Respiratory Medicine 117 (2016) 237e242

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Respiratory Medicine
journal homepage: www.elsevier.com/locate/rmed

Impact of hyponatremia on mortality and morbidity in patients with

COPD exacerbations
Roberto Chalela a, b, c, Jose
Gregorio Gonza
lez-García a, Juan Jose

Chillaro

n d, e,
Leticia Valera-Herna
ndez a, Carlos Montoya-Rangel a, Diana Badenes a, b, c, Sergi Mojal e, f,
a, b, c, *
Joaquim Gea
a
Servei de Pneumologia, Hospital del Mar e IMIM, Barcelona, Spain
b
Universitat Pompeu Fabra, Barcelona, Spain
c
CIBER de Enfermedades Respiratorias (CibeRes), ISCIII, Spain
d
, Hospital del Mar e IMIM, Barcelona, Spain
Servei d’Endocrinologia i Nutricio
e noma de Barcelona, Barcelona, Spain
Universitat Auto
f
Methodological Consulting in Biomedical Research, IMIM, Barcelona, Spain

a r t i c l e i n f o a b s t r a c t

Article history: Hyponatremia is the most common electrolyte disorder in hospitalized patients, being associated with
Received 16 February 2016 increased morbidity and mortality in different clinical conditions. However, the prevalence and impact of
Received in revised form this electrolytic disorder in patients hospitalized for an exacerbation of COPD still remains unknown. The
28 April 2016
aim of the present study was to clarify these points. A total of 424 patients hospitalized due to a COPD
Accepted 3 May 2016
Available online 29 June 2016
exacerbation were consecutively included, showing a frequency of hyponatremia of 15.8% (hyposmolar in
most cases). Even though patients with and without hyponatremia showed a similar age, comorbidities,
lung function impairment, presence of previous exacerbations, hospitalizations, most of the comorbid-
Keywords:
Hyponatremia
ities and the overall severity index (APACHE II), their clinical outcomes were worse. Indeed, their hos-
COPD pitalization length, mechanical ventilation requirements and deaths (both during admission and within
Exacerbations the months following discharge) were higher than those of non-hyponatremic patients. A sodium
Clinical outcomes threshold lower than 129.7 mEq/L exhibited the better discriminatory power for death prediction. We
conclude that hyponatremia (especially if severe) is a predictive marker for a bad clinical course in COPD
exacerbations and therefore, patients with this electrolyte abnormality should be carefully monitored.
© 2016 Elsevier Ltd. All rights reserved.

1. Introduction initial symptoms of acute hyponatremia include nausea, vomiting

Hyponatremia is the most common electrolyte disorder in
hospitalized patients, with a prevalence ranging between 15% and
37% depending on the definition, population and healthcare system
[1e5]. However, the most accepted lower limit of normality for
serum sodium is 135 mEq/L. Below this value there is growing
evidence that hyponatremia associates with increased morbidity,
mortality and health costs in different clinical scenarios and dis-
eases, including heart failure, myocardial infarction, lung diseases,
stroke, cancer, cirrhosis, pulmonary embolism and hypertension,
chronic renal failure and the postoperative period [6e25]. The
* Corresponding author. Servei de Pneumologia, Hospital del Mar, Passeig Mar-
ítim, 25-29, E-08003, Barcelona, Spain.
E-mail address: jgea@parcdesalutmar.cat (J. Gea).
and headaches. However, as sodium levels further decrease, sei-
zures, altered mental status, coma or even death can also occur.
Therefore, the etiologic diagnosis and treatment of this condition is
a challenge for health professionals [26]. Nevertheless, the preva-
lence of hyponatremia in the general population is estimated at
1e2%, and is also associated with increased mortality [27,28]. This
association raises the question of whether hyponatremia may
independently contribute to mortality or if it is just a bad prog-
nostic marker in advanced diseases [29]. Chronic obstructive pul-
monary disease (COPD) is also a major cause of morbidity and
mortality worldwide [30,31], especially due to acute exacerbations
[32e36]. In fact, COPD exacerbations requiring hospitalization are
one of the major contributors to the all-cause mortality in hospitals
[37]. Hyponatremia can occur in COPD patients as a manifestation
of secondary water retention in comorbidities such as heart or renal

http://dx.doi.org/10.1016/j.rmed.2016.05.003
0954-6111/© 2016 Elsevier Ltd. All rights reserved.
238 R. Chalela et al. / Respiratory Medicine 117 (2016) 237e242
failure. In addition, as in other lung diseases, hyponatremia can
appear as a consequence of different drug treatments, adrenal
insufficiency (i.e. corticosteroid withdrawal) or a syndrome of
inappropriate secretion of antidiuretic hormone (SIADH), recently
renamed as the syndrome of inappropriate antidiuresis (SIA)
[38e40]. However, the mechanism of development of hypona-
tremia in either stable or exacerbated COPD patients still remains
incompletely understood [41]. Moreover, the prevalence of hypo-
natremia and its impact on morbi-mortality in such patients has
not yet been established. The aim of the present study was to assess
the frequency of hyponatremia in patients with COPD exacerba-
tions requiring hospitalization, and to examine if the serum sodium
level at admission is associated with morbidity and mortality in
such patients.
2. Methods
This was an observational and prospective study conducted
between January 2014 and July 2015 in a teaching hospital to assess
the frequency of hyponatremia and its relationship with in-hospital
morbidity and mortality, and all-cause mortality within the 90 days
after discharge. Hyponatremia was defined as an initial serum so-
dium level of less than 135 mEq/L, after correction for the presence
of hyperglycemia using the equation described by Hillier et al. [42].
In those patients showing hyponatremia, this was rated according
to the classification proposed by Spasovski et al. (mild,
130e134 mEq/l; moderate, 125e129 mEq/l; and severe, <125 mEq/
l) [43].
2.1. Patients
All COPD patients aged 40 years or older, requiring hospitali-
zation due to an exacerbation were consecutively included. The
diagnosis of COPD was always confirmed by a respiratory medicine
specialist using data from medical history and spirometry, ac-
cording to GOLD criteria [31], whereas exacerbation was defined as
a sustained acute worsening of the patient’s condition that required
additional treatment [44]. Patients always had an initial complete
blood test with basic metabolic panel and arterial blood gases
within 6 h of emergency arrival. Subjects with pregnancy or drug
intoxication were excluded. The study was carried out in accor-
dance with the ethical guidelines of the Declaration of Helsinki, and
was approved by the hospital’s Ethics Committee. All subjects gave
their written informed consent after being informed of the pur-
poses and details of the investigation.
2.2. Data
General and clinical data were collected at inclusion, discharge
and 90 days after leaving the hospital. These data included
anthropometric and sociodemographic characteristics, medical
past history (including Charlson’s index of comorbidity and details
from previous COPD exacerbations and hospitalizations), lung
function tests, clinical characteristics of the present exacerbation
(vital signs, physical examination, etiology, treatment), “Acute
Physiology and Chronic Health Evaluation” (APACHE II) score and
routine blood analysis (cell count, glucose, liver and renal function,
electrolytes and arterial gases). Hospital care data including dura-
tion of hospital stay, admission to an intensive care unit, mechan-
ical ventilation requirements, complications, and mortality were
also recorded. Finally, the 90-day mortality after discharge was also
assessed from clinical records, local health system reports and
phone calls.
2.3. Statistical analysis
While categorical variables were described as frequencies and
percentages, continuous variables were expressed as
mean ± standard deviation. To compare categorical variables be-
tween groups, Pearson’s Chi-Square or Fisher exact tests were used
as appropriate. The non-parametric Mann-Whitney U test was used
to assess the differences between continuous variables, whereas
the nonparametric Kruskal-Wallis test was used for those variables
categorized according to the initial sodium level.
ROC-curve exploratory analysis was performed in order to
establish different cut-off points of sodium serum level potentially
related with a higher mortality. P values equal or less than 0.05
were considered statistically significant. All analyses were per-
formed with SPSS 18.0 (IBM Corp.).
3. Results
3.1. Patient characteristics
During the recruitment period, 678 patients were admitted to
our institution with COPD exacerbation. Of these, 254 were
excluded for different causes and therefore, the remaining 424
patients were finally followed up for the study. Their mean plasma
sodium concentration was 137.8 ± 3.7 mEq/L, being 15.8% the fre-
quency of hyponatremia (14.9% in males vs. 19.2% in females). The
frequency of different electrolytic and acid-balance disturbances at
admission is shown in Table 1. Hypochloremia followed by hypo-
natremia were the most frequently observed electrolytic disorders
in our population.
Baseline characteristics of patients with and without hypona-
tremia at hospital admission can be seen in Table 2. Patients in both
groups were similar in age, sex distribution, presence of previous
exacerbations and hospitalizations, the overall severity index
(APACHE II), and most of the comorbidities and lung function pa-
rameters. However, patients with hyponatremia showed lower
weight and BMI and less occurrence of sleep apnea than those
without this serum abnormality. With regards to respiratory
function, patients with hyponatremia showed less severe air trap-
ping, hypercapnia and DLco impairment than the other group. The
use of drugs with potential effects on sodium levels was very
similar in both groups, with the use of diuretics being 17% in the
hyponatremic patients.
Using calculation of plasma osmolarity, hyponatremia was
classified as hypotonic, which was observed in the vast majority of
patients (91%), whereas isotonic hyponatremia accounted for the
others. No patient showed an increased osmolarity. Among those
patients with hypotonic hiponatremia, normovolemic characteris-
tics were predominant (64% of all patients), followed by hyper-
volemic and hypovolemic ones (14 and 12%, respectively).
Pneumonias were present in one quarter of the patients with
Table 1
Prevalence of electrolytic and acid-balance disorders at admission.
Type of disorder Prevalence, n (%)
Hypochloremia 110 (25.9)
Hyperchloremia 16 (3.8)
Hyponatremia 67 (15.8)
Hypernatremia 4 (0.9)
Hypokalemia 10 (2.4)
Hyperkalemia 21 (5.0)
Respiratory acidosis 94 (22.2)
Respiratory alkalosis 86 (20.3)
Metabolic acidosis 11 (2.6)
Metabolic alkalosis 10 (2.4)
 R. Chalela et al. / Respiratory Medicine 117 (2016) 237e242 239

normovolemic hyponatremia. Hypervolemic hyponatremias in 4. Discussion

turn, were mostly associated with heart failure and only in one case
to a mild renal failure. Finally, hypovolemic hyponatremias
appeared mostly in patients treated with diuretics.
Regarding the evolution of hyponatremia, the vast majority of
patients corrected this electrolyte abnormality with treatment
within the first 48 h of admission (81%). From the remaining pa-
tients, only 6% persisted with low sodium levels either at their
death or the time of discharge.
3.2. Hyponatremia and hospital care outcomes
Pneumonia was the only concomitant diagnosis that was more
frequent in hyponatremic than in non-hyponatremic individuals
(Table 3). Furthermore, COPD patients with abnormally low plasma
sodium levels showed poorer outcomes in terms of hospital care
(Table 4). Their hospitalization length, mechanical ventilation re-
quirements, in-hospital deaths and all-cause deaths during the
months following hospitalization were higher than those of non-
hyponatremic patients. The only exception was the rate of new
exacerbations and hospitalizations during this same period that
was similar. Moreover, the severity of hyponatremia had impact on
most of the outcomes analyzed when patients were subdivided
according to their sodium serum levels (Table 5).
3.3. Cut-off point of sodium serum level related with higher
mortality
ROC-curves were used to establish the best threshold for sodium
serum levels with respect to a higher mortality. Interestingly,
although the commonly accepted lower value for normality, a 135-
mEq/L cut-off, showed no discrimination power for mortality, so-
dium levels lower than 129.7 mEq/L did. As much as 22.2% of pa-
tients with values below this threshold died, in comparison with
only 1.6% in the other group (p < 0.001).
The results of the present study clearly demonstrate that the
presence of hyponatremia at the time of hospitalization for a COPD
exacerbation is relatively common and associates with a worse
clinical course. Indeed, patients with this electrolytic disorder show
a longer hospital stay, greater needs for ventilatory support and are
more likely to die, both during hospitalization and in the months
following discharge. In many of these outcomes, a worse outcome
was directly related with the severity of the electrolytic disorder.
The frequency of hyponatremia in the patients included in this
study is higher than that reported in the general population [27],
although within the wide range previously described by other au-
thors in patients hospitalized for different conditions [45e49]. As
already mentioned, these broad limits are probably the conse-
quence of the differences in the populations included and the
diagnostic criteria.
A still controversial point is whether hyponatremia is the factor
that leads to a worse prognosis, or simply a surrogate for disease
severity [27,50,51] However, it should be noted that the risk of
death associated with hyponatremia is very high, even in subjects
without known comorbidities [27]. In the case of COPD, severity
classification is commonly based on lung function, although in
recent years additional elements such as the presence of exacer-
bations, severity of symptoms, body weight or exercise capacity
have been added [31,52,53]. However, in the present study the level
of FEV1 impairment, the number of exacerbations in the previous
year, the APACHE II index and most of comorbidities were similar in
both groups of patients. However, subjects with hyponatremia
showed a lower weight and BMI but still within normal limits. This
may be related to the lower presence of sleep apnea syndrome also
observed in these patients.
Regarding new cardiovascular events, which appear to be one of
the associations with greater presence and impact in the clinical
outcomes of patients with other diseases [54e59], their occurrence

Table 2
Comparisons of general and clinical characteristics at hospital admission.

Variable Non-hyponatremic patients n ¼ 357 Hyponatremic patients n ¼ 67 p value

General characteristics
- Age, yrs 71 ± 10.3 69.9 ± 10.9 0.41
- Male, n (%) 279 (78.6) 49 (73.1) 0.33
- Weight, kg 74.8 ± 16.9 68.1 ± 13 0.00
- Body mass index, kg/m2 27.4 ± 6.2 25.0 ± 4.7 0.01
- Admissions (prior year) 1.9 ± 2.4 1.7 ± 2.4 0.58
- Exacerbations (prior year) 2.2 ± 3.1 1.9 (±2.4) 0.80
- Charlson score 5.0 ± 2.6 5.5 ± 2.5 0.16
- Comorbidities, n (%)
Diabetes mellitus 113 (31.7) 20 (29.9) 0.77
Chronic kidney disease 40 (11.2) 5 (7.5) 0.36
Cardiovascular disease 128 (35.9) 23 (34.3) 0.81
Dyslipidemia 167 (46.8) 35 (52) 0.41
Arterial hypertension 221 (61.9) 39 (59.1) 0.67
Obstructive sleep apnea 74 (20.7) 7 (10.4) 0.05
Cancer 31 (8.7) 7 (10.4) 0.64
- APACHE II 13.3 ± 4.8 13.3 ± 4.3 0.69
Lung function tests
- FEV1, % ref. 37.9 ± 16.9 40.9 ± 18.3 0.22
- TLC, % ref. 98.7 ± 22.5 99.8 ± 13.3 0.46
- RV/TLC, % 62.4 ± 10.5 57.7 ± 10.3 0.01
- DLco, % ref. 43.0 ± 19.9 48.0 ± 18.5 0.06
Blood analyses
- Potassium, mEq/L 4.5 ± 0.5 4.5 ± 0.6 0.20
- Chloride, mEq/L 99.3 ± 5.4 94.5 ± 5.5 0.00
- Arterial bicarbonate, mmol/L 32.8 ± 20.4 29.8 ± 8.0 0.01
- pH 7.39 ± 0.07 7.41 ± 0.09 0.01
- PaO2/FIO2, mm Hg 276 ± 71.6 261 ± 42.9 0.57
- PaCO2, mm Hg 52.2 ± 18 48.4 ± 19 0.01
240 R. Chalela et al. / Respiratory Medicine 117 (2016) 237e242

Table 3
Concomitant diagnoses during admission.

Variable Non-hyponatremic patients n ¼ 357 Hyponatremic patients n ¼ 67 p value

Congestive heart failure 52 (14.6) 9 (13.4) 0.81

New onset atrial fibrillation 8 (2.2) 2(3.0) 0.66
Other cardiac arrhythmias 70 (19.6) 14 (20.9) 0.81
Acute renal failure 49 (13.7) 14 (20.9) 0.13
Pseudomonas aeruginosa airway infection 80 (22.4) 15 (22.4) 0.99
Pneumonia 50 (14) 18 (26.9) 0.01

Table 4
Hyponatremia and clinical outcomes.

Variable Non-hyponatremic patients n ¼ 357 Hyponatremic patients n ¼ 67 p value

Hospital stay, days 7.7 ± 4.6 12.8 ± 8.6 <0.001

Invasive mechanical ventilation, days (%) 0.04 ± 0.4 (1.4) 0.49 ± 2.6 (6.0) 0.02 (0.04)
Non-Invasive mechanical ventilation, days (%) 0.35 ± 0.9 (16.2) 0.84 ± 2.8 (16.4) 0.85 (0.98)
Admissions within 90 d after discharge, n 1.5 ± 1.9 1.9 ± 1.9 0.13
Exacerbations within 90 d after discharge, n 1.4 ± 1.9 1.5 ± 1.9 0.46
In-hospital deaths, n (%) 9 (2.5) 5 (7.5) 0.05
All-cause death at 90 days, n (%) 40 (11.2) 14 (20.9) 0.03

Table 5
Severity of hyponatremia and main clinical outcomes.

Initial sodium level (mEq/L) P value

<125 125e129 130e134 >134

Endotracheal intubation NO 4 (100%) 7 (87%) 52 (95%) 352 (99%) 0.04

YES 0 (0%) 1 (13%) 3 (5%) 5 (1%)
Days e 0.38 ± 0.10 0.55 ± 0.29 0.04 ± 0.04 0.04
Hospital stay Days 18.7 ± 11.8 16.8 ± 11.5 11.9 ± 7.8 7.7 ± 4.6 <0.001
Death during hospitalization NO 3 (75%) 7 (88%) 52 (94%) 348 (97%) 0.03
YES 1 (25%) 1 (12%) 3 (6%) 9 (3%)
Death 90 days after discharge NO 2 (50%) 6 (75%) 45 (82%) 317 (89%) 0.03
YES 2 (50%) 2 (25%) 10 (18%) 40 (11%)

was not higher in our hyponatremic COPD patients when compared
with non-hyponatremic. However, chronic heart failure was pre-
sent in most of the patients showing hypotonic-hypervolemic
hyponatremia. Our results also indicate the lack of differences be-
tween hyponatremic and non-hyponatremic groups for new COPD
exacerbations or hospitalizations. However, this was probably due,
at least in part, to the observed increased mortality in patients with
hyponatremia.
An aspect of particular interest from a clinical point of view is
that the cut-off of plasma sodium that showed the better
discriminatory power to predict the risk of mortality corresponds
to a marked hyponatremia. Therefore, these are the patients who
should be most carefully monitored during hospitalization. In
contrast, previous studies, such as that of Mohan et al. [27], found
no clear serum sodium threshold for the prediction of adverse
clinical events. Nevertheless, a still unresolved issue is the likely
impact of the correction of hyponatremia on clinical outcomes,
since there are no intervention studies on either hospitalized pa-
tients in general, or on individuals with specific disorders. However,
given the deleterious associations repeatedly observed in different
clinical conditions, it seems advisable to monitor hyponatremic
patients, and initiate measures aimed at the normalization of
plasmatic sodium.
Since there were no clinical signs of hypovolemia, urea plasma
levels were within normal ranges and only a small portion of pa-
tients showed edema or other indicators of volume overload, it is
reasonable to conclude that the predominant hypotonic hypona-
tremia (91%) was a normovolemic disorder in most cases (64%).
4.1. Study limitations
The present study does not allow us to clearly establish the
actual cause of hyponatremia. However, low osmolarity was pre-
sent in the vast majority of patients. Most of them showed signs of
normovolemia, which might be attributed to the presence of SIADH
(or SIA). Although it was impossible to get data on the level of ADH
or measured urine osmolality to confirm the etiology in our pa-
tients, it is very well established that abnormalities in the secretion
or action of this hormone may occur with relative frequency in
patients with parenchymal lung diseases (even though this does
not involve a well-defined SIADH in many cases) [60,61]. Our hy-
pothesis is reinforced by the higher prevalence of pneumonia
observed in patients belonging to the normovolemic hyponatremia
group. Hypervolemic hyponatremias in turn, could be attributable
to the concomitant heart or renal failure, whereas diuretic treat-
ment could have accounted for hypovolemic electrolyte abnor-
mality. By contrast, the use of other treatments that can modify
sodium levels, such as angiotensin-converting-enzyme (ACE) in-
hibitors, angiotensin sodium level receptor blockers (ARBs) and/or
serotonin-specific reuptake inhibitors (SSRIs) was similar for the
two main groups of patients. No data are available on the pituitary-
adrenal axis, which does not allow us to completely rule out ad-
renal insufficiency as a cause of hyponatremia. However, the blood
test was made in the first 6 h (before steroid use) and previous
exacerbations/hospitalizations were similar.
Finally, the relative low prevalence of women with COPD in our
geographical area does not allow us to draw clear conclusions about
the potential differential relevance of hyponatremia in female
 R. Chalela et al. / Respiratory Medicine 117 (2016) 237e242
patients. Previous studies suggest that at least in the general pop-
ulation, women show a higher presence of hyponatremia than men.
In conclusion, patients admitted with exacerbation of COPD
associating hyponatremia have a worse clinical course. More spe-
cifically, they show longer hospital stays, greater need for me-
chanical ventilation and an increased mortality rate (both in
hospital and the months following discharge). The increase in
mortality is especially evident in those cases of severe hypona-
tremia. Therefore, it seems convenient to monitor hyponatremic
patients, to determine the specific etiology and, although inter-
ventional studies are still needed, to normalize plasmatic levels of
sodium as soon as possible.
Acknowledgments
To Jonathan McFarland for his editing help. Funded by Plan

n Científica, Desarrollo e Innovacio
Nacional de Investigacio
n Tec-

gica. MINECO. SPAIN (ref. SAF2011-26908 & SAF2014-54371).
nolo
Transparency document
Transparency document related to this article can be found
online at http://dx.doi.org/10.1016/j.rmed.2016.05.003.
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