Clinical Research in Stroke
Cerebrovasc Dis
DOI: 10.1159/000510751
Prognostic Significance of Hyponatremia
in Acute Stroke: A Systematic Review
and Meta-Analysis
Shogo Shima a, b Yasunari Niimi b Yosuke Moteki c Osamu Takahashi d
Shinsuke Sato a, b Tatsuya Inoue a, b Yoshikazu Okada a
aDepartment of Neurosurgery, St. Luke’s International Hospital, Tokyo, Japan; bDepartment of Neuroendovascular
Therapy, St. Luke’s International Hospital, Tokyo, Japan; cDepartment of Neurosurgery, Ebina General Hospital,
Ebina, Japan; dDivision of General Internal Medicine, Department of Medicine, St. Luke’s International Hospital,
Tokyo, Japan
Keywords
Stroke · Hyponatremia · Mortality · Meta-Analysis
Abstract
Objective: Hyponatremia is a common electrolyte disorder
in patients with stroke, which leads to various fatal complica-
tions. We performed a systematic review and meta-analysis
to investigate the outcomes of acute stroke patients with
hyponatremia. Methods: We searched MEDLINE, EMBASE,
and the Cochrane Library databases for relevant literature in
English published up to March 2020. Two review authors in-
dependently screened and selected the studies by assessing
the eligibility and validity based on the inclusion criteria.
Mortality at 90 days was set as the primary end point, and
in-hospital mortality and length of hospital stay were set as
the secondary end points. We conducted the data synthesis
and analyzed the outcomes by calculating the odds ratio
(OR) and mean difference. Results: Of 835 studies, 15 studies
met the inclusion criteria (n = 10,745). The prevalence rate of
stroke patients with hyponatremia was 7.0–59.2%. They had
significantly higher 90-day mortality (OR, 1.73; 95% confi-
dence interval (CI), 1.24–2.42) and longer length of hospital
stay (mean difference, 10.68 days; 95% CI, 7.14–14.22) than
© 2020 S. Karger AG, Basel
karger@karger.com
www.karger.com/ced
Received: June 4, 2020
Accepted: August 4, 2020
Published online: October 5, 2020
patients without hyponatremia. Patients with hyponatremia
had a higher tendency of in-hospital mortality than those
without hyponatremia (OR, 1.61; 95% CI, 0.97–2.69). Conclu-
sions: The development of hyponatremia in the clinical
course of stroke is associated with higher short-term mortal-
ity and a longer hospital stay. Although the causal relation-
ship is unclear, hyponatremia could be a significant predic-
tor of poor outcomes after stroke. © 2020 S. Karger AG, Basel
Introduction
Stroke patients frequently develop electrolyte distur-
bances in their clinical course, of which hyponatremia is
especially a trigger that exacerbates neurological symp-
toms. The etiologies of this electrolyte abnormality after
stroke are mainly considered to be cerebral salt-wasting
syndrome or syndrome of inappropriate antidiuretic hor-
mone secretion [1–4]. Aside from these syndromes, other
conditions such as vomiting, diarrhea, and iatrogenic fac-
tors are responsible mechanisms [5]. Its prevalence rate
in stroke patients is approximately ≥10% compared with
1–2% in generally hospitalized patients [6–9]. When the
129.100.58.76 - 10/12/2020 4:58:28 PM
Shogo Shima
University of Western Ontario
Department of Neurosurgery, St. Luke’s International Hospital
9-1 Akashi-cho, Chuo-ku
Tokyo 104-8560 (Japan)
Downloaded by:
shisho @ luke.ac.jp
level of sodium in the blood is low, it could be the cause
of cerebral edema, seizures, and disturbance of conscious-
ness [10, 11]. In addition, low sodium status may cause
volume depletion leading to cerebral ischemia and cere-
bral infarction [12]. Moreover, an inappropriate correc-
tion rate of serum sodium can cause a demyelinating dis-
ease of the pons known as central pontine myelinolysis
[13, 14]. From these viewpoints, this electrolyte abnor-
mality has an unfavorable and sometimes fatal effect on
stroke patients in their clinical course.
Although previous studies have shown the causes of
hyponatremia in patients with 1 type of stroke, its prog-
nostic significance has not been sufficiently examined.
Through this study, we aimed to investigate the charac-
teristics of stroke patients with hyponatremia compre-
hensively and assessed the influence on the clinical out-
comes by conducting a systematic review and a meta-
analysis.
Methods
Search Methods
A computer-based search of MEDLINE, EMBASE, and the Co-
chrane Central Register of Controlled Trials (Cochrane Library
databases) for relevant literature published between January 1966
and March 2020, January 1974 and March 2020, and January 1970
and March 2020, respectively, was performed based on the search
strategy using the queries described in the supplemental file. We
compiled the systematic review for the observational studies ac-
cording to the MOOSE guidelines [15].
We set 90-day mortality as the primary outcome and in-hospi-
tal mortality and length of hospital stay as the secondary outcomes.
Through the screening of titles and abstracts, research articles ad-
dressing outcomes of stroke patients with hyponatremia were ex-
tracted. Then, the studies that fulfilled the following inclusion cri-
teria were adopted for review: (1) study design is an observational
study including cohort study, case-control study, and cross-sec-
tional study; (2) subjects are patients of any age with ischemic
stroke, intracerebral hemorrhage (ICH), or subarachnoid hem­
orrhage (SAH); (3) study reports at least one outcome of interest;
(4) study is written in English. Studies reporting outcomes of no
interest were not included. If articles separately dealt with hypona-
tremia and outcomes and did not report the relationships between
them, they were also excluded.
Selection of Studies and Data Collection
Two reviewers (S.S. and Y.M.) independently screened articles’
titles and abstracts for eligibility, retrieved the data, and assessed
the qualities of studies. We solved disagreements by discussing it
with a third reviewer (Y.N.).
We collected the following data from the reviewed studies: au-
thors’ names, publication year, study period, treatment facilities,
countries, mean or median age, sex, types of stroke, the definition
of hyponatremia, timing of hyponatremia, prevalence rate of hy-
ponatremia, and outcomes. To assess the qualities of the studies,
2 Cerebrovasc Dis
DOI: 10.1159/000510751
we used the Newcastle-Ottawa Scale (quality assessment scale of
nonrandomized studies in meta-analyses ranged from 0 to 9, with
0–4 points indicating low quality, 5–6 indicating moderate quality,
and 7–9 indicating high quality) [16, 17].
Data Synthesis and Statistical Analysis
Statistical analysis was performed with RevMan version 5.3
(Nordic Cochrane Center, Cochrane Collaboration, Copenhagen,
Denmark, 2014). For continuous variables, we calculated the mean
difference using the means and standard deviations of each study.
In addition, pooled odds ratio (OR) and 95% confidence intervals
(CIs) were calculated for dichotomous outcomes using the Man-
tel-Haenszel method. We applied a random effects model (REM)
if statistical heterogeneity among trial results existed. Otherwise, a
fixed effects model was applied. Statistical heterogeneity was as-
sessed with the Cochran Q test (χ2) and I2 statistic. We used tau2
values to assess the heterogeneity for a REM. An I2 ≥ 50% or a Q
test p value <0.10 indicated statistical heterogeneity. Publication
bias was assessed using funnel plots and Egger’s test if there were
at least 10 studies in the meta-analysis. We performed this assess-
ment using Stata version 11.1 (Stata Corp LP, College Station, TX,
USA, 2009).
Subgroup and Sensitivity Analyses
Subgroup analysis was performed to investigate the difference
of the effect by dividing the articles into 2 groups based on stroke
type (ischemic stroke and ICH or SAH). Sensitivity analysis was
performed based on the results of heterogeneity.
Results
Results of the Search and Data Quality
Of 835 studies from the database search, 31 studies
were extracted through title and abstract screening.
Among them, 2 articles were excluded because they had
a different study design, 13 articles were excluded because
they were not the population or outcome of interest, and
1 article was excluded because it was not in English. As a
result, 15 studies (n = 10,745) met the inclusion criteria
under full text evaluation and 14 studies (n = 10,259) were
adopted for meta-analysis (shown in Fig. 1). All studies
were designed as observational studies assessing the out-
comes of stroke patients and the influence of hyponatre-
mia. Most of the studies had moderate to high quality,
except for 1 study that ranked as low according to the
Newcastle-Ottawa Scale, and it was not incorporated into
the meta-analyses because of the lack of data.
Characteristics of Stroke Patients with Hyponatremia
Patient data are shown in Table 1. Among the total pa-
tients, 31–61% were men and the mean age was 67.2 years.
Of the patients who developed hyponatremia, 38.5–78.3%
were men and the mean age was 65.5 years. Seven articles
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Shima/Niimi/Moteki/Takahashi/Sato/
University of Western Ontario
Inoue/Okada
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 Medline, Embase, Cochrane library
(n = 835)

Duplicate (n = 35)

Relevant studies for title screening

(n = 800)

Not study design of interest (n = 58)

Relevant studies for abstract screening Non-stroke population (n = 3)
(n = 144) Not outcome of interest (n = 24)
Review (n = 17)
Case report (n = 4)
No abstract (n = 2)
Full text evaluations Protocol, guidelines (n = 2)
(n = 31) Conference abstract (n = 2)
Not English (n = 1)

Not study design of interest (n = 2)

Not population and outcome of
interest (n = 13)
Not English (n = 1)

Systematic review (n = 15) and

meta-analysis (n = 14)
Fig. 1. Flowchart of the studies included in
the systematic review.

reported patients with ICH (39%, n = 4,222) [6, 18–23], 5
reported ischemic stroke (50%, n = 5,387) [20, 22, 24–26],
and 5 reported SAH (11%, n = 1,136) [2, 4, 27–29]. Most
of the studies defined hyponatremia as a serum sodium
concentration <135 mmol/L, except for 1 study that de-
fined it as ≤135 mmol/L and another that defined it as
<131 mmol/L; 1 study did not provide a definition. All
studies except for 3 specified the timing of measurement.
The incidence rate of hyponatremia varied from 7 to
59.2%, and this range was driven by 2 studies that report-
ed on patients with SAH. The difference in the rate ac-
cording to stroke type was 12–51% in ICH, 7–34% in isch-
emic stroke, and 19.8–59.2% in SAH.
Outcomes
Five studies (n = 8,215) [6, 18, 21, 25, 26] reported the
outcome of the 90-day mortality (shown in Fig. 2). Stroke
patients with hyponatremia had significantly higher mor-
tality at 3 months than those without hyponatremia (23%
[n = 285/1,233] vs. 15% [n = 1,058/6,982]), resulting in
roughly doubled pooled OR (OR, 1.73; 95% CI, 1.24–
2.42). The higher mortality rate of patients with hypona-
tremia in the Kuramatsu 2014 study presumably led to
high heterogeneity in the comparative investigation of
the 90-day mortality. The Kuramatsu 2014 study showed
a higher percentage of patients with mechanical ventila-
tion (43%), respiratory infection (56%), and sepsis (13%)
compared with other studies. The high complication
rates were considered to be the cause of the high mortal-
ity of the study. We conducted a sensitivity analysis for
the 90-day mortality by excluding the study and it showed
homogeneity (OR, 1.50; 95% CI, 1.28–1.76; χ2 test, p =
0.38; I2 = 2%) (shown in Fig. 2).
Ten studies (n = 6,316) examined the difference in in-
hospital mortality between the hyponatremia and nonhy-
ponatremia groups (shown in Fig. 3). The evaluation of
all-cause in-hospital mortality revealed that 16% (n =
168/1,068) of patients with hyponatremia versus 10% (n
= 520/5,248) of patients without hyponatremia had died.
Patients with hyponatremia had a higher tendency of in-
hospital death (OR, 1.61; 95% CI, 0.97–2.69). The sub-
group analysis assessing the outcome of in-hospital mor-
tality in patients with ischemic stroke or ICH (shown in
Fig. 3) also demonstrated that patients with hyponatre-
mia had significantly higher mortality than those without
hyponatremia (OR, 2.04; 95% CI, 1.15–3.63). The sub-
group analysis of in-hospital mortality in patients with
SAH revealed that hyponatremia was not associated with
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Hyponatremia in Acute Stroke: Cerebrovasc Dis 3

University of Western Ontario

A Systematic Review DOI: 10.1159/000510751

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 4
Table 1. Characteristics of studies included in the systematic review

Author and Study period/facility/country Mean or median age, years, Type of Definition of hyponatremia, Prevalence of patients with Outcomes
year of publication proportion of male sex stroke measurement timing hyponatremia/total

total hyponatremia

Sherlock Jan 2002–Sep 2003 (19 months)/Neurosurgical center/ 50 (16–85),† 52.9% Not stated SAH <135 mEq/L, during 179/316 (56.6%) Length of hospital stay, in-hospital mortality
et al. [32] Ireland hospital stay

Kao Jan 2004–Jul 2007 (3.5 years)/University hospital/USA 56 (19–97),† 38% 57.1±0.9,* 38.5% SAH <135 mEq/L, during 187/316 (59.2%) Length of hospital stay, mortality
et al. [27] hospitalization

Fofi 18 months/Stroke unit/Italy 67±15,* 53.9% Not stated CI 34/475 (7%) In-hospital mortality, neurological status
et al. [24]
≦135 mEq/L, on admission

Huang Jan 2001–Dec 2003 (3 years)/Stroke unit of the 69.5,* 52.5% 70.5±11.6,* 55.1% CI 107/925 (11.6%) Stroke recurrence, in-hospital mortality, mortality after
et al. [25] Department of Neurology/Taiwan after onset discharge up to 3 years, acute ward stay, complication

Cerebrovasc Dis
≦134 mEq/L, within 3 days

Sreeraj Aug 2006–Dec 2008 (29 months)/Department of Not stated Not stated ICH, CI Not stated 148/486 (30.5%), Length of hospital stay, mortality
et al. [22] Neurology at a medical college hospital/India ICH 24/87 (27.6%),
CI 124/399 (31.1%)

DOI: 10.1159/000510751
Saramma Jan–Jul 2010 (6 months)/Neurosurgical intensive care 50.5,* 50.8% Not stated SAH <131 mEq/L, during 22/59 (33%) Length of hospital/ICU stay, outcome at discharge
et al. [28] unit at a tertiary hospital/India hospital stay

Gray Jan 2006–Jul 2009 (3.5 years)/Neurointensive care unit 58.8,* 61% 59.4±12.1,* 75% ICH <135 mEq/L, during 24/99 (24%) Length of hospital/ICU stay, in-hospital mortality,
et al. [19] /USA hospitalization complication

Rodrigues 2004–2011 (8 years)/Stroke center/USA 71,* 51% 71±14.9,* 52.9% CI <135 mEq/L, on admission 565/3541 (16%) In-hospital mortality, neurological status, disability,
et al. [26] mortality after discharge up to 12 months, functional
outcome at discharge

Kuramatsu 2006–2010 (5 years)/Department of Neurology at a 69.6,* 45% 69.8±13.6,* 47% ICH <135 mEq/L, on admission 66/422 (15.6%) Length of hospital stay, in-hospital mortality, mortality
et al. [6] university hospital and peripheral hospitals/Germany at 3 month, functional outcome at 3 month

Koivunen Jan 2000–Mar 2010 (10 years)/University hospital/ 42 (34–47),† 59.5% Not stated ICH <135 mEq/L, during 146/325 (44.9%) Mortality at 3 months
et al. [21] Finland hospital stay

Carcel Nov 2005–Apr 2007, 2008–2012/Clinical hospital sites 64,* 62.8% 64±13,* 61% ICH <135 mEq/L, at presentation 349/3002 (12%) Mortality at 90 days, major disability at 90 days
et al. [18], 20165 in 21 countries

Kalita Jan 2014–Jan 2016 (13 months)/Neurology service/ 62 (18–90),† 69% 60.4±12.3,* 72.1% ICH, CI <135 mEq/L, within the 43/100 (43%), In-hospital mortality, disability on discharge
et al. [20] India first 14 days ICH 27/53 (51%),
CI 16/47 (34%)

Spatenkova 10 years/Neurocritical care unit/ Czech Republic 51.9,* 35.3% 54.9±13.7,* 46% SAH <135 mEq/L, not stated 68/344 (19.8%) In-hospital mortality, poor outcome at 30 days
et al. [4]

Ridwan 2 years (from 2007)/Neurointensive care unit at the 52 (24–79),† 30.7% Not stated SAH <135 mEq/L, within the 33/101 (32.7%) Length of hospital/ICU stay, in-hospital mortality,
et al. [29] university hospital/Germany first 21 days mortality and GOS and mRS at 6, 12 month

Shah Jul.–Dec. 2018 (6 months)/A tertiary care public Not stated 59.1±9.1,* 78.3% ICH <135 mEq/L, not stated 106/234 (45.3%) Length of hospital stay, functional outcome, in-hospital
et al. [23] hospital/Pakistan mortality

Inoue/Okada
percentile).
ICH, intracerebral hemorrhage; CI, cerebral infarction; SAH, subarachnoid hemorrhage; NOS, Newcastle-Ottawa Scale; ICU, intensive care unit; GOS, Glasgow Outcome Scale; mRS, modified Rankin Scale. * Mean±SD. † Median (interquartile range: 25–75th

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 Color version available online
a Hyponatremia Control
Weight, Odds ratio Odds ratio
Study or subgroup events total events total % M-H, random, 95% Cl M-H, random, 95% Cl
Huang, 2012 8 107 60 818 11.9 1.02 [0.47, 2.20]
Koivunen, 2015 29 146 26 179 16.3 1.46 [0.82, 2.61]
Kuramatsu, 2014 39 66 99 356 17.4 3.75 [2.18, 6.45]
Carcel, 2016 64 349 289 2,653 25.7 1.84 [1.36, 2.47]
Rodrigues, 2014 145 565 584 2,976 28.7 1.41 [1.15, 1.74]

Total (95% Cl) 1,233 6,982 100.0 1.73 [1.24, 2.42]

Total events 285 1,058
Heterogeneity: τ = 0.09, χ = 13.01, df = 4 (p = 0.01); I = 69%
2 2 2
0.02 0.1 1 10 50
Test for overall effect: Z = 3.23 (p = 0.001) Favors non-hypo Na Favors hypo Na

b Hyponatremia Control
Weight, Odds ratio Odds ratio
Study or subgroup events total events total % M-H, fixed, 95% Cl M-H, fixed, 95% Cl
Huang, 2012 8 107 60 818 5.7 1.02 [0.47, 2.20]
Koivunen, 2015 29 146 26 179 8.3 1.46 [0.82, 2.61]
Carcel, 2016 64 349 289 2,653 24.4 1.84 [1.36, 2.47]
Rodrigues, 2014 145 565 584 2,976 61.6 1.41 [1.15, 1.74]

Total (95% Cl) 1,167 6,626 100.0 1.50 [1.28, 1.76]

Total events 246 959
Heterogeneity: χ2 = 3.07, df = 3 (p = 0.38); I2 = 2%
Test for overall effect: Z = 4.93 (p < 0.00001) 0.02 0.1 1 10 50
Favors non-hypo Na Favors hypo Na

Fig. 2. a Forest plots of the 90-day mortality in stroke patients with and without hyponatremia. The pooled OR
of the 5 studies was calculated by the REM. b Forest plots of the sensitivity analysis for stroke patients with and
without hyponatremia demonstrating 90-day mortality. The pooled OR of the 4 studies was calculated by the
FEM. OR, odds ratio; REM, random effects model; FEM, fixed effects model.

mortality (OR, 0.60; 95% CI, 0.27–1.31) (shown in Fig. 3).
We could not conduct a subgroup analysis of the 90-day
mortality in patients with SAH because of the lack of data.
Patients with hyponatremia stayed longer than those
without hyponatremia in all studies reporting on hospi-
talization duration. We were able to utilize the data of the
3 studies (n = 722) [2, 20, 27] to synthesize the length of
hospital stay, and patients with hyponatremia stayed lon-
ger by an average of 11 days (mean difference, 10.68 days;
95% CI, 7.14–14.22) compared with those without hypo-
natremia (shown in Fig. 4).
subgroup analysis of in-hospital mortality of SAH (χ2 test,
p = 0.72; I2 = 0%) and the sensitivity analysis of the 90-day
mortality (χ2 test, p = 0.38; I2 = 2%).
Publication bias was assessed in the meta-analysis of
the in-hospital mortality. The funnel plots are visually
symmetrical (shown in Fig. 3) and the result of Egger’s
test was not significant (p = 0.87), suggesting the low pos-
sibility of publication bias.
Discussion

Heterogeneity and Publication Bias
Heterogeneities were observed in some analyses for
the outcomes of interest. Tests for heterogeneity of 90-
day mortality (χ2 test, p = 0.01; I2 = 69%), in-hospital mor-
tality (χ2 test, p = 0.0002; I2 = 72%), in-hospital mortality
of ischemic stroke or ICH (χ2 test, p = 0.0002; I2 = 77%),
and length of hospital stay (χ2 test, p = 0.003; I2 = 83%)
were statistically significant. Hence, we applied REM for
these analyses. A fixed effects model was applied to the
This systematic review investigated the outcomes of all
types of stroke patients with hyponatremia. The prevalence
rate was 10–60% in patients with ischemic stroke or ICH,
and 20–60% in patients with SAH. We could confirm the
association of hyponatremia with poor outcomes in pa-
tients. The patients with post-stroke hyponatremia were 1.7
times more likely to die within 90 days and had high mor-
tality during hospitalization. In addition, post-stroke hypo-
natremia could lengthen the hospital stay by an average of
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 Color version available online
a Hyponatremia Control
Weight, Odds ratio Odds ratio
Study or subgroup events total events total % M-H, random, 95% Cl M-H, random, 95% Cl
Saramma, 2013 1 22 1 37 2.7 1.71 [0.10, 28.86]
Kalita, 2017 5 43 5 47 7.9 1.11 [0.30, 4.12]
Spatenkova, 2017 3 68 23 262 8.5 0.48 [0.14, 1.65]
Ridwan, 2019 5 33 15 68 9.3 0.63 [0.21, 1.92]
Gray, 2014 6 24 24 75 9.8 0.71 [0.25, 2.01]
Shah, 2019 33 106 5 128 10.3 11.12 [4.16, 29.75]
Fofi, 2012 6 34 22 437 10.3 4.04 [1.52, 10.78]
Huang, 2012 6 107 39 818 11.1 1.19 [0.49, 2.87]
Kuramatsu, 2014 27 66 75 356 13.9 2.59 [1.49, 4.51]
Rodrigues, 2014 76 565 311 3,020 15.9 1.35 [1.03, 1.77]

Total (95% Cl) 1,068 5,248 100.0 1.61 [0.97, 2.69]

Total events 168 520
Heterogeneity: τ2 = 0.41, χ2 = 32.16, df = 9 (p = 0.0002); I2 = 72% 0.02 0.1 1 10 50
Test for overall effect: Z = 1.82 (p = 0.07) Favors non-hypo Na Favors hypo Na
b Hyponatremia Control
Weight, Odds ratio Odds ratio
Study or subgroup events total events total % M-H, random, 95% Cl M-H, random, 95% Cl
Kalita, 2017 5 43 5 47 10.0 1.11 [0.30, 4.12]
Gray, 2014 6 24 24 75 12.4 0.71 [0.25, 2.01]
Shah, 2019 33 106 5 128 13.0 11.12 [4.16, 29.75]
Fofi, 2012 6 34 22 437 13.0 4.04 [1.52, 10.78]
Huang, 2012 6 107 39 818 14.0 1.19 [0.49, 2.87]
Kuramatsu, 2014 27 66 75 356 17.5 2.59 [1.49, 4.51]
Rodrigues, 2014 76 565 311 3,020 20.0 1.35 [1.03, 1.77]

Total (95% Cl) 945 4,881 100.0 2.04 [1.15, 3.63]

Total events 159 481
Heterogeneity: τ = 0.41, χ = 25.81, df = 6 (p = 0.0002); I = 77%
2 2 2 0.02 0.1 1 10 50
Test for overall effect: Z = 2.43 (p = 0.02) Favors non-hypo Na Favors hypo Na

c Hyponatremia Control
Weight, Odds ratio Odds ratio
Study or subgroup events total events total % M-H, fixed, 95% Cl M-H, fixed, 95% Cl
Saramma, 2013 1 22 1 37 3.9 1.71 [0.10, 28.86]
Ridwan, 2019 5 33 15 68 46.0 0.63 [0.21, 1.92]
Spatenkova, 2017 3 68 23 262 50.1 0.48 [0.14, 1.65]

Total (95% Cl) 123 367 100.0 0.60 [0.27, 1.31]

Total events 9 39
Heterogeneity: χ2 = 0.67, df = 2 (p = 0.72); I2 = 0% 0.02 0.1 1 10 50
Test for overall effect: Z = 1.29 (p = 0.20) Favors non-hypo Na Favors hypo Na

Funnel plot with pseudo 95% confidence limits

0
Standard error of log OR

0.5

1.0

1.5
–2 –1 0 1 2 3
d log odds ratio

3
(For legend see next page.)
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6 Cerebrovasc Dis Shima/Niimi/Moteki/Takahashi/Sato/

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DOI: 10.1159/000510751 Inoue/Okada

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11 days. However, there was no relationship between hypo-
natremia and mortality in patients with SAH.
The main causes of hyponatremia after stroke can be
attributed to cerebral salt-wasting syndrome character-
ized by natriuresis with extracellular fluid depletion or
syndrome of inappropriate antidiuretic hormone secre-
tion, in which free water retention caused by excessive
secretion of the antidiuretic hormone leads to hypo-os-
molar hyponatremia [1, 27, 30, 31]. Despite the etiologies,
this electrolyte disorder causes ionic and osmotic chang-
es in brain tissues. Ionic imbalance affects the cell’s mem-
brane potential, disturbing the acid-base equilibrium and
synaptic activities [32, 33]. In order to maintain osmotic
homeostasis, hypo-osmolarity due to hyponatremia pro-
motes water to shift to intracellular compartments, thus
causing cell or glial swelling [32, 33]. The ionic and os-
motic changes in the hyponatremic state may aggravate
cerebral hypoperfusion resulting from increased intra-
cranial pressure caused by stroke. Although these chang-
es are usually kept to a minimum by cerebral autoregula-
tion [26], the self-regulatory mechanism deteriorates in
the acute phase of stroke, which would decrease the toler-
ance for brain damage. Whereas our analysis investigat-
ing the outcome of patients with ischemic stroke or ICH
showed the relationship between hyponatremia and poor
mortality, the present meta-analysis also demonstrated
no increased in-hospital mortality in SAH patients. It was
mentioned in the systematic review of SAH conducted by
Hyponatremia Control
Study or subgroup mean SD total mean SD total
Kalita, 2017 24.3 17.4 43 11.5 6.10 47
Kao, 2009 17.1 10.9 187 9.6 12.50 129
Sherlock, 2006 24 2.6 179 11.8 0.75 137
Total (95% Cl) 409 313
Heterogeneity: τ2 = 7.46, χ2 = 11.76, df = 2 (p = 0.003); I2 = 83%
Test for overall effect: Z = 5.91 (p < 0.00001)
Fig. 4. Forest plots of the length of hospital stay of the patients with and without hyponatremia. The mean difference of the 3 studies was
calculated by the REM. REM, random effects model.
Fig. 3. a Forest plots of in-hospital mortality in stroke patients with
and without hyponatremia. The pooled OR of the 8 studies was
calculated by the REM. b Forest plots of the subgroup analysis of
the patients with ischemic stroke or intracerebral hemorrhage,
demonstrating in-hospital mortality in patients with or without
hyponatoremia. The pooled OR of the 6 studies was calculated by
Hyponatremia in Acute Stroke:
A Systematic Review
Mapa et al. [34] that hyponatremia does not affect short-
term mortality. These consequences are seemingly attrib-
uted to the influence of fluid restriction. Clinicians ordi-
narily restrict the rehydration of patients with severe isch-
emic stroke or ICH in an attempt to prevent brain edema;
however, it might carry a risk of hypoperfusion, which
can be fatal, especially for patients with hyponatremia.
Meanwhile, in the case of SAH, clinicians regulate the flu-
id balance of patients to prevent hypovolemia and pre-
vent them from developing vasospasm. We infer that this
treatment could also be effective for maintaining the ce-
rebral perfusion of patients with hyponatremia.
The length of hospital stay of patients with hyponatre-
mia was significantly longer than that of patients without
hyponatremia in the present study. It is obvious that the
increased length of stay is due to the treatment of serum
sodium abnormality. Some studies showed that hypona-
tremia lengthened the intensive care unit stay of stroke
patients [28, 35]. Management of other complications
such as infections and epileptic seizures could be another
reason for the extended hospital stay. One study reported
that the frequency of pneumonia and urinary tract infec-
tion was higher in hyponatremic patients than in nor-
monatremic patients during admission [25]. Hyponatre-
mia could also be a precipitating factor for epileptic sei-
zures by lowering the seizure threshold; post-stroke
epilepsy contributes to high morbidity and mortality [36–
38].
Color version available online
Weight, Mean difference Mean difference
% IV, random, 95% Cl IV, random, 95% Cl
21.4 12.80 [7.31, 18.29]
35.1 7.50 [4.84, 10.16]
43.5 12.20 [11.80, 12.60]
100.0 10.68 [7.14, 14.22]
–20 –10 1 10 20
Favors non-hypo Na Favors hypo Na
the random effects model. c Forest plots of the subgroup analysis
of the patients with SAH, demonstrating in-hospital mortality in
patients with or without hyponatoremia. The pooled OR of the 2
studies was calculated by the FEM. d Funnel plots for the in-hos-
pital mortality. OR, odds ratio; SAH, subarachnoid hemorrhage;
REM, random effects model; FEM, fixed effects model.
129.100.58.76 - 10/12/2020 4:58:28 PM
Cerebrovasc Dis 7
University of Western Ontario
DOI: 10.1159/000510751
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 Our study has its limitations and strengths. First, there
could have been some potential biases in the review pro-
cess. Articles published in languages other than English
were excluded. We also excluded studies investigating
outcomes that were of no interest to this study, which
may have led to selection bias. Despite the possibility of
biases, the quality of the reviewed literature was good.
Most of the studies defined the validated diagnosis of hy-
ponatremia and assessed the explicitly predetermined
outcomes. From the perspective of lack of data and qual-
ity, we did not adopt prognostic variables if articles did
not specify the assessment period of mortality. In addi-
tion, the study ranked low in quality was not incorporat-
ed into the meta-analysis. Second, outcomes except for
90-day mortality, in-hospital mortality, and length of
hospital stay were not evaluated in the present study. For
instance, long-term mortality or functional outcomes
were not examined, but they may be influenced by hypo-
natremia. Finally, we did not consider the relationship
between stroke severity and hyponatremia. Stroke sever-
ity could influence the extent of hyponatremia, and severe
stroke may cause high mortality. Furthermore, the results
of this meta-analysis were not adjusted with confounders
that may exert unfavorable effects on stroke patients’ out-
comes. Therefore, a large prospective study is required to
investigate the causal relationship between hyponatremia
and poor outcomes after stroke. Meanwhile, the conse-
quences of our research are thought to be useful for risk
stratification in clinical settings. Hyponatremia in pa-
tients with ischemic stroke or ICH could be a predictor of
poor outcomes.
Conclusion
Stroke patients occasionally develop hyponatremia in
the clinical course, and it is related to higher mortality at
3 months and a longer hospital stay. Clinicians may be
able to predict these poor outcomes by timely detection
of hyponatremia.
Statement of Ethics
No human subjects were involved in this study. We collected
and dealt with the published data, and the extracted data were all
anonymized. This study applies to internationally accepted stan-
dards based on the MOOSE guideline.
Conflict of Interest Statement
The authors have no conflicts of interest to disclose.
Funding Sources
The authors did not receive any funding.
Author Contributions
Shogo Shima contributed to study design, acquisition of data,
statistical analysis, interpretation of data, and drafting the article.
Yasunari Niimi contributed to interpretation of data and study
supervision. Yosuke Moteki contributed to acquisition of data and
interpretation of data. Osamu Takahashi contributed to statistical
analysis and interpretation of data. Shinsuke Sato contributed to
acquisition of data. Tatsuya Inoue contributed to acquisition of
data. Yoshikazu Okada contributed to study supervision.

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