Management of refractory heart failure

Management

of Refractory

Heart

Failure

N. BREST

By ALBERT

ATIENTS WITH CARDIAC DECOMPENSATION who fail to res,pond to the ordinary regimens of digitalis, diuretics, rest, and saIt restriction can be categorized as having refractory heart failure. Successful management in these cases demands a careful reexamination of the underlying cardiac disturbance, contributing factors, digitalis requirements, and adequacy of the diuretic drug regimen, Occasionally. mechanical measures, such as peritoneal dialysis, provide additional, important therapeutic impetus.

P

GENJXRAL APPROACH

A systematic approach should be applied routinely in the management of cardiac decompensation. In every case, it is important to define (1) the type of heart disease, (2) the conditions which precipitated the cardiac failure, and (3) the existence of any remediable factors contributing to the cardiac failure. The need to establish a correct cardiac diagnosis is self-evident. All necessary diagnostic methods should be employed. Equally important, however, is the need to recognize that invariably there are one or more disorders that precipitate cardiac failure. These disorders should be sought, rather than assumed, and actively treated. The most common initiating factors are infection, acute myocardial infarction, and arrhythmias. Pneumonia is the most frequent precipitating infection. Myocardial infarction may be responsible for heart failure, even though clinically silent. Similarly, arrhythmias, such as atria1 fibrillation, may precipitate or aggravate cardiac decompensation. Remediable extracardiac conditions may include inadequate restriction of physical activity or salt intake, or both. Inadequate dosage of digitalis can also contribute to refractory heart failure. Although toxic reactions to digitalis are prone to develop in patients with severe cardiac decompensation, it may nonetheless be helpful to increase digitalis dosage in certain instances. This should be done gradually with short-acting digitalis preparations, such as digoxin or gitalin. Use of the latter preparations allows for more rapid dissipation of untoward effects should digitalis intoxication occur. Increase in diuretic drug dosage, from the usual maintenance dosage to maximum effective dosage, may ako result in improved edema control. Occasionally, however, electrolyte imbalance induced by diuretics may contribute to refractoriness in patients previously responsive to diuretic therapy. Hyperkinetic states (such as hyperthyroidism, anemia, arteriovenous fistula, and fever), as well as certain pulmonary disturbances (including infection, emboli, and effusion), can also be included among the remediable extracardiac conditions contributing to heart failure. Finally, hypertension should be remembered as one of the most important of From the Pennsylvania

Division

ALBERTN. Philadelphia,

558

of

Cardiology,

BREST, M.D.: Pennsylvania. P~roc~rm

Jcferson

Division

IN

Medical

of Cardiology,

Ca~w10\-.4sc:u~.4n

College and Hospital, Jeferson

DISEASE,

Medical

\‘oL.

College

XII,

Philadelphia, and

No. 6 (\lay),

Hospital,

1970

MANACEMENT

OF REFRACTORY

HEART

FAILURE

559

the potentially remediable extracardiac causes of refractory cardiac failure. The recognition of remediable cardiac conditions responsible for refractory cardiac decompensation frequently requires a high index of clinical suspicion. These conditions include constrictive pericarditis, cardiac tumors, congenital heart defects, acquired valvular lesions, bacterial cndocarditis, myocarditis. and arrhythmias. TREATMENT

As described in the previous section, therapy for patients with refractory heart failure must begin with the establishment of a complete and accurate diagnosis and the correction of all remediable cardiac and extracardiac conditions. Secondly. optimal conditions for diuresis must be secured by establishing electrolyte balance, full digitalization, and bed rest. Few of these patients demonstrate an adequate diuresis with a single diuretic agent. Instead, they usually require combinations of potent diuretics. Special considerations regarding digitalis administration are discussed in the next section. DIGITALIS

Digitalis has long been considered the therapeutic sine qua non in the management of cardiac failure. As a result, the drug is often administered indiscriminately. Instead, the physician should recognize that there are situations in which digitalis is only relatively effective or ineffective, and that there are also situations where its use will exacerbate cardiac decompensation? Digitalis is most useful when heart failure results from chronic myocardial malfunction or from systolic or diastolic overload on the ventricles, e.g., cardiac decompensation due to coronary artery disease, cardiomyopathy, hypertension, or aortic valvular disease. On the other hand, the glycosides are much less effective when heart failure is due to active myocarditis, hyperkinetic disturbances such as thyrotoxicosis or anemia, or hypervolemic states such as acute glomerulonephritis. Furthermore, digitalis is ineffective when heart failure is due to extramyocardial causes, such as constrictive pericarditis or mitral stenosis with sinus rhythm. Administering digitalis in the latter situations merely exposes the patient to potential digitalis toxicity, without the likelihood that the cardiac failure will improve. Finally, there are cardiac conditions in which the glycosides wil1 worsen the congest& state. For example, in patients with idiopathic hypertrophic subaortic stenosis, the inotropic effect of digitalis generally acts only to increase the degree of left ventricular outflow tract obstruction and thereby to exacerbate rather than improve the cardiac failure.” It should also be recognized that digitalis toxicity may contribute to refracexcess may manifest itself as bradycardia or tory cardiac failure. Digitalis ta&ycar&a. Thus, a very slow ventricular response in the patient with atria1 fibrillation may reflect complete atrioventricular dissociation, or a rapid ventricular rate may represent nodal tachycardia. Such arrhythmias are easily overlooked or misdiagnosed. On the other hand, administration of additional digit& under such circumstances generally serves only to amplify the refractorv failure. Even worse, a fatal cardiac arrhythmia may be induced.

Finally, extracardiac conditions must be carefully assessed when detcrmining digitalis requirements. The usual digitalizing or maintcnancc dosages of the glycosides are influenced considerably by such factors as electrolyte balance or renal and hepatic function. Agents which promote potassium Ioss, e.g., diuretics or adrenal corticosteroids, may precipitate digitalis intoxication; hypercalcemia similarly enhances the arrhythmia-producing actions of the glycosides by the kidney and detoxification by the liver. Therefore, impaired renal or hepatic functions generally reduce digitalis needs. The hypoxic state associated with car pulmonale is also thought to increase the toxic actions of digitalis. Thus there are numerous extracardiac factors which influence digitalis requirements. Administration of ordinary digitalis dosages in these special situations exposes the patient unduly to digitalis toxicity and possible enhancement of refractory cardiac failure. DIURETIC DRUGS Thiazide Drugs and Related Sulfonamide Compounds. Since the synthesis of chlorothiazide in 1957, there have been numerous structural modifications of this molecule resulting in the introduction of many other benzothiadiazine derivatives (Table 1). In addition, two other related diuretics-chlorthalidone ( a phthalimidine compound ) and quinethazone ( a quinazoline compound) have been introduced. Although these two oral sulfonamide diuretics are not benzothiadiazine compounds, their pharmacodynamic actions, side effects and clinical application are essentially the same as those of the thiazide diuretics. These drugs are absorbed rapidly from the gastrointestinal tract. Their onset of action, as demonstrated by natriuresis, occurs within the first hour after oral administration. Their duration of action varies with the individual compound. Most of the thiazide drugs have a duration of action from 12 to 24 hours. Quinethazone exerts its diuretic effect for 18 to 24 hours, whereas chlorthalidone produces increased natriuresis for 48 to 72 hours. Despite much intensive investigation, the specific mechanism of action of the thiazide drugs has not been precisely defined. Although these agents have been shown to inhibit carbonic anhydrase in vitro and also at high dosage in viva, this action does not account for their diuretic activity; nor do they increase renal blood flow or rate of glomerular filtration. Instead, their primary pharmacodynamic mechanism is probably related to the inhibition of sodium and chloride reabsorption in the distal tubule.“,’ Administration of these agents produces an increase in the excretion of sodium, potassium, and chloride. Although the patterns of electrolyte excretion produced by these drugs vary slightly, it is doubtful that any one of these agents possesses pharmacologic properties that make it superior to the others. On the other hand, data on dose response clearly indicate that maximal natriuresis is achieved at dosages higher than those commonly employed; thus, the maximal effective dose of hydrochlorothiazide is between 200 and 300 mg instead of the usual daily dosage of 100 mg. The untoward effects encountered with these potent oral thiazide diuretics include biochemical alterations, systemic and hematologic effects, and metabolic changes.s-ll

?rfAXACEhfENT

OF REFRACTORY

HEART

Table

Generic

561

FAILURS

l.-Diuretic

Drugs

Name

Trade A.

Thiazides

Bendroflumethiazide Benzthiazide Chlorothiazide Cyclothiazide Hvdrochlorothiazide

and

Name

Related

Drugs

Hydroflumethiazide hlethyclothiazide Polythiazide Trichlonnethiazide Chlorthalidone Quinethazone

Renuron, Naturetin Exna Diuril Anhydron Esidrix, Hydrodiuril, Oretic Saluron Enduron Renese hletahydrin, Nacp~a Hygroton Hydromox

Meralluride hlercaptomerin

Mercuhydrin Thiomerin

B.

C. Spironolactone-A Triamterene

acid

Potassium-Sparing

Very

5-10 50-150 500-1500 2-4 50-150 50-150 5-10 2-8 4-8 50-100 50-150

Mercurials 2 cc 2 cc Drugs

Aldactone Dyrenium D.

Ethacnnic Fnrosemide

Usual Daily Dosage bg)

Potent

Edecrin Lasix

100 200 Diuretics 50-200 40-200

The thiazides and related sulfonamide diuretics are the agents of choice in the treatment of cardiac edema of mild to moderate severity. Despite diiferences in milligram potency among these drugs, maximal effective doses of the various compounds are approximately equipotent.12 Therefore, most patients with severe edema require more potent diuretics or combination diuretic drug therapy. Mercurial Diuretics. The parenteral mercurial diuretics, once the mainstay of the diuretic armamentarium, have been largely supplanted by the potent oral diuretics. However, the mercurial diuretics are still useful when a moderately rapid diuresis is needed or as adjunctivc measuresin combination with orally effective diuretic agents. Although oral mercurial diuretics are available, their erratic absorption and high incidence of gastrointestinal side effects markedly limit their clinical usefulness. When given intramuscularly, the organomercurials have an onset of action in I to 2 hours, with peak effect in about 6 hours and duration of action from I2 to 24 hours. The mercurial diuretics are normally excreted by the kidneys within 24 hours. In patients with impaired renal function, however, excretion may be greatly delayed, with possible cumulation and resultant toxicity. Mercurial diuretics act on the kidney to prevent the reabsorption of sodium,

562

ALBERT

N.

13l
chloride, and water. The natriuresis appears to par&l the excretion of the mercurial in the urine. It had long been considered that the mercurials exert their primary action in the proximal renal tubule, but more recent invcstigations indicate that the drug predominantly affects the distal renal tubuIc.lZ*l.~ Despite the relative safety of the parenteral organomercurials, a variety of untoward reactions have been reported.15 Parenteral mercurials arc recommended primarily for the following situations: ( 1) when a moderately rapid diuresis is desired; or (2) when companion therapy is required in patients who do not demonstrate an adequate response to oral diuretic therapy. Refractory edema can sometimes bc managed successfully by daily maintenance therapy with oral diuretics plus intermittent injections of parenteral mcrcurials. Finally, although most patients with hyperglycemia or hyperuricemia can bc effectively trcatcd with oral diuretics, occasionally it may be preferable to use intermittent parentrral mercurials in these patients to obviate the exacerbation of hyperglycemia or hyperuricemia. Potassium-Sparin, 0 Drugs. The spirolactone compound, spironolactone, is the only commercially available antialdosteronc agent whose pharmacodynamic mechanism of action is competitive inhibition with aldosterone. Although triamterene has natriuretic and antikaluretic properties in the presence or absence of aldosterone. its phartmaco,lo.gic actions and clinical efficacy are similar to those of spironolactone. At present, spironolactone and triamterene are the only commercially available diuretic agents that induce potassium-sparing effects.ls Spironolactone competitively antagonizes the effects of aldosterone and desoxycorticosterone. The drug has no effect in patients after udrenalcctomy and only slight action in normal subjects whose secretion of aldosterone is low. In addition to increasing excretion of sodium, spironolactone promotes retention of potassium and diminishes excretion of hydrogen. The drug has a relatively slow onset of action and must be continued for at least 3 days for maximal effect. Spironolactone-A, whose particulate form is finer than the original spironolactone, appears to be better absorbed. Correspondingly, its onset of action occurs somewhat earlier (8 to 24 hours), and maximal activity is observed 24 to 48 hours after oral administration. Trinmterene is a pteridine diuretic that acts primarily on the distal tubule. Like spironolactone, it promotes potassium retention; however, in contrast, it also exerts a diuretic action in animals after adrenalectomy. Diuresis may be observed with triamterene during the first day of therapy, but maximal effects usually are not seen for several days. The most important potential untoward effect encountered with these agents Therefore, potassium supplementation should not be given is hyperkalemia. these agents should be used concomitantly with these drugs. Furthermore, with caution in patients with impairment of renal function. In all instances, periodic determinations of the serum potassium level should be obtained. Since neither spironolactone nor triamterene is a potent diuretic drug when used alone, it is recommended that these agents be used in combination with

MANAGEMENT

OF REFRACTORY

HEART

FAILVRE

563

other, more potent diuretic agents. When either drug is administered with mercurials, thiazides, ethacrynic acid, or furosemide, true synergism occurs, and the potassium loss produced by the more potent diuretic agents is reduced. In the presence of secondary aldosteronism, as observed in patients with refractory heart failure, these drugs are particularly effective. In some patients with marked secondary aldostcronism, spironolactone or triamtcrene alone mav elicit a significant diuresis. Amihide (MK 870) is a recently developed, nonsteroidal potassium-sparing drug that is currently under investigation. Like triamterene, this newer agent exerts a direct pharmacodynamic action on the distal tubule, and its natriuretic and antikaluretic effects are exhibited in the presence, as well as in the absence, of endogenous aldosterone. In our studies, both the natriuretic and antikaluretic effects of the newer drug appear to bc greater than those of triamtercne.17 However, both drugs reversed the kalurctic effect of hydrochlorothiazide to the same extent. Ethacrynic Acid and Furosemide. These newer agents are structurally unrelated to the thiazide, quinazoline, or phthalimidine compounds. Ethacrynic acid is an alpha beta unsaturated ketone derivative of aryloxyacetic acid. Furosemide differs from the thiazides in that the thiadiazine ring has been replaced by a furfuryl group on the amino nitrogen of the anthranilic acid. These two drugs appear to have a common pharmacodynamic mechanism of action and both are characterized by very marked diuretic potency.18,19 The onset of action after oral administration of either drug occurs in about 1 hour, and duration of action is from 6 to 8 hours. The onset of activity and the time of peak action occur much earlier with parenteral administration, Peak natriuretic and diuretic effects occur within the first hour of intravenous administration, and onset of action is ahnost immediate. The mode of action of these drugs appears to be significantly different from that of other diuretic agents. Specifically, they inhibit the reabsorption of sodium in the ascending limb of the loop of Her&. This unique mechanism accounts for their marked natriuretic and diuretic potency, which is greater than that of any of the aforementioned agents. Excretion of potassium and hydrogen is also increased, but to a lesser extent than excretion of sodium and chloride. The major side effects encountered with these drugs are due to their marked diuretic potency.?O The potential untoward effects include hyponatremia, hypokalcmia and hypochloremic alkalosis. In addition, excessive diuresis may result in dehydration and reduction in blood volume resulting in circulatory collapse and the possibility of vascular thrombosis and embolism. Excessive loss of potassium in patients receiving digitalis may precipitate digitalis toxicity, Metabolic changes may include hyperuriccmia and hyperglycemia. Other untoward effects that have been encountered are agranulocytosis and acute transient hearing lo~s.~~J~ In contrast with other diuretic agents, these two drugs may be remarkably effective even when renal function is substantially impaired. Their ability to reduce renal vascular resistance and to readjust blood flow within the renal parcnchyma (from the inner cortex and outer medulla to the outer cortical re-

gion) apparently account, at least in part, for their beneficial activity under conditions of reduced renal function.Z3’Z4 Because of their great potency, these drugs should be reserved for those conditions of edema that are refractory to treatment with less potent diuretic compounds. However, as already indicated, they may be uniquely useful in states of edema with coexistent renal insufficiency. In addition, because of their rapid onset of activity and marked diuretic potency, these drugs administered parenterally have become the diuretics of choice in the treatment of acute pulmonary edema. Combination Diuretic Drug Therapy. There are no data available to indicate that the combination of two thiazides (or related sulfonamide diuretics) will yield any greater natriuretic or diuretic effect than that obtained with maximal dosage of any one thiazide diuretic. On the other hand, the diuretic efficacy of the thiazides can be enhanced by combined therapy with ( 1) a mercurial diuretic, (2) ethacrynic acid or furosemide, (3) spironolactone or triamterene, or (4) a carbonic anhydrase inhibitor such as acetazolamide.25-28 Similarly, the natriuretic response to ethacrynic acid or furosemide can be increased by combining either drug with (1) a thiazide diuretic, (2) spironolactone or triamterene, or (3) a carbonic anhydrase inhibitor. Furthermore, the co-administration of ethacrynic acid or furosemide with spironolactone or triamterene plus a thiazide diuretic or acetazolamide, or both, will often yield natriuretic effects that equal or exceed the additive effects obtained when these drugs are given separately. The potentiated effects induced by the latter (triple or quadruple drug) regimens are achieved presumably because these several diuretic agents act by different mechanisms and, in some cases, at different sites in the nephron. An overall diuretic regimen for patients with cardiac edema is summarized in Table 2. With the availability of more potent diuretic agents, acetazolamide or other acidifying drugs are rarely used alone in the treatment of cardiac edema. HowTable

B.-Diuretic

Drug

Initial

Therapy

Severity Mild Moderate

Chlorothiazide* Chlorothiazdie* potassium-sparing

Management

of Cardiac

Failure Additions, If Necessary

Potassium-sparing

dmgf

plus

Mercurial

dqf

Severe

or Ethacrynic acid furosemide Ethacrynic acid plus potassium

or

Potassium-sparing

or furosemide sparing

Chlorothiazide”

dmgf

dmgf “May use results.

other

thiazide,

phthalimidine,

fTriamterene or spironolactone.

or

quinazoline

diuretics

with

equally

good

MANAGEMENT

OF REFRACTORylIEART

FAILUR'?

565

ever, as indicated previously, significant benefit may be obtained by combining a carbonic anhydrase inhibitor with other agents. The unusual benefit achieved by the combination of acetazolamide with ethacrynic acid or furosemide probably occurs because acetazolamide depresses proximal tubular reabsorption of sodium bicarbonate, thereby delivering more sodium to the loop of Henle, where the more potent diuretics arc active. The osmotic diuretics, such (1s mnnnitol, block the reabsorption of sodium and water at the proximal tubule. In addition, mannitol exhibits certain beneficial renal hemodynamic effects, including decrease in renal vascular resistance and increase in renal blood flow. Accordingly, mannitol may at times be useful in the management of refractory cardiac edema, especially when used in combination with distal tubular blocking drugs such as mercurials, thiazides, or ethacrynic acid or furosemide.2g A potential deleterious effect after infusion of mannitol is cardiocirculatory overload, owing to increase in plasma volume; however, the transient hypervolemia is usually rapidly overcome by the accompanying diuresis. DIALYSIS

If the previously described regimens fail to control refractory heart failure, hemodialysis or peritoneal dialysis should be considered.“OJ1 Because peritoneal dialysis is usually more effective in removing fluid, it is most commonly employed. Twenty-four to thirty-six hours of peritoneal dialysis with a solution of 1000 cc of 1.5 per cent dextrose mixed with 1000 cc of 7 per cent dextrose per exchange can result in the removal of 10 to 15 pounds of edema fluid while correcting or maintaining internal electrolyte balance. Dialysis represents an effective means of removing water in excess of sodium, and, therefore, may be especially valuable in controlling dilutional hyponatremia.3” Dialysis may also be useful in treating refractory cardiac edema associated with renal failure. In addition, responsiveness to diuretic agents may at times be restored following dialysis.“” OTHER

THERAPY

Thoracentesis or abdominal paracentesis may, at times, markedly facilitate a diuretic response. Also, an occasional patient with refractory cardiac decompensation improves after a course of radioiodine therapy, despite a prior euthyroid status.34 Other approaches to therapy include attempts to use mechanical devices, such as cardiopulmonary bypass with either pump oxygenators or mechanical pumps, and methods to provide diastolic augmentation of the circulation with aortic balloon inflation and counterpulsation for short periods.35-37 SUMMARY

When dealing with refractory heart failure, the physician should first secure a complete and accurate diagnosis. Then all remediable cardiac and extracardisc conditions should be corrected, Next, he should attain optimal conditions for diuresis by establishing electrolyte balance, full digitalization, and complete bed rest. Once these conditions have been achieved, diuresis in patients

566

ALBERT

N.

BREST

with so-called refractory edema can usuaIIy be achieved by using combination diuretic drug therapy. Dialytic procedures may be useful in patients with otherwise intractable cardiac decompensation. REFERENCES 1. Mason, D. T., and Braunwald, E.: Digitalis and related preparations. In Brest, A. N., and Moyer, J. H. (Eds.): Cardiovascular Disorders. Philaddphia, F. A. Davis, 1968, p. 383. 2. Braunwald, E., Brockenbrough, E. D., and Frye, R. L.: Studies on digitalis. V. Comparison of the effects of oubain on left ventricular dynamics in valvular aortic stenosis and hypertrophic subaortic stenosis. Circulation 26:166, 1962. 3. Beyer, K. H.: The mechanism of action of chlorothiazide. Ann N. Y. Acad. Sci. 71: 363, 1958. 4. Walker, W. G., and Cooke, C. R.: Diuretics and electrolyte abnormalities in congestive heart failure. Mod. Cont. Cardiovast. Dis. 34:7, 1965. 5. Baker, D., Schroder, W., and Hitchcock, C.: Small bowel ulceration apparently associated with thiazide and potassium therapy. J.A.M.A. 190:586, 1964. 6. Brest, A. N., and Moyer, J. H.: Untoward effects of diuretic drugs, J. Med. Ass. Pennsylvania 66:27, 1963. 7. Bjomberg, A., and Gisslen, zides: A cause of necrotizing Lancet 2:982, 1965.

H.: Thiavasculitis?

8. Post, J.: Yellow vision in a patient taking chlorothiazide. New Eng. J. Med. 263: 398, 1960. 9. Rodriguez, S. U., Leikin, S. L., and Hiller, M.D.: Neonatal thrombocytopenia associated with antepartum administration of thiazide drugs. New Eng. J. Med. 270: 881, 1964. 10. Brest, A. N., Heider, C., Mehbod, H., and Onesti, G.: Drug control of diureticinduced hyperuricemia. J.A.M.A. 195:42, 1966. 11. Rapoport, M. I., and Hurd, H. F.: Thiazide-induced glucose intolerance treated with potassium. Arch. Intern. Med. 113:405, 1964. 12. Swartz, C., Seller, R., Fuchs, M., Brest, A. N., and Moyer, J. H.: Five years’ experience with the evaluation of diuretic agents. Circulation Z&1042, 1963. 13. Vander, A. J., Malvin, R. L., Wilde,

W. S., and Sullivan, L. P.: Localization of the site of action of mercurial diuretics by the stop flow technique. Amer. J. Physiol. 195:558, 1958. 14. Levitt, M. F., Goldstein. M. H., Lenz, P. R., and Wedeen, R.: Mercurial diuretics. Ann. N. Y. Acad. Sci. 139:375, 1966. 15. Brest, A. N., Seller, R., Onesti, G., Ramirez, O., Swartz, C., and Moyer, J. H.: Clinical selection of diuretic drugs in the management of cardiac edema. Amer. J. Cardiol. 22:168, 1968. IG. onists

Sci.

Liddle, C. W.: and triamterene. 139:466, 1966.

Aldosterone Ann. N.

Y.

antagAcad.

17. Schwartz, A., Seller, R. Onesti, G., Kim. Ii.. Swartz, C., and Brest, A. N.: Phamracodynamic effects of a new potassimn-sparing diuretic, amiloride. J. Clin. Phamracol. 9217, 1969. 18. Brest, A. N., Onesti, G., Seller, R., Ramirez, O., Heider, C., and Moyer, J. H.: Pharmacodynamic effects of a new diuretic drug, ethacrynic acid. Amer. J, Cardiol., 16:99,

1965.

19. Brest, A. N., Seller, R., Ramirez, O., Onesti, G., and Moyer, J. H.: Comparative diuretic efficacy of furosemide. J. New Drugs 5:329, 1965. 20. Hilton, J. G., and Kessler, E.: Toxic reactions to ethacrynic acid, a new oral diuretic. J. New Drugs 4:93, 1964. 21. Walker, complicating Ann. Intern.

J. C.: Fatal treatment with Med. 64:1303,

agranulocytosis ethacxynic acid. 1966.

22. Schneider, W. J., and Becker, E. L.: Acute transient hearing loss after ethacrynic acid therapy. Arch. Intern. Med. 117:715, 1966. 2.3. Hook, J. B., Blatt, A. H., Brody, M. J., and Williamson, H. E.: Effects of several saluretic-diuretic agents on renal hemodynamics. J. Pharmacol. Exp. Ther. 154:667, 1966. 24. Barger, A. C.: Renal hemodynamic factors in congestive heart failure. Ann. N. Y, Acad. Sci. 139:276, 1966. 25. Seller, R. H., Fuchs, M., Swartz, C., Brest. A. N.. and Mover, 1. H.: Treatment

MANAGEMENT

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FAILURE

of edema by the combined administration of chemically different diuretic agents. Amer. J. Cnrdiol. 12:828, 1963. 26. Seller, R. H., Swartz, C., RamirezMuxo, O., Brest, A. N., and Moyer, J. H.: Aldosterone antagonists in diuretic therapy. Arch. Intern. Med. 113:350, 1964. 27. Detth, L., and Spring, P.: Therapy with combinations of diuretic agents. Ann. N. Y. Acad. Sci. 139:471, 1966. 28. Laragh, J. H., Cannon, P. J., Stason, W. B., and Heinemann, H. 0.: Physiologic and clinical observations on furosemide and ethacrynic acid. Ann. N. Y. Acad. Sci. 139: 453, 1966. 29. Barry, K. G, and Elkins, J. T.: Mannitol infusion: An effective foundation for diuresis in the treatment of ascites. In Mazzie, R. I., and Barry, K. G. (Eds.): Symposium on the Clinical and Experimental lrse of Mannitol. Washington, Walter Reed Army Institute of Research. 1962, p. 29. 30. Schmeierson, S. J.: Continuous peritoneal irrigation in the treatment of intractable edema of cardiac origin. Amer. J. Med. Sci. 218:76, 1949. 31. Bercu, V., Heinz, J. N., and Anderson, R.: Treatment of congestive failure

567

with peritoneal dialysis. J. hlich. Med. Sci. 62:1105, 1963. 32. Cairns, K. B.. Porter, G. A., Kloster, F. E., Bristow, J. D., and Griswold, H. E.: Clinical and hemodynamic results of peritoneal dialysis for severe cardiac failure. Amer. Heart J. 76:227, 1968. 33. Mailloux, L. U., Swartz, C. D., Onesti G., Heider, C.. Ramirez, O., and Brest, A. N.: Peritoneal dialysis for refractory congestive heart failure. J.A.M.A. 199: 873, 1967. 34. Blumgart, H. L., Freedburg, A. S., and Kurland, C. S.: Radioactive iodine in the treatment of angina pectoris and congestive heart failure. Circulation 16: 110, 1957. 35. Kirsch, U. E., Nasseri, M., and Bucherl, E. S.: Left ventricular bypass in experimental left heart failure. Trans. Amer. Sot. Artif. Intern. Organs 12:53, 1966. 36. Brown, B. G., Goldfarb, D., Topaz, S. R., and Gott, V. L.: Diastolic augmentation by intraaortic balloon. Circulatory hemodynamics and treatment of severe, acute left ventricular failure in dogs. J. Thorac. Cardiovasc. Surg. 53:789, 1967. 37. Cooper, T., and Dempsey, P. J.: Assisted circulation. Mod. Corm. Cardiovasc. Dis. 37:95, 1968.