Original Paper

Cerebrovasc Dis 2012;34:5562 Received: August 17, 2011

Accepted: April 16, 2012
DOI: 10.1159/000338906
Published online: June 29, 2012

Association of Hyponatremia in Acute

Stroke Stage with Three-Year Mortality in
Patients with First-Ever Ischemic Stroke
Wen-Yi Huang a Wei-Chieh Weng a Tsung-I Peng a Yu-Yi Chien a Chia-Lun Wu a
Meng Lee b Cheng-Chieh Hung c Kuan-Hsing Chen c
a
Department of Neurology, Chang-Gung Memorial Hospital, Keelung Branch, and b Department of Neurology,
Chang-Gung Memorial Hospital, Chiayi Branch, and c Department of Nephrology, Chang Gung Memorial Hospital,
Lin-Kou Medical Center, School of Medicine, Chang Gung University, Taipei, Taiwan, ROC

Key Words
Hyponatremia Mortality Ischemic stroke First-ever
ischemic stroke
Abstract
Background: Hyponatremia is the most common electro-
lyte disorder in hospitalized patients, and is frequently a
marker of a significant underlying disease. The prognostic
value of hyponatremia in patients with acute first-ever isch-
emic stroke is not known. We aimed to analyze whether hy-
ponatremia in the acute stroke stage contributed to the risk
of mortality or recurrent stroke in these patients. Methods:
We studied 925 patients presenting with acute first-ever
ischemic stroke between 2002 and 2004. Sodium levels were
obtained on arrival at the emergency room within 3 days of
acute stroke onset. Hyponatremia was defined as a serum
sodium concentration of 134 mmol/l or less. Clinical presen-
tation, stroke risk factors, associated medical disease, and
outcome were recorded. All patients were followed for 3
years for survival analysis. A multivariate Cox proportional
hazards model was used to identify risk factors for 3-year
mortality in these patients. We also constructed Kaplan-Mei-
er survival curves, and compared groups with hyponatremia
and normonatremia by means of log rank tests for significant
differences. Results: Among the patients with acute first-ev-
er ischemic stroke, 107 (11.6%) were hyponatremic. Among
stroke risk factors, the prevalence of diabetes mellitus was
significantly higher among hyponatremic patients (p !
0.001). Prevalence of chronic renal insufficiency was also
higher in the hyponatremic group (p = 0.002). Clinical pre-
sentations, such as the length of acute ward stay, initial im-
paired consciousness, and clinical course in acute stroke
were similar among normo- and hyponatremic patients.
Among the complications, pneumonia and urinary tract in-
fection were significantly higher in hyponatremic than in
normonatremic patients. After multivariate logistic regres-
sion analysis, diabetes mellitus and chronic renal insufficien-
cy were associated with hyponatremia in these patients.
Kaplan-Meier analysis indicated that the survival rate was
significantly lower in hyponatremic patients than in nor-
monatremic patients (log rank test; p value !0.001). After
multivariate Cox proportional hazards model analysis, hypo-
natremia was a significant predictor of 3-year mortality in
these patients after adjustment for related variables (p val-
ue = 0.003, hazard ratio = 2.23, 95% confidence interval:
1.303.82). Conclusion: Hyponatremia in the acute stroke
stage is a predictor of 3-year mortality in patients with acute
first-ever ischemic stroke that is independent of other clini-
cal predictors of adverse outcome.
Copyright 2012 S. Karger AG, Basel

2012 S. Karger AG, Basel Kuan-Hsing Chen, MD

10159770/12/03410055$38.00/0 Division of Nephrology
Fax +41 61 306 12 34 Chang Gung Memorial Hospital, 5, Fu Hsing Street
E-Mail karger@karger.ch Accessible online at: Taoyuan, Taiwan (ROC)
www.karger.com www.karger.com/ced Tel. +886 3 328 1200 8181, E-Mail guanhsing@yahoo.com.tw
 Introduction
Hyponatremia is the most common electrolyte disor-
der in hospitalized patients in various clinical settings [1].
It is frequently a marker of a significant underlying dis-
ease and is, therefore, associated with poor short-term
prognosis, even when the serum sodium level is only
mildly reduced [14]. For example, hyponatremia in-
creases the risk of death and myocardial infarction (MI)
in middle-aged and elderly community subjects [5]. Hy-
ponatremia is associated with 30-day adverse outcomes
in patients with acute coronary syndrome or non-ST el-
evation MI [6]. In addition, hyponatremia in the early
phase of ST elevation MI is a predictor of long-term mor-
tality and heart failure [2]. In patients with pulmonary
arterial hypertension, hyponatremia can predict right
heart failure [7]. In patients with aneurysmal subarach-
noid hemorrhage (aSAH), hyponatremia is associated
with reversible neurological deterioration, an increased
risk of brain ischemia and vasospasm, cerebral edema
and mass effect, seizures, and death [8]. However, hypo-
natremia did not predict poor outcome in all-grade aSAH
patients in another study [9].
Little is known about the relationship between hypo-
natremia and clinical outcomes in patients with acute
ischemic stroke. The clinical significance of hyponatre-
mia in patients with acute, first-ever ischemic stroke has
not been investigated previously. This 3-year longitudi-
nal study investigated the incidence and factors associ-
ated with hyponatremia by clinically examining patients
with acute, first-ever ischemic stroke. Furthermore, this
study analyzed whether hyponatremia contributed to the
risk of mortality or recurrent stroke in these patients. To
our knowledge, only one previous study has reported an
inverse relationship between serum sodium level and risk
of stroke within the normal range of serum sodium con-
centration [10].
Methods
This clinical study followed the Declaration of Helsinki, and
was approved by the Medical Ethics Committee of Chang Gung
Memorial Hospital, Keelung, Taiwan.
Study Patients
All patients involved in this study were recruited from the
stroke unit of the Department of Neurology, Chang Gung Memo-
rial Hospital, from January 1, 2001, until December 31, 2003. Only
consecutive patients with first-ever ischemic stroke were enrolled.
Individuals with previous stroke, infarction or hemorrhage, or a
diagnosis of uncertain stroke were excluded from the study. Pa-
56 Cerebrovasc Dis 2012;34:5562
tients admitted within 3 days after stroke symptom onset were
included in this study. Patients with serious comorbidities such as
pulmonary or endocrine disease, hepatic failure, renal failure
with dialysis, or cancer, were excluded. Furthermore, patients
who used diuretics before the acute stroke attack were also ex-
cluded. All patients had a clinical diagnosis of acute ischemic
stroke according to the World Health Organization criteria,
which was further confirmed by brain computed tomography or
magnetic resonance imaging (MRI) scan in the hospital [11]. The
most common symptoms of patients with acute ischemic stroke
were sudden focal motor or sensory symptoms. Other symptoms
included acute confusion or unconsciousness, aphasia, limitation
of extraocular movement, defect of visual field, unsteady gait, diz-
ziness, and loss of balance or coordination. All patients with un-
certain clinical diagnosis of acute ischemic stroke, such as those
who presented with only acute decrease in consciousness or acute
vertigo, underwent brain MRI (which included diffusion-weight-
ed images and apparent diffusion coefficient maps). Patients with
uncertain clinical diagnosis were excluded from the study if the
brain MRI did not suggest acute cerebral infarction. The duration
of clinical symptoms in most patients diagnosed with acute isch-
emic stroke lasted longer than 24 h. Patients exhibiting clinical
symptoms for less than 24 h also received a brain MRI study, and
only those with acute cerebral infarction confirmed by the brain
MRI were included. Patients with clinical symptoms lasting less
than 24 h without evidence of acute cerebral infarction in the
brain MRI were diagnosed as having undergone a transient isch-
emic attack (TIA) and were excluded from the study.
Comorbid conditions were determined after an in-depth re-
view of medical records, including history and physical examina-
tion, progress notes, discharge summaries, and consultations.
Hypertension was defined as known hypertension diagnosed by
a clinician, or systolic blood pressure 1160 mm Hg and/or dia-
stolic blood pressure 195 mm Hg on 2 different occasions, where
the second measurement was made more than 5 days after stroke
onset. Diabetes mellitus (DM) was defined as previous diagnosis
and treatment of DM, a fasting plasma glucose equal or more than
7.0 mmol/l (126 mg/dl), a 2-hour value in the oral glucose toler-
ance test, or a random plasma glucose concentration 611.1
mmol/l (200 mg/dl), in the presence of classic symptoms of hyper-
glycemia or hyperglycemic crisis [12]. In hyperglycemic patients
without previous diagnosis and treatment of DM, repeated testing
was performed during admission and 1 month after discharge.
Patients with only transient hyperglycemia were classified into
non-DM. Hyperlipidemia was defined as a fasting blood choles-
terol level that was 65.18 mmol/l (200 mg/dl) and/or a triglycer-
ide level that was 61.695 mmol/l (150 mg/dl). Atrial fibrillation
was diagnosed when present on a standard 12-lead electrocardio-
gram. Coronary artery disease (CAD) was defined by past inci-
dences of acute MI or angina pectoris. Congestive heart failure
(CHF) was present if the patient was previously diagnosed by a
cardiologist or if the condition was found by physical examina-
tion and confirmed by transthoracic cardiac echo study. Chronic
renal insufficiency (CRI) was defined as creatinine (Cr) 6132.6
mol/l (1.5 mg/dl). Cigarette smoking was defined as a current
smoker or a smoker with cessation less than 5 years ago.
Patients who met the inclusion criteria were classified into 2
groups, i.e. hyponatremic and normonatremic patients. Sodium
levels were obtained on arrival in the emergency room within 3
days of acute stroke onset. Sodium levels were corrected by the
Huang /Weng /Peng /Chien /Wu /Lee /
Hung /Chen
Katz formula, which increases sodium by 1.6 mmol/l for every
5.55 mmol/l (100 mg/dl) increase in glucose concentration above
5.55 mmol/l (100 mg/dl), and patients with pseudohyponatremia
were excluded [13]. Patients with extreme hypernatremia (serum
sodium concentration 1150 mmol/l) were also excluded from the
study. Hyponatremia was defined as a serum sodium concentra-
tion of 134 mmol/l or less and normonatremia was a sodium con-
centration of greater than 134 mmol/l, on the basis of previously
published reports [5, 6, 14].
Definition and Clinical Subtypes of Ischemic Stroke
Clinical subtypes of ischemic stroke were rated according to
the classification of the Oxfordshire Community Stroke Project
as partial anterior circulation syndrome, total anterior circulation
syndrome (TACS), posterior circulation syndrome, and lacunar
syndrome (LACS) [15]. TIA was defined by the new tissue-based
definition endorsed by the American Heart Association/Ameri-
can Stroke Association [16]. TIA mimics such as epileptic sei-
zures, complicated migraine, psychogenic hyperventilation, or
transient global amnesia were excluded from the study [17]. The
clinical course in the acute stage of stroke, mean length of acute
ward stay, in-acute ward mortality, and frequency of medical
complications were monitored. Clinical functional outcome upon
discharge was assessed according to the modified Rankin Scale
(mRS) [18]. Functionally dependent was defined as having an
mRS score of 3, 4 or 5.
Laboratory Measurements
All laboratory values, including blood cell counts, and bio-
chemical data were measured by automated and standardized
methods. All blood samples from patients were obtained on ad-
mission, centrifuged, and stored at 70 C until use in assays. Se-
rum albumin, Cr, cholesterol, triglyceride, white blood cell count,
and hemoglobin levels were assayed and recorded. All other
markers were analyzed by standard automated laboratory meth-
ods.
Follow-Up
Patients were followed up for 3 years after initial assessment.
Follow-up consisted of clinical examinations at 1 and 3 months
after first stroke and then every 3 months. End points of this study
included recurrent ischemic stroke or death. Recurrent stroke was
defined as any new focal neurological deficit of sudden onset last-
ing at least 24 h for which no cause could be found other than
ischemic stroke. A diagnosis of recurrence was not made where
symptoms could be attributed to edema, mass effect, brain shift
syndrome, or hemorrhagic transformation, and could not be di-
agnosed within 24 h of the index stroke. Each death occurring
during the follow-up period was reviewed.
Statistical Analysis
Unless otherwise stated, continuous variables are expressed as
mean 8 standard deviation (SD), and categorical variables are
expressed as number or percentage of each parameter. Compari-
sons between the 2 patient groups were analyzed by 2 or Students
t test. The relative risks of independent associations between hy-
ponatremia and variables were analyzed by logistic regression. A
variable with p ! 0.1 in univariate logistic regression was consid-
ered to be associated with hyponatremia, and was entered into
backward stepwise multivariate logistic regression analysis. The
Hyponatremia and Mortality in Ischemic
Stroke Patients
risk ratio and 95% confidence intervals (CI) were measured. To
assess the relationship between hyponatremia and mortality,
Kaplan-Meier curves were compared using the log rank test. The
Cox proportional hazards model was used to evaluate all variables
and determine the significance of variables for predicting the all-
cause 3-year mortality. To determine the risk of death, hazard
ratio (HR) and 95% CI were obtained using the Cox proportional
hazards model. A univariate Cox model that assessed all previ-
ously identified important variables was used to calculate the HR
for mortality. A backward stepwise multivariate Cox regression
model was also used to identify the risk factors for 3-year mortal-
ity in these patients. All statistical calculations were performed
with SPSS for Windows (SAS Institute, Cary, N.C., USA).
Results
Patient Characteristics
Among 949 patients, 22 were excluded due to a final
diagnosis of TIA but not acute first-ever ischemic stroke,
and 2 patients were excluded due to extreme hypernatre-
mia with unknown cause (sodium levels, 152 and 159
mmol/l, respectively). A total of 925 patients (486 men,
439 women) were analyzed (table1). The clinical proper-
ties, including age, gender and comorbidity data, are list-
ed in table1. Mean patient age was 69.48 8 11.62 years,
and 107 patients (11.6%) were hyponatremic (Na+ ^134
mmol/l). There was no difference in age or gender be-
tween the hypo- and normonatremic groups. Stroke risk
factors and their distributions in the 2 groups are also
listed in table1. The prevalence of DM and CRI was sig-
nificantly higher in hyponatremic patients than in nor-
monatremic patients. Differences in the prevalence of
other stroke risk factors and clinical presentations were
not statistically significant between normo- and hypona-
tremic patients.
Determinants of Hyponatremia in Patients with
Acute, First-Ever Ischemic Stroke
Univariate logistic regression analysis revealed that
DM, CRI, and CAD were positively associated with hy-
ponatremia in patients with acute, first-ever ischemic
stroke. After adjusting for these potential variables (p !
0.1) in the forward stepwise multivariate logistic regres-
sion analysis, the presence of DM and CRI were positive-
ly associated with hyponatremia (table2).
Clinical Course in Patients with Acute Stage of
First-Ever Ischemic Stroke
The length of acute ward stay, whether the patient
experienced initial impaired consciousness, and clinical
course in the acute stroke stage were not significantly
Cerebrovasc Dis 2012;34:5562 57
 Table 1. Demographic and clinical characteristics of first-ever ischemic stroke patients divided according to
serum sodium level

Sodium >134 mmol/l Sodium 134 mmol/l OR (95% CI) p value

(n = 818) (n = 107)

Age, years 69.4811.6 70.5811.6 0.351

Female 391 (47.8%) 48 (44.9%) 0.89 (0.591.33) 0.320
Risk factors
Hypertension 590 (72.1%) 78 (72.9%) 1.04 (0.661.64) 0.484
DM 286 (35.0%) 73 (68.2%) 3.99 (2.596.15) <0.001*
Smoking 269 (32.9%) 34 (31.8%) 0.95 (0.621.47) 0.456
Hyperlipidemia 320 (39.1%) 46 (43.0%) 1.17 (0.781.76) 0.252
CAD 48 (5.9%) 11 (10.3%) 1.84 (0.923.66) 0.068
Atrial fibrillation 121 (14.8%) 14 (13.1%) 0.87 (0.481.57) 0.382
CHF 16 (2.0%) 3 (2.8%) 1.45 (0.415.05) 0.380
CRI 73 (8.9%) 20 (18.7%) 2.35 (1.364.04) 0.002*
Previous TIA 45 (5.5%) 6 (5.6%) 1.02 (0.432.45) 0.551
Clinical syndromes
TACS 104 (12.7%) 14 (13.1%) 1.03 (0.571.88) 0.507
PACS 235 (28.7%) 37 (34.6%) 1.31 (0.862.01) 0.129
LACS 337 (41.2%) 35 (32.7%) 0.69 (0.451.06) 0.056
POCS 142 (17.4%) 21 (19.6%) 1.17 (0.701.95) 0.311

Data are presented as mean 8 standard deviation or number (%).

OR = Odds ratio; PACS = partial anterior circulation syndrome; POCS = posterior circulation syndrome.
* p < 0.05, 2 or Students t test.

Table 2. Determinants of hyponatremia in patients with first-ever ischemic stroke

Potential variables Univariate logistic p value Stepwise multivariate p value

regression analysis, logistic regression
risk ratio (95% CI) analysis, risk ratio (95% CI)

Age, years 1.00 (0.981.02) 0.827

Anemia 1.79 (0.774.16) 0.174
Hypertension 1.04 (0.651.66) 0.875
DM 4.08 (2.616.38) <0.001* 4.07 (2.596.39) <0.001
TIA 0.91 (0.352.35) 0.849
Hyperlipidemia 1.25 (0.821.90) 0.299
CAD 1.57 (0.753.30) 0.235
CHF 1.60 (0.465.59) 0.462
Atrial fibrillation 0.79 (0.421.49) 0.468
Smoking 0.89 (0.561.39) 0.598
CRI 2.60 (1.514.49) 0.001* 2.59 (1.474.56) 0.001
TACS 1.04 (0.561.93) 0.902

* p < 0.05, univariate logistic regression; p < 0.05, multivariate logistic regression.

different between the normo- and hyponatremic groups.
Among complications, pneumonia and urinary tract in-
fection were higher in hyponatremic patients than in
normonatremic patients (p value = 0.004 and 0.034, re-
spectively). In addition, the functional status at the time
of discharge, in-hospital mortality rate, and rate of
stroke recurrence were not significantly different be-
tween the normo- and hyponatremic groups. However,
the death rate within 3 years of stoke onset was signifi-
cantly higher in hyponatremic patients (p value !0.001).

58 Cerebrovasc Dis 2012;34:5562 Huang /Weng /Peng /Chien /Wu /Lee /

Hung /Chen

Table 3. Clinical course in the acute stage of stroke, mortality, and stroke recurrence within 3 years of first-ever ischemic stroke onset
grouped according to sodium level

Sodium >134 mmol/l Sodium 134 mmol/l OR (95% CI) p value

(n = 818) (n = 107)

Mean length of acute-ward stay, days 14.7813.2 14.4810.2 1.32 (2.89 to 2.29) 0.818
Initial impaired consciousness 107 (13.1%) 20 (18.7%) 1.53 (0.902.59) 0.079
Course in acute stage of stroke
In evolution 201 (24.6%) 31 (29.0%) 1.25 (0.801.96) 0.191
Stationary 370 (45.2%) 52 (48.6%) 1.15 (0.771.71) 0.289
Improving 247 (30.2%) 24 (22.4%) 0.67 (0.411.08) 0.059
Complication
Pneumonia 79 (9.7%) 20 (18.7%) 2.15 (1.263.69) 0.004*
GI bleeding 66 (8.1%) 9 (8.4%) 1.05 (0.512.17) 0.510
UTI 96 (11.7%) 20 (18.7%) 1.73 (1.022.94) 0.034*
mRS score 3 at discharge 523 (63.9%) 73 (68.2%) 1.21 (0.791.86) 0.224
Range of follow-up duration, days 31,095 51,095
Median of follow-up time, days 1,095 1,095
In-hospital mortality 39 (4.8%) 6 (5.6%) 1.32 (0.543.19) 0.341
Stroke recurrence 129 (15.8%) 22 (20.6%) 1.38 (0.832.29) 0.132
Death 62 (7.6%) 19 (17.8%) 2.63 (1.514.61) <0.001*

Data are presented as mean 8 standard deviation or number (%). GI = Gastrointestinal; UTI = urinary tract infection. * p < 0.05,
2 or Students t test.

Kaplan-Meier Survival Analysis for 3-Year Mortality

1.0
in Patients with Acute, First-Ever Ischemic Stroke
At the end of the 3-year observation period, the follow-
0.8 ing data were obtained: 81 patients had died (81/925 =
8.76%), including 62 patients (7.6%) from the normona-
Cumulative survival

0.6
tremic group and 19 patients (17.8%) from the hypona-
tremic group. Of the 19 hyponatremic patients with first-
ever ischemic stroke who died during the 3-year observa-
0.4 Na+ >134 mmol/l tion period, 7 (36.8%) died from infection, 6 (31.6%) from
Na+ 134 mmol/l
cardiovascular disease, 2 (10.5%) from recurrent stroke,
0.2 1 (5.3%) within the acute stage of stroke, 2 (10.5%) from
cancer and 1 (5.3%) from uremia. Kaplan-Meier survival
0
analysis indicated that the hyponatremic group had a
0 200 400 600 800 1,000 1,200 higher mortality rate than the normonatremic group (log
Time (days) rank test: p ! 0.001; fig.1).
Cases of short-term mortality with a follow-up time of
1 or 3 months were sub-analyzed, and no significant dif-
Fig. 1. Kaplan-Meier analysis of patient survival (all-cause mor-
tality) during the 3-year study. Log rank test: p ! 0.001.
ferences were seen between normonatremic and hypona-
tremic groups. At the 1-month follow-up, the mortality
rates were 5 patients (4.7%) in the hyponatremic group
and 35 patients (4.3%) in the normonatremic group (log
During the 3-year follow-up time, 4 (3.7%) patients were rank test: p = 0.680). At the 3-month follow-up, the mor-
lost to follow-up in the hyponatremic group, and 23 tality rates were 8 patients (7.5%) in the hyponatremic
(2.8%) patients were lost to follow-up in the normona- group and 60 patients (7.3%) in the normonatremic group
tremic group. The above findings are summarized in (log rank test: p = 0.735). Among the patients who sur-
table3. vived at the 1- or 3-month follow-ups and returned for

Hyponatremia and Mortality in Ischemic Cerebrovasc Dis 2012;34:5562 59

Stroke Patients
 Table 4. Cox regression analysis of patient survival during the 3-year study

Univariate Cox regression analysis Multivariate Cox regression analysis

p value HR (95% CI) p value HR (95% CI)

Age 0.001* 1.04 (1.021.06) 0.007 1.03 (1.011.05)

Gender 0.137 0.71 (0.461.11)
Sodium level 134 mmol/l 0.001* 2.45 (1.464.09) 0.003 2.23 (1.303.82)
Recurrent stroke 0.964 0.98 (0.491.99)
Hypertension 0.949 1.02 (0.621.66)
DM 0.365 1.23 (0.791.90)
CAD 0.007* 2.41 (1.284.55) 0.007 2.43 (1.284.63)
Atrial fibrillation <0.001* 2.48 (1.534.02) 0.071 1.63 (0.962.78)
CHF 0.045* 2.79 (1.027.62)
Smoking 0.760 0.93 (0.581.49)
Hyperlipidemia 0.011* 0.52 (0.320.86)
CRI 0.028* 1.90 (1.073.39) 0.059 1.76 (0.983.13)
TACS <0.001* 2.86 (1.764.67) 0.014 1.97 (1.153.38)

* p < 0.05, univariate Cox regression. p < 0.05, multivariate Cox regression.

the 3-year follow-up, the 3-year mortality rate was sig-
nificantly higher in hyponatremic patients (log rank test:
p ! 0.001 and p = 0.001, respectively).
Cox Regression Multivariate Analysis for 3-Year
Mortality in Patients with Acute, First-Ever Stroke
Univariate Cox regression analysis indicated that age,
hyponatremia, history of CAD, history of atrial fibrilla-
tion, history of CHF, TACS, hyperlipidemia and CRI
were variables (p ! 0.05) likely to be associated with mor-
tality in patients with acute, first-ever ischemic stroke.
These variables were entered into the multivariate Cox
proportional hazards model (table4). A backward step-
wise multivariate Cox proportional hazards model dem-
onstrated that hyponatremia was a significant risk factor
for all-cause 3-year mortality in these patients after ad-
justment for related variables (HR: 2.23; 95% CI: 1.30
3.82; p = 0.003; table4). Univariate Cox regression analy-
sis was also performed to sub-analyze short-term (1- and
3-month) mortality; no significant differences were seen
between normonatremic and hyponatremic groups (HR,
1.22, 95% CI: 0.483.11, p = 0.681, and HR, 1.14, 95% CI:
0.542.37, p = 0.736, respectively). Among patients who
survived the 1- and 3-month follow-ups, the mortality
rate at the 3-year follow-up was higher in hyponatremic
patients (HR, 3.15, 95% CI: 1.675.92, p ! 0.001, and HR,
3.10, 95% CI: 1.566.16, p = 0.001, respectively). After
multivariate Cox regression analysis and adjustment for
related variables, hyponatremia remained a significant
risk factor for all-cause 3-year mortality in patients who
survived at 1 and 3 months and returned for the 3-year
follow-up (HR, 2.86, 95% CI: 1.515.40, p = 0.001, and
HR, 2.80, 95% CI: 1.405.58, p = 0.003, respectively).
Discussion
The current study demonstrated a novel association
between hyponatremia and increased 3-year mortality
in patients with acute, first-ever ischemic stroke, even
after adjustment for established clinical predictors of ad-
verse outcome, including age and CAD, and greater
stroke severity. Furthermore, hyponatremia was not as-
sociated with short-term mortality (either in-hospital,
1-month or 3-month mortality), but was correlated with
long-term mortality in patients with acute, first-ever
ischemic stroke. Our results also indicated that hypona-
tremia in the acute phase of first-ever ischemic stroke
was more common in the patients with DM or CRI. In
addition, pneumonia was more frequently a complica-
tion in hyponatremic patients than in normonatremic
patients.
Determinants of hyponatremia in patients with acute,
first-ever stroke were also evaluated. From univariate and
multivariate logistic regression analyses, the presence of
DM and CRI (Cr 6132.6 mol/l or 1.5 mg/dl) were sig-
nificant determinants of hyponatremia in first-ever isch-
emic stroke patients. DM was reported to be associated

60 Cerebrovasc Dis 2012;34:5562 Huang /Weng /Peng /Chien /Wu /Lee /

Hung /Chen

with hyponatremia in previous studies [2, 5, 6]. Renal in-
sufficiency was also noted to be associated with hypona-
tremia in patients with pulmonary arterial hypertension
[7] and acute coronary syndrome [6].
The exact cause for the higher long-term mortality
rate observed in patients with hyponatremia associated
with acute first-ever ischemic stroke remains to be deter-
mined and requires further investigation. Only one pre-
vious study has shown that all-cause and non-cardiovas-
cular mortality were significantly increased at serum so-
dium levels ^138 mmol/l in stroke patients, but the study
included all types of stroke (including hemorrhage) and
was performed only in middle-aged male patients [10]. In
the present study, the reason for the association of hypo-
natremia with long-term, but not short-term, mortality in
acute first-ever ischemic stroke patient is unknown. Re-
cent hyponatremia treatment guidelines state the follow-
ing: hyponatremia remains incompletely understood
because of its association with a plethora of underlying
disease states, and its multiple etiologies with differing
pathophysiologic mechanisms [5, 19]. In cardiovascular
diseases, hyponatremia is frequently encountered in pa-
tients with advanced heart failure and is an established
indicator of heart failure progression and death; this re-
lationship is probably due to the activation of the renin-
angiotensin-aldosterone system [1, 2, 3, 6]. In patients
with MI, the development of hyponatremia may reflect
neurohormonal activation, which affects left ventricular
remodeling and leads to higher long-term risk for heart
failure and mortality [4, 7].
Our study failed to show an association between hy-
ponatremia and a higher risk of recurrent stroke in pa-
tients with acute first-ever ischemic stroke. Only one pre-
vious study has suggested that the risk of stroke rose
significantly when the sodium concentration decreased
below 144 mmol/l, but the study included patients with
all types of stroke (including hemorrhage), and was per-
formed only in middle-aged male patients [10]. Further
study is warranted to clarify whether sodium level is as-
sociated with risk of recurrent stroke.
Hyponatremia frequently accompanies pulmonary
diseases, both infectious and neoplastic [20]. Recent stud-
ies have suggested that hyponatremia is highly prevalent
in pneumonia patients and frequently accompanies lon-
ger hospitalization times [14, 21]. Therefore, our finding
that the incidence of pneumonia was higher in hypona-
tremic patients than in normonatremic patients was in
agreement with previous reports. However, the clinical
course in the acute stage of stroke or ward stay did not
differ between the 2 groups of patients.
Hyponatremia and Mortality in Ischemic
Stroke Patients
This study has several limitations. First, we did not
survey the etiology of hyponatremia in all patients,
although most of the hyponatremic patients were eu-
volemic. The syndrome of inappropriate antidiuretic
hormone secretion (SIADH) and central salt wasting
syndrome are common causes of hyponatremia in pa-
tients with neurologic disease. However, in a previous
Japanese study, the incidence of SIADH in patients with
cerebral infarction was only 2.2% [22], and we did not
check urinary sodium concentration and urine osmolar-
ity. Second, we did not collect information about serum
sodium levels after discharge; therefore, we cannot clari-
fy whether the hyponatremia was transient or persistent
in our patients. Third, we did not evaluate the stroke se-
verity by National Institutes of Health Stroke Scale score
since a number of patients did not receive this scoring
while in admission. Instead, we used the classification of
the OSCP to evaluate stroke severity; LACS was regarded
as a less severe and TACS as a more severe stroke. We had
forced added TACS into the Cox regression analysis. Al-
though some limitations existed in our investigation, we
clearly demonstrated that hyponatremia was an indepen-
dent factor associated with increased 3-year mortality in
acute, first-ever ischemic stroke patients.
In conclusion, this is the first study that demonstrated
that hyponatremia is an independent predictor of 3-year
mortality in patients with acute, first-ever ischemic
stroke. In addition, hyponatremia occurred more fre-
quently in patients with DM or CRI, and pneumonia was
more frequently observed in hyponatremic patients than
in normonatremic patients at the time of hospital admis-
sion. Larger groups and further investigations are re-
quired to confirm our clinical observations and to deter-
mine whether correcting the blood sodium level during
the acute stroke stage could improve clinical outcomes in
acute ischemic stroke patients. In addition, the mecha-
nisms behind hyponatremia in acute ischemic stroke pa-
tients require further investigation.
Acknowledgements
This work was supported by grants from the Chang-Gung Me-
morial Hospital CMRPG 270331, CMRPG 270332 and CMRPG
270333.
Cerebrovasc Dis 2012;34:5562 61
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