77

(4 x 10’ per ml.). Net water secretion was noted in the

jejunum and ileum.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 diminishedvitamin-B12 absorption. At this point, tetracycline (250 mg.q.i.d.) was administered. After 48 hours of treatment, vitamin-B12 urinary excretion had risen to 7-9% and xylose wasincreased to 4-1 g. per 24 hours; three consecutive fsecal fatexcretions were 3-3, 2-5, and 2-2 g. per 24 hours, respectively.No coliforms or anaerobes could be isolated from the smallintestine. Net water movement was now reversed in the

jejunum and ileum leading to normal water absorption in bothareas.

Discussion

Sequential sampling of the small intestine of six patientswith idiopathic tropical malabsorption syndrome revealedabnormalities of the microflora (mostly coliforms) in theupper small bowel. That these microorganisms interferedwith absorptive processes is suggested by the correlationbetween the degree of bacteriological abnormality andvitamin-B12 absorption and also by the effect of antibiotics.Two patients were investigated after only 48 hours oftetracycline treatment in order to examine the immediateresults of bacterial clearance before a new mucosal-cell

population was established: Lipkin et al. (1963) suggestedthat epithelial cell turnover in the human intestine takes3-5 days. In this manner, the dramatic improvement invitamin-B12 and fat absorption and net water flux could bedirectly related to reductions in the bacterial populations.

Previous work on small-bowel microflora in tropicalsprue is often described as being inconclusive but in factthese earlier data are not entirely inconsistent with ourfindings. Intubation specimens were generally obtainedfrom the upper jejunum: Desai et al. (1966) reported thatseven patients (out of twenty-eight) had coliforms and fiveothers had other intestinal bacteria; Milanes et al. (1946)found seven patients positive for coliforms out of twenty-one ; Nadel and Gardner (1956) found two out of six " oldsprue " cases harboured coliforms; and Klipstein et al.

(1966) noted that three of six cases had coliforms in thejejunum. In our series, only three of six cases were

positive for coliforms at the upper jejunal site, butexamination of more distal sites revealed abnormalities ofthe microflora in the other three patients. The majordisagreement concerns the definition of what is normalsmall-bowel microflora in people living in the tropics.Eight healthy Bengalis had only a few coliforms in the upperileum and none in the jejunum. Using these guidelines,all six patients with idiopathic malabsorption syndromehad abnormal small-bowel microflora.

Although the two patients treated with short-termantibiotics showed dramatic improvement, there was stillsome evidence of residual impairment of intestinal func-tion. Similar findings have been previously reported byother investigators (Booth and Mollin 1964, Guerra et al.1965). In the patient with chronic malabsorption (case 1),microorgnaisms were reduced but could not be completelyeliminated from the small bowel due to the emergence ofantibiotic-resistant strains. However, even when themicroorganisms could be totally suppressed in the smallbowel (as in case 3), vitamin-B12 and xylose absorptionstill remained slightly below normal levels. This suggestsan underlying mucosal defect contributing to the mal-absorption.

This investigation was partially supported by U.S. Public HealthService 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 JohnsHopkins 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) Gastro-

enterology, 51, 975.

TRANSIENT AND PERMANENT DEAFNESS

FOLLOWING TREATMENT WITH

ETHACRYNIC ACID IN RENAL FAILURE

VEERASAMY K. G. PILLAY FRANKLIN D. SCHWARTZ

KENJI AIMI ROBERT M. KARKFROM THE DEPARTMENTS OF MEDICINE AND OTOLARYNGOLOGY,

UNIVERSITY OF ILLINOIS COLLEGE OF MEDICINE,RESEARCH AND EDUCATIONAL HOSPITALS, ANDPRESBYTERIAN-ST. LUKE’S HOSPITAL, CHICAGO

Summary Five uræmic patients in whom deafnessfollowed ethacrynic-acid treatment are

described. In three the deafness was permanent. Thecause of the deafness is unknown, but seems to be relatedto the retention of congeners of ethacrynic acid. Etha-

crynic acid should be used cautiously in uræmic patients.

Introduction

NUMEROUS adverse effects of ethacrynic acid have beenreported (Cannon et al. 1965, Maher and Schreiner 1965,Brest et a]. 1965, Hagedorn 1965). An unusual side-effect has been the development of acute transient deaf-ness (Maher and Schreiner 1965, Schneider and Becker1966, Schmidt and Friedman 1967). We describe herethis complication in five uraemic patients treated withethacrynic acid. In three the deafness was permanent,and, to our knowledge, this has not previously beenreported.

Case-reportsCase 1

A 40-year-old woman was first admitted to Presbyterian-St. Luke’s Hospital on Sept. 6, 1964, because of difficulty inbreathing. She was pregnant and was found to have pro-teinuria and hypertension. Her respiratory difficulty was dueto bronchial asthma and bronchitis. She responded satis-

factorily to treatment and subsequently delivered normally,but was afflicted with recurrent attacks of bronchial asthma.She was readmitted 2 months later because of dyspnoea, chestpain on exertion, and swelling of the legs. She was in heart-failure with a blood-pressure (B.P.) of 170/110 mm. Hg, andhad 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-hoururine protein 4 g.The patient was initially treated with 40 mg. of furosemide

and 500 mg. chlorothiazide daily by mouth. Because of poorresponse to diuretics, peritoneal dialysis was undertaken. Shewas discharged and readmitted on several occasions for

repeated peritoneal dialysis. She was readmitted for theninth time in June, 1967. Before this, she was maintained asan outpatient on digitalis and 200 mg. ethacrynic acid orallytwice a day for several weeks. On this regimen, she had aurine volume of 1000 ml. per day. On admission, she wasnoted to have bilateral nerve deafness. She denied anyhearing loss before taking ethacrynic acid. An audiogram wasnot done. The B.u.N. was 258 mg. per 100 ml., the serum-creatinine 24 mg. per 100 ml., and the hacmatocrit 13. Duringperitoneal dialysis, she had grand-mal seizures. Her deafnessdid 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 for24-36 hours following ingestion of several tablets of ’ Speed ’(methedrine). She awoke with malaise, cramping abdominalpain, nausea, vomiting, and temperature of 105°F. She wasadmitted to a local hospital, where she was found to be oliguric,and was subsequently transferred to Presbyterian-St. Luke’sHospital on March 7, 1968. The patient stated that shesmoked marihuana occasionally, and her college roommatelater informed us that the patient had been taking ampheta-mine tablets for long periods and had also been " sniffing "carbonne (carbon tetrachloride). Examination was essentiallyunremarkable; B.P. 112/8.0.

Investigations (see accompanying table) revealed renalfailure and some liver damage.

RESULTS OF INVESTIGATIONS IN CASE 2

On March 8, 200 mg. ethacrynic acid and 25 g. mannitolwere administered intravenously. 90 minutes later she com-plained of nausea, fullness in the stomach, and inability to hear.The hearing improved somewhat, but deafness reappeared 6days later and persisted throughout her stay in hospital. Shewas also noted to be unsteady on her feet. On March 18 openrenal biopsy gave a result consistent with acute tubularnecrosis in the healing stage. The patient had one peritonealdialysis, and subsequently had spontaneous diuresis. At dis-

charge on March 29, 1968, the unsteadiness had disappeared,but the hearing deficit persisted. Renal function has sub-

sequently returned to normal. She has required the assistanceof hearing-aids to continue her college education.Case 3

A 25-year-old woman with chronic renal disease and nohistory of hearing loss was admitted to Presbyterian-St. Luke’sHospital for the third time on June 23, 1968, because of re-current nausea, vomiting, fatigue, and dyspnoea on exertion.The skin and mucosas were pale, and the B.P. was 180/110.The hasmatocrit was 19, the B.u.N. 81 mg. per 100 ml., and

serum-creatinine 13-5 mg. per 100 ml. Chest X-ray revealedan enlarged heart and congested lungs. An electrocardiogramshowed left ventricular hypertrophy.The patient was treated with aldomet, chlorothiazide,

mannitol, and 800 mg. of intravenous ethacrynic acid daily. 2

days later she complained of earache and difficulty in hearing,which persisted while ethacrynic acid was continued, but

cleared soon after it was stopped. Otoscopic examination wasnormal.

Case 4

A 52-year-old woman was admitted to Presbyterian-St.Luke’s Hospital on May 15, 1967. She gave a 3-year historyof headaches, malaise, and hypertension. Hearing was normal.In the preceding 6 months, she had been admitted to anotherhospital on several occasions for blood-transfusions. She hada B.P. of 180/50 and aortic incompetence. The B.U.N. was180 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 wasreadmitted on June 10, 1967, and treated similarly. She was

discharged on oral ethacrynic acid on July 1, 1967. Her thirdadmission was on July 20, 1967. 7 days before admission, shehad developed dizziness and became completely deaf. Shethen regained the ability to hear. On the day of admissionshe was given 300 mg. ethacrynic acid orally. On the follow-

ing day, an audiogram demonstrated mild to moderate sensori-neural loss. A week later some improvement was noted.During this period the patient had serum hepatitis, which hadresolved at the time of discharge. Her final admission wason Aug. 16, 1967. She was in severe urasmia and was treatedwith peritoneal dialysis; her hearing remained unchanged. Shedied in urasmic coma a month after admission.

Case 5

A 28-year-old man was in chronic renal failure because ofcongenital bladder-neck obstruction. There was no historyof hearing loss. He was maintained on periodic peritonealdialysis. He also had severe peripheral neuropathy. He wastreated with oral ethacrynic acid 200 mg. three times a day fromDec. 15 to 18, 1967. On Dec. 17, he became deaf. The

patient died in uraemia on Jan. 2, 1968, without regaining theability to hear.

Discussion

The exact cause of deafness following ethacrynic acidis unknown. Schneider and Becker (1966) suggestedthat it could be related to an alteration in the formation of

perilymph in the cochlea, but discounted the possibilityin view of the lack of vertigo and nausea in their patients.It is of interest that one patient in the present series hadnausea and severe vertigo (case 2), and another (case 4)experienced dizziness in association with hearing loss. Inanimal experiments Schneider and Becker found that

20-30% of the ethacrynic acid recovered in the urineresembled the cysteine adduct of ethacrynic acid-asubstance which was withdrawn from clinical trial becauseof the high incidence of transient hearing loss (Wilkinson,cited by Schneider and Becker 1966). Retention of thissubstance in patients with renal insufficiency has beenconsidered to be the cause of hearing loss. However,direct toxicity to the auditory nerves by ethacrynic acidis a possibility.

Permanent deafness following ethacrynic acid has notbeen described previously. It is a distressing complica-tion in patients already disabled by other effects of uraemia.In general, patients with significant renal insufficiency(serum-creatinine 5-6 mg. per 100 ml.) fail to respond tousual doses of the various diuretic agents. In our

experience, urine volume can be increased considerablyby use of larger doses, such as those reported here.Nevertheless, it would be desirable to use other diureticagents initially in urxmic patients and to reserve etha-crynic acid for resistant cases; and, even then, it would beprudent to observe the patient carefully for evidence ofhearing loss, preferably with serial audiograms. The

drug should be stopped at the first sign of hearing deficit.Even if hearing loss proves transient, ethacrynic acid

79

should not be exhibited again for fear of inducingpermanent deafness.This study was supported in part by grants from the United

States Public Health Service (HE-02253) and (TI-AM 5505).Requests for reprints should be addressed to F. D. S., Depart-

ment of Medicine, Presbyterian-St. Luke’s Hospital, 1753 West

Congress Parkway, Chicago, Illinois 60612.

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).

ACQUIRED RESISTANCE TOTREATMENT WITH ARVIN

W. R. PITNEY C. BRAY*

P. J. L. HOLT GILLIAN BOLTON

FROM THE DEPARTMENTS OF HÆMATOLOGY AND MEDICINE,ROYAL POSTGRADUATE MEDICAL SCHOOL, LONDON W.12

Summary 2 patients who underwent therapeuticdefibrination with ’ Arvin ’ were found to

be refractory to a second course of treatment. Plasmafrom both neutralised the clotting effect of arvin added invitro, and a similar abnormality was observed in 2 of 14other plasma-samples. Resistance to arvin has beendemonstrated in 3 of 4 patients treated by the intra-muscular route, but in only 1 of 12 patients treatedintravenously. It is probable that arvin is weakly anti-genic and that resistance is due to the production ofantibodies.

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

Introduction

ARVIN’ is a purified fraction of the venom of theMalayan pit-viper (Agkistrodon rhodostoma) which has aspecific coagulant action on fibrinogen (Esnouf andTunnah 1967, Bell, Bolton, and Pitney 1968). When in-jected parenterally into animals or man, arvin convertsplasma-fibrinogen into fibrin microclots which are

removed from the circulation by fibrinolysis and throughreticuloendothelial phagocytosis (Regoeczi et al. 1966,Pitney, Bell, and Bolton 1969). Plasma-fibrinogen valuesfall and the blood may fail to clot, but hxmorrhage usuallydoes not occur. The procedure has been termed thera-peutic defibrination and has been used in the treatment ofpatients with thromboembolic disorders (Bell, Pitney, etal. 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 isabout 30,000 (Esnouf and Tunnah 1967). It is therefore

potentially antigenic, but the development of resistance totherapy has not been reported up to now. We have, how-ever, recently observed 2 patients treated previously witharvin in whom a second attempt to induce defibrinationwas unsuccessful. Plasma-samples from these patientsreacted abnormally to the addition of arvin in vitro, andsimilar abnormal findings were shown by plasma-samplesfrom 2 of 14 other patients previously treated.

Patients and Methods

Defibrination was induced in all patients by slow intravenous(i.v.) infusion of arvin, 1 unit per kg. of body-weight adminis-tered in 100 ml. of sterile isotonic saline solution over a periodof 4-6 hours by means of a constant infusion pump. At the endof the infusion each patient was given a further dose of 1 unitper kg. in 20 ml. saline over 10 minutes. Thereafter patientswere 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) 3-5units per kg. intramuscularly (LM.) every 24 hours. The dailydose of arvin was adjusted during treatment from plasma-fibrinogen levels measured by the method of Ratnoff and Men-zie (1951), the aim being to maintain a value of about 50 mg.per 100 ml.

Details of treatment of the 4 patients who developed resist-ance to arvin are shown in table i. Patient no. 26 was treated for

TABLE I-TREATMENT DETAILS OF RESISTANT CASES

13 days for cerebral embolism associated with a prostheticmitral valve. There were no complications of therapy, and theplasma-fibrinogen concentration on the last day of treatment was49 mg. per 100 ml. She was readmitted to hospital 3 monthslater with a further cerebral embolism. Defibrination was againattempted by slow i.v. infusion of arvin, 1 unit per kg., followedby a similar dose at 6 hours. The plasma-fibrinogen was 210mg. per 100 ml. before beginning therapy and it fell only to165 mg. per 100 ml. after the two i.v. doses; further therapywith arvin was therefore abandoned.An " escape " phenomenon was observed in patient no. 27

after the 14th day of treatment when the plasma-fibrinogenconcentration increased to 100 mg. per 100 ml. and continuedto rise despite further I.M. injections (see accompanying figure).Arvin was discontinued on the 18th day, and 5 days later anattempt was made to reinduce defibrination. Following thestandard slow infusion, an i.v. dose was given at 6 hours andanother at 18 hours. There was no significant change in plasma-fibrinogen values during this time.

Details of treatment and plasma-fibrinogen values in patient no. 27.