From the Departments of Neurosurgery, Shinshiro Municipal Hospital,
Shinshiro, Japan (M.T., M.M., K.Y.), and Hamamatsu University School of
Medicine, Hamamatsu, Japan (K.U.).
Methods—Plasma BNP concentrations were measured by
immunoradiometric assay in 18 patients at 0 to 2 days (period 1), 7 to
9 days (period 2), and >14 days (period 3) after SAH. Plasma
concentrations of antidiuretic hormone (ADH), atrial
natriuretic peptide (ANP), and noradrenaline
were also measured during period 2.
Results—The 11 patients with hyponatremia (serum
sodium concentration of <135 mEq/L) had much higher plasma BNP
concentrations during each period than did healthy controls
(P<0.05), whereas the 7 patients with normonatremia did
not show statistically higher values. In the patients with
hyponatremia, the plasma BNP concentration during
period 2 was statistically higher than that during periods 1 and 3
(P<0.05). The plasma noradrenaline
concentration during period 2 was higher in patients with
hyponatremia than in those with normonatremia
(P<0.05), whereas the plasma concentrations of ADH and
ANP during period 2 were not statistically different between the
hyponatremic and normonatremic patients.
Conclusions—We conclude that BNP may be related to
hyponatremia associated with natriuresis following SAH.
The increase of noradrenaline may promote the secretion of
BNP.
Methods
Plasma BNP concentrations were determined by a recently developed
highly sensitive 2-site immunoradiometric assay (SHIONORIA BNP,
Shionogi & Co, Ltd). Two monoclonal antibodies, BC-203 (which
recognizes the C-terminal region of BNP) and KY-BNP-2 (which recognizes
the disulfide bond ring structure of BNP), were used. A mixture of
standard BNP (100 µL) or sample (100 µL),
125I-labeled KY-BNP-2 (200 µL), and a bead
coated with immobilized BC-203 were incubated at 2°C to
8°C for 18 to 22 hours. The buffer for the calibrators was 0.1 mol/L
sodium phosphate containing 0.3 mol/L NaCl, 106
KIU/L aprotinin, 1 mmol/L EDTA-2Na, 1 g/L
NaN3, 0.2 mmol/L cystine, 2 g/L bovine serum
albumin, and 0.05 g/L mouse
Statistical Analysis
Table 2
Table 3
Some authors2 3 12 have reported that
hyponatremia results from CSW in most patients with
SAH, while others have reported hyponatremia may result
from the syndrome of inappropriate secretion of
ADH.13 In our study, hyponatremia
was associated with natriuresis and diuresis in all patients,
and the plasma concentration of ADH was normal in the patients with
hyponatremia. Therefore, we believe that all the
hyponatremia in our present series resulted from
CSW. The etiology of CSW is controversial, with several substances
having been proposed as the cause. ANP has been investigated as a
promising factor.4 5 However, some authors have
pointed out that ANP alone is not sufficient to cause
hyponatremia.7 14 In the
present study, the mean plasma ANP concentration on days 7 to 9 was
within the normal range in both the hyponatremic and normonatremic
groups.
BNP is another natriuretic peptide consisting of 32
amino acids that was found in 1988.9 It has as
much effect on diuresis and natriuresis as ANP; however, there
are some differences.15 16 The primary stimulus
is the load on the cardiac ventricles for BNP, whereas it is the atrial
load for ANP; the plasma half-time of BNP is approximately 20 minutes,
which is about twice as long as that of ANP; and the response of BNP to
cardiac failure is faster than that of ANP. Berendes et
al17 suggested that BNP may induce
hyponatremia due to salt wasting in patients with SAH
by subsequent suppression of aldosterone synthesis.
Wijdicks et al18 also concluded that both BNP and
ANP increase after SAH, which results in a negative fluid balance. In
the present study, the plasma BNP concentration was statistically
higher in the hyponatremic group than in the healthy volunteers, and
the plasma BNP concentration on days 7 to 9 was approximately twofold
that on days 0 to 2 and after day 14 in the hyponatremic group.
Therefore, we speculate that the increase of plasma BNP may induce
hyponatremia. Two patients in our normonatremic group
showed very high plasma BNP concentrations on days 0 to 2 (>100
pg/mL), which decreased gradually. However, a surge of BNP within 2
days of SAH should not in itself induce hyponatremia
around day 9, because the plasma half-life of BNP is about 20
minutes.15 Therefore, a second increase of BNP
around days 4 to 9 or a persistent high concentration of BNP may be
necessary to induce hyponatremia.
In the present study, the plasma noradrenaline
level and the incidence of symptomatic vasospasm were
higher in the hyponatremic group than in the normonatremic group. Some
authors have reported that an increase of plasma
noradrenaline is related to symptomatic
vasospasm19 and that patients with
symptomatic vasospasm frequently have
hyponatremia.5 Although the
mechanism of the release of BNP after SAH still remains unknown,
Berendes et al17 speculated that BNP release may
result from the stress response to surgery or intensive care as well as
damage to the hypothalamic region. Our results raise the possibility
that noradrenaline may cause an increase in the load on the
cardiac ventricles, which may stimulate BNP secretion, and that the
increase of BNP then induces hyponatremia associated
with volume depletion that may lead to symptomatic
vasospasm.
In contrast, Isotani et al4 reported that
plasma BNP was not significantly higher in patients with SAH than in
the normal control group, although BNP levels on days 0 to 2 were above
normal. We speculate that this difference may result from variations in
the sodium load and clinical condition. We loaded our patients with
approximately twice as much sodium as did Isotani et al. Such an amount
of sodium, which was also administered to the patients of Berendes et
al17 and Wijdicks et al,18
may increase the plasma BNP concentration. Moreover, the precise
cardiac status of the patients was not estimated in our study or in
their studies. Therefore, the response of the left cardiac ventricle to
a mild volume load may have been different between the 2 studies.
We conclude that BNP may play an important role in
hyponatremia in patients with SAH. However, the studies
on BNP in SAH performed to date (including ours) have involved small
populations; further investigations focusing on cardiac
ventricular function are needed.
Received March 25, 1998;
revision received May 7, 1998;
accepted May 7, 1998.
© 1998 American Heart Association, Inc.
Original Contributions
Plasma Concentrations of Brain Natriuretic Peptide in Patients With Subarachnoid Hemorrhage
Abstract
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Background and
Purpose—Hyponatremia after subarachnoid
hemorrhage (SAH) is commonly associated with diuresis
and natriuresis, but the causes are still controversial. We
investigated whether brain natriuretic peptide (BNP) was
related to such hyponatremia.
Key Words: hyponatremia • natriuretic peptide, brain • subarachnoid hemorrhage
Introduction
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Hyponatremia after
SAH has been reported to have an incidence of 30% to 40%. Recent
studies have demonstrated that this phenomenon is frequently associated
with hypovolemia, which is caused not by the syndrome of inappropriate
secretion of ADH but by CSW.1 2 3 However, the
cause of CSW is still controversial. Some authors have reported that
ANP4 5 and digoxinlike
peptides6 may cause the
hyponatremia, while others have suggested that these
agents are not involved.7 8 BNP, which was
isolated from porcine brain in 1988,9 causes
natriuresis and diuresis. It has recently become possible to
measure BNP accurately by immunoradiometric assay. We investigated
whether BNP was related to hyponatremia after SAH by
measuring plasma BNP concentrations with use of an immunoradiometric
assay in patients with acute SAH.
Subjects and Methods
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Patients and Management
Eighteen patients (4 men and 14 women without cardiac, renal, or
endocrine diseases; mean±SD age, 62.3±10.8 years) with SAH verified
by CT scan were investigated from January 1995 through December 1996.
All patients underwent cerebral angiography and aneurysm
clipping within 48 hours of the onset, except for 1 patient in whom
angiography failed to identify the source of hemorrhage. Each
patient received intravenous fluid at approximately 2500 to
3000 mL/d to maintain a central venous pressure of 4 to 12 cm
H2O. Sodium administration ranged from 280 to 320
mEq/d in patients without hyponatremia, while sodium
loss was replaced according to urinary excretion when
hyponatremia occurred. When symptomatic
vasospasm occurred, ozagrel sodium (Xanbon, Kissei Pharmaceutical Co
Ltd) was intravenously administered at 80 mg/d in patients
treated from January 1995 through July 1995, and fasudil hydrochloride
(Eril, Asahi Chemical Industries) was intravenously
administered at 60 to 90 mg/d in patients treated from August 1995
through December 1996. Daily fluid and sodium balances were
recorded until day 14 from the onset.
Blood samples were collected into tubes containing 1 mg/mL EDTA
and 1000 KIU/mL aprotinin and were then centrifuged at 2500 rpm
at 4°C. Plasma was stored at -40°C. Plasma BNP concentrations were
measured 3 times during the study at 0 to 2 days (period 1), 7 to 9
days (period 2), and >14 days (period 3) after SAH. Plasma ANP, ADH,
and noradrenaline were measured once during period 2, and
the serum sodium concentration was measured at least every 3
days. 
-globulin. After removing the
supernatant by aspiration, we washed the antibody bead twice with 2 mL
washing buffer (0.01 mol/L sodium phosphate containing 0.15 mol/L NaCl,
0.2 mL/L Tween 20, and 1 g/L NaN3). Then the
radioactivity bound to the bead was counted with a gamma counter
(ARC950, Aloka Inc). A plot of radioactivity counts versus the
concentrations of BNP calibrator was used to estimate plasma BNP
concentration. The detection limit was 0.2 pg/mL. The interassay and
intra-assay coefficients of variation were 2.30% to 10.6% and 6.98%
to 10.9%, respectively. Cross-reactivity between
natriuretic peptides was less than 0.1%. The plasma BNP
concentration determined in 106 healthy volunteers (56 men and 50
women) was 6.68±4.89 pg/mL (data provided by SRL Inc). Plasma ANP
concentrations were also measured by immunoradiometric assay (SHIONORIA
ANP, Shionogi & Co, Ltd), ADH levels were measured by radioimmunoassay
(AVP RIA "Mitsubishi," Mitsubishi Chemical Corporation, Inc), and
noradrenaline levels were measured by
high-performance liquid chromatography.
Values were expressed as mean±SD. Statistical analysis
was performed using Welch's t test to compare differences
among plasma concentrations of BNP during each period and for
comparison with the normal control values. The unpaired Student
t test was used to assess differences between the
hyponatremic and normonatremic groups with respect to the plasma
concentrations of ANP, BNP, ADH, and noradrenaline on days
7 to 9 as well as differences in the water and sodium balances. The
2 test was used for assessing differences of
symptomatic vasospasm between the 2 groups. Results were
interpreted as significant at the level of 5% probability.
Results
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
We defined hyponatremia as a serum sodium
concentration of <135 mEq/L. Hyponatremia occurred in
11 patients (serum sodium, 127±4.2 mEq/L; duration, 5.9±2.7 days;
nadir time, 9.8±2.7 days). Table 1
shows
the age, Hunt and Kosnik grade10 on admission,
Fisher's classification11 on initial CT scan,
and location of aneurysms in the hyponatremic and normonatremic
groups. The cumulative water balance until day 7 (insensible loss of
water was defined as 500 mL/d) was -2600±1600 mL in the hyponatremic
group and -950±1500 mL in the normonatremic group
(P<0.05); the cumulative sodium balance until day 7 was
-173±285 mEq in the hyponatremic group and 90.8±195 mEq in the
normonatremic group. Symptomatic vasospasm, including mild
deterioration of consciousness, occurred in 11 patients; 10 of these
belonged to the hyponatremic group and only 1 to the normonatremic
group (P<0.01).
View this table:
[in a new window]
Table 1. Clinical and CT Grading and Location of
Aneurysms in Hyponatremic and Normonatremic Groups shows plasma BNP concentrations
in the hyponatremic and normonatremic groups. In the hyponatremic
group, the BNP level at 7 to 9 days was statistically higher than at 0
to 2 days and after 14 days (P<0.05), whereas BNP levels
tended to decrease in the normonatremic group. Plasma BNP
concentrations in the hyponatremic group were always statistically
higher than in the healthy controls (P<0.05), while levels
in the normonatremic group were not. However, the plasma BNP
concentration on days 7 to 9 was not statistically higher in the
hyponatremic group than in the normonatremic group.
View this table:
[in a new window]
Table 2. Plasma Concentrations of BNP in Each Period shows plasma concentrations of
ANP, ADH, and noradrenaline on days 7 to 9. There were no
statistical differences between the 2 groups for ANP and ADH levels.
However, plasma noradrenaline levels were higher in the
hyponatremic group than in the normonatremic group
(P<0.05).
View this table:
[in a new window]
Table 3. Plasma Concentrations of ANP, ADH, and NA on Days 7
to 9
Discussion
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Our results suggested that BNP may cause diuresis and
natriuresis after SAH. Both diuresis and natriuresis were more
severe in the hyponatremic group than in the normonatremic group.
Plasma BNP concentrations during the study period were higher in the
hyponatremic group than in healthy volunteers. Moreover, plasma BNP
concentration on days 7 to 9 was statistically higher than on days 0 to
2 and after day 14 in the hyponatremic group.
Selected Abbreviations and Acronyms
ADH
=
antidiuretic hormone
ANP
=
atrial natriuretic peptide
BNP
=
brain natriuretic peptide
CSW
=
cerebral salt-wasting syndrome
KIU
=
kallikrein inhibitor units
SAH
=
subarachnoid hemorrhage
Acknowledgments
We thank SRL Inc for measuring plasma BNP concentrations in our
patients and providing the data on BNP in healthy volunteers. We also
thank Noriyuki Makiishi for a precise explanation of the
immunoradiometric assay for BNP.
Footnotes
Reprint requests to M. Tomida, MD, Department of Neurosurgery, Shinshiro Municipal Hospital, 32–1 Kitabata, Shinshiro, Aichi 441-1387, Japan.
References
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
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