TRANSIENT AND PERMANENT DEAFNESS FOLLOWING TREATMENT WITH ETHACRYNIC ACID IN RENAL FAILURE

77

(4 x 10’ per ml.). jejunum and ileum.

Net

water

secretion

was

noted in the

After 3 weeks on a standard diet, the patient had gained 2’3 kg. and was passing one to two formed stools per day. However, he continued to have steatorrhoea and diminished vitamin-B12 absorption. At this point, tetracycline (250 mg. q.i.d.) was administered. After 48 hours of treatment, vitaminB12 urinary excretion had risen to 7-9% and xylose was increased to 4-1 g. per 24 hours; three consecutive fsecal fat excretions were 3-3, 2-5, and 2-2 g. per 24 hours, respectively. No coliforms or anaerobes could be isolated from the small intestine. Net water movement was now reversed in the jejunum and ileum leading to normal water absorption in both areas.

Sequential sampling

Discussion of the small intestine of six patients

with idiopathic tropical malabsorption syndrome revealed abnormalities of the microflora (mostly coliforms) in the upper small bowel. That these microorganisms interfered with absorptive processes is suggested by the correlation between the degree of bacteriological abnormality and vitamin-B12 absorption and also by the effect of antibiotics. Two patients were investigated after only 48 hours of tetracycline treatment in order to examine the immediate results of bacterial clearance before a new mucosal-cell population was established: Lipkin et al. (1963) suggested that epithelial cell turnover in the human intestine takes 3-5 days. In this manner, the dramatic improvement in vitamin-B12 and fat absorption and net water flux could be directly related to reductions in the bacterial populations. Previous work on small-bowel microflora in tropical sprue is often described as being inconclusive but in fact these earlier data are not entirely inconsistent with our findings. Intubation specimens were generally obtained from the upper jejunum: Desai et al. (1966) reported that seven patients (out of twenty-eight) had coliforms and five others had other intestinal bacteria; Milanes et al. (1946) found seven patients positive for coliforms out of twentyone ; Nadel and Gardner (1956) found two out of six " old sprue " cases harboured coliforms; and Klipstein et al. (1966) noted that three of six cases had coliforms in the jejunum. In our series, only three of six cases were positive for coliforms at the upper jejunal site, but examination of more distal sites revealed abnormalities of the microflora in the other three patients. The major disagreement concerns the definition of what is normal small-bowel microflora in people living in the tropics. Eight healthy Bengalis had only a few coliforms in the upper ileum and none in the jejunum. Using these guidelines, all six patients with idiopathic malabsorption syndrome had abnormal small-bowel microflora. Although the two patients treated with short-term antibiotics showed dramatic improvement, there was still some evidence of residual impairment of intestinal function. Similar findings have been previously reported by other investigators (Booth and Mollin 1964, Guerra et al. 1965). In the patient with chronic malabsorption (case 1), microorgnaisms were reduced but could not be completely eliminated from the small bowel due to the emergence of antibiotic-resistant strains. However, even when the microorganisms could be totally suppressed in the small bowel (as in case 3), vitamin-B12 and xylose absorption still remained slightly below normal levels. This suggests an underlying mucosal defect contributing to the mal-

absorption. This investigation was partially supported by U.S. Public Health Service research grants no. 5R07 TW00141-06, no. AI 07628-01, and no. 5x4317 from the National Institutes of Health.

Requests for reprints should be addressed to S. L. G., the Johns Hopkins University Center for Medical Research and Training, 4A Orient

Row, Calcutta 17, India. REFERENCES

Baker, A. J., Mathan, V. I., Joseph, I. (1962) Wld. Congr. Gastroent. 2, 4. Banwell, J. G., Pierce, N. F., Mitra, R., Caranasos, G. J., Keimowitz, R. I., Mondal, A., Manji, P. M. (1968) Indian J. med. Res. 56, 633. Booth, C. C., Mollin, D. L. (1964) Am. J. digest. Dis. 9, 770. Desai, H. G., Parekh, D. V. Jeejeebhoy, K. N. (1966) J. Ass. Physns India, 14, 203. French, J. M., Gaddie, R., Smith, N. M. (1956) Q. Jl Med. 25, 333. Gorbach, S. L., Plaut, A. G., Spanknebel, G., Levitan, R., Weinstein, L. (1967) Gastroenterology, 53, 856. Tabaqchali, S. (1969). Unpublished. Guerra, R., Wheby, M. S., Bayless, T. M. (1965) Ann. inter. Med. 63, 619. King, M. J., Joske, R. A. (1960) Br. med. J. i, 1324. Klipstein, F. A., Samloff, I. M., Schenk, E. A. (1966) Ann. intern. Med. 64, 575. Lipkin, M., Sherlock, P., Bell, B. (1963) Gastroenterology, 45, 721. Milanes, F., Curbelo, A., Rodriguez, A., Kouri, P., Spies, T. D. (1946) ibid. 7, 306. Nadel, H., Gardner, F. H. (1956) Am. J. trop. Med. 5, 686. Roe, J. G., Rice, E. W. (1948) J. biol. Chem. 173, 507. Sheehy, T. W., Cohen, W. C., Wallace, D. K., Legters, L. J. (1965) J. Am. med. Ass. 194, 1069. Tabaqchali, S., Booth, C. C. (1967) Br. med. Bull. 23, 285. van de Kamer, J. H., ten Bokkel Hinink, H., Weyers, H. A. (1949) J. biol. Chem. 177, 347. Whalen, G. E., Harris, J. A., Geenen, J. E., Soergal, K. H. (1966) Gastroenterology, 51, 975. —

TRANSIENT AND PERMANENT DEAFNESS FOLLOWING TREATMENT WITH ETHACRYNIC ACID IN RENAL FAILURE VEERASAMY K. G. PILLAY

KENJI

AIMI

FRANKLIN D. SCHWARTZ ROBERT M. KARK

FROM THE DEPARTMENTS OF MEDICINE AND OTOLARYNGOLOGY, UNIVERSITY OF ILLINOIS COLLEGE OF MEDICINE, RESEARCH AND

EDUCATIONAL HOSPITALS, AND LUKE’S HOSPITAL, CHICAGO

PRESBYTERIAN-ST.

Five uræmic patients in whom deafness followed ethacrynic-acid treatment are described. In three the deafness was permanent. The cause of the deafness is unknown, but seems to be related to the retention of congeners of ethacrynic acid. Ethacrynic acid should be used cautiously in uræmic patients.

Sum ary

Introduction NUMEROUS adverse effects of ethacrynic acid have been reported (Cannon et al. 1965, Maher and Schreiner 1965, Brest et a]. 1965, Hagedorn 1965). An unusual sideeffect has been the development of acute transient deafness (Maher and Schreiner 1965, Schneider and Becker 1966, Schmidt and Friedman 1967). We describe here this complication in five uraemic patients treated with ethacrynic acid. In three the deafness was permanent, and, to our knowledge, this has not previously been

reported. Case-reports Case 1 A 40-year-old woman was first admitted to PresbyterianSt. Luke’s Hospital on Sept. 6, 1964, because of difficulty in breathing. She was pregnant and was found to have proteinuria and hypertension. Her respiratory difficulty was due to bronchial asthma and bronchitis. She responded satisfactorily to treatment and subsequently delivered normally, but was afflicted with recurrent attacks of bronchial asthma. She was readmitted 2 months later because of dyspnoea, chest pain on exertion, and swelling of the legs. She was in heartfailure with a blood-pressure (B.P.) of 170/110 mm. Hg, and had a large umbilical hernia.

78 The hasmatocrit was 22, the blood-urea-nitrogen (B.U.N.) 84 mg. per 100 ml., the serum-creatinine 13-2 mg. per 100 ml., the creatinine clearance 3-3 ml. per minute, and the 24-hour urine protein 4 g. The patient was initially treated with 40 mg. of furosemide and 500 mg. chlorothiazide daily by mouth. Because of poor response to diuretics, peritoneal dialysis was undertaken. She was discharged and readmitted on several occasions for repeated peritoneal dialysis. She was readmitted for the ninth time in June, 1967. Before this, she was maintained as an outpatient on digitalis and 200 mg. ethacrynic acid orally twice a day for several weeks. On this regimen, she had a urine volume of 1000 ml. per day. On admission, she was noted to have bilateral nerve deafness. She denied any hearing loss before taking ethacrynic acid. An audiogram was not done. The B.u.N. was 258 mg. per 100 ml., the serumcreatinine 24 mg. per 100 ml., and the hacmatocrit 13. During peritoneal dialysis, she had grand-mal seizures. Her deafness did not improve, and she died in uraemia on Sept. 19, 1967. Permission for post-mortem examination was not granted. Case 2 A 20-year-old female college student suffered amnesia for 24-36 hours following ingestion of several tablets of ’Speed ’ (methedrine). She awoke with malaise, cramping abdominal pain, nausea, vomiting, and temperature of 105°F. She was admitted to a local hospital, where she was found to be oliguric, and was subsequently transferred to Presbyterian-St. Luke’s Hospital on March 7, 1968. The patient stated that she smoked marihuana occasionally, and her college roommate later informed us that the patient had been taking amphetamine tablets for long periods and had also been " sniffing " carbonne (carbon tetrachloride). Examination was essentially

unremarkable;

B.P.

112/8.0.

Investigations (see accompanying table) revealed renal failure and

some

liver damage.

RESULTS OF INVESTIGATIONS IN CASE

2

cleared soon after it normal. Case 4

was

stopped. Otoscopic examination

was

A 52-year-old woman was admitted to Presbyterian-St. Luke’s Hospital on May 15, 1967. She gave a 3-year history of headaches, malaise, and hypertension. Hearing was normal. In the preceding 6 months, she had been admitted to another hospital on several occasions for blood-transfusions. She had a B.P. of 180/50 and aortic incompetence. The B.U.N. was 180 mg. per 100 ml. and serum-creatinine 18-6 mg. per 100 ml.

The patient was treated with intravenous mannitol and ethacrynic acid and discharged on May 25, 1967. She was readmitted on June 10, 1967, and treated similarly. She was discharged on oral ethacrynic acid on July 1, 1967. Her third admission was on July 20, 1967. 7 days before admission, she had developed dizziness and became completely deaf. She then regained the ability to hear. On the day of admission she was given 300 mg. ethacrynic acid orally. On the following day, an audiogram demonstrated mild to moderate sensorineural loss. A week later some improvement was noted. During this period the patient had serum hepatitis, which had resolved at the time of discharge. Her final admission was She was in severe urasmia and was treated on Aug. 16, 1967. with peritoneal dialysis; her hearing remained unchanged. She died in urasmic

coma a

month after admission.

Case 5 A 28-year-old man was in chronic renal failure because of congenital bladder-neck obstruction. There was no history of hearing loss. He was maintained on periodic peritoneal dialysis. He also had severe peripheral neuropathy. He was treated with oral ethacrynic acid 200 mg. three times a day from Dec. 15 to 18, 1967. On Dec. 17, he became deaf. The patient died in uraemia on Jan. 2, 1968, without regaining the ability to hear. Discussion

The exact cause of deafness following ethacrynic acid is unknown. Schneider and Becker (1966) suggested that it could be related to an alteration in the formation of perilymph in the cochlea, but discounted the possibility in view of the lack of vertigo and nausea in their patients. It is of interest that one patient in the present series had nausea and severe vertigo (case 2), and another (case 4) experienced dizziness in association with hearing loss. In animal experiments Schneider and Becker found that 20-30% of the ethacrynic acid recovered in the urine resembled the cysteine adduct of ethacrynic acid-a substance which was withdrawn from clinical trial because of the high incidence of transient hearing loss (Wilkinson, cited by Schneider and Becker 1966). Retention of this substance in patients with renal insufficiency has been considered to be the cause of hearing loss. However, direct toxicity to the auditory nerves by ethacrynic acid is a possibility.

On March 8, 200 mg. ethacrynic acid and 25 g. mannitol administered intravenously. 90 minutes later she complained of nausea, fullness in the stomach, and inability to hear. The hearing improved somewhat, but deafness reappeared 6 days later and persisted throughout her stay in hospital. She On March 18 open was also noted to be unsteady on her feet. renal biopsy gave a result consistent with acute tubular necrosis in the healing stage. The patient had one peritoneal dialysis, and subsequently had spontaneous diuresis. At discharge on March 29, 1968, the unsteadiness had disappeared, but the hearing deficit persisted. Renal function has subsequently returned to normal. She has required the assistance Permanent deafness following ethacrynic acid has not of hearing-aids to continue her college education. been described previously. It is a distressing complication in patients already disabled by other effects of uraemia. Case 3 In general, patients with significant renal insufficiency A 25-year-old woman with chronic renal disease and no history of hearing loss was admitted to Presbyterian-St. Luke’s (serum-creatinine 5-6 mg. per 100 ml.) fail to respond to Hospital for the third time on June 23, 1968, because of re- usual doses of the various diuretic agents. In our current nausea, vomiting, fatigue, and dyspnoea on exertion. experience, urine volume can be increased considerably The skin and mucosas were pale, and the B.P. was 180/110. by use of larger doses, such as those reported here. The hasmatocrit was 19, the B.u.N. 81 mg. per 100 ml., and Nevertheless, it would be desirable to use other diuretic serum-creatinine 13-5 mg. per 100 ml. Chest X-ray revealed agents initially in urxmic patients and to reserve ethaan enlarged heart and congested lungs. An electrocardiogram crynic acid for resistant cases; and, even then, it would be showed left ventricular hypertrophy. prudent to observe the patient carefully for evidence of The patient was treated with aldomet, chlorothiazide, mannitol, and 800 mg. of intravenous ethacrynic acid daily. 2 hearing loss, preferably with serial audiograms. The days later she complained of earache and difficulty in hearing, drug should be stopped at the first sign of hearing deficit. Even if hearing loss proves transient, ethacrynic acid which persisted while ethacrynic acid was continued, but were

79

be exhibited again for fear of inducing deafness. permanent This study was supported in part by grants from the United States Public Health Service (HE-02253) and (TI-AM 5505).

should

not

Requests for reprints should be addressed to F. D. S., DepartMedicine, Presbyterian-St. Luke’s Hospital, 1753 West Congress Parkway, Chicago, Illinois 60612. ment of

REFERENCES

Brest, A. N., Onesti, G., Seller, R., Ramirez, O., Heider, C., Moyer, J. H. (1965) Am. J. Cardiol. 16, 99. Cannon, P. J., Heinemann, H. O., Stason, W. B., Laragh, J. H. (1965) Circulation, 31, 5. Hagedorn, C. W. (1965) New Engl. J. Med. 272, 1152. Maher, J. F., Schreiner, G. E. (1965) Ann. intern. Med. 62, 15. Schmidt, P., Friedman, I. S. (1967) N.Y. St. J. Med. 67, 1438. Schneider, W. J., Becker, E. L. (1966) Archs intern. Med. 117, 715. Wilkinson, W. H. Cited by Schneider, W. J., Becker, E. L. (1966).

Patients and Methods Defibrination was induced in all patients by slow intravenous (i.v.) infusion of arvin, 1 unit per kg. of body-weight administered in 100 ml. of sterile isotonic saline solution over a period of 4-6 hours by means of a constant infusion pump. At the end of the infusion each patient was given a further dose of 1 unit per kg. in 20 ml. saline over 10 minutes. Thereafter patients were treated by one of three schedules: (a) 1-2 units per kg. i.v. every 12 hours; (b) 1-2 units per k.g i.v. every 24 hours; (c) 3-5 units per kg. intramuscularly (LM.) every 24 hours. The daily dose of arvin was adjusted during treatment from plasmafibrinogen levels measured by the method of Ratnoff and Menzie (1951), the aim being to maintain a value of about 50 mg. per 100 ml. Details of treatment of the 4 patients who developed resistance to arvin are shown in table i. Patient no. 26 was treated for TABLE I-TREATMENT DETAILS OF RESISTANT CASES

RESISTANCE TO TREATMENT WITH ARVIN

ACQUIRED

C. BRAY* GILLIAN BOLTON

W. R. PITNEY P. J. L. HOLT

FROM THE DEPARTMENTS OF HÆMATOLOGY AND

ROYAL POSTGRADUATE MEDICAL

2

MEDICINE, SCHOOL, LONDON W.12

who underwent

patients Summary defibrination with ’ Arvin ’

therapeutic

found to be refractory to a second course of treatment. Plasma from both neutralised the clotting effect of arvin added in vitro, and a similar abnormality was observed in 2 of 14 other plasma-samples. Resistance to arvin has been demonstrated in 3 of 4 patients treated by the intramuscular route, but in only 1 of 12 patients treated intravenously. It is probable that arvin is weakly antigenic and that resistance is due to the production of were

antibodies. Introduction

ARVIN’ is

purified fraction of the venom of the Malayan pit-viper (Agkistrodon rhodostoma) which has a specific coagulant action on fibrinogen (Esnouf and Tunnah 1967, Bell, Bolton, and Pitney 1968). When injected parenterally into animals or man, arvin converts plasma-fibrinogen into fibrin microclots which are removed from the circulation by fibrinolysis and through reticuloendothelial phagocytosis (Regoeczi et al. 1966, Pitney, Bell, and Bolton 1969). Plasma-fibrinogen values fall and the blood may fail to clot, but hxmorrhage usually does not occur. The procedure has been termed therapeutic defibrination and has been used in the treatment of patients with thromboembolic disorders (Bell, Pitney, et al. 1968, Sharp et al. 1968, Gilles et al. 1968). Arvin is a protein which occurs in both monomer and dimer forms; the molecular weight of the monomer is about 30,000 (Esnouf and Tunnah 1967). It is therefore potentially antigenic, but the development of resistance to therapy has not been reported up to now. We have, however, recently observed 2 patients treated previously with a

13 days for cerebral embolism associated with a prosthetic mitral valve. There were no complications of therapy, and the plasma-fibrinogen concentration on the last day of treatment was 49 mg. per 100 ml. She was readmitted to hospital 3 months later with a further cerebral embolism. Defibrination was again attempted by slow i.v. infusion of arvin, 1 unit per kg., followed by a similar dose at 6 hours. The plasma-fibrinogen was 210 mg. per 100 ml. before beginning therapy and it fell only to 165 mg. per 100 ml. after the two i.v. doses; further therapy with arvin was therefore abandoned. An " escape " phenomenon was observed in patient no. 27 after the 14th day of treatment when the plasma-fibrinogen concentration increased to 100 mg. per 100 ml. and continued to rise despite further I.M. injections (see accompanying figure). Arvin was discontinued on the 18th day, and 5 days later an attempt was made to reinduce defibrination. Following the standard slow infusion, an i.v. dose was given at 6 hours and another at 18 hours. There was no significant change in plasmafibrinogen values during this time.

arvin in whom a second attempt to induce defibrination was unsuccessful. Plasma-samples from these patients reacted abnormally to the addition of arvin in vitro, and similar abnormal findings were shown by plasma-samples from 2 of 14 other patients previously treated. *

Present appointment: consultant physician, Manchester Royal and Baguley Hospital, Wythenshawe.

Infirmary, Details of treatment and

plasma-fibrinogen values in patient

no.

27.