The Qanadicin SMedieal oAssociation Journal

e lournal de VAssociation medicale canadienne^

July 18,1970/Volume 103, Number 2

Experiences with high doses of furosemide in

renal 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, one
to congestive heart failure and two to chronic renal failure,
are reported in which furosemide was administered in oral
doses higher than those usually prescribed (up to 720 mg. a day),
in order to ohtain a satisfactory diuresis. In one case of severe prerenal
failure secondary to cardiogenic shock and in one case of acute tubular
necrosis secondary to hypotension at the time of operation, intravenous
doses up to 990 and 1400 mg. per day respectively were able to reverse
the oliguria. In eight additional patients who were on chronic hemo
dialysis, furosemide was administered to the amount of 1000 mg. per day
in divided doses for two weeks, and produced a moderate diureorally
tic response.
The use of high doses of furosemide in edema and renal failure resistant to the usual therapeutic measures appears to be safe and effec
tive.

sterone

antagonist,

thiazide,

mercurial diuretic and furosemide

in the usually prescribed dose (up
to 200 mg. per day) had failed to
promote a diuresis; in Cases 5 and
6 no diuretic therapy other than
the conventional doses of furose
mide had been used. Furosemide
was then administered in increas
ing doses, starting with 40 mg. two
to three times a day and gradually

increasing

at two- to

three-day in-

tervals by 80 to 120 mg. per day

until a diuresis was obtained which
was sufficient to restore the pa
tient's weight to normal.

(Lasix-Hoechst)

is a tic syndrome, congestive heart

2
diuretic that has failure, and acute or chronic renal Group
Two
patients with acute renal
been shown to be very effective in failure who were resistant to the
were studied; one case was
failure
the treatment of edema resistant to conventional doses of furosemide.
to acute myocardial in
secondary
other diuretics.15 Unlike most Doses up to 1000 mg. per day farction with
pulmonary edema
diuretic agents it appears to be orally and 1400 mg. per day in and
and
the
other secondary
shock,
in
very effective even in the presence6 travenously were successful pro to
hypotension brought about at
of impaired renal function.2-3> moting diuresis.
time of reimplantation of a
the
However, patients are occasionally
for heart block. In these
pacemaker
seen who do not respond satisfac- Material
intravenous doses of
daily
patients
torily to furosemide in the doses Group 1 (Table I)
and
1400 mg. per day
990
to
up
In
such
pa
usually recommended.
administered to
were
tients the administration of much This group consisted of six pa respectively
a
diuretic
response.
higher doses, even up to 4000 mg.in tients, three with the nephrotic produce
syndrome (previously reported),1
per day,2 has been successful
Group 3 (Table II)
one with congestive heart failure
promoting a diuresis.
Over the past two years we have secondary to coronary artery dis This group comprised eight pa
studied patients with the nephro- ease, and two with chronic renal tients with chronic renal failure
failure. In the three patients with who were being maintained on
From the Renal Department, University
the
nephrotic syndrome the nature twice-weekly hemodialysis using a
of Alberta, Edmonton, Alberta, and Uni
versity of Saskatchewan, Saskatoon, Sas- of the renal lesion was determined Kolff twin coil. Each dialysis lasted
katchewan
Presented at the Annual Meeting- of The
by percutaneous renal biopsy; in six hours. The creatinine clearance
Royal Collegre of Physicians and Surgeons all three membranous
glomerulone in these patients ranged from 0.5
of Canada, Montreal, January 23, 1970.
Reprint requests to: Dr. Donald S. phritis was found. In Cases 1 to 4 to 2 ml. per min. per 1.73 m.2 The
Silverberg, Dialysis Unit, University of
Alberta Hospital, Edmonton, Alberta.
various combinations of an aldo- study was divided into two parts,

Furosemide

relatively

new

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

Mg. 400
0

Kg.

Furosemide

.ttk-tt't

Ktiiffii<$&$imursn 100

60
56

mg

Aldactone 75 mg.

Weight

ml. 2000

1000

mEq.

Urine volume /'

per lit. 4

Serum potassium

7.45

Mg.

7.35

Blood pH

per cent 50

Mg.

30

per cent 3

BUN.
Serum creatinine

Days

10

FIG. 3.Case 3. A 61-year-old woman

with membranous glomerulonephritis of
unknown etiologry.

each of two weeks' duration. Dur

ing the first two weeks no furose

mide was administered, and during
the second two weeks 1000 mg. was
given in a dose of 250 mg. four
times daily. During the study the
patients were continued on dialyssis in the usual manner. Each pa
tient was given a 40-g. protein diet
and allowed an amount of water
equal to the previous day's urine
output plus insensible loss. Salt in-

take

vious

to potassium supplementapostprandial blood sugar. urine ponded

tion with or without the addition
In Group 3 the values of
volume and daily sodium, potas of aldactone. In Cases 1, 3 and 4,
a

sium, chloride,

and creatinine
each two-week
period were averaged because of
the variation in daily urine vol
ume which occurs during chronic
hemodialysis. All blood studies
were performed immediately be
fore dialysis on the first, fourteenth
and twenty-eighth days of the

once
diuretic response occurred,
reaccumulation of fluid could be
prevented 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.

Results

65-year-old obese woman was ad

on May 1, 1969, in shock.
Twenty-four hours previously she had

excretion

urea

over

equal to that of the pre study.

day's urine salt excretion.

was

Group 2 Case 7 (Fig. 4)

mitted

Group 1 (Table I)
a vague retrosternal discomfort
All patients responded to the noted
which
until the time of ad
with a mission.continued
high doses of furosemide
An electrocardiogram on ad
diuresis sufficient to return their mission showed evidence of a recent
weight to normal. In no patient anterior myocardial infarction. Her
was a reduction in renal function blood pressure on admission was
noted as judged by BUN, serum 100/60, and the pulse was 96 and
creatinine or creatinine clearance; thready. Her skin appeared cold and
in Case 3 a marked improvement clammy. Soft moist rales were heard
in these parameters occurred. Hypokalemia was seen in two of the
three nephrotic patients (Figs. 1,
2 and 3) and in the patient with
congestive heart failure, but res
Methods
In all three groups observations
were made of body weight, urinaly-

sis, urine volume, urine sodium,

potassium, chloride, urea and crea
tinine, blood urea nitrogen, serum
creatinine and uric acid, serum

glutamic oxaloacetic transaminase

(SGOT), serum lactic acid dehydrogenase (LDH), serum alkaline
phosphatase, hemoglobin, red cell
count, differential count, platelet
count and fasting and two-hour

Day*

FIG. 1.Case 1. A 28-year-old woman

with diabetes and membranous glomerulo

nephritis.

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

Days

.10

FIG. 2.Case 2. A 62-year-old man with

lupus erythematosus and membranous

grlomerulonephritis.

both lung bases. The central venous

pressure was 12 cm. of water. The
liver was difficult to palpate owing
to the obesity. A chest radiograph
showed evidence of minimal pulmon
ary congestion. A Foley catheter
was inserted at the time of admission.
She was treated with morphine and
digoxin, the latter in a dose of 0.75
mg. intravenously initially followed
by 0.25 mg. every four hours for
three doses. An isoproterenol infusion
was also begun. Despite this therapy
her pulmonary congestion and blood
pressure changed very little and the
urine volume averaged only 10 ml.
per hour during the first 17 hours
after admission. Her BUN at that
time 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 to
3 hyaline and 1 to 2 granular casts
per h.p.f. The urine sodium concen
tration was 5 mEq./l. These findings
were consistent with pre-renal oli
guria, which was thought to be due to
a reduced cardiac output.

DIALYSIS

at

FIG. 4.Case 7. A 65-year-old woman

with prerenal failure secondary to cardiogrenic shock.

Seventeen hours after admission

100 mg. of furosemide was given in
travenously. Since there was little
diuretic response, another 100 mg.

given in the 19th hour and again

in the 20th hour. The urine output

was

hours first increased

up to 40 ml. per hour, but gradually
fell again to 15 ml. per hour. Furose
mide, 40, 100 and 50 mg., was ad
ministered intravenously during the
33rd, 34th and 36th hours respec
tively, but by the 38th hour the urine
output had only risen to 33 ml. per
hour. 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 volume
had risen to 90 ml. per hour. An ad
ditional 100 mg. of furosemide at this
time maintained the urine volume at
this level for the next two hours, and
in the 46th hour another 100 mg. was
given. The urine volume rose to 170
ml. per hour. The diuresis was asso
ciated with a clearing of the pulover

the

next 13

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.

congestion and a reduction in

the ventral venous pressure to normal.
It was only after the diuresis had be
gun, in the 46th hour, that her blood
pressure 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 and
200 ml. per hour by only occasional
injections of furosemide. The patient
went on to recovery. Her BUN
reached a maximum of 115 mg. per
100 ml. on the fifth day and then
gradually fell to normal by the 16th
day. The serum creatinine reached a
maximum of 4.5 mg. per 100 ml. on
the fifth day and gradually fell to
normal by the 14th day. Mild hypokalemia developed during the diure
sis but was easily controlled with in
travenous potassium chloride.
monary

Case 8 (Fig. 5)
A 48-year-old man was admitted on
May 13, 1969, for reimplantation of
a cardiac pacemaker. He had had
rheumatic fever at age 14 and had
developed aortic insufficiency thereafter. In 1966 he began to have syn-

day after operation, the BUN was 144

mg. per 100 ml., and serum crea
tinine 7.5 mg. per 100 ml. Urinalysis
revealed a specific gravity of 1015
with 2+ protein, 80 to 100 R.B.C/s
per h.p.f., 1 to 4 leukocytes per h.p.f.
and occasional hyaline casts. No red
cell 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 were
both 335 mOsm per 1. Retrograde
pyelography was normal. It was con
cluded that the patient had acute
tubular necrosis. Melena was noted
five days postoperatively and a gas
trointestinal series revealed a duode
nal ulcer. He was treated with a 40g. protein diet and aluminum hydroxide, taken hourly. On the seventh
postoperative day, 60 mg. furosemide
was given and a slight diuretic res
ponse was noted. On the eighth day
100 mg. furosemide was given intra
venously every three hours for a total
dose of 800 mg. This was associated
with a marked increase in the urine
volume. The next day 700 mg. was
administered and the urine volume
remained high. Despite the absence
of oliguria the BUN and serum crea
tinine rose and on the ninth post

copal episodes. Third-degree heart

was found and a transvenous
pacemaker was implanted. Because operative day hemodialysis was per
of recurrent skin infections this pace formed. Afterwards high doses of
maker was removed on May 23, 1969, furosemide, up to 1400 mg. per day,
and another one implanted. The pre were administered intravenously. The
operative urinalysis and BUN were urine volume remained high and
normal. During operation his blood serum creatinine was stabilized at
pressure fell from 180/80 to 90/60 about 8 mg. per 100 ml. Neverthemm. Hg. Postoperatively a Foley
less the BUN continued to rise, pos
catheter was inserted; despite ade sibly because of the continued bleed
quate hydration he became progres- ing from the duodenal ulcer.
sively more oliguric. On the sixth Furosemide was discontinued after
block

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

the twelfth day. The urine output fell

over the next 48 hours to 550 ml.
per day, and subsequently to as low
as 40 ml. per day on the twentieth

mg. of furosemide increased the

average daily urine volume by
49%, sodium excretion by 105%,
potassium excretion by 17% and
chloride excretion by 155%. All
these changes are significant at the
5% level. The average excretions of
urea and creatinine were not sig
nificantly altered. No significant
changes in the BUN or serum
creatinine were noted.

day. Hemodialysis was performed on

the ninth, fourteenth, eighteenth,
twentieth and twenty-sixth days. On
the twenty-fourth day the urine out
put began to increase spontaneously,
and by the thirty-second day it was
over 3000 ml. per day. The BUN and
serum creatinine returned to normal
by the forty-second day.
Adverse reactions
Group 3 (Table II, Fig. 6)

In the eight hemodialysis pa

tients the administration of 1000

300]

O<5200

DOSE

FIG. 6.Response of eig-ht patients on

chronic hemodialysis to 1 g. of furo
semide administered orally in divided
doses over a 2 4-hour period.

Hypokalemia was common if the

diuresis was marked. It responded
rapidly, however, to oral or intra
venous potassium chloride therapy,
with or without aldactone. No
changes were noted in the fasting
and two-hour post-prandial blood
sugars. In the one patient with
diabetes (Case 1) there was no
change in the blood sugar or insulin
requirements throughout the course
of therapy. Postural hypotension
was frequently noted when the
diuresis was very marked, but was
short-lived. No significant alterations in hemoglobin, hematocrit,
leukocytes, differential leukocyte
count, platelets, bilirubin, SGOT,
LDH or alkaline phosphatase were
noted. The uric acid levels were
elevated owing to renal
frequently
failure and tended to rise slightly
during therapy, but there were no

in two patients with

severe

chronic

failure, doses up to 720 mg.

a day orally were required. In the

renal

patients with acute renal fail

intravenous doses of up to 990
mg. and 1400 mg. a day were used
with no observed toxic effects.
Most patients with edema
two
ure

secondary to congestive heart fail

ure, cirrhosis or the nephrotic syn
drome respond to the usual doses
of furosemide. Why some patients
with identical creatinine clearances
should require much higher doses
of the diuretic remains unknown.
Furosemide in the usually admin
istered doses blocks sodium reabsorption primarily in the ascend
ing limb of Henle.7,8 In higher
doses than those ordinarily used
it may also reduce sodium reabsorption in the proximal tubule.9
It is possibly the combined action
at the two sites that accounts for
the diuresis when higher doses are

used. There is also some evidence

that furosemide increases renal
blood flow and glomerular filtration
rate even in the presence of re
duced. renal function.6,10 It has
been suggested that this is accomplished by an inhibition of
renin-release from the juxtaglomerular apparatus.11 By reducing
renal vascular resistance furo
semide produces better renal tissue
perfusion and more of the diuretic
cases of clinical gout. No gastro
will be allowed to perfuse the
intestinal symptoms, skin rashes or tubular
cells, where it can exert a
signs of auditory toxicity were natriuretic
action.
noted.
The role of furosemide in severe
chronic renal failure is less well
Discussion
defined than in the other edema
When no diuretic response occurs states, where clearances are high.
with the usual doses of a diuretic In most patients with chronic renal
the tendency is to add another failure, edema will improve with
diuretic agent to the therapeutic moderate to severe salt restriction,
program rather than to increase the and by the time salt restriction fails
dose of the original agent. Recent to improve it the BUN and serum
experience with furosemide and creatinine are usually so high that
ethacrynic acid15 indicates that the patient requires dialysis or
merely raising the doses of these transplantation in any case. How
drugs may at times produce a ever, a group of patients remains
diuresis when usual doses are un- in whom creatinine clearances are
successful. The recommended dose between 3 and 5 ml. per min. per
of furosemide is 40 to 200 mg. per 1.73 m.2 They have minimal uremic
day. However, doses up to 4000 symptoms other than those related
mg. a day have been used on oc- to fluid retention and hypertension,
casion with no toxic effects being and cannot remain edema-free on
noted.2 In our three cases of neph severe salt restriction. For these
rotic syndrome, doses up to 600 few patients, high doses of furo
mg. a day orally were required to semide may offer a reprieve from
produce a diuresis. In one patient dialysis or transplantation for
with congestive heart failure 360 several months.
Most chronic hemodialysis pamg. a day orally was needed, and

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

tients are allowed only 600 to 1000

ml. of fluid per day. Excessive fluid
intake in these patients will produce edema and hypertension. As
we have demonstrated, the ad..
ministration of 1000 mg. of furosemide per day will increase their
urine volume and allow a greater
intake of salt, water and potassium.
On the other hand most patients
on chronic hemodialysis adapt
quite well to a low protein, salt,
potassium and water diet, and
there would seem to be little sense
in submitting them to the expense
of 1000 mg. of furosemide a day
for the sake of a little extra daily
fluid intake.
The role of furosemide in acute
renal failure is still not clearly defined. In Case 7, the high urine
specffic gravity and low urine
sodium concentration indicated a
"functional" or "prerenal" etiology.
In this case very high doses of furosemide, 990 mg. intravenously over
a 13-hour period, succeeded in reversing the oliguria. The BUN and
serum creatinine steadily fell to
normal levels during the following
two weeks.
In Case 8 the low urinary specffic
gravity and low osmolality, coupled
with a high urinary sodium concentration, pointed to a diagnosis
of acute tubular necrosis. Here
again the furosemide appeared to
produce a diuretic response, and
the* serum creatinine, which had
been climbing steadily prior to its
administration, levelled off at 8
mg. per 100 ml. Unfortunately, this
patient's bleeding duodenal ulcer
caused the BUN to rise at a rapid
rate, necessitating more frequent
dialysis. Had there not been this
complication, it might have been
possible to maintain a high urine
output with furosemide and avoid
dialysis.
Faced with the oliguric patient
one first attempts to rule out
hypovolemia, circulatory failure,
urinary tract obstruction, toxic

nephropathy and other causes of

renal failure. With these excluded, if it is considered likely
that the patient has impending or
actual tubular necrosis it is our
policy to administer 40 mg. of
furosemide orally, intramuscularly
or intravenously, depending on the
circumstances. If no diuretic response occurs within two hours, the
dose is raised to 100 mg., and if no
response is noted within the next
two hours, the dose is increased to
200 mg. If within the next two
hours there is still no effect, 250
ml. of 20% mannitol is infused over
the next 60 minutes, provided
there is no evidence of circulatory
overload. If there is no result within the following three hours,
another 200 mg. of furosemide is
given, and if the situation is still
unchanged furosemide is discontinued and the patient is treated as
a case of acute tubular necrosis. It
is frequently more advisable to
begin therapy with furosemide
rather than with mannitol because
furosemide appears to be more
consistently successful and because
mannitol administration may precipitate pulmonary edema in the
overhydrated patient.
Once a diuretic response is obtained the diuresis may continue
on its own, or intermittent furosemide therapy in doses ranging
from 40 to 200 mg. at a time may
be needed.
In edematous states where the
edema is not life-threatening but is
resistant to the usual doses of furosemide, the dose can be increased
by 80 to 120 mg. a day until a
diuretic response occurs. Another
approach is to add other diuretic
agents to the program when 200
mg. of furosemide has failed to
produce a diuresis, since synergistic effects have been reported
on furosemide by thiazides, mercurial diuretics and aldactone.4' 12
If 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.
Resume

Essais de fortes doses de

furos.mide dans les ru.phropathies
et les 4d.mes rebelles
Nous rapportons ici six cas d'6d.me
(trois relevant d'un syndrome n6phrotique, un caus6 par une insuffisance cardiaque et deux par
une 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'obtenir
une diur.se satisfaisante. Dans un
cas d'insuffisance pr6r6nale s6v.re,
secondaire . un choc cardiog.ne et
dans un autre cas de n6crose tubulaire aigue, secondaire .i une hypotension perop6ratoire, on est parvenu . supprimer l'oligurie au
moyen de doses intraveineuses de
990 et de 1400 mg par jour respectivement. Chez huit autres malades
soumis . une h6modialyse chronique, le furos6mide, administr6
pendant deux semaines, par voie
orale, . la dose quotidienne de 1000
mg, par prises fractionn6es, a
abouti . une diur.se mod6r6e.
De fortes doses de furos6mide,
administr6es dans des cas rebelles
d'6d.me et d'insuffisance r6nale est
donc consid6r6e comme une m6dication sCire et efficace.
References
1. 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 ENoKIBARA, H.: Nature (London), 208: 80,
1965.
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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