Ethacrynic acid can be effective for refractory congestive heart failure and ascites.

Abstract: Ethacrynic acid is a loop diuretic little used today because of its side-effect profile and the availability of multiple alternative agents. However, in our clinical experience, ethacrynic acid can alleviate acute congestive heart failure and ascites resistant to other diuretics. Two patients aged 89 and 94 in life-threatening pulmonary edema were stabilized by ethacrynic acid after furosemide proved ineffective. A third patient, aged 83, with a pleural effusion and ascites secondary to end-stage hepatitis B and C, responded to ethacrynic acid when spironolactone and furosemide produced little urine output. Ethacrynic acid may have a unique niche as a diuretic of last resort, especially in geriatric practice.

Key Words: ascites, ethacrynic acid, heart failure

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Ethacrynic acid is a loop diuretic that was first introduced in the 1960s for treatment of congestive heart failure (CHF) and ascites (1-3) Although extremely potent, ethacrynic acid has been almost completely superseded by furosemide and bumetanide because ethacrynic acid has enhanced ototoxicity and vestibulotoxicity. (4-6) Ethacrynic acid is now mainly reserved for patients with severe sulfonamide allergies that preclude the use of other loop diuretics. (4) We present here three case histories illustrating how the efficacy of ethacrynic acid sometimes outweighs potential side effects. These patients, under our care from 1999 to 2003, all were frail elderly patients with multiple comorbidities who otherwise would have required dialysis, mechanical ventilation, or invasive procedures.

Discussion

For all three patients reported here, administration of ethacrynic was accompanied by decisive improvement. This result was seen for ethacrynic acid monotherapy (Patients 1 and 2) and with spironolactone as an augmenting agent (Patient 3). Our vignettes suggest that ethacrynic acid is sometimes superior to furosemide, allowing treatment of refractory heart failure and ascites at a relatively low cost even in patients older than 80 years. Given the rapidly increasing expenditures for care in the last 6 months of life, more detailed clinical studies of ethacrynic acid in the future would be of tremendous value, especially large-scale head-to-head comparisons against furosemide with comparisons in systolic versus diastolic heart failure and noncardiac ascites. Currently, data relating to ethacrynic acid are limited. A few dozen smaller clinical studies and case reports attest to the value of ethacrynic acid, most dating before 1980, but there are no multicenter, randomized, placebo-controlled trials, which are the "gold standard" of evidence-based medicine. Recent research has focused on the possible use of ethacrynic acid in cancer chemotherapy rather than in heart failure. (7) Reflecting the lack of demand for ethacrynic acid, the sole supplier in the United States, Merck, had discontinued production of oral ethacrynic acid in 2002, although the IV form is still available. Merck anticipates bringing back the oral preparation in the last quarter of 2003 (Merck company headquarters, personal communication).

Further basic science investigations into the renal physiology of ethacrynic acid would also be very useful. It is currently believed that ethacrynic acid acts primarily on the [Na.sup.+][K.sup.+] -ATPase of the ascending loop of Henle, whereas furosemide acts throughout most of the entire nephron, although the ascending loop of Henle is still the primary site of action. (3) Perhaps the fact that ethacrynic acid binds to a cysteine complex might be the reason that ethacrynic acid can have a pharmacologic effect even after furosemide-binding sites are saturated or down-regulated. In this way, ethacrynic acid can ameliorate hypervolemic states that are the final common pathway of both cardiac and noncardiac causes.

Conclusion

In the absence of experimentally validated protocols, for now, clinicians should simply keep ethacrynic acid in mind as a final diuretic to be tried before either giving up or resorting to invasive interventions. It is hoped that this article will be a catalyst for the re-examination of ethacrynic acid by physicians in private practice and in academia. Inexpensive, postpatent wonder drugs are needed now more than ever.

Key Points

* Ethacrynic acid is little used today because of ototoxicity, but this concern must be balanced against the immediate clinical acuity if other diuretics prove ineffective.

* Two patients with life-threatening congestive heart failure unresponsive to furosemide were successfully treated with intravenous ethacrynic acid.

* A third patient with ascites and a pleural effusion secondary to liver cirrhosis had minimal urine output from high doses of spironolactone and furosemide but diuresed more than 5 L urine in 2 days with ethacrynic acid.

* Clinicians should be aware of ethacrynic acid as part of the available armamentarium for treating congestive heart failure and liver cirrhosis.

Man is never happy, but spends his whole life striving After something he thinks will make him so.

--Arthur Schopenhauer

From the Division of General Internal Medicine, Marshfield Clinic, and the Marshfield Clinic Research Foundation (JMA), Marshfield, and the Victory Medical Center (TFT), Stanley, WI.

We have no proprietary interest in any of the medications discussed in this article.

Reprint requests to Joseph M. Alisky, MD, PhD, Division of General Internal Medicine, Marshfield Clinic-Thorp Center, 704 South Clark, Thorp, WI 54771. Email: [e-mail]

Accepted May 13, 2003.

Copyright [c] 2003 by The Southern Medical Association

0038-4348/03/9611-1148

References

1. Siegel W, Gifford RW Jr. Efficacy of ethacrynic acid in patients with refractory congestive heart failure resistant to meralluride. Am J Cardiol 1968;22:260-265.

2. Lieberman FL, Reynolds TB. The use of ethacrynic acid in patients with cirrhosis and ascites. Gastroenterology 1965;49:531-538.

3. Davies DL, Wilson GM. Diuretics: Mechanism of action and clinical application. Drugs 1975;9:178-226.

4. Wall GC, Bigner D, Craig S. Ethacrynic acid and the sulfa-sensitive patient. Arch Intern Med 2003;163:116-117.

5. Gomolin IH, Garschick E. Ethacrynic acid-induced deafness accompanied by nystagmus. N Engl J Med 1980;303:702 (letter).

6. Mathog RH. Vestibulotoxicity of ethacrynic acid. Laryngoscope 1977;87:1791-1808.

7. Caffrey PB, Zhu M, Zhang Y, et al. Rapid development of glutathione-S-transferase-dependent drug resistance in vitro and its prevention by ethacrynic acid. Cancer Lett 1999;136:47-52.

RELATED ARTICLE: Case Reports

Patient 1

An 89-year-old woman with a history of recurrent CHF secondary to hypertensive cardiomyopathy (three hospitalizations in 3 months, systolic and diastolic dysfunction by echocardiogram, ejection fraction of 40%, on home oxygen at 2 L/min), type 2 diabetes, and chronic renal insufficiency (glomerular filtration rate of 20 ml/min) was undergoing rehabilitation after hospitalization for pyelonephritis when her oxygen saturation dropped acutely from 92% to 60% on 6 L of oxygen by nasal cannula. The patient had previously specified that she wanted medical management only, and mechanical ventilation was not an option. With morphine and sublingual nitroglycerine and 100% oxygen by nonrebreather mask, her saturation reached 80%. Chest film showed pulmonary vascular congestion and large bilateral pleural effusions new from a film 3 days previously. IV furosemide at 120 mg with 5 mg of oral metolazone did not produce any diuresis; these doses had always been effective during previous hospitalizations. IV ethacrynic acid was administered at 50 mg, restoring urine output and improving oxygen saturation to 92% on the nonbreather mask 2 hours after the infusion. A second IV 50-mg dose was administered, and 4 hours after the initial decompensation she was maintaining a saturation of 95% on 6 L of oxygen by nasal cannula. IV ethacrynic acid was then scheduled at 100 mg twice daily for the next 4 days, by which time pulmonary edema and pleural effusions had completely resolved and oxygen saturation was greater than 95% on room air. At this point, ethacrynic acid was discontinued, and the patient was restarted on oral furosemide and metolazone. She was discharged 10 days later still requiring no supplemental oxygen.

Patient 2

A 94-year-old white woman with atrial fibrillation and hypertension underwent emergent surgery to resect an acutely obstructing colon cancer. Preoperative echocardiographic measurement of systolic function was not available. The postoperative course was complicated by hypotension and sepsis. By the second postoperative day, the patient was in oliguric renal failure and pulmonary edema, with pulmonary capillary wedge pressures of 24 mm Hg and oxygen saturation at 87% on 5 L of oxygen by nasal cannula. IV furosemide at a dose of 180 mg and renal dose dopamine yielded no improvement. As with the first patient, an advanced directive specified conservative medical management only, preempting consideration of mechanical ventilation or renal dialysis. On postoperative Day 3, furosemide was discontinued in favor of IV ethacrynic acid. The dose was 100 mg twice daily on Days 3 to 4, 50 mg twice daily on Day 5, and 25 mg once a day on Day 7. Urine output was restored with the first dose of ethacrynic acid, pulmonary edema quickly resolved, and serum creatinine peaked at 3.1 mg/dl from a baseline of 1.4 mg/dl. The patient was maintained in a state of nonoliguric renal failure and transferred out of intensive care on postoperative Day 7, receiving oral ethacrynic acid 25 mg daily. After a 3-week course of physical therapy, serum creatinine was 1.7 mg/dl, and the patient was discharged to a nursing home on oral ethacrynic acid at 25 mg/d. Four months later, the patient died as a result of a deep venous thrombosis and new metastases from the original colon cancer. At the time of presentation, she was still taking ethacrynic acid at 25 mg/d, serum creatinine was 1.6 mg/dl, and she had had no congestive heart failure hospitalizations in the interval history.

Patient 3

An 83-year-old white man with coronary artery disease, prostate cancer, obesity, type 2 diabetes mellitus, and hypertension was admitted with progressive shortness of breath and lower-extremity edema. Computed tomographic scan showed prominent ascites, a cirrhotic liver, and a left pleural effusion. The patient proved to have end-stage liver cirrhosis secondary to hepatitis B and C rather than heart failure. Brain natriuretic peptide was 76 pg/ml (<100 pg/ml correlating with absence of heart failure), and amylase was 20 U/L (normal, 25-125 U/L), aspartate aminotransferase was 132 U/L (normal, 8-20 U/L), and alanine aminotransferase was 105 U/L (normal, 8-20 U/L). Serologies were positive for both hepatitis B and C. After an unsuccessful attempt to perform a thoracentesis, the patient was begun on IV furosemide 40 mg/d and oral spironolactone at 25 mg. There was no diuresis of the pleural effusion or the ascites even with steadily escalating doses of both furosemide and spironolactone (up to 80 mg of furosemide and 400 mg of spironolactone daily), as evidenced by lack of significant urine output, decreased pleural effusion on chest film, and decreased palpable fluid wave by physical examination. On the fifth hospital day, furosemide but not spironolactone was discontinued; IV ethacrynic acid was initiated at 100 mg twice daily. The patient diuresed 5.5 L over the next 2 days, improving walking and mobility enough to delay nursing home placement at least for the short term. The patient was discharged to home on oral ethacrynic acid at 100 mg/d and spironolactone at 100 mg four times per day.

Joseph M. Alisky, MD, PHD, and Thomas F. Tuttle, MD