is different in Blacks. Fig. 1shows that, for sodium-excretion levels up to 100

meq. per day, the values for P.R.A. in Black normo-tensive controls are frequently lower than those ofcomparable normotensive Whites. Indeed, removalof the White volunteers from fig. 1 reduces the

dynamic hyperbolic relationship between P.R.A. andsodium excretion described by Brunner et al. Furtherstudies are under way with normotensive Blackvolunteers to determine the exact relation of P.R.A.

to sodium excretion in this population. The incidenceof low-renin hypertension in this study is suspectedto be even higher than the 47% reported, since manyof the patients were on unrestricted sodium diets.If only those patients with sodium excretion below125 meq. daily are considered, then 62% of these

patients could be classified as having low plasma-renin activity. Probably many of the patients withrelatively low P.R.A. values that fall into the " normal-renin" group due to their high sodium excretionwould be categorised as having low-renin hyper-tension if restudied after sodium restriction. Fromobservations in hypertensive patients and fromstudies on the effects of furosemide administrationin normotensive volunteers, we have found that,regardless of the level of sodium excretion, the

majority of Black patients with low P.R.A. levels (lessthan 1.0 ng. per ml. per hour) appear to have sup-pressed P.R.A. that cannot be stimulated with furose-mide, upright posture, intravenous diazoxide, or

intravenous hydrallazine. The mechanism of this

suppression of renin responsiveness has yet to be

adequately explained.Comparison of the patients in the present study

with those of the New York study reveals certainadditional differences (see table). The level of blood-pressure was higher in our low-renin hypertensivepatients and there was no significant difference inthe serum-creatinine in the three renin subgroups.By contrast, the high-renin group described byBrunner et al." showed significant elevations ofdiastolic blood-pressure and urea-nitrogen, and in-cluded a significant number of patients with retinalhaemorrhages and exudates. Thus, the supposedvasculotoxic effect of renin was based upon obser-vations on a group of patients with features ofaccelerated or malignant hypertension in whom

complications in the renal circulation had alreadycommenced.14 The mean serum-creatinine con-

centration in our patients with high renin levels andstrokes was significantly elevated, which is consistentwith the tendency to generalised vascular complica-tions in male patients with more marked elevationof diastolic blood-pressure. With regard to age, thedifference between the renin subgroups was not sig-nificant, but the patients with vascular complicationsshowed a significant inverse relation between age andrenin levels.A possible explanation for some of the differences

between our results and the New York study is that95% of our patients were referred to our clinic fromeither screening programmes or the hospital emer-gency room. Our patients therefore did not representa selected group of hypertensive patients but rather areasonable cross-section of the general Black hyper-tensive population. Similar studies in White patientswill have to be done to evaluate if race has a sig-nificant influence on the results reported here.

It was concluded on the basis of this study of 371hypertensive Black patients that plasma-reninactivity is not related to the incidence of myocardialinfarction or cerebrovascular accidents, that the

presence of high levels of plasma-renin activity donot appear to be

" vasculotoxic " (i.e., associated withmyocardial infarction or cerebrovascular accidents),and that low-renin hypertension is a common but asyet unexplained phenomenon in the urban Black

hypertensive population. Although the plasma-reninactivity was not related to the development of myo-cardial infarctions or cerebrovascular accidents, recog-nised risk factors such as age, sex, and elevated blood-

pressure were clearly important in the development ofthese complications. Therefore, we recommend thatall hypertensive patients should receive effective anti-hypertensive therapy regardless of the level of the

plasma-renin activity, and that " low-renin hyper-tension " should not be regarded as a benign con-dition.

Requests for reprints should be addressed to W. J. M., Box355, District of Columbia General Hospital, Washington, D.C.20003, U.S.A.

REFERENCES

1. Conn, J. W., Rovner, D. R., Cohen, E. L. Ann. intern. Med. 1965,63, 266.

2. Creditor, M. C., Loschky, U. K. Am. J. Med. 1967, 43, 371.3. Gunnels, J. C., Jr., Grim, C. E., Robinson, R. R., Wildermann,

N. M. Archs intern. Med. 1967, 119, 323.4. Harris, J. J., Cranne, M. G., Jones, V. J. Ann. intern. Med. 1967,

66, 1036.5. Kuchel, O., Fishman, L. M., Liddle, G. W., Michelakis, A. ibid.

1967, 67, 791.6. Ledingham, J. G. G., Bull, M. D., Laragh, J. H. Circulation Res.

1967, 20, suppl. II, p. ii.7. Creditor, M. D., Loschky, U. K. Circulation, 1968, 37, 1027.8. Kaneko, Y., Ikeda, T., Takeda, T., Inoue, G., Tagawa, H., Ueda, H.

ibid. 1968, 38, 353.9. Weinberger, M. H., Dowdy, A. J., Nokes, G. W., Luetscher, J. A.

J. clin. Endocr. Metab. 1968, 28, 359.10. Channick, B. J., Adlin, E. V., Marks, A. D. Archs intern. Med.

1969, 123, 131.11. Jose, A., Kaplan, N. M. ibid. p. 141.12. Jose, A., Crout, J. R., Kaplan, N. M. Ann. intern. Med. 1970, 72, 9.13. Melby, J. C., Dole, S. L., Wilson, T. E. Circulation Res. 1971, 28,

suppl. II, p. 143.14. Brunner, H. R., Laragh, J. H., Baer, L., Newton, M. A., Goodwin,

F. G., Krakoff, L. R., Bard, R. H., Buhler, F. R. New Engl. J.Med. 1972, 286, 441.

15. Laragh, J. H., Baer, L., Brunner, H. R., Buhler, F. R., Sealy, J. E.,Vaughan, E. D., Jr. Am. J. Med. 1972, 52, 633.

16. Laragh, J. J., Sealy, J., Brunner, H. R. ibid. 1972, 53, 649.

469

17. Laragh, J. H. (Editorial). Circulation, 1971, 44, 971.18. Editorial, Lancet, 1972, i, 1273.19. Editorial, Br. med. J. 1972, ii, 121.20. Boyle, E. ’J. Am. med. Ass. 1970, 213, 1637.21. Finnerty, F. A., Jr. (Editorial). ibid. 1971, 216, 1634.22. Rodbard, D., Lewald, J. E. Acta endocr. 1970, 64, suppl. 147, p. 79.23. Gulati, S. C., Adlin, E. V., Biddle, C. M., Marks, A. D., Channick,

B. J. (abstract). Ann. intern. Med. 1973, 78, 828.24. Doyle, A. E., Jerums, G., Johnson, C. I., Louis, W. J. Br. med. J.

1973, ii, 206.25. Genest, J., Boucher, R., Kuchel, O. Can. med. Ass. J. (in the press).26. Kem, D. C., Kramer, N. J., Blend, S., Hemphill, R., Gomez-

Sanchez, C., White, M., Kaplan, N. M. Clin. Res. 1972, 20, 776.27. Amery, A., Stroobanot, R., Fagard, R. (letter). New Engl. J. Med.

1973, 288, 267.28. Schalenkamp, M. A. D. H., Birkenhager, W. H. (letter). ibid. 1972,

286, 1319.29. Goldby, F. S., Beilin, L. J. (letter). Br. med. J. 1972, ii, 594.

CONTINUOUS POSITIVE-AIRWAY PRESSUREAFTER OPEN-HEART OPERATIONS IN

INFANCY

D. J. HATCHB. W. TAYLORW. J. GLOVER

J. J. COGSWELLE. F. BATTERSBY

A. A. KERR

Departments of Anœsthesia and Respiratory Function,The Hospital for Sick Children,

Great Ormond Street, London WC1N 3JH

Summary In an attempt to assess the effects ofcontinuous positive-airway pressure

(C.P.A.P.) on oxygenation, arterial blood-gas measure-ments were made on 13 infants between 2 and 24hours after open-heart operations. Samples were

taken during intermittent positive-pressure ventila-

tion, and also whilst breathing spontaneously before,during, and after the application of C.P.A.P. Inspiredoxygen concentration was kept constant for eachinfant. Total static compliance of the respiratorysystem was measured in 10 cases. The use of C.P.A.P.

produced a significant increase in arterial oxygen ten-sion in infants with preoperative pulmonary venousobstruction, and in these infants postoperative com-pliance was low. C.P.A.P. produced no significantchange in infants with transposition of the greatarteries or ventricular septal defect where postopera-tive compliance was normal. It is suggested that theuse of C.P.A.P. should be restricted to those conditionsin which pulmonary compliance is low.

Introduction

CONTINUOUS positive-airway pressure (C.P.A.P.) habeen shown to improve arterial oxygenation in adult:with advanced respiratory failure 1 and in newborrbabies with the idiopathic respiratory distress syn-drome (R.D.S.).2 The use of C.P.A.P. has now beeradvocated in the postoperative management of infantsundergoing major cardiac surgery.3This paper compares the effects of intermitteni

positive-pressure ventilation (I.P.P.V.) and spontaneousventilation with or without C.P.A.P. on the arteria:oxygen and carbon-dioxide tensions of infants afte]

open-heart operations. An attempt is made to corre-late changes in arterial oxygen tension with static

pulmonary compliance.

Subjects13 infants under 12 months of age were studied between

2 and 24 hours after open-heart operations (table i).Operations were performed during circulatory arrest withprofound hypothermia in all except 3 infants (nos. 1, 3,and 5) in whom cardiopulmonary bypass with moderatehypothermia was used.

Methods

Arterial blood-gas samples were drawn during Lr.r.v.,and also whilst breathing spontaneously before, during,and after the application of C.P.A.P. Samples were takenfrom an indwelling catheter in the radial or brachialartery after the 10 or 15 minute period allowed forstabilisation of arterial blood-gas levels. Inspired

TABLE I-AGE AND DIAGNOSIS OF 13 INFANTS STUDIED AFTER

CARDIAC SURGERY

oxygen fraction (Fio2) was measured with a Beckman

oxygen analyser (model D2S) before each arterial samplewas taken, and C.P.A.P. was kept constant throughout eachstudy. The concentration of oxygen depended on theclinical condition of the patient. Blood samples were

analysed immediately. Arterial oxygen tension (Pao2) wasmeasured by a Clark-type micro oxygen electrode (Radio-meter E5046) which was calibrated between samples. ThePaco2 was measured by Astrup’s method of intrapolationfrom the pH.4The circuit used for spontaneous ventilation with or

without C.P.A.P. was a humidified T-piece which could beapplied directly to the endotracheal tube (fig. 1). The

air/oxygen mixture was passed through a Bennett’ Cascade’ humidifier, and C.P.A.P. was applied by theaddition of one of a series of calibrated resistances to theopen end of the reservoir bag on the expiratory limb ofthe T-piece. The level of C.P.A.P. applied was checkedwith a K.D.G. Instruments aneroid manometer (model679195/1), and the circuit incorporated a safety blow-offvalve set at 20 cm. H20.

Static compliance of the whole respiratory system wasmeasured at the time of the arterial blood-gas study in10 of the infants by the method of Milner et a1.5

Results

Arterial oxygen tensions throughout each study areshown in table 11.

Group A.-In the 7 patients with transposition ofthe great arteries or ventricular septal defect, therewas no significant difference between postoperativearterial oxygen tensions measured during i.P.P.v. andthose measured during spontaneous ventilation with