From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
Syndrome
of Recurrent
Increased
Secretion
of Antidiuretic
Hormone
Following
Multiple
Doses
of Vincristine
By Marie
J. Stuart,
Charles
Cuoso,
Myron
The
syndrome
of
inappropriate
antidiuretic
hormone
secretion
(SIADH)
has
been recognized
to occur following
treatment with vincristine.
None of the reports
have provided
information
regarding
its
potential
for recurrence
on further
chalIenge
with
vincristine
(VCR),
an agent
generally
required
for repeated
use in patients
with
malignancies.
Symptomatic
hyponatremia
and SIADH that occurred
8
days following
administration
of VCR in a
HE
SYNDROME
OF
inappropriate
(SIADH)
was first recognized
in 1957.’
variety
of clinical
conditions
which
include
malignant
alkaloid,
In two
measured
None
provided
fact that
malignancies.
The
of the
this
agent
of
regarding
is generally
treatment
lymphatic
excretion
of
antidiuretic
elevated
SIADH
its
ADH
was
for
by
the
by
for
during
the basis
treatment
(ADH)
period
use
excretion
as
hy-
therapy
despite
in
a
with
levels,
of
vincristine
recurrence,
repeated
in ADH
AND
and
produced
elevations
measured
A. Oski
hormone
secretion
found
to accompany
of the central
nervous
hormone
during
potential
with vincristine
leukemia,
forms
MATERIALS
Urinary
Frank
infections,2
required
of recurrent
repeated
for acute
antidiuretic
It has been
disorders
pulmonary
reports
information
documentation
following
therapy
acute
of the case reports,9”#{176} serum
by bioassay,
were
markedly
ponatremia.
have
tumors,2
vincristine.3’0
and
child with acute lymphatic
leukemia
was
documented
with specific radioimmunoassay of urinary
ADH levels.
The further
occurrence
of recurrent
elevations
in ADH
excretion
8-10
days following
repeated
treatment
with
VCR was also observed.
However,
SIADH
was
prevented
by
prophylactic
rigorous
fluid
restriction.
The occurrence
of SIADH
following
VCR
therefore
does not preclude
the further
safe usage of this drug.
T
system,2
the ymca
Miller,
patients
the
with
in one
patient,
the course
of her
of this report.
chemo-
METHODS
specific
radioimmunoassay”
on
24-hr
urine
collections.
CASE
KS, a 4-yr-old
white
easy bruising.
Following
amination),
a diagnosis
ture was normal,
and
meq/liter,
potassium
of
The blood pressure
was
From
ical
Address
Hospital,
© 1975
of Pediatrics
and the Veterans
Submitted
Blood,
female,
was hospitalized
on
appropriate
hematologic
of acute lymphatic
leukemia
initial electrolytes
included
a
4.4 meq/ liter, bicarbonate
of
105/75 mm Hg.
the Departments
Center.
August
for
reprint
REPORT
and
Administration
8, 1974;
accepted
requests:
750 East
Adams
by Grune
& Stratton.
Marie
Street.
Medicine.
State
Hospital.
Syracuse,
September
J. Stuart,
Syracuse.
May 29, 1973 for evaluation
of pallor
and
investigations
(including
bone marrow
exwas made.
A routine
initial lumbar
puncsodium
of 138 meq/liter,
chloride
of 104
24 meq/liter,
and a BUN of 19 mg/lOO
ml.
N.Y.
University
of New
York,
Upstate
Med-
N. Y. 13210.
12. 1974.
M.D.,
Department
of
Pediatrics,
State
University
13210.
Inc.
Vol. 45, No. 3 (March), 1975
315
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STUART
316
The
patient
was
started
on
a chemotherapeutic
regimen
of
oral
dexamethasone,
ET AL.
6 mg/sq
m
daily, and intravenous
vincristine,
2 mg/sq
m weekly for three doses, the first two of which were
administered
on hospital
days 2 and 9 (Fig. I).
The early hospital
course
proved
uneventful,
but by hospital
day 7, the patient
had developed abdominal
distention
and constipation.
These symptoms
disappeared
by day 9. On day
9, the patient
experienced
two episodes
of generalized
seizures.
These
were controlled
with
intravenous
valium.
Examination
at this time revealed
that the patient
had a blood pressure
of
160/90 mm Hg, and a small retinal hemorrhage
inferior-medial
to the disc margin.
No evidence
of volume
depletion
or overload
was present,
and laboratory
data revealed
a BUN of 5 mg/
100 ml,
sodium
of 118 meq/liter,
chloride
of 84 meq/liter,
potassium
of 4.1 meq/liter,
bicarbonate
of
urine
osmolality
(Fig.
I).
and
The
x-rays
21
meq/liter,
of
blood
of the
a
483
sugar,
skull
were
serum
osmolality
osmoles/liter,
M
serum
calcium
of
243
and
a
urinary
and
phosphorus,
M
osmoles/liter
sodium
urine
with
excretion
analysis,
a
of
concomitant
130
lumbar
meq/liter
puncture,
all normal.
The hyponatremia
was initially treated with 37 ml of 3% NaCI,
followed
by 160 ml of 3% NaCI
over the next 4 hr. This was followed
by a therapeutic
trial of 5 cc ethanol.
The hyponatremia,
however,
remained
uncorrected
by these therapeutic
modalities.
Twelve
hours after the seizures,
284
60
0
50
40
‘_%
30
EE
20
Q.0
toNormal
>>
Range
,
1
1
290
_J
>‘
1
1
000
X-URINE
280
r-7
0-PLASMA
800
..#{149}#{149}
270
- - -
)()cXx
600
)(
260
400
250
200,...
U)
U)
0
240
2-5
2
0’
11-5
II
0-5
600
mI/
V
<400
mI/day
Maintenance
II
day
Fluids
-4
140
30
4)
20
110
.?
-D
(w
E
RUM
AE
V-URINE
OQ
50
30
I0
II1!’II’
Ill
VCR
ii!itiiiiiiii
5
4’lO
15
VCR
DAYS
iii
4’20
VCR
OF
HOSPITALIZATION
25
30
Fig. 1. Hospital
course
of patient
KS, with pertinent laboratory
data,
in
relation
to VCR administration.
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
SECRETION
OF
ANTIDIURETIC
HORMONE
317
60
CRANIAL
‘5O
E
IRRADIATION
-
2
9/2-9/27
40
0
::
NORMAL
lot
VCR
VCR
6/6/73
//flI
1f1VCR
-,.l.
VCR
5/30/73
6/16/73
VCR
8/3/73
Fig. 2.
Twenty-four-hour
urinary
and later maintenance
therapy
and
irradiation.
the
patient
was
placed
on a regimen
VCR
9/25/73
TIME
VCR
0/2/73
VCR
0/30/73
11/26/73
(Days)
excretion
of ADH obtained
during
its relation
to VCR administration
of fluid
RANGE
restriction
at approximately
course of initial
and prophylactic
50%
induction
cranial
maintenance
(Fig.
I).
Complete
normalization
of the serum sodium
level occurred
following
total fluid restriction
by
hospital
day 18 (Fig. I). On June 16, 1973, KS received
her third dose of vincristine
while continuing
on approximately
50% maintenance
fluids,
and while under
close surveillance
for recurrent
hyponatremia.
The patient
remained
clinically
asymptomatic
and did not manifest
a drop
in her serum sodium
level (Fig. l). Fluid restriction
was thereafter
gradually
withdrawn,
and
the patient discharged
on hospital
day 35 following
a bone marrow
examination
that revealed
her
to be in remission.
An EEG, brain scan, and creatinine
clearance
performed
prior to discharge
were normal,
and a Risa 125i measurement
of total blood
volume
revealed
a value
of 80.2
ml/kg (normal,
66-88 mI/kg),
with a plasma volume of 52.9 mI/kg
(normal,
36-49
mI/kg).
The patient
was continued
on maintenance
chemotherapy,
during the course
of which she received subsequent
doses of vincristine
(Fig. 2). The patient
was on no fluid restrictions
during
these subsequent
dosages,
and remained
asymptomatic
with normal
serum sodiums.
She received
prophylactic
cranial
irradiation
(2500
R) during the period
September
12, 1973 to September
27,
1973, and at the present
time continues
in remission
without
evidence
of central
nervous
system
involvement.
She manifests
some signs of vincristine
neurotoxicity,
including
decreased
deep
tendon reflexes, alopecia,
and ptosis.
RESULTS
Urinary excretion of ADH
(mU/24
hr/sq m) obtained
whenever
during
the course
of the patient’s
initial
hospitalization,
and thereafter
ing subsequent
dosages
of vincristine
during
maintenance
chemotherapy,
depicted in Fig. 2.
Urinary
ADH
excretion
tomatic
hyponatremia
was
days
following
the
patient’s
at the time
of the
markedly
elevated.
initial
dose
patient’s
initial
This
rise had
of vincristine
on
May
period
occurred
30,
possible
followare
of sympeither
8
1973,
or
the
day following her second dosage on June 6, 1973. Subsequent
followup values
revealed that the peak excretions of ADH
occurred from 8 to 10 days following
subsequent
vincristine
ing prophylactic
cranial
ments
vember
after
26,
subsequent
1973 did
not
dosages on June 16, 1973
irradiation
in September
and August
1973, urinary
3, 1973.
ADH
vincristine
dosages
on October
2, October
reveal
evidence
of increased
ADH
excretion
Followmeasure-
30, and No(Fig. 2).
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
3 18
STUART
ET AL.
DISCUSSION
ing
The cardinal
hypo-osmolality
features
of SIADH
the serum
of
include
(1) hyponatremia
and extracellular
fluid,
(2)
with correspondcontinued
renal
excretion
of sodium,
(3) absence
of clinical
evidence
of volume
depletion,
(4)
osmolality
of the urine
greater
than
that
appropriate
for the concomitant
tonicity
of the plasma,
i.e., urine
less than
maximally
dilute,
(5) normal
renal
and adrenal
function,
and (6) improvement
in both
hyponatremia
and
renal
loss of sodium
by fluid restriction.2”2
In addition,
recent
studies
have
demonstrated
that
cretion
is related
urinary
Our
including
patient
the
excretion
to the
fulfills
all
documentation
concomitant
severe
In asymptomatic
correction
severely
the
expansion,
in SIADH
necessary
for the diagnosis
urinary
ADH
excretion
during
SIADH,
the
accepted
has been
to produce
intake.
In patients
included
the
and
most
occurred
posterior
in our
pituitary
patient
(Fig.
by the use
Hantman
et al.’5
have
of the
mode
sodium
chloride
proposed
another
tients,
serum
ing
the
ture
with
tion
recognized
days
of
ADH
period
levels
as measured
on the potential
for
vincristine
in patients
also
the
fluid
occur.
in the
restriction
face
that
during
the
enon.’6
time
It is possible
that
subsequent
inability
cretion
in our patient.
patients.
It has been suggested
body
and
that
In
view
the
of
the
for
that
peripheral
the
period
in which
fact
cranial
to
observation
the
that
rapid
correc-
the
effect
markedly
elevated
available
in the
of
syn-
following
ADH
durlitera-
administraexcretion.
It
by documenting
repeated
symptomatic
can
be prevented
the
SIADH
repeated
hypoby rigorous
is most
likely
to
(Fig. 2) was a factor
increase
in ADH
seconfirmation
is on
is a secondary
with
pa-
challenge
following
of vincristine
patients
repeated
occurred.
syndrome
require
demyelination
most
as
of furosemide
replacement
secretion,
irradiation
provoke
an
will
primary
nerve
of
secretion
prophylactic
of vincristine
This
of the
presumably
ADH
the
solution.
SIADH,
following
has once
occurrence
of increased
are
of SIADH
of urinary
recurrence
and
excreted,
release
from
the
in our patient.
consists
by
were
however,
of SIADH
this syndrome
for
excretion,
doses
of vincristine.
Our
findings
indicate
in the
data,
recurrence
in whom
potential
in ADH
natremia
by bioassay
No
a hypertonic
produce
fur-
of symptomatic
hyponatremia
(Table
I). In two of these
documents
the occurrence
by the direct
measurement
demonstrates
increase
the occurrence
administration
of hyponatremia.
This case report
of vincristine
an
due
to
vincristine
by
of
can
method
concentrated
electrolyte
of vincristine-induced
was
4-10
the
is rapidly
urinary
electrolyte
losses
In the eight
previous
a more
reports
of SIADH,
a period
of
for
to inhibit
ADH
proved
unsuccessful
of SIADH
which
balance,
accompanied
drome
within
ex-
water
balance
and
symptomatic
administration
of sodium
tion of the symptomatic
hyponatremia
diuresis
to achieve
a negative
water
with
case
ADH
of therapy
a negative
with
acute
the rapid
administration
1). Attempts
of alcohol’4
recently
when
osmolality.’3
criteria
ofhigh
hyponatremia.
patients
with
therapy
has
Unfortunately,
volume
is increased
ofplasma
of hyponatremia
restricting
water
hyponatremia,
saline
solution.
ther
of ADH
level
SIADH
in
the
other
nerve
cell
phenominduced
by
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
SECRETION
OF
ANTIDIURETIC
HORMONE
319
Table 1. Tabulation
of Previous
Following
Age
Bioassay
for ADH
11 mo
Not done
References
Fine et
Vin cristine
Case
of SIADH
Reports
Administration
Onset of Hyponatremia
After Vincristine
Neurologic
Complications
7 days post
Paresthesias,
DTRs,
absent
flaccidity,
ptosis, ileus
Slater
et al.4
7 yr
Not done
10 days
post
Absent
DTRs, ileus,
bilateral
footdrop,
and
ataxia
Meriwether5
34 yr
Not done
Unknown
Paresthesias,
absent
DTRs,
and ileus
Cutting6
54 yr
Not done
4 days post
Peripheral neuropathy
and
severe ileus
Oldham
et al.7
52 yr
Not done
7 days post
Areflexia, dysarthria, and
2 yr
Not done
17 days following
Absent
ileus
Nicholson
et oI.
initial
DTRs and ileus
vincristine
dose or 8 days after
second dose
Suskind et al.9
3 yr
5 days post
+
Decreased
DTRs, bladder
atonia,
ileus, and
paresthesias
Robertson
et 01.10
50 yr
3-4
+
days post
Decreased
DTRs
and ileus
vincristine have also manifested
other moderately
to markedly
severe signs of
vincristine neurotoxicity, the SIADH
in these patients is possibly due to a direct
neurotoxic
effect
of vincristine
on the hypothalamus,
the neurohypophyseal
tract, or the posterior pituitary itself, involving sites of ADH
formation
and
storage.
In summary,
in all the reports to date in which SIADH
has occurred following vincristine therapy, no patient was rechallenged
with the drug because of
the risk of repeated
ments
the fact that
that
increased
the
ADH
serious
electrolyte
hyponatremia
secretion
disturbances.’6
This case
induced
by vincristine
is true
following
repeated
challenge
with
report
SIADH,
docuand
vincristine
is a
reproducible finding. This does not preclude the safe usage of repeated doses of
vincristine in the patient with malignancy,
in whom
repeated doses of the drug
may
be deemed
a therapeutic
necessity.
REFERENCES
1.
Barlter
and
Schwartz
WB,
FC:
A syndrome
hyponatremia
appropriate
Am
J Med
Bennett
probably
secretion
23:529,
2. Barlter
FC,
of inappropriate
of
W,
Curelop
renal
sodium
resulting
112:256,
from
of antidiuretic
in-
hormone.
1957
Schwartz
WB:
secretion
of antidiuretic
1966
4.
Slater
cristine
LM,
The
syndrome
hor-
cer23:l22,
HypoJ Dis
an
HO:
Serpick
AA:
Vin-
hyponatremia.
Am
syndrome
Vincristine
adult.
Can-
J Med
toxicity with
Oncology
Inappropriate
hormone
7. Oldham
duced
WD:
in
1971
6. Cutting
therapy.
RA,
with
1969
5. Meriwether
antidiuretic
NA:
Am
Wainer
neurotoxicity
hyponatremia
mone. Am J Med 42:790,
1967
3. Fine RN, Clarke
RR, Shore
natremia
and vincristine
therapy.
Child
S,
loss
secondary
25:234,
secretion
of
to vincristine
51:269, 1971
RK,
Pomeroy
of
TC:
inappropriate
Vincristine
in-
secretion
of
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STUART
antidiuretic
hormone.
South
Med
J
65:1010,
8. Nicholson
RG,
Feldman
natremia
in association
Can
Assoc
Med
9.
Suskind
drome
of
diuretic
RM,
Brusilow
bioassay
Hypo-
1972
Goldbert
Zehr
secretion
produced
of ADH
J:
GL,
Vincristine
of
Med
132:717,
II.
antidiuretic
Miller
of
Med
say of urinary
Response
normal
to
subjects.
537, 1972
with
abnormal
Arch
Epstein
evaluation
antidiuretic
water
load
J Clin
35:293,
se-
15.
Intern
Radioimmunoashormone
and
Endocrinol
in man:
dehydration
Metab
in
34:
AM:
in polyuric
the
hor-
Urinary
anti-
disorders
and
Ann
syndrome.
in
Intern
1972
Kleeman
FH:
and
antidiuretic
l963
Moses
ADH
CR,
Studies
Hantman
R: Rapid
Rubini
ME,
on alcohol
of ethyl
neurohypophysis.
Schrier
AM:
77:715,
14.
N, Zelkowitz
hormone.
Moses
of
M,
anti-
1973
M,
Hyponatremia
J Med
Miller
inappropriate
by
vincristine
level). J Pediatr
Bhoopalam
neurotoxicity
cretion
Am
13.
Syn-
81:90, 1972
10. Robertson
mone.
M:
secretion
diuretic hormone
SW,
inappropriate
(with
W:
with vincristine therapy.
J 106:356,
hormone
toxicity
U:
12.
inappropriate
1972
ET AL.
alcohol
J Clin
D,
34:448,
B,
of
E,
II. The
as an inhibitor
Invest
Rossier
correction
Landin
diuresis.
of the
1955
Zohlman
hyponatremia
R,
in
the syndrome
of inappropriate
secretion
of antidiuretic
hormone.
An alternative
treatment
to
hypertonic
saline. Ann Intern Med 78:870,
1973
16. Rosenthal
5, Kaufman
neurotoxicity.
Ann Intern Med
5: Vincristine
80:733, 1974
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
1975 45: 315-320
Syndrome of recurrent increased secretion of antidiuretic hormone
following multiple doses of vincristine
MJ Stuart, C Cuaso, M Miller and FA Oski
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