Effect of single-dose of tolvaptan in neurocritical patients with hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion
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CARTAS
CIENTÍFICAS
501
aparecer
y
ocasionalmente
revertir
a
ritmo
sinusal
de
forma
espontánea,
por
lo
que
existe
la
posibilidad
de
que,
coin-
cidentemente
a
la
administración
de
propofol,
la
arritmia
hubiese
finalizado
de
manera
fortuita.
Por
último,
la
admi-
nistración
previa
de
amiodarona
en
los
casos
de
FA
podría
haber
influido
en
la
reversión
tras
la
administración
de
pro-
pofol,
si
bien
inicialmente
(tras
la
dosis
total
de
1.200
mg
de
amiodarona
en
24
h)
no
logró
el
objetivo
del
control
del
ritmo.
A
modo
de
conclusión,
y
en
base
a
la
evidencia
dis-
ponible,
los
autores
creemos
que
deberían
plantearse
estudios
prospectivos
y
comparativos
que
evalúen
la
eficacia
real
del
fármaco
en
contexto
de
taquiarritmias
supra-
ventriculares
estables
que
no
responden
a
otras
medidas
farmacológicas.
Conflicto
de
intereses
Los
autores
declaran
que
no
existe
ningún
conflicto
de
inte-
reses
ni
fuentes
de
financiación
provenientes
de
entidades
públicas
o
privadas,
de
investigación
o
fundaciones.
Bibliografía
1.
Reves
JG,
Glass
PSA,
Lubarsky
DA,
McEvoy
MD,
Martinez-Ruiz
R.
Intravenous
Anesthetics.
En:
Miller
RD,
editor.
Miller’s
Anesthe-
sia.
7.
a
edición
Elsevier
Espa
̃
na;
2009.
p.
719---68.
2.
Vasileiou
I,
Xanthos
T,
Koudouna
E,
Perrea
D,
Klonaris
C,
Kat-
sargyris
A,
et
al.
Propofol:
A
review
of
its
non-anaesthetic
effects.
Eur
J
Pharmacol.
2009;605:1---8.
3.
Warpechowski
P,
dos
Santos
AT,
Pereira
PJ,
de
Lima
GG.
Effects
of
propofol
on
the
cardiac
conduction
system.
Rev
Bras
Aneste-
siol.
2010;60:438---44.
4.
Yang
L,
Liu
H,
Sun
HY,
Li
GR.
Intravenous
anesthetic
propofol
inhibits
multiple
human
cardiac
potassium
channels.
Anesthe-
siology.
2015;122:571---84.
5.
Cervigo
́
ın
R,
Moreno
J,
Pérez-Villacasti
́
ın
J,
Castells
F.
Profound
sedation
with
propofol
modifies
atrial
fibrillation
dynamics.
Pacing
Clin
Electrophysiol.
2013;36:1176---88.
6.
Kannan
S,
Sherwood
N.
Termination
of
supraventricular
tachy-
cardia
by
propofol.
Br
J
Anaesth.
2002;88:874---5.
7.
Magaldi
M,
Fontanals
J,
Pérez
J.
Sinusal
reversion
of
atrial
flut-
ter
after
intravenous
propofol
administration.
Med
Intensiva.
2014;38:127---8.
8.
Choi
EK,
Jee
DL.
Conversion
of
supraventricular
arrhythmia
to
normal
rhythm
by
propofol
and
remifentanil:
Three
cases
report.
Korean
J
Anesthesiol.
2014;66:244---7.
9.
Miró
O,
de
la
Red
G,
Fontanals
J.
Cessation
of
paroxysmal
atrial
fibrillation
during
acute
intravenous
propofol
administration.
Anesthesiology.
2000;92:910.
10.
Win
NN,
Fukayama
H,
Kohase
H,
Umino
M.
The
different
effects
of
intravenous
propofol
and
midazolam
sedation
on
hemody-
namic
and
heart
rate
variability.
Anesth
Analg.
2005;101:
97---102.
J.
Montero-Tinnirello
,
M.
Magaldi,
J.
Fontanals,
P.
Masgoret
y
J.C.
Bravo
Servicio
de
Anestesiología,
Reanimación
y
Tratamiento
del
Dolor,
Hospital
Clínic,
Barcelona,
Espa
̃
na
Autor
para
correspondencia.
Correo
electrónico:
jamontero@clinic.cat
(J.
Montero-Tinnirello).
http://dx.doi.org/10.1016/j.medin.2016.10.002
0210-5691/
©
2016
Elsevier
Espa
̃
na,
S.L.U.
y
SEMICYUC.
Todos
los
derechos
reservados.
Effect
of
single-dose
of
tolvaptan
in
neurocritical
patients
with
hyponatremia
due
to
syndrome
of
inappropriate
antidiuretic
hormone
secretion
Efecto
de
una
dosis
única
de
tolvaptán
en
pacientes
neurocríticos
con
hiponatremia
debido
a
SIADH
Dear
Editor,
Hyponatremia
constitutes
the
most
common
electrolyte
abnormality
found
in
patients
with
acquired
brain
injury,
1,2
being
present
in
up
to
20%
of
patients
with
traumatic
brain
injury
(TBI)
and
50%
of
patients
with
subarachnoid
hemorr-
hage
(SAH).
1
In
most
cases,
the
underlying
cause
of
euvolemic
hypo-
natremia
in
brain
injured
patients
is
the
syndrome
of
inappropriate
secretion
of
antidiuretic
hormone
(SIADH).
3
In
this
syndrome,
an
abnormal
water/sodium
handling
is
associated
with
an
osmotic
gradient
that
promotes
the
shift
of
water
into
brain
cells,
thereby
worsening
cerebral
edema
and
resulting
in
deteriorating
neurological
condition
with
seizures,
coma,
increased
intracranial
pressure
end
eventually
death.
1,2,4
An
appropriate
correction
of
hypona-
tremia
was
associated
with
increased
survival.
5
In
the
recent
years,
tolvaptan,
an
orally
active,
selec-
tive,
nonpeptide
antagonist
that
blocks
arginine
vasopressin
from
binding
to
V2
receptors
of
the
distal
nephron
induc-
ing
the
excretion
of
electrolyte-free
water
(the
so-called
‘‘aquaretic
effect’’)
showed
it
effectiveness
in
the
treat-
ment
of
hyponatremia
in
randomized
controlled
trials,
6
but
its
use
in
neurocritically
ill
patients
remains
limited.
2
Con-
cerns
with
the
potential
risk
of
overcorrection
and
secondary
osmotic
demyelinating
syndrome
(ODS)
arose,
although
the
incidence
of
overcorrection
can
be
even
higher
when
using
the
commonly
accepted
3%
hypertonic
saline.
7
When
tolvap-
tan
is
used,
initial
doses
of
7.5
or
15
mg
are
recommended.
8
Some
authors
recommend
its
use
as
a
treatment
of
SIADH
induced
hyponatremia
when
first
line
therapies
including
fluid
restriction
have
failed.
9
In
this
report,
we
studied
the
effects
of
a
sin-
gle
dose
of
tolvaptan
in
hyponatremic
neurocritically
ill
patients.
502
CARTAS
CIENTÍFICAS
144
16
14
12
10
8
6
4
2
0
16
14
12
10
8
6
4
2
0
–5
–4
–3
–2
–1
0
1
142
140
138
136
134
132
130
128
126
0
Baseline
24 h
Fluid balance (L)
r
2
=.5
P=.
05
Plasma Na (mEq/L)
plasma Na (mEq/L)
Figure
1
Linear
regression
analysis
of
24
h
fluid
balance
and

natremia
after
the
first
dose
of
tolvaptan.
The
study
was
approved
by
our
Hospital
Research
Com-
mittee.
The
need
of
informed
consent
was
waived
due
to
the
descriptive
and
retrospective
nature
of
the
study.
All
patients
fulfilled
the
following
definition
of
SIADH
1
:
Plasma
sodium
<
135
mEq/L
Plasma
osmolality
<
280
mOsm/kg
of
water
Urine
osmolality
>
100
mOsm/kg
of
water
Urine
sodium
>
40
mmol/L
Normal
thyroid
and
adrenal
function
Clinical
euvolemia
or
hypervolemia
Absence
of
recent
diuretics
use
Overcorrection
was
defined
when
the

natremia
was
>8
mEq/L/24
h.
1
We
retrospectively
analyzed
the
effect
on
the
sodium
levels
and
fluid
balance
in
the
first
24
h
after
tolvaptan
was
given.
Quantitative
data
were
reported
as
median
(Interquartile
Range
(IQR)
25---75)
and
categorical
data
as
number
and
percentage.
Differences
between
natremia
were
compared
using
Mann---Whitney---Wilcoxon
test
and
the
association
between
24
h
fluid
balance
and

natremia
using
linear
regression.
A
value
of
p
<
0.05
was
considered
signifi-
cant.
Statistical
analysis
was
performed
with
SPSS
®
20
(IBM
Corporation
2011).
Eight
neurocritically
ill
patients
admitted
to
our
ICU
ful-
filled
the
above
mentioned
criteria
of
SIADH.
During
their
ICU
stay,
all
patients
developed
hyponatremia
and
were
unsuccessfully
treated
with
oral
sodium
chloride
and
3%
hypertonic
saline.
In
such
cases,
an
initial
dose
of
7.5
mg
tol-
vaptan
was
given
in
the
morning
shift
(in
one
patient
15
mg
were
administered).
Of
note,
all
patients
increased
their
sodium
levels
and
even
in
3
patients
(37.5%)
no
additional
doses
were
deemed
necessary.
Only
one
patient
(12.5%)
pre-
sented
overcorrection
requiring
treatment
with
intravenous
dextrose
and
parenteral
desmopressin.
This
patient
recei-
ved
a
15
mg
initial
dose
and
had
risk
factors
for
ODS
such
as
advanced
liver
disease
and
alcoholism.
No
clinical
features
of
ODS
were
observed
in
the
follow
up.
Baseline
and
clinical
data
in
response
to
the
admi-
nistration
of
tolvaptan
in
the
eight
patients
analyzed
are
shown
(
Table
1
).
A
moderate
association
between

Natremia
and
24
h
fluid
balance
was
found
(
p
=
0.05)
(
Fig.
1
).
Our
results
showed
that
a
single
7.5
mg
dose
of
tolvaptan
was
effective
and
safe
in
the
treatment
of
hyponatremia
due
to
SIADH
in
neurocritically
ill
patients.
Some
issues
must
be
taking
into
consideration
when
evaluating
our
results:
Tolvaptan
resulted
in
an
increase
of
sodium
levels
in
all
patients.
The
effect
of
a
single
dose
of
tolvaptan
was
enough
to
solve
the
hyponatremia
in
some
cases,
therefore
minimi-
zing
the
cost
of
the
therapy.
Follow
up
doses
were
used
in
5
patients,
when
natremia
decreased
after
the
initial
48
h.
An
initial
increase
lasting
48
h
has
been
previously
described.
2
Due
to
the
etiology
of
severe
injury,
our
patients
had
limited
access
to
water.
Unlimited
access
to
water
was
deemed
mandatory
to
avoid
secondary
hypovolemia.
10
We
believe
that
in
the
ICU
setting
and
with
close
monitoring
of
fluid
balance
and
sodium
levels,
such
requirement
should
not
be
considered
necessary.
Tolvaptan
was
safe
at
the
7.5
mg
dose
in
all
cases.
The
only
episode
of
overcorrection
occurred
with
a
15
mg
dose
in
a
patient
with
additional
risk
factors
for
overcorrection
and
ODS.
11
Related
factors
include
advanced
liver
disease,
mal-
nourishment,
hypophosphatemia,
hypokalemia,
etc.
11
We
would
recommend
using
the
7.5
mg
dose
for
initiating
tol-
vaptan
in
neurocritically
ill
patients.
As
stated,
median

Natremia
was
5
(4---8)
mEq/24
h
in
our
sample.
Moreover,
we
defined
overcorrection
as

natremia
>
8
mEq/L/24
h,
but
some
authors
would
even
accept

natremia
12
mEq/L/24
h
safe
in
this
setting.
The
main
limitation
of
this
preliminary
study
is
the
retros-
pective
and
observational
design.
In
addition,
the
limited
number
of
patients
generates
weakness
in
the
linear
regres-
sion
analysis
due
to
extreme
values
and
precludes
more
complex
analysis.
In
conclusion,
in
neurocritically
ill
patients,
a
low
dose
of
7.5
mg
of
tolvaptan
was
effective
and
safe
in
the
treatment
of
hyponatremia
due
to
SIADH.
Future
studies
will
deter-
mine
its
exact
role
in
the
management
of
hyponatremia
in
the
whole
ICU
population.
A
prospective
comparison
with
3%
hypertonic
saline
is
necessary.
CARTAS
CIENTÍFICAS
503
Table
1
Baseline
and
clinical
data
of
the
eight
patients
studied.
Patient
number
Diagnosis
Gender
Age
(years)
Day
Natremia
before
tolvaptan
Natremia
24
h
after
tolvaptan

Natremia
24
h
Natremia
48
h
after
tolvaptan
24
h
fluid
balance
(ml)
Follow
up
doses
1
ICH
Male
45
15
132
135
3
135
1440
Yes
2
*
ICH
Female
55
11
127
142
15
139
3425
No
3
TBI
Female
45
12
131
138
7
137
1850
Yes
4
SAH
Male
48
21
132
137
5
136
122
Yes
5
SAH
Female
57
8
133
138
5
136
744
Yes
6
Cerebral
abcess
Male
28
30
132
140
8
140
4372
No
7
SAH
Male
50
19
131
136
5
137
1726
No
8
TBI
Male
29
25
134
136
2
136
456
Yes
Median
(IQR)
46
(33---54)
17
(11---24)
132
(131---133)
138
(136---140)
5
(4---8)
136
(136---138)
1600
(
3000
to
500)
ICH:
intracerebral
hemorrhage;
TBI
:
traumatic
brain
injury;
SAH:
subarachnoid
hemorrhage.
*
Means
that
this
patient
received
a
single
15
mg-dose.
Conflict
of
interest
Dr.
Llompart-Pou
declares
having
received
honoraria
from
Otsuka
for
participating
in
a
consensus
document
in
the
management
of
hyponatremia
in
critically
ill
patients.
Dr.
Pérez-Bárcena,
Novo
and
Raurich
declare
no
financial
disclosure.
Bibliografía
1.
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A,
Hannon
MJ,
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M,
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JG.
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2016;33:615---24.
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SB,
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HA,
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C,
Kim
MC,
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N,
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receptor
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MJ,
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FM,
Sherlock
M,
Agha
A,
Thompson
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homeostasis
in
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C,
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A.
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G,
Giuliani
C,
Verbalis
JG,
Forti
G,
Maggi
M,
Peri
A.
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improvement
is
associated
with
a
reduced
risk
of
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evidence
from
a
meta-analysis.
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RW,
Gross
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M,
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JG,
Czer-
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FS,
et
al.,
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V2-receptor
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for
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SR,
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RW,
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RH,
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I,
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A,
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10.
http://www.ema.europa.eu/docs/es
ES/document
library/
EPAR
-
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BK,
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AM,
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J.A.
Llompart-Pou
a
,
b
,
,
J.
Pérez-Bárcena
a
,
b
,
M.
Novo
a
,
J.M.
Raurich
a
a
Servei
de
Medicina
Intensiva,
Hospital
Universitari
Son
Espases,
Palma
de
Mallorca,
Spain
b
Instituto
de
Investigación
Sanitaria
de
Palma
(IdISPa),
Palma
de
Mallorca,
Spain
Corresponding
author.
E-mail
address:
juanantonio.llompart@ssib.es
(J.A.
Llompart-Pou).
http://dx.doi.org/10.1016/j.medin.2016.11.007
0210-5691/
©
2016
Elsevier
Espa
̃
na,
S.L.U.
y
SEMICYUC.
All
rights
reserved.

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