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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 differences. Results: Among the patients with acute first-ev-
Hyponatremia Mortality Ischemic stroke First-ever er ischemic stroke, 107 (11.6%) were hyponatremic. Among
ischemic stroke stroke risk factors, the prevalence of diabetes mellitus was
significantly higher among hyponatremic patients (p !
0.001). Prevalence of chronic renal insufficiency was also
Abstract higher in the hyponatremic group (p = 0.002). Clinical pre-
Background: Hyponatremia is the most common electro- sentations, such as the length of acute ward stay, initial im-
lyte disorder in hospitalized patients, and is frequently a paired consciousness, and clinical course in acute stroke
marker of a significant underlying disease. The prognostic were similar among normo- and hyponatremic patients.
value of hyponatremia in patients with acute first-ever isch- Among the complications, pneumonia and urinary tract in-
emic stroke is not known. We aimed to analyze whether hy- fection were significantly higher in hyponatremic than in
ponatremia in the acute stroke stage contributed to the risk normonatremic patients. After multivariate logistic regres-
of mortality or recurrent stroke in these patients. Methods: sion analysis, diabetes mellitus and chronic renal insufficien-
We studied 925 patients presenting with acute first-ever cy were associated with hyponatremia in these patients.
ischemic stroke between 2002 and 2004. Sodium levels were Kaplan-Meier analysis indicated that the survival rate was
obtained on arrival at the emergency room within 3 days of significantly lower in hyponatremic patients than in nor-
acute stroke onset. Hyponatremia was defined as a serum monatremic patients (log rank test; p value !0.001). After
sodium concentration of 134 mmol/l or less. Clinical presen- multivariate Cox proportional hazards model analysis, hypo-
tation, stroke risk factors, associated medical disease, and natremia was a significant predictor of 3-year mortality in
outcome were recorded. All patients were followed for 3 these patients after adjustment for related variables (p val-
years for survival analysis. A multivariate Cox proportional ue = 0.003, hazard ratio = 2.23, 95% confidence interval:
hazards model was used to identify risk factors for 3-year 1.303.82). Conclusion: Hyponatremia in the acute stroke
mortality in these patients. We also constructed Kaplan-Mei- stage is a predictor of 3-year mortality in patients with acute
er survival curves, and compared groups with hyponatremia first-ever ischemic stroke that is independent of other clini-
and normonatremia by means of log rank tests for significant 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 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
Hyponatremia is the most common electrolyte disor- with dialysis, or cancer, were excluded. Furthermore, patients
der in hospitalized patients in various clinical settings [1]. who used diuretics before the acute stroke attack were also ex-
It is frequently a marker of a significant underlying dis- cluded. All patients had a clinical diagnosis of acute ischemic
ease and is, therefore, associated with poor short-term stroke according to the World Health Organization criteria,
prognosis, even when the serum sodium level is only which was further confirmed by brain computed tomography or
magnetic resonance imaging (MRI) scan in the hospital [11]. The
mildly reduced [14]. For example, hyponatremia in- most common symptoms of patients with acute ischemic stroke
creases the risk of death and myocardial infarction (MI) were sudden focal motor or sensory symptoms. Other symptoms
in middle-aged and elderly community subjects [5]. Hy- included acute confusion or unconsciousness, aphasia, limitation
ponatremia is associated with 30-day adverse outcomes of extraocular movement, defect of visual field, unsteady gait, diz-
in patients with acute coronary syndrome or non-ST el- ziness, and loss of balance or coordination. All patients with un-
certain clinical diagnosis of acute ischemic stroke, such as those
evation MI [6]. In addition, hyponatremia in the early who presented with only acute decrease in consciousness or acute
phase of ST elevation MI is a predictor of long-term mor- vertigo, underwent brain MRI (which included diffusion-weight-
tality and heart failure [2]. In patients with pulmonary ed images and apparent diffusion coefficient maps). Patients with
arterial hypertension, hyponatremia can predict right uncertain clinical diagnosis were excluded from the study if the
heart failure [7]. In patients with aneurysmal subarach- brain MRI did not suggest acute cerebral infarction. The duration
of clinical symptoms in most patients diagnosed with acute isch-
noid hemorrhage (aSAH), hyponatremia is associated emic stroke lasted longer than 24 h. Patients exhibiting clinical
with reversible neurological deterioration, an increased symptoms for less than 24 h also received a brain MRI study, and
risk of brain ischemia and vasospasm, cerebral edema only those with acute cerebral infarction confirmed by the brain
and mass effect, seizures, and death [8]. However, hypo- MRI were included. Patients with clinical symptoms lasting less
natremia did not predict poor outcome in all-grade aSAH than 24 h without evidence of acute cerebral infarction in the
brain MRI were diagnosed as having undergone a transient isch-
patients in another study [9]. emic attack (TIA) and were excluded from the study.
Little is known about the relationship between hypo- Comorbid conditions were determined after an in-depth re-
natremia and clinical outcomes in patients with acute view of medical records, including history and physical examina-
ischemic stroke. The clinical significance of hyponatre- tion, progress notes, discharge summaries, and consultations.
mia in patients with acute, first-ever ischemic stroke has Hypertension was defined as known hypertension diagnosed by
a clinician, or systolic blood pressure 1160 mm Hg and/or dia-
not been investigated previously. This 3-year longitudi- stolic blood pressure 195 mm Hg on 2 different occasions, where
nal study investigated the incidence and factors associ- the second measurement was made more than 5 days after stroke
ated with hyponatremia by clinically examining patients onset. Diabetes mellitus (DM) was defined as previous diagnosis
with acute, first-ever ischemic stroke. Furthermore, this and treatment of DM, a fasting plasma glucose equal or more than
study analyzed whether hyponatremia contributed to the 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
risk of mortality or recurrent stroke in these patients. To mmol/l (200 mg/dl), in the presence of classic symptoms of hyper-
our knowledge, only one previous study has reported an glycemia or hyperglycemic crisis [12]. In hyperglycemic patients
inverse relationship between serum sodium level and risk without previous diagnosis and treatment of DM, repeated testing
of stroke within the normal range of serum sodium con- was performed during admission and 1 month after discharge.
centration [10]. 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
Methods was diagnosed when present on a standard 12-lead electrocardio-
gram. Coronary artery disease (CAD) was defined by past inci-
This clinical study followed the Declaration of Helsinki, and dences of acute MI or angina pectoris. Congestive heart failure
was approved by the Medical Ethics Committee of Chang Gung (CHF) was present if the patient was previously diagnosed by a
Memorial Hospital, Keelung, Taiwan. cardiologist or if the condition was found by physical examina-
tion and confirmed by transthoracic cardiac echo study. Chronic
Study Patients renal insufficiency (CRI) was defined as creatinine (Cr) 6132.6
All patients involved in this study were recruited from the mol/l (1.5 mg/dl). Cigarette smoking was defined as a current
stroke unit of the Department of Neurology, Chang Gung Memo- smoker or a smoker with cessation less than 5 years ago.
rial Hospital, from January 1, 2001, until December 31, 2003. Only Patients who met the inclusion criteria were classified into 2
consecutive patients with first-ever ischemic stroke were enrolled. groups, i.e. hyponatremic and normonatremic patients. Sodium
Individuals with previous stroke, infarction or hemorrhage, or a levels were obtained on arrival in the emergency room within 3
diagnosis of uncertain stroke were excluded from the study. Pa- days of acute stroke onset. Sodium levels were corrected by the

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


Hung /Chen

Katz formula, which increases sodium by 1.6 mmol/l for every risk ratio and 95% confidence intervals (CI) were measured. To
5.55 mmol/l (100 mg/dl) increase in glucose concentration above assess the relationship between hyponatremia and mortality,
5.55 mmol/l (100 mg/dl), and patients with pseudohyponatremia Kaplan-Meier curves were compared using the log rank test. The
were excluded [13]. Patients with extreme hypernatremia (serum Cox proportional hazards model was used to evaluate all variables
sodium concentration 1150 mmol/l) were also excluded from the and determine the significance of variables for predicting the all-
study. Hyponatremia was defined as a serum sodium concentra- cause 3-year mortality. To determine the risk of death, hazard
tion of 134 mmol/l or less and normonatremia was a sodium con- ratio (HR) and 95% CI were obtained using the Cox proportional
centration of greater than 134 mmol/l, on the basis of previously hazards model. A univariate Cox model that assessed all previ-
published reports [5, 6, 14]. ously identified important variables was used to calculate the HR
for mortality. A backward stepwise multivariate Cox regression
Definition and Clinical Subtypes of Ischemic Stroke model was also used to identify the risk factors for 3-year mortal-
Clinical subtypes of ischemic stroke were rated according to ity in these patients. All statistical calculations were performed
the classification of the Oxfordshire Community Stroke Project with SPSS for Windows (SAS Institute, Cary, N.C., USA).
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- Results
can Stroke Association [16]. TIA mimics such as epileptic sei-
zures, complicated migraine, psychogenic hyperventilation, or Patient Characteristics
transient global amnesia were excluded from the study [17]. The Among 949 patients, 22 were excluded due to a final
clinical course in the acute stage of stroke, mean length of acute
ward stay, in-acute ward mortality, and frequency of medical diagnosis of TIA but not acute first-ever ischemic stroke,
complications were monitored. Clinical functional outcome upon and 2 patients were excluded due to extreme hypernatre-
discharge was assessed according to the modified Rankin Scale mia with unknown cause (sodium levels, 152 and 159
(mRS) [18]. Functionally dependent was defined as having an mmol/l, respectively). A total of 925 patients (486 men,
mRS score of 3, 4 or 5. 439 women) were analyzed (table1). The clinical proper-
Laboratory Measurements ties, including age, gender and comorbidity data, are list-
All laboratory values, including blood cell counts, and bio- ed in table1. Mean patient age was 69.48 8 11.62 years,
chemical data were measured by automated and standardized and 107 patients (11.6%) were hyponatremic (Na+ ^134
methods. All blood samples from patients were obtained on ad- mmol/l). There was no difference in age or gender be-
mission, centrifuged, and stored at 70 C until use in assays. Se-

tween the hypo- and normonatremic groups. Stroke risk
rum albumin, Cr, cholesterol, triglyceride, white blood cell count,
and hemoglobin levels were assayed and recorded. All other factors and their distributions in the 2 groups are also
markers were analyzed by standard automated laboratory meth- listed in table1. The prevalence of DM and CRI was sig-
ods. nificantly higher in hyponatremic patients than in nor-
monatremic patients. Differences in the prevalence of
Follow-Up other stroke risk factors and clinical presentations were
Patients were followed up for 3 years after initial assessment.
Follow-up consisted of clinical examinations at 1 and 3 months not statistically significant between normo- and hypona-
after first stroke and then every 3 months. End points of this study tremic patients.
included recurrent ischemic stroke or death. Recurrent stroke was
defined as any new focal neurological deficit of sudden onset last- Determinants of Hyponatremia in Patients with
ing at least 24 h for which no cause could be found other than Acute, First-Ever Ischemic Stroke
ischemic stroke. A diagnosis of recurrence was not made where
symptoms could be attributed to edema, mass effect, brain shift Univariate logistic regression analysis revealed that
syndrome, or hemorrhagic transformation, and could not be di- DM, CRI, and CAD were positively associated with hy-
agnosed within 24 h of the index stroke. Each death occurring ponatremia in patients with acute, first-ever ischemic
during the follow-up period was reviewed. stroke. After adjusting for these potential variables (p !
0.1) in the forward stepwise multivariate logistic regres-
Statistical Analysis
Unless otherwise stated, continuous variables are expressed as sion analysis, the presence of DM and CRI were positive-
mean 8 standard deviation (SD), and categorical variables are ly associated with hyponatremia (table2).
expressed as number or percentage of each parameter. Compari-
sons between the 2 patient groups were analyzed by 2 or Students Clinical Course in Patients with Acute Stage of
t test. The relative risks of independent associations between hy- First-Ever Ischemic Stroke
ponatremia and variables were analyzed by logistic regression. A
variable with p ! 0.1 in univariate logistic regression was consid- The length of acute ward stay, whether the patient
ered to be associated with hyponatremia, and was entered into experienced initial impaired consciousness, and clinical
backward stepwise multivariate logistic regression analysis. The course in the acute stroke stage were not significantly

Hyponatremia and Mortality in Ischemic Cerebrovasc Dis 2012;34:5562 57


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

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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- risk factor for all-cause 3-year mortality in patients who
nificantly higher in hyponatremic patients (log rank test: survived at 1 and 3 months and returned for the 3-year
p ! 0.001 and p = 0.001, respectively). 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).
Cox Regression Multivariate Analysis for 3-Year
Mortality in Patients with Acute, First-Ever Stroke
Univariate Cox regression analysis indicated that age, Discussion
hyponatremia, history of CAD, history of atrial fibrilla-
tion, history of CHF, TACS, hyperlipidemia and CRI The current study demonstrated a novel association
were variables (p ! 0.05) likely to be associated with mor- between hyponatremia and increased 3-year mortality
tality in patients with acute, first-ever ischemic stroke. in patients with acute, first-ever ischemic stroke, even
These variables were entered into the multivariate Cox after adjustment for established clinical predictors of ad-
proportional hazards model (table4). A backward step- verse outcome, including age and CAD, and greater
wise multivariate Cox proportional hazards model dem- stroke severity. Furthermore, hyponatremia was not as-
onstrated that hyponatremia was a significant risk factor sociated with short-term mortality (either in-hospital,
for all-cause 3-year mortality in these patients after ad- 1-month or 3-month mortality), but was correlated with
justment for related variables (HR: 2.23; 95% CI: 1.30 long-term mortality in patients with acute, first-ever
3.82; p = 0.003; table4). Univariate Cox regression analy- ischemic stroke. Our results also indicated that hypona-
sis was also performed to sub-analyze short-term (1- and tremia in the acute phase of first-ever ischemic stroke
3-month) mortality; no significant differences were seen was more common in the patients with DM or CRI. In
between normonatremic and hyponatremic groups (HR, addition, pneumonia was more frequently a complica-
1.22, 95% CI: 0.483.11, p = 0.681, and HR, 1.14, 95% CI: tion in hyponatremic patients than in normonatremic
0.542.37, p = 0.736, respectively). Among patients who patients.
survived the 1- and 3-month follow-ups, the mortality Determinants of hyponatremia in patients with acute,
rate at the 3-year follow-up was higher in hyponatremic first-ever stroke were also evaluated. From univariate and
patients (HR, 3.15, 95% CI: 1.675.92, p ! 0.001, and HR, multivariate logistic regression analyses, the presence of
3.10, 95% CI: 1.566.16, p = 0.001, respectively). After DM and CRI (Cr 6132.6 mol/l or 1.5 mg/dl) were sig-
multivariate Cox regression analysis and adjustment for nificant determinants of hyponatremia in first-ever isch-
related variables, hyponatremia remained a significant 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- This study has several limitations. First, we did not
sufficiency was also noted to be associated with hypona- survey the etiology of hyponatremia in all patients,
tremia in patients with pulmonary arterial hypertension although most of the hyponatremic patients were eu-
[7] and acute coronary syndrome [6]. volemic. The syndrome of inappropriate antidiuretic
The exact cause for the higher long-term mortality hormone secretion (SIADH) and central salt wasting
rate observed in patients with hyponatremia associated syndrome are common causes of hyponatremia in pa-
with acute first-ever ischemic stroke remains to be deter- tients with neurologic disease. However, in a previous
mined and requires further investigation. Only one pre- Japanese study, the incidence of SIADH in patients with
vious study has shown that all-cause and non-cardiovas- cerebral infarction was only 2.2% [22], and we did not
cular mortality were significantly increased at serum so- check urinary sodium concentration and urine osmolar-
dium levels ^138 mmol/l in stroke patients, but the study ity. Second, we did not collect information about serum
included all types of stroke (including hemorrhage) and sodium levels after discharge; therefore, we cannot clari-
was performed only in middle-aged male patients [10]. In fy whether the hyponatremia was transient or persistent
the present study, the reason for the association of hypo- in our patients. Third, we did not evaluate the stroke se-
natremia with long-term, but not short-term, mortality in verity by National Institutes of Health Stroke Scale score
acute first-ever ischemic stroke patient is unknown. Re- since a number of patients did not receive this scoring
cent hyponatremia treatment guidelines state the follow- while in admission. Instead, we used the classification of
ing: hyponatremia remains incompletely understood the OSCP to evaluate stroke severity; LACS was regarded
because of its association with a plethora of underlying as a less severe and TACS as a more severe stroke. We had
disease states, and its multiple etiologies with differing forced added TACS into the Cox regression analysis. Al-
pathophysiologic mechanisms [5, 19]. In cardiovascular though some limitations existed in our investigation, we
diseases, hyponatremia is frequently encountered in pa- clearly demonstrated that hyponatremia was an indepen-
tients with advanced heart failure and is an established dent factor associated with increased 3-year mortality in
indicator of heart failure progression and death; this re- acute, first-ever ischemic stroke patients.
lationship is probably due to the activation of the renin- In conclusion, this is the first study that demonstrated
angiotensin-aldosterone system [1, 2, 3, 6]. In patients that hyponatremia is an independent predictor of 3-year
with MI, the development of hyponatremia may reflect mortality in patients with acute, first-ever ischemic
neurohormonal activation, which affects left ventricular stroke. In addition, hyponatremia occurred more fre-
remodeling and leads to higher long-term risk for heart quently in patients with DM or CRI, and pneumonia was
failure and mortality [4, 7]. more frequently observed in hyponatremic patients than
Our study failed to show an association between hy- in normonatremic patients at the time of hospital admis-
ponatremia and a higher risk of recurrent stroke in pa- sion. Larger groups and further investigations are re-
tients with acute first-ever ischemic stroke. Only one pre- quired to confirm our clinical observations and to deter-
vious study has suggested that the risk of stroke rose mine whether correcting the blood sodium level during
significantly when the sodium concentration decreased the acute stroke stage could improve clinical outcomes in
below 144 mmol/l, but the study included patients with acute ischemic stroke patients. In addition, the mecha-
all types of stroke (including hemorrhage), and was per- nisms behind hyponatremia in acute ischemic stroke pa-
formed only in middle-aged male patients [10]. Further tients require further investigation.
study is warranted to clarify whether sodium level is as-
sociated with risk of recurrent stroke.
Hyponatremia frequently accompanies pulmonary Acknowledgements
diseases, both infectious and neoplastic [20]. Recent stud-
This work was supported by grants from the Chang-Gung Me-
ies have suggested that hyponatremia is highly prevalent
morial Hospital CMRPG 270331, CMRPG 270332 and CMRPG
in pneumonia patients and frequently accompanies lon- 270333.
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 Cerebrovasc Dis 2012;34:5562 61


Stroke Patients
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62 Cerebrovasc Dis 2012;34:5562 Huang /Weng /Peng /Chien /Wu /Lee /


Hung /Chen

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