Angioneurotic Edema, Agranulocytosis, and Fatal Septicemia following Captopril Therapy

MANUEL SUAREZ, M.D. Captopril, an angiotensin converting enzyme inhibitor used in the PETER WAN LYE HO, M.D. treatment of hypertension, has been associated with hematologic as EDWARD S. JOHNSON, M.D. well as dermatologic side effects. Two patients with captopril-induced GEORGE PEREZ, M.D. angioneurotic edema, one of whom had fatal granulocytopenia and

Newark, New Jersey

From the Division of infectious Diseases, De- partment of Internal Medicine, Saint Michael’s Medical Center, Newark, New Jersey. Requests for reprints should be addressed to Dr. Manuel Suarez, Division of Infectious Diseases, Depart- ment of Internal Medicine, Saint Michael’s Medi- cal Center, 306 Dr. Martin Luther King Boule- vard, Newark, New Jersey 07102. Manuscript accepted May 8, 1986.

overwhelming polymicrobial sepsis, are presented.

Captopril, an angiotensin converting enzyme inhibitor, has been used increasingly for the treatment of hypertension [1,2]. Numerous side effects have been noted with the administration of captopril. These include skin rash and atthralgias, partial or total suppression of the hematopoietic system, proteinuria and the nephrotic syndrome, com- plete and partial ageusia [3], and angioneurotic edema [4]. Fatal cases of pancytopenia have been reported [5,6]. We report two cases of severe captopril-induced angioneurotic edema, one with fatal agranulocytosis.

CASE REPORTS

Patient 1. A 49yearold black woman undergoing hemodialysis for end- stage renal disease secondary to chronic essential hypertension was admitted on February 25, 1984 for a one-week history of progressive facial edema and fever. The patient had been receiving furosemide and hydrala- zine therapy for many years. Because of increasing resistant hypertension, administration of captopril 150 mg per day divided into three doses had been initiated nine weeks prior to admission. Eight weeks after captopril therapy was begun, facial edema and a diffuse rash mainly on the upper trunk were noted. Captopril was immediately discontinued. Despite this, the facial edema worsened with severe bilateral periorbital involvement. One day prior to admission, a slight cough and fever developed. Seropurulent discharge was noted in the eyes bilaterally and she was unable to open her eyes. Physical examination at admission revealed a febrile patient with severe bilateral periorbital edema with seropurulent discharge (Figure 1). Gram stain of the discharge revealed gram-positive cocci in clusters. Blood and throat cultures were taken. Computed axial tomography of the brain with special focus on the orbits revealed marked symmetric soft tissue swelling of the eyelids and proptosis of the eyes. No evidence of retiobulbar inflammatory process was found, and the brain was normal. Admission laboratory tests revealed normal levels of electrolytes, glucose level 115 mg/dl, creatinine level 11.2 mg/dl, and negative results of indirect and direct Coombs’ test. The hematocrit was 22 percent, leukocyte count was 900/mm3 with a differential of 4 percent neutrophils and 96 percent lymphocytes, and platelet count was 186,000/mm3. Vancomycin, gentami- tin, and metronidazole were given intravenously. Bone marrow smear and biopsy revealed a reactive bone marrow with decreased granulocytic elements, compatible with a toxic drug effect. Blood cultures showed growth of Staphylococcus aureus and Pseudomonas aeruginosa. Piperacil- lin was added to the previous regimen. The patient had a cardiopulmonary arrest and died on February 27, 1984.

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Patient 2. A 55-year-old black man was admitted for hypertensive crisis. He was a known long-standing hyper- tensive patient with renal insufficiency. He also had a histo- ry of gout treated with colchicine. At the time of admission, the initial creatinine level was 6.3 mg/dl, and uric acid level was 9.4 mg/dl. After the hypertensive crisis was controlled with intravenous hydralazine, administration of sublingual nifedipine, oral prazosin, and transdermal nitrates was be- gun and doses were titrated to control his hypertension. On the fourth hospital day, captopril 12.5 mg three times daily was added and increased to 25 mg three times daily on the seventh hospital day. On the morning of the eighth hospital day, massive facial edema developed with mild swelling of the upper extremities and diffuse pruritus (Figure 2). The captopril was discontinued and the patient was treated with intravenous diphenhydramine hydrochloride and methyl- prednisolone sodium succinate. All other medications re- mained the same. The facial edema and pruritus cleared completely within 24 hours and the patient was discharged on the 12th hospital day.

COMMENTS

The combination of agranulocytosis and angioneurotic edema secondary to captopril therapy as seen in Patient 1 has not been previously reported. The agranulocytosis associated with captopril therapy has been seen in pa- tients with a wide range of underlying medical conditions [5,7]. Elijovisch and Krakoff [8] described agranulocytosis in a patient treated with captopril for resistant hyperten- sion after renal transplantation in whom S. aureus septi- cemia developed; the patient’s leukocyte count returned to normal after one week of withdrawal of the offending drug. Edwards et al [9] observed reversible neutropenia in, a patient with impaired renal function taking captopril at doses of 100 mg three times per day. When therapy was reinstituted at 12.5 mg three times per day, no neutro- penia was noted. In our patient, withdrawal of the drug was not accompanied by return of the leukocyte count to normal, and the patient had fatal septicemia.

Reports of captopril-induced angioneurotic edema are well documented [4]. The most common presentation is one in which high doses and long treatment with the drug have been present, along with some evidence of renal insufficiency. Potentiation of captopril-induced reactions, especially those involving the skin, has been documented with concomitant use of allopurinol [IO]; neither patient described was taking this drug. The onset of angioneurotic edema after only a few doses of the drug, especially small doses, is extremely rare. To our knowledge, Patient 2 had the lowest reported dosage causing this phenomenon. This would point to two different mechanisms by which captopril causes angioneurotic edema, one as an idiosyn- cratic reaction and one that is dose-related. The angio- neurotic edema caused by captopril therapy responds quickly to withdrawal of the drug along with treatment with antihistaminic and steroid agents, and unless associated with other complications, the episode of angioneurotic

Figure 1. Massive periorbital edema with seropurulent discharge present at time of admission.

Figure 2. Buccal edema that resolved completely after withdrawal of captopril and use of diphenhydramine hydr@ chloride.

edema resolves without further therapy and does not recur.

Captopril represents a considerable therapeutic ad- vance in certain patients with refractory hypertension. The most serious complication of agranulocytosis occurs usually between three and 12 weeks after the initiation of therapy [ Ill. Complete blood counts should be performed

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during this time, especially in those patients with signifi- ACKNOWLEDGMENT cant inderlying dis&ses.- Patients should be alerted to check with their physician shotild sore throat or fever develbp. New related compounds with equal efficacy and lower incidence of toxicity are currently in use in Europe and may soon be available in the United Siates.

This report is dedicated to the memory of Dr. Peter Wan Lye Ho, who passed away during the writing of this report. We also thank Ms. Joanne McKeown for her clerical help, as well as the Infectious Diseases department for their support.

REFERENCES

hypertensve patients Ann Intern Me: 1979; 90: 19-23. 2.

1. Brunner HR. Garras H, Waeber B, et al: Oral angiotensin

Atkinson AB, Lever AF, Brown JJ, Robertson JIS: Combined treatment of severe intractable hypertension with capto- pril and diuretic. Lancet 1980; II: 105-107.

3.

convertino enzvme inhibitor in lona term treatment of

Studer A, Luscher T, Greminge P, Siegenthaler W, Vetter W: Captopril in therapy resistant essential and renovascular hypertension. In: Brunner HR, Gross F, eds. Recent ad- vances in hypertension therapy: captopril. Amsterdam: Excerpta Medica, 1981; 31-40.

4. Wilkin JK, Hammond JJ, Kirkendale WM: The captopril in- duced eruption. Arch Dermatol 1980; 116: 9021965.

5. Gavras I, Graff LG, Rose BD, et al: Fatal pancytopenia associated with the use of captopril. Ann Intern Med 1981; 94: 158-159.

7. Captbpr/l. Benefits and risks in severe hypertension (editori- al). Lancet 1980; II: 129-130.

6.

8.

Safar ME: Fatal bone marrow suppression associated with

Elijovisch F, Krakoff LR: Captopril associated granulocyto- penia in hybertension after renal transplantation. Lancet

captopril. Br Med J 1961; 282: 791-792.

1980; I: 927-928. 9. Edwards CRW, Drury P, Penketh A, Damliyi SA: Successful

reintroduction of captopril following neutropenia (letter). Lancet 1981,; t: 723.

10. Samanta A, Burden AC: Fever, myalgia, and arthralgia in a patient on captopril and allopurinol (letter). Lancet 1984; I: 679.

11. Staessen J, Boogaerts M, Fagard R, Amery A: Mechanisms of captopril indutied agranulocytosis. Acta Clin Belg 1981; 36: 88-90.

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