The Qanadicin SMedieal oAssociation Journal£e lournal de VAssociation medicale canadienne^July 18,1970/Volume 103, Number 2

Experiences with high doses of furosemide inrenal disease and resistant edematous states

DONALD S. SlLVERBERG, M.D., M.SC, F.R.C.P.[c], RAYMOND A. ULAN, M.D., F.R.C.P. [c],Marcel A. Baltzan, m.d., f.r.c.p. [c] and Richard B. Baltzan, m.d., f.r.c.p. [c].

Summary: Six cases of edema, three due to the nephrotic syndrome, oneto congestive heart failure and two to chronic renal failure,are reported in which furosemide was administered in oraldoses higher than those usually prescribed (up to 720 mg. a day),in order to ohtain a satisfactory diuresis. In one case of severe prerenalfailure secondary to cardiogenic shock and in one case of acute tubularnecrosis secondary to hypotension at the time of operation, intravenousdoses up to 990 and 1400 mg. per day respectively were able to reversethe oliguria. In eight additional patients who were on chronic hemo¬dialysis, furosemide was administered to the amount of 1000 mg. per dayorally in divided doses for two weeks, and produced a moderate diure-tic response.

The use of high doses of furosemide in edema and renal failure re-sistant to the usual therapeutic measures appears to be safe and effec¬tive.

Furosemide (Lasix-Hoechst) is a

relatively new diuretic that hasbeen shown to be very effective inthe treatment of edema resistant toother diuretics.15 Unlike mostdiuretic agents it appears to bevery effective even in the presenceof impaired renal function.2-3> 6

However, patients are occasionallyseen who do not respond satisfac-torily to furosemide in the dosesusually recommended. In such pa¬tients the administration of muchhigher doses, even up to 4000 mg.per day,2 has been successful inpromoting a diuresis.Over the past two years we have

studied patients with the nephro-From the Renal Department, Universityof Alberta, Edmonton, Alberta, and Uni¬versity of Saskatchewan, Saskatoon, Sas-katchewanPresented at the Annual Meeting- of TheRoyal Collegre of Physicians and Surgeonsof Canada, Montreal, January 23, 1970.Reprint requests to: Dr. Donald S.Silverberg, Dialysis Unit, University ofAlberta Hospital, Edmonton, Alberta.

tic syndrome, congestive heartfailure, and acute or chronic renalfailure who were resistant to theconventional doses of furosemide.Doses up to 1000 mg. per dayorally and 1400 mg. per day in¬travenously were successful in pro¬moting diuresis.

MaterialGroup 1 (Table I)This group consisted of six pa¬tients, three with the nephroticsyndrome (previously reported),1one with congestive heart failuresecondary to coronary artery dis¬ease, and two with chronic renalfailure. In the three patients withthe nephrotic syndrome the natureof the renal lesion was determinedby percutaneous renal biopsy; inall three membranous glomerulone¬phritis was found. In Cases 1 to 4various combinations of an aldo-

sterone antagonist, a thiazide, amercurial diuretic and furosemidein the usually prescribed dose (upto 200 mg. per day) had failed topromote a diuresis; in Cases 5 and6 no diuretic therapy other thanthe conventional doses of furose¬mide had been used. Furosemidewas then administered in increas¬ing doses, starting with 40 mg. twoto three times a day and graduallyincreasing at two- to three-day in-tervals by 80 to 120 mg. per dayuntil a diuresis was obtained whichwas sufficient to restore the pa¬tient's weight to normal.

Group 2Two patients with acute renalfailure were studied; one case was

secondary to acute myocardial in¬farction with pulmonary edemaand shock, and the other secondaryto hypotension brought about atthe time of reimplantation of a

pacemaker for heart block. In thesepatients daily intravenous doses ofup to 990 and 1400 mg. per dayrespectively were administered toproduce a diuretic response.

Group 3 (Table II)This group comprised eight pa¬tients with chronic renal failurewho were being maintained on

twice-weekly hemodialysis using aKolff twin coil. Each dialysis lastedsix hours. The creatinine clearancein these patients ranged from 0.5to 2 ml. per min. per 1.73 m.2 Thestudy was divided into two parts,

C.M.A. JOURNAL/JULY 18, 1970/VOL. 103 129

Mg. 4000

Kg. 6056

ml. 20001000

mEq. per lit. 4

3

7.457.35

Mg. per cent 5030

Mg. per cent 3

2

Days

Furosemide .ttk-tt't

Kti£iffii<$&£$imursn 100 mg

Aldactone 75 mg.

Weight

Urine volume /'

Serum potassium

Blood pH

BUN.

Serum creatinine

10FIG. 3.Case 3. A 61-year-old womanwith membranous glomerulonephritis ofunknown etiologry.

each of two weeks' duration. Dur¬ing the first two weeks no furose¬mide was administered, and duringthe second two weeks 1000 mg. was

given in a dose of 250 mg. fourtimes daily. During the study thepatients were continued on dialys-sis in the usual manner. Each pa¬tient was given a 40-g. protein dietand allowed an amount of waterequal to the previous day's urineoutput plus insensible loss. Salt in-take was equal to that of the pre¬vious day's urine salt excretion.

MethodsIn all three groups observationswere made of body weight, urinaly-sis, urine volume, urine sodium,potassium, chloride, urea and crea¬

tinine, blood urea nitrogen, serumcreatinine and uric acid, serum

glutamic oxaloacetic transaminase(SGOT), serum lactic acid dehy-drogenase (LDH), serum alkalinephosphatase, hemoglobin, red cellcount, differential count, plateletcount and fasting and two-hour

postprandial blood sugar.In Group 3 the values of urine

volume and daily sodium, potas¬sium, chloride, urea and creatinineexcretion over each two-weekperiod were averaged because ofthe variation in daily urine vol¬ume which occurs during chronichemodialysis. All blood studieswere performed immediately be¬fore dialysis on the first, fourteenthand twenty-eighth days of thestudy.ResultsGroup 1 (Table I)All patients responded to thehigh doses of furosemide with adiuresis sufficient to return theirweight to normal. In no patientwas a reduction in renal functionnoted as judged by BUN, serumcreatinine or creatinine clearance;in Case 3 a marked improvementin these parameters occurred. Hy-pokalemia was seen in two of thethree nephrotic patients (Figs. 1,2 and 3) and in the patient withcongestive heart failure, but res¬

ponded to potassium supplementa-tion with or without the additionof aldactone. In Cases 1, 3 and 4,once a diuretic response occurred,reaccumulation of fluid could beprevented by a lower dose of furo¬semide. In Cases 2, 5 and 6, how¬ever, continuous high doses were

necessary to control the edema.The urine Na/K ratio in the dif¬ferent cases varied from 2:1 to 8:1.

Group 2 Case 7 (Fig. 4)A 65-year-old obese woman was ad¬mitted on May 1, 1969, in shock.Twenty-four hours previously she hadnoted a vague retrosternal discomfortwhich continued until the time of ad¬mission. An electrocardiogram on ad¬mission showed evidence of a recentanterior myocardial infarction. Herblood pressure on admission was

100/60, and the pulse was 96 andthready. Her skin appeared cold andclammy. Soft moist rales were heard

Day*

FIG. 1.Case 1. A 28-year-old womanwith diabetes and membranous glomerulo¬nephritis.

Days 0 .10FIG. 2.Case 2. A 62-year-old man withlupus erythematosus and membranousgrlomerulonephritis.

130 C.M.A. JOURNAL/JULY 18, 1970/VOL. 103

at both lung bases. The central venous

pressure was 12 cm. of water. Theliver was difficult to palpate owingto the obesity. A chest radiographshowed evidence of minimal pulmon¬ary congestion. A Foley catheterwas inserted at the time of admission.She was treated with morphine anddigoxin, the latter in a dose of 0.75mg. intravenously initially followedby 0.25 mg. every four hours forthree doses. An isoproterenol infusionwas also begun. Despite this therapyher pulmonary congestion and bloodpressure changed very little and theurine volume averaged only 10 ml.per hour during the first 17 hoursafter admission. Her BUN at thattime was 83 mg. and the serum crea¬tinine was 2.5 mg. The urine had a

specific gravity of 1.021 with 3 +protein, 40 to 50 R.B.C.s per h.p.f.,15 to 20 leukocytes per h.p.f., 2 to3 hyaline and 1 to 2 granular castsper h.p.f. The urine sodium concen¬tration was 5 mEq./l. These findingswere consistent with pre-renal oli¬guria, which was thought to be due toa reduced cardiac output.

DIALYSIS

FIG. 4.Case 7. A 65-year-old womanwith prerenal failure secondary to cardio-grenic shock.

Seventeen hours after admission100 mg. of furosemide was given in¬travenously. Since there was littlediuretic response, another 100 mg.was given in the 19th hour and againin the 20th hour. The urine outputover the next 13 hours first increasedup to 40 ml. per hour, but graduallyfell again to 15 ml. per hour. Furose¬mide, 40, 100 and 50 mg., was ad¬ministered intravenously during the33rd, 34th and 36th hours respec¬tively, but by the 38th hour the urineoutput had only risen to 33 ml. perhour. For this reason three 200-mg.doses of furosemide were given dur¬ing the 38th, 39th and 40th hours.By the 43rd hour the urine volumehad risen to 90 ml. per hour. An ad¬ditional 100 mg. of furosemide at thistime maintained the urine volume atthis level for the next two hours, andin the 46th hour another 100 mg. was

given. The urine volume rose to 170ml. per hour. The diuresis was asso¬ciated with a clearing of the pul-

DIALYSIS .DIALYSIS

iffiiAfffiiFHffi

FIG. 5.Case 8. A 48-year-old man with acute tubular necrosis secondary to hypo¬tension at time of pacemaker implantation.

monary congestion and a reduction inthe ventral venous pressure to normal.It was only after the diuresis had be¬gun, in the 46th hour, that her bloodpressure rose to 120/70 from the pre¬vious pressures of 100/60 mm. Hg.From this time onward the urine out¬put was maintained between 70 and200 ml. per hour by only occasionalinjections of furosemide. The patientwent on to recovery. Her BUNreached a maximum of 115 mg. per100 ml. on the fifth day and thengradually fell to normal by the 16thday. The serum creatinine reached amaximum of 4.5 mg. per 100 ml. onthe fifth day and gradually fell tonormal by the 14th day. Mild hypo-kalemia developed during the diure¬sis but was easily controlled with in¬travenous potassium chloride.

Case 8 (Fig. 5)A 48-year-old man was admitted on

May 13, 1969, for reimplantation ofa cardiac pacemaker. He had hadrheumatic fever at age 14 and haddeveloped aortic insufficiency there-after. In 1966 he began to have syn-copal episodes. Third-degree heartblock was found and a transvenouspacemaker was implanted. Becauseof recurrent skin infections this pace¬maker was removed on May 23, 1969,and another one implanted. The pre¬operative urinalysis and BUN werenormal. During operation his bloodpressure fell from 180/80 to 90/60mm. Hg. Postoperatively a Foleycatheter was inserted; despite ade¬quate hydration he became progres-sively more oliguric. On the sixth

day after operation, the BUN was 144mg. per 100 ml., and serum crea¬tinine 7.5 mg. per 100 ml. Urinalysisrevealed a specific gravity of 1015with 2+ protein, 80 to 100 R.B.C/sper h.p.f., 1 to 4 leukocytes per h.p.f.and occasional hyaline casts. No redcell casts were noted. The urine sodi¬um concentration was 40 mEq. per 1.,and K concentration 47 mEq per 1.The serum and urine osmolarity wereboth 335 mOsm per 1. Retrogradepyelography was normal. It was con¬cluded that the patient had acutetubular necrosis. Melena was notedfive days postoperatively and a gas¬trointestinal series revealed a duode¬nal ulcer. He was treated with a 40-g. protein diet and aluminum hy-droxide, taken hourly. On the seventhpostoperative day, 60 mg. furosemidewas given and a slight diuretic res¬ponse was noted. On the eighth day100 mg. furosemide was given intra¬venously every three hours for a totaldose of 800 mg. This was associatedwith a marked increase in the urinevolume. The next day 700 mg. wasadministered and the urine volumeremained high. Despite the absenceof oliguria the BUN and serum crea¬tinine rose and on the ninth post¬operative day hemodialysis was per¬formed. Afterwards high doses offurosemide, up to 1400 mg. per day,were administered intravenously. Theurine volume remained high andserum creatinine was stabilized atabout 8 mg. per 100 ml. Neverthe-less the BUN continued to rise, pos¬sibly because of the continued bleed¬ing from the duodenal ulcer.Furosemide was discontinued after

C.M.A. JOURNAL/JULY 18, 1970/VOL. 103 131

the twelfth day. The urine output fellover the next 48 hours to 550 ml.per day, and subsequently to as lowas 40 ml. per day on the twentiethday. Hemodialysis was performed onthe ninth, fourteenth, eighteenth,twentieth and twenty-sixth days. Onthe twenty-fourth day the urine out¬put began to increase spontaneously,and by the thirty-second day it wasover 3000 ml. per day. The BUN andserum creatinine returned to normalby the forty-second day.Group 3 (Table II, Fig. 6)In the eight hemodialysis pa¬tients the administration of 1000

300]O<5200

DOSEFIG. 6.Response of eig-ht patients onchronic hemodialysis to 1 g. of furo¬semide administered orally in divideddoses over a 24-hour period.

mg. of furosemide increased theaverage daily urine volume by49%, sodium excretion by 105%,potassium excretion by 17% andchloride excretion by 155%. Allthese changes are significant at the5% level. The average excretions ofurea and creatinine were not sig¬nificantly altered. No significantchanges in the BUN or serumcreatinine were noted.

Adverse reactionsHypokalemia was common if thediuresis was marked. It respondedrapidly, however, to oral or intra¬venous potassium chloride therapy,with or without aldactone. Nochanges were noted in the fastingand two-hour post-prandial bloodsugars. In the one patient withdiabetes (Case 1) there was no

change in the blood sugar or insulinrequirements throughout the courseof therapy. Postural hypotensionwas frequently noted when thediuresis was very marked, but wasshort-lived. No significant altera-tions in hemoglobin, hematocrit,leukocytes, differential leukocytecount, platelets, bilirubin, SGOT,LDH or alkaline phosphatase werenoted. The uric acid levels werefrequently elevated owing to renalfailure and tended to rise slightlyduring therapy, but there were nocases of clinical gout. No gastro¬intestinal symptoms, skin rashes orsigns of auditory toxicity werenoted.

DiscussionWhen no diuretic response occurswith the usual doses of a diureticthe tendency is to add anotherdiuretic agent to the therapeuticprogram rather than to increase thedose of the original agent. Recentexperience with furosemide andethacrynic acid15 indicates thatmerely raising the doses of thesedrugs may at times produce adiuresis when usual doses are un-successful. The recommended doseof furosemide is 40 to 200 mg. perday. However, doses up to 4000mg. a day have been used on oc-casion with no toxic effects beingnoted.2 In our three cases of neph¬rotic syndrome, doses up to 600mg. a day orally were required toproduce a diuresis. In one patientwith congestive heart failure 360mg. a day orally was needed, and

in two patients with severe chronicrenal failure, doses up to 720 mg.a day orally were required. In thetwo patients with acute renal fail¬ure intravenous doses of up to 990mg. and 1400 mg. a day were usedwith no observed toxic effects.Most patients with edema

secondary to congestive heart fail¬ure, cirrhosis or the nephrotic syn¬drome respond to the usual dosesof furosemide. Why some patientswith identical creatinine clearancesshould require much higher dosesof the diuretic remains unknown.Furosemide in the usually admin¬istered doses blocks sodium re-

absorption primarily in the ascend¬ing limb of Henle.7,8 In higherdoses than those ordinarily usedit may also reduce sodium re-

absorption in the proximal tubule.9It is possibly the combined actionat the two sites that accounts forthe diuresis when higher doses areused. There is also some evidencethat furosemide increases renalblood flow and glomerular filtrationrate even in the presence of re¬duced. renal function.6,10 It hasbeen suggested that this is ac-

complished by an inhibition ofrenin-release from the juxtaglom-erular apparatus.11 By reducingrenal vascular resistance furo¬semide produces better renal tissueperfusion and more of the diureticwill be allowed to perfuse thetubular cells, where it can exert anatriuretic action.The role of furosemide in severe

chronic renal failure is less welldefined than in the other edemastates, where clearances are high.In most patients with chronic renalfailure, edema will improve withmoderate to severe salt restriction,and by the time salt restriction failsto improve it the BUN and serumcreatinine are usually so high thatthe patient requires dialysis or

transplantation in any case. How¬ever, a group of patients remainsin whom creatinine clearances arebetween 3 and 5 ml. per min. per1.73 m.2 They have minimal uremicsymptoms other than those relatedto fluid retention and hypertension,and cannot remain edema-free onsevere salt restriction. For thesefew patients, high doses of furo¬semide may offer a reprieve fromdialysis or transplantation forseveral months.Most chronic hemodialysis pa-

132 C.M.A. JOURNAL/JULY 18, 1970/VOL. 103

tients are allowed only 600 to 1000ml. of fluid per day. Excessive fluidintake in these patients will pro-duce edema and hypertension. Aswe have demonstrated, the ad..ministration of 1000 mg. of furo-semide per day will increase theirurine volume and allow a greaterintake of salt, water and potassium.On the other hand most patientson chronic hemodialysis adaptquite well to a low protein, salt,potassium and water diet, andthere would seem to be little sensein submitting them to the expenseof 1000 mg. of furosemide a dayfor the sake of a little extra dailyfluid intake.The role of furosemide in acute

renal failure is still not clearly de-fined. In Case 7, the high urinespecffic gravity and low urinesodium concentration indicated a"functional" or "prerenal" etiology.In this case very high doses of furo-semide, 990 mg. intravenously overa 13-hour period, succeeded in re-versing the oliguria. The BUN andserum creatinine steadily fell tonormal levels during the followingtwo weeks.

In Case 8 the low urinary specfficgravity and low osmolality, coupledwith a high urinary sodium con-centration, pointed to a diagnosisof acute tubular necrosis. Hereagain the furosemide appeared toproduce a diuretic response, andthe* serum creatinine, which hadbeen climbing steadily prior to itsadministration, levelled off at 8mg. per 100 ml. Unfortunately, thispatient's bleeding duodenal ulcercaused the BUN to rise at a rapidrate, necessitating more frequentdialysis. Had there not been thiscomplication, it might have beenpossible to maintain a high urineoutput with furosemide and avoiddialysis.Faced with the oliguric patient

one first attempts to rule outhypovolemia, circulatory failure,urinary tract obstruction, toxic

nephropathy and other causes ofrenal failure. With these ex-cluded, if it is considered likelythat the patient has impending oractual tubular necrosis it is ourpolicy to administer 40 mg. offurosemide orally, intramuscularlyor intravenously, depending on thecircumstances. If no diuretic re-sponse occurs within two hours, thedose is raised to 100 mg., and if noresponse is noted within the nexttwo hours, the dose is increased to200 mg. If within the next twohours there is still no effect, 250ml. of 20% mannitol is infused overthe next 60 minutes, providedthere is no evidence of circulatoryoverload. If there is no result with-in the following three hours,another 200 mg. of furosemide isgiven, and if the situation is stillunchanged furosemide is discon-tinued and the patient is treated asa case of acute tubular necrosis. Itis frequently more advisable tobegin therapy with furosemiderather than with mannitol becausefurosemide appears to be moreconsistently successful and becausemannitol administration may pre-cipitate pulmonary edema in theoverhydrated patient.Once a diuretic response is ob-

tained the diuresis may continueon its own, or intermittent furo-semide therapy in doses rangingfrom 40 to 200 mg. at a time maybe needed.

In edematous states where theedema is not life-threatening but isresistant to the usual doses of furo-semide, the dose can be increasedby 80 to 120 mg. a day until adiuretic response occurs. Anotherapproach is to add other diureticagents to the program when 200mg. of furosemide has failed toproduce a diuresis, since syner-gistic effects have been reportedon furosemide by thiazides, mer-curial diuretics and aldactone.4' 12If there is still no diuretic response,the dose of furosemide can then be

further increased by 80 to 120 mg.per day until an effect is obtained.

ResumeEssais de fortes doses defuros.mide dans les ru.phropathieset les 4d.mes rebellesNous rapportons ici six cas d'6d.me(trois relevant d'un syndrome n6-phrotique, un caus6 par une in-suffisance cardiaque et deux parune insuffisance r6nale chronique)oii le furos6mide a 6t6 administr6. des doses orale tr.s sup6rieures. la posologie normale (jusqu'.720 mg par jour) en vue d'obtenirune diur.se satisfaisante. Dans uncas d'insuffisance pr6r6nale s6v.re,secondaire . un choc cardiog.ne etdans un autre cas de n6crose tubu-laire aigue, secondaire .i une hypo-tension perop6ratoire, on est par-venu . supprimer l'oligurie aumoyen de doses intraveineuses de990 et de 1400 mg par jour respec-tivement. Chez huit autres maladessoumis . une h6modialyse chroni-que, le furos6mide, administr6pendant deux semaines, par voieorale, . la dose quotidienne de 1000mg, par prises fractionn6es, aabouti . une diur.se mod6r6e.De fortes doses de furos6mide,

administr6es dans des cas rebellesd'6d.me et d'insuffisance r6nale estdonc consid6r6e comme une m6-dication sCire et efficace.

References1. SILVERBERG, D. S. AND KJELLSTRAND,

c. M.: Acta Med. Scand., 184: 473,1968.

2. MUTH. R. G.: Ann. Intern. Med., 69:249. 1968.

3. Idem: .7. A. M. A., 195: 1066, 1966.4. LARAGH. J. H. et al.: Ann. N.Y. Acad.

Set., 139: 453. 1966.5. MCKENZIE, I. F., FAIRLEY, K. F. AND

BAIRD, C. W.: Med. .7. Aust., 1: 879,1966.

6. JOYNT. M. S. AND MORRIN, P. A.:Canad. Med. Ass. .7., 99: 1256, 1968.

7. DEETJEN. P.: Ann. N.Y. Acad. Sci.,139: 408. 1966.

8. MALNIC, G., VIEIRA, F. L. AND ENoKI-BARA, H.: Nature (London), 208: 80,1965.

9. SELDIN, D. W. et al.: Ann. N.Y. Acad.Sci., 139: 328, 1966.

10. REUBI, F. C.: Ibid., 139: 433, 1966.11. THURATJ, K.: Ibid., 139: 388, 1966.12. DETTLI, L. AND SPRING, P.: Ibid., 139:

471. 1966.

C.M.A. JOURNAL/JULY 18, 1970/VOL. 103 133