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Outcome Differences in Community- versus Hospital-Acquired
Hyponatremia in Patients with a Diagnosis of Heart Failure
Shchekochikhin et al: Community vs. Hospital-Acquired Hyponatremia in HF
Dmitry Y. Shchekochikhin, MD1; Robert W. Schrier, MD1;
JoAnn Lindenfeld, MD1; Lori Lyn Price, MAS2;
Bertrand L. Jaber, MD2; Nicolaos E. Madias, MD2
1University of Colorado, 2Tufts Medical Center
Correspondence to Robert W. Schrier, MD University of Colorado Division of Renal Diseases and Hypertension 12700 East 19th Avenue, C281 Aurora, CO 80045 Phone: 303-724-4837 Fax: 303-724-4686 Email: [email protected] DOI: 10.1161/CIRCHEARTFAILURE.112.000106 Journal Subject Codes: Heart failure [10], Cardio-renal physiology/pathophysiology
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Abstract
Background—Hyponatremia at hospital admission is a well-known risk factor of morbidity
and mortality in patients with heart failure (HF). However, there are few data about
hyponatremia developing during hospitalization in patients with HF. The present study
compares hospital-acquired hyponatremia (HAH) with community-acquired hyponatremia
(CAH) in HF patients with respect to outcome.
Methods and Results—5,347 consecutive hospitalized patients with a diagnosis of HF were
analyzed. CAH was defined as a serum sodium value of 135 mEq/L or less at the time of
hospital admission. HAH was defined as development of a serum sodium level of 135 mEq/L
or less during hospitalization in the setting of a serum sodium value above 135 mEq/L on
admission. In-hospital mortality, LOS), worsening kidney function, and discharge to short-
/long-term care facilities were analyzed. CAH and HAH were identified in 1,039 patients
(19.4%) and in 1,302 patients (24.4%) of the 5,347 patients admitted, respectively. Both types
of hyponatremia were associated with increased mortality, LOS, rate of discharge to short-
/long-term care facilities, and worsening kidney function. In-hospital mortality did not differ
between CAH and HAH, but differences in demographics and comorbidities were present.
Conclusions—The present results identified HAH as a risk factor for increased mortality in
HF as has been previously described for CAH. HAH was associated with increased LOS,
discharge to short-/long-term care facilities, and development of cardio-renal failure. Thus,
hyponatremia in hospitalized patients with a diagnosis of HF, either on admission or during
hospitalization, is a prognostic marker for poor outcomes.
Key Words: hyponatremia, heart failure, renal disease
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,302 patients (24.4%) of the 5,347 patients admitted, respectivel
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There are nearly one million hospitalizations each year in the United States for acute
decompensated heart failure (HF). Patients with a hospitalization for decompensated HF have
a poor prognosis. In-hospital mortality occurs in 3% to 4% of these patients, and 60- to 90-
day post-discharge mortality and re-hospitalization rates have been reported to be 35% to
50% (1-5). Hyponatremia, defined as a serum sodium concentration of 135 mEq/L or less
(6,7), is the most common electrolyte disorder among hospitalized patients, occurring in 15%
to 22% of admissions. It is a frequent finding in patients with HF, with prevalence rates
ranging from 8% to 28%, depending on HF severity (8-11).
Hyponatremia in patients with HF at hospital admission is an important marker
for hemodynamic deterioration, prolonged hospital stay, and higher rates of re-hospitalization
(12-15). Moreover, hyponatremia is a marker for increased short-term and long-term
mortality in patients with HF (4,16-29). In the OPTIMIZE-HF registry, a mortality risk
increase was observed at admission serum sodium levels lower than 130 mEq/L (4).
To date, however, data are scarce for hospital-acquired hyponatremia in patients
with HF. In a large single-center cohort study, community- and hospital-acquired
hyponatremia in unselected hospitalizations was associated with increased hospital length of
stay (LOS), increased in-hospital mortality, and increased rate of discharge to a short- or a
long-term care facility (30). The objective of our current study was to further characterize and
compare in-hospital outcomes of patients with HF and hospital-versus community-acquired
hyponatremia in the parent cohort, in terms of in-hospital mortality, worsening kidney
function, and among survivors, hospital LOS and discharge disposition to home setting or
short-/long-term care facilities.
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ents with HF (4,16-29). In the OPTIMIZE-HF regist , a mortali
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Methods
Data Source
This was a single-center retrospective cohort study utilizing a dataset that contained fully de-
identified hospital discharges at a community-based tertiary acute care facility (St.
Elizabeth’s Medical Center, Boston, Massachusetts) over a 7-year period (2000-2007).
Information was provided on patient’s age, sex, race, admission service, and up to 15
International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM)
diagnosis codes. The discharge file was linked with the hospital’s electronic laboratory
database, which allowed extraction of serum sodium values for the corresponding
hospitalization. Only hospitalizations with a diagnosis of HF were considered for the current
analysis. Institutional Review Board approval was obtained.
Hyponatremia Definitions
Community-acquired hyponatremia was defined as a serum sodium value of 135 mEq/L or
less at the time of hospital admission (either on the day of or prior to admission). Hospital-
acquired hyponatremia was defined as development of a nadir serum sodium level of 135
mEq/L or less during hospitalization in the setting of a serum sodium value above 135 mEq/L
on admission.
Owing to the confounding effect on serum sodium of water translocated from
cells to the extracellular fluid with hyperglycemia, serum sodium values were adjusted
upward by 2 mEq/L for each 100-mg/dL increment in serum glucose above 100 mg/dl
(31,32).
Outcomes of Interest
In-hospital mortality, hospital LOS, worsening kidney function, and patient disposition were
evaluated. Worsening kidney function was defined as an increase in serum creatinine equal
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uired hyponatremia was defined as a serum sodium value of 1
utioioioioonananananal lll ReReReReReviiiiieeewee Board approval wwwawawass obtaineddddd.
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to or greater than 0.3 mg/dl using the difference between the peak and nadir (see below) value
during hospitalization, in accordance with a previously published method. For disposition
status, the event of interest was discharge to a short- or long-term care facility; discharges to
home and departures from the hospital against medical advice comprised the reference
category. Hospitalizations during which the patient died were excluded from analyses
examining LOS and discharge disposition status.
Description of Covariates
The Deyo-Charlson Comorbidity Index was used to assess comorbidities. (33,34). This index
incorporates a patient’s history of comorbidities using ICD-9-CM diagnosis codes, with
increasing numerical values reflecting greater comorbidity. For each hospitalization, the
Deyo-Charlson Comorbidity Index was used to generate a score, and hospitalizations were
categorized based on scores of 0 through 3 or higher. Presence of acute respiratory infections
(ICD-9-CM diagnosis codes 460–466), pneumonia and influenza (ICD-9-CM codes 480–
488), psychosis (ICD-9-CM diagnosis codes 290–299), neurotic disorders, personality
disorders, and other nonpsychotic mental disorders (ICD-9-CM diagnosis codes 300–316),
and malignant neoplasm of respiratory and intrathoracic organs (ICD-9-CM diagnosis codes
160-165) were used as additional covariates due to their potential confounding effect on
serum sodium concentration.
The baseline serum creatinine was defined as the nadir value recorded in the first
3 days of hospitalization (35). Using this baseline serum creatinine, the baseline estimated
glomerular filtration rate (eGFR) was calculated using the CKD-EPI equation (36).
Statistical Analyses
Continuous variables are described as means (with standard deviations) or medians (with
25th and 75th percentiles) as appropriate. Categorical variables are expressed as frequencies
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gnosis codes 460–466), pneumonia and influenza (ICD-9-CM
(ICD 9 CM diagnosis codes 290 299), neurotic disorders, perso
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gnosis codes 460–464646466)6)6)6)6), , , ,, pnpnpnpnpneueuueuumommm niniia a a a anananananddd dd ininnnnflflflflueueueueuenznznznznza (ICD-9-CM co
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(with percentages). For continuous variables, comparisons between groups were made by the
t-test and analysis of variance (ANOVA) for normally distributed data, and by the Wilcoxon
rank sum test and Kruskal-Wallis test for non-normally distributed data, and for categorical
variables by the Chi square test.
We constructed a restrictive cubic spline to ascertain the crude relationship
between the admission serum sodium (145 mEq/L or less) and in-hospital mortality. The
independent association of the hyponatremia subtypes (community-, and hospital-acquired)
with in-hospital mortality, worsening kidney function, hospital LOS, and discharge to a short-
or long-term care facility were evaluated after adjustment for age, sex, race, admission
service, and comorbidities, as measured by the Charlson-Deyo comorbidity index.
Multivariable logistic regression was used to evaluate the association between hyponatremia
subtype and the outcomes of in-hospital death, worsening kidney function, and discharge to
short-/long-term care facility, while negative binomial regression was used to evaluate the
association between hyponatremia subtype and LOS in days. The odds ratio generated by this
analysis reflects the proportional change in the LOS compared with the reference category.
Patients who died in the hospital were excluded from all analyses involving discharge
disposition and LOS. To explore the consistency of the findings, sensitivity analyses were
performed that were restricted to hospitalized subjects with a primary diagnosis of HF, based
on ICD-9 CM diagnosis code ranking, as well as to subjects with a primary diagnosis of HD
and hospitalization on the cardiology service. All of the analyses were generated using SAS
version 9.2 (Cary, NC). The restrictive cubic spline was generated in R version 2.11 (Free
Software Foundation, Boston). P < 0.05 was considered statistically significant.
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gistic regression was used to evaluate the association between hy
outcomes of in-hospital death, worsening kidney function, and d
care facility, while negative binomial regression was used to e a
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care facility, whillleeeee nennenn gagggg tive bbbinomomomomiaiaial lll l reregrggg ession was used to eva
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Results
Analytic Dataset
There were 97,472 hospitalizations during the 7-year study period, representing 51,207
subjects (30). 84,042 hospitalizations (representing 47,301 subjects) were excluded upfront
for any of the following reasons: absence of a diagnosis of HF (ICD-9 code 428.xx), or being
admitted to one of the following services: Newborn, Obstetrics, Psychiatry, Neonatology, or
missing data on service. Of the remaining 13,430 hospitalizations, which represented 7,042
subjects, 4,606 subjects experienced a single hospitalization. For the remaining 2,436
subjects who were hospitalized more than once, the first hospitalization was selected. Among
these 7,042 subjects, 1,695 were excluded due to absence of admission serum sodium
measurement (n = 1,383) or because the admission serum sodium value was >145 mEq/l (n =
312). The final analytic dataset thus comprised 5,347 subjects with a diagnosis of HF.
Approximately 30% of patients were discharged within 3 days of admission. Nadir-to-peak
serum creatinine could be calculated on 89% of patients (n = 4764).
Community-Acquired Hyponatremia vs. Normonatremia
Community-acquired hyponatremia was identified in 1,039 patients with a diagnosis of HF
(19.4%). Median serum sodium in this group was 133 mEq/l (131,135). Community-acquired
hyponatremia patients did not differ significantly from normonatremic patients in terms of
age and sex, but there was a significant difference in racial breakdown (P = 0.0003) (Table 1).
Patients with a diagnosis of HF and community-acquired hyponatremia had a higher
prevalence of comorbidities, as evidenced by a higher mean Deyo-Charlson comorbidity
index (P = 0.0001). Community-acquired hyponatremia was associated with increased in-
hospital mortality (9.7% vs. 5.7%; P < 0.0001), prolonged LOS (median 6 days [4,10] vs. 4
days [3, 7]; P < 0.0001) and increased discharge to short-/long-term care facility (48.6% vs.
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30% of patients were discharged within 3 days of admission. Nad
could be calculated on 89% of patients (n = 4764).
= 11111,333338383838383))))) orrrrr bbbbbecause the admissiooooonn serum sooooodiumumumumum value was >14
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40.4%; P < 0.0001) (Table 2). The Figure displays the restrictive cubic spline examining the
crude relationship between admission serum sodium (145 mEq/L or less) and in-hospital
mortality. As shown in the Figure, a U-shaped relationship was observed, with a serum
sodium value of 140 mEql/L associated with the lowest mortality risk.
Hospital-Acquired Hyponatremia vs. Normonatremia
Hospital-acquired hyponatremia was identified in 1,302 patients with a diagnosis of HF
(30.2% of the 4,308 normonatremic patients at admission). Median serum sodium in this
group was 134 mEq/L (132-135) and median time for developing hospital-acquired
hyponatremia was 4 days (2-8). Patients with a diagnosis of HF and hospital-acquired
hyponatremia were younger, more likely to be male, and more likely to be non-white
compared to normonatremic patients. However, patients with hospital-acquired hyponatremia
had more comorbidities, as evidenced by a higher Deyo-Charlson comorbidity index (P =
0.0001; Table 1). As with community-acquired hyponatremia, mortality, LOS, and discharge
to short-/long-term care facilities were increased in patients with HF and hospital-acquired
hyponatremia (Table 2) compared to normonatremic patients with HF.
Community-Acquired Hyponatremia vs. Hospital-Acquired Hyponatremia
There were some differences among patients with a diagnosis of HF and community- vs.
hospital-acquired hyponatremia. Compared with hospital-acquired hyponatremia, patients
with a diagnosis of HF and community-acquired hyponatremia tended to be older (75.9 ±
12.4 vs. 74.6 ± 12.0, P = 0.01), and were more likely to be women (55.3% vs. 48.0%, P =
0.0005) (Table 1). Significantly more patients with a diagnosis of HF and community-
acquired hyponatremia were admitted to the medical service (94.4% vs. 86.6%, P < 0.0001).
Patients with a diagnosis of HF and hospital-acquired hyponatremia had a significantly higher
Deyo-Charlson comorbidity index (2.4 ± 1.5 vs. 2.3 ± 1.6; P = 0.03), with more patients
having a score of 3 or more (34.5% vs. 28.9%; p =0.004) compared to patients with a
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monatremic patients. However, patients with hospital-acquired h
bidities, as evidenced by a higher Deyo-Charlson comorbidity in
. As with community-acquired hyponatremia, mortality, LOS, an
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diagnosis of HF and community-acquired hyponatremia. Patients with hospital-acquired
hyponatremia had a higher prevalence of low baseline eGFR of less than 60 mL/min/1.73 m2
(7.8% vs. 5.6%; p=0.03) and a history of myocardial infarction (37.1% vs. 23.8%; p<0.0001).
In-hospital mortality was increased in both hyponatremic groups compared to
normonatremic patients with a diagnosis of HF. However, there was no statistically
significant difference in mortality between these hyponatremic subtypes (9.7% vs. 9.1%, P =
0.58). Patients with hospital-acquired hyponatremia had increased hospital LOS compared to
patients with community-acquired hyponatremia (9 days [5, 14] vs. 6 days [4, 10], P <
0.0001) and were more likely to be discharged to long/short term care facilities (54.7% vs.
48.6%, P = 0.0005).
Worsening Kidney Function
As shown in Table 2, 41.4% of patients with a diagnosis of HF and community-acquired
hyponatremia experienced in-hospital worsening kidney function, compared to 55.4% among
patients with hospital-acquired hyponatremia, and 30.0% among those who were
normonatremic (P < 0.0001). Worsening kidney function was associated with increased
hospital LOS in all 3 groups (normonatremia 7 [4,11] vs. 4 [3,7],p<0.0001; community-
acquired hyponatremia 10 [6,14] vs. 6 [4,8] p<0.0001; hospital-acquired hyponatremia 11
[7,18] vs. 7 [5,10], p<0.0001).
Multivariable Analyses
After adjustment for age, sex, race, hospital service, and the Deyo-Charlson comorbidity
index, patients with a diagnosis of HF and either community- or hospital-acquired
hyponatremia had a higher risk of in-hospital mortality compared with normonatremic
patients with a diagnosis of HF, with an adjusted odds ratio of 1.7 (95% CI 1.3, 2.3) and 1.6
(95% CI 1.3, 2.1), respectively (Table 3). In addition, patients with a diagnosis of HF and
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xperienced in-hospital worsening kidney function, compared to 5
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either community- or hospital-acquired hyponatremia experienced a heightened likelihood of
discharge to a short- or long-term care facility ([adjusted OR 1.4; 95% CI 1.2, 1.7]; and [1.8;
95% CI 1.6, 2.1], respectively) compared to normonatremic patients with a diagnosis of HF.
Patients with community- or hospital-acquired hyponatremia had an increased likelihood of
LOS prolongation (adjusted OR 1.4 [1.201-7] and 1.8 [1.6, 2.1], respectively). Both
community-acquired and hospital-acquired hyponatremia were associated with worsening
kidney function (1.6 [1.3, 1.9] and 2.7 [2.3, 3.1], respectively). All these effect estimates
remained significant after expanding the multivariable models with the addition of several
covariates, including presence of psychosis, mental illness, and pneumonia/influenza (Table
3).
Sensitivity Analyses
After adjustment for age, sex and the Deyo-Charlson comorbidity index, these multivariable
associations persisted on sensitivity analyses restricted to hospitalized patients with a primary
diagnosis of HF, based on ICD-9 CM diagnosis code ranking (Table 3), as well as among
patients with a diagnosis of HF hospitalized on the cardiology service (data not shown). Of
note, hospitalized patients with a primary diagnosis of HF did not significantly differ in terms
of demographic characteristics compared to patients with a non-primary diagnosis of HF
(Table 4). However, patients with a primary diagnosis of HF had significantly fewer
comorbitities, as evidenced by a lower Deyo-Charlson comorbidity index, and specific
comorbitities, such as myocardial infarction, cerebrovascular disease, liver disease,
malignancies, and neurologic and psychiatric illnesses, as well as acute respiratory infections.
By contrast, patients with a primary diagnosis of HF had more advanced stages of chronic
kidney disease (eGFR < 60 ml/min/1.73 m2). In-hospital mortality was significantly lower in
patients with a primary diagnosis of HF compared to patients with a non-primary diagnosis of
HF (2.4% vs. 7.3%), which might have been due in part to the presence of fewer
yses
t for age, sex and the Deyo-Charlson comorbidity index, these m
sisted on sensitivity analyses restricted to hospitalized patients w
based on ICD 9 CM diagnosis code ranking (Table 3), as well a
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comorbidities.
Discussion
In the present sub-analysis of 5,347 hospitalized patients with a diagnosis of HF, we
demonstrate that hospital-acquired hyponatremia is even more common than community-
acquired hyponatremia. Moreover, similar to community-acquired hyponatremia, hospital-
acquired hyponatremia is associated with poor outcomes compared to patients with a
diagnosis of HF who are normonatremic at hospital admission. Our study is the first to
analyze the implications of hospital-acquired hyponatremia in patients with a diagnosis of HF
in juxtaposition with the community-acquired hyponatremic cohort.
In agreement with previous reports (2,4,8), the prevalence of community-acquired
hyponatremia in hospitalized patients with a diagnosis of HF in our study was 19.4%.
Notably, no less than 30.2% of our patients developed hospital-acquired hyponatremia, for an
aggregate prevalence of 49.6%. Thus, more than half of the hyponatremic cases in
hospitalized patients with a diagnosis of HF are hospital acquired. Both hyponatremic cohorts
fared worse than their normonatremic counterpart. Compared to each other, the hospital-
acquired hyponatremia cohort had the same poor prognosis as the community-acquired
hyponatremia cohort in terms of hospital mortality, but had a longer median LOS and more
discharges to special-care facilities. The data indicate that both hyponatremic presentations in
patients with a diagnosis of HF are independently associated with increased in-hospital
mortality and heightened resource consumption.
Hyponatremia in HF is dilutional in nature and is termed hypervolemic
hyponatremia. With a decrease in cardiac output the arterial stretch baroreceptors in the
carotid sinus and aortic arch are unloaded (15).Thus, the normal tonic inhibitory effect to the
atients with a didiiiiiiaa
hort.
greement with previous reports (2,4,8), the prevalence of comm n
hospitalized patients with a diagnosis of HF in our study was 9
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central nervous system via the vagus and glossopharyngeal nerves is removed with a resultant
increase in sympathetic efferent activity. In turn, increased sympathetic activity is associated
with stimulation of the renin-angiotensin-aldosterone system (RAAS) and the non-osmotic
release of arginine vasopressin (AVP) (37). The resultant systemic and renal vasoconstriction,
as well as the sodium and water retention, attenuate the arterial underfilling, but ultimately at
the expense of hyponatremia, pulmonary congestion, and diminished kidney function. In
addition to the proposed baroreceptor-mediated arterial underfilling stimulating AVP, direct
central effects of the sympathetic and renin-angiotensin systems on AVP synthesis and release
must also be considered. More severe HF produces more severe hyponatremia (38). The
longer the duration of impaired circulation and neurohumoral activation, the more prolonged
the hyponatremia. Results of the ESCAPE trial reported community-acquired hyponatremia
in 23.8% of hospitalized patients with HF. The hyponatremia was an independent predictor of
mortality and rehospitalization even when adjusted for clinical and hemodynamic
improvements similar to those in HF patients without hyponatremia (23). In another study,
patients with HF who demonstrated persistent hyponatremia for up to 60 to 270 days after
discharge had the worst long-term survival (39).
Development of hospital-acquired hyponatremia in patients with HF could reflect
worsening hemodynamics and aggravation of neurohumoral alterations due to comorbidities
or complications during the hospital course. Medications and increased intake of electrolyte-
free water might also be implicated. In the present study patients with a diagnosis of HF and
hospital-acquired hyponatremia tended to be more ill at baseline, with more comorbitities,
including a higher prevalence of chronic kidney disease and myocardial infarction, compared
to patients with a diagnosis of HF and either normonatremia or community-acquired
hyponatremia. Approximately 15% of patients with a diagnosis of HF and hospital-acquired
hyponatremia were admitted to non-medical services as compared to 4% of normonatremic
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pitalized atients with HF. The h onatremia was an ind enden
hospitalization even when adjusted for clinical and hemodynamic
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patients and 6% of patients with community-acquired hyponatremia. Median time for
developing hospital-acquired hyponatremia was 4 days of hospitalization. In the present study
a strong association was observed between hyponatremia (both hospital-acquired and
community-acquired hyponatremia) in hospitalized patients with HF and worsening kidney
function. Not surprisingly, worsening kidney function in hynonatremic (hospital- or
community-acquired) as well as normonatremic patients with a diagnosis of HF was
associated with increased LOS. Moreover, the incidence of worsening kidney function was
increased in patients with hospital-acquired hyponatremia compared to those with
community-acquired hyponatremia (55.4% vs. 41.4%). It is likely that worsening kidney
function contributed to the development of hospital-acquired hyponatremia by aggravating
hemodynamics and neurohumoral stimulation as well as limiting the amount of filtrate that
reaches the collecting duct.
Strengths of our study include its large size encompassing a population with HF
and an array of comorbidities cared for at a single medical center. Hyponatremia was
corrected for the effect of hyperglycemia. A unique feature of the analysis was that both
community-acquired hyponatremia and hospital-acquired hyponatremia were examined and
their impact on in-hospital mortality and resource utilization was contrasted.
1. Our study has several limitations. Individual comorbidities were identified using
administrative codes that do not offer information on the severity of the corresponding
condition (with the exception of chronic kidney disease). That deficiency coupled
with the potential omission of certain comorbidities might be responsible for some
unmeasured confounding in the multivariable analyses. Nevertheless, we used a well-
validated instrument for representing the global burden of illness for each patient. In
further reference to that limitation, we did not analyze patients admitted to the
hospital because of decompensated HF but rather hospitalized patients whose codified
popopopopopoponananananananatrtrtrtrtrtrtremememememememiaiaiaiaiaiaia bbbbbbby y y y y y y agagagagagagag
g theeeeeee amamamamamamamououououououountntntntntntnt ooooooofffff fg
ngths of our study include its large size encompassing a populat o
comorbidities cared for at a single medical center. Hyponatremia
g
ccctiiiiing duct.ttt
ngths of our study iiiincncncncclude its lllargegegeg sizzzzze eeee ene compppppassing a populatio
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discharge abstract included the diagnosis code of HF. We did not use generalized
estimating equations which would have allowed us to analyze all evaluable
hospitalizations of patients with heart failure rather compared to the approach that we
adopted where we limited the analysis to the first heart-failure-associated
hospitalization per patient.
However, the strength of our conclusions is bolstered by the sensitivity analysis,
which was restricted to patients in whom the diagnosis code of HF was ranked first among
the discharge diagnoses (the primacy in the diagnostic rank being taken as a surrogate for the
severity of HF). Finally, our database is restricted to in-hospital events and, thus, we were
unable to extend our observations to events that occurred after discharge.
In conclusion, hyponatremia in hospitalized patients with a diagnosis of HF,
either present on admission or developing during the in-hospital course, is common and
independently associated with poor outcomes, including increased mortality, LOS, and
likelihood of discharge to special-care facilities. As a corollary, is this “independent
association” merely associative or causative? Indeed, the critical question is whether mild to
moderate hyponatremia in HF (as well as in other chronic disorders) is simply a prognostic
marker of poor outcomes as a reflection of the severity of the underlying condition or actually
imparts risk contributing directly to morbidity and mortality. The prevailing view favors the
former option. However, we are intrigued by the recent recognition that mild, seemingly
asymptomatic, hyponatremia is associated with attention impairment, gait instability, falls,
osteoporosis, and fractures (40). Strong evidence has been produced for the development of
osteoporosis in an experimental model of the syndrome of inappropriate antidiuresis (41). We
consider it conceivable that hyponatremia itself or associated factors (e.g., hypotonicity,
changes in cell composition and transport, increased levels of arginine vasopressin) might
impart adversity on the cardiovascular and other organ systems and thus contribute directly to
didiiiiiiscscscscscscschahahahahahahargrgrgrgrgrgrge.e.e.e.e.e.e.
onclusion, hyponatremia in hospitalized patients with a diagnosis
n m
ssociated with poor outcomes, including increased mortality, LO
charge to special-care facilities. As a corollary, is this “indepen
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ssociated with poororororr oooooutcomes,s,s, incncncn lululudiidiidingnnngn increased mortality, LO
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poor outcomes. For example, there is experimental evidence that hyponatremia impairs
cardiomyocyte function (42).
Disclosures
Dr. Schrier is a consultant for Otsuka America Pharmaceutical and Janssen Pharmaceutical.
Dr. Madias serves as a consultant for Otsuka America Pharmaceutical. Drs. Shchekochikhin,
Lindenfeld, Price, and Jaber have no disclosures to report.
Sources of Funding
Dr. Shchekochikhin’s cardiorenal fellowship was sponsored by Russian President’s
Scholarship for Studying Abroad and Gambro Ultrafiltration Solutions, Inc.
References
1. Fonarow GC, Adams KF Jr, Abraham WT, Yancy CW, Boscardin WJ. Risk stratification for in-hospital mortality in acutely decompensated heart failure: classification and regression tree analysis. JAMA. 2005; 293:572-580.
2. Cuffe MS, Califf RM, Adams KF Jr, Benza R, Bourge R, Colucci WS, Massie BM, O'Connor CM, Pina I, Quigg R, Silver MA, Gheorghiade M; Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) Investigators. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. JAMA. 2002; 287:1541-1547.
3. Gattis WA, O’Connor CM, Gallup DS, Hasselblad V, Gheorghiade M. Predischarge initiation of carvedilol in patients hospitalized for decompensated heart failure: results of the Initiation Management Predischarge: Process for Assessment of Carvedilol Therapy in Heart Failure (IMPACT-HF) trial. J Am Coll Cardiol. 2004; 43:1534-1541.
4. Gheorghiade M, Abraham WT, Albert NM, Gattis Stough W, Greenberg BH, O'Connor CM, She L, Yancy CW, Young J, Fonarow GC; OPTIMIZE-HF Investigators and Coordinators.Relationship between admission serum sodium concentration and clinical outcomes in patients hospitalized for heart failure: an analysis from the OPTIMIZE-HF registry. Eur Heart J. 2007; 28:980-988.
5. Gheorghiade M, Abraham WT, Albert NM, Greenberg BH, O'Connor CM, She L, Stough WG, Yancy CW, Young JB, Fonarow GC; OPTIMIZE-HF Investigators and Coordinators. Systolic blood pressure at admission, clinical characteristics, and outcomes in patients hospitalized with acute heart failure. JAMA. 2006; 296:2217-2226.
Russsisisisisissianan PPPPPPPrereeeeeesisissisisidededededededenn
SStttttudududududyinggggg AAAbrbrbbroad and Gambro Ultttrrafiltrar tiononononon Sollollutu ionsns,,,,, Inc.
ReReReRR fefefefferereerencncncncnceseseee
by guest on June 28, 2018http://circheartfailure.ahajournals.org/
Dow
nloaded from
6. Janicic N, Verbalis JG. Evaluation and management of hypo-osmolality in hospitalized patients. Endocrinol Metab Clin North Am. 2003; 32:459–481.
7. Upadhyay A, Jaber BL, Madias NE. Incidence and prevalence of hyponatremia. Am J Med. 2006; 119:S30 –S35.
8. Gheorghiade M, Gattis WA, O'Connor CM, Adams KF Jr, Elkayam U, Barbagelata A, Ghali JK, Benza RL, McGrew FA, Klapholz M, Ouyang J, Orlandi C; Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Congestive Heart Failure (ACTIV in CHF) Investigators.Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: a randomized controlled trial. JAMA. 2004; 291:1963–1971.
9. Gheorghiade M, Niazi I, Ouyang J, Czerwiec F, Kambayashi J, Zampino M, Orlandi C; Tolvaptan Investigators.Vasopressin V2-receptor blockade with Tolvaptan in patients with chronic heart failure: results from a double-blind randomized trial. Circulation. 2003; 107:2690–2696.
10. Konstam M, Gheorghiade M, Burnett J, Grinfeld L, Maggioni A, Swedberg K, Udelson J, Zannad F, Cook T, Ouyang J, Zimmer C, Orlandi C, for the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) Investigators. Effects of Oral Tolvaptan in Patients Hospitalized for Worsening Heart Failure: The EVEREST Outcome Trial. JAMA. 2007; 297:1319 –1331.
11. Gheorghiade M, Konstam MA, Burnett JC Jr, Grinfeld L, Maggioni AP, Swedberg K, Udelson JE, Zannad F, Cook T, Ouyang J, Zimmer C, Orlandi C; Efficacy ofVasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) Investigators. Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST clinical status trials. JAMA. 2007; 297:1332–1343.
12. Adrogue´ HJ, Madias NE. Hyponatremia. N Engl J Med. 2000; 342:1581-1589. 13. Shah MR, O’Connor CM, Sopko G, Hasselblad V, Califf RM, Stevenson LW. Evaluation
Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE): design and rationale. Am Heart J. 2001; 141:528-535.
14. Binanay C, Califf RM, Hasselblad V, O'Connor CM, Shah MR, Sopko G, Stevenson LW, Francis GS, Leier CV, Miller LW; ESCAPE Investigators and ESCAPE Study Coordinators. Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness: the ESCAPE trial. JAMA.2005; 294:1625-1633.
15. Schrier RW, Abraham WT. Hormones and hemodynamics in heart failure. N Engl J Med. 1999; 341:577-585.
16. Schrier RW, Berl T, Anderson RJ. Osmotic and nonosmotic control of vasopressin release. Am J Physiol. 1979; 236:F321-F332.
17. Cohn JN, Levine TB, Francis GS, Goldsmith S. Neurohumoral control mechanisms in congestive heart failure. Am Heart J. 1981; 102(pt 2):509-514.
18. Dzau VJ, Colucci WS, Hollenberg NK, Williams GH. Relation of the renin-angiotensin-aldosterone system to clinical state in congestive heart failure. Circulation. 1981; 63:645-651.
19. Dzau VJ, Packer M, Lilly LS, Swartz SL, Hollenberg NK, Williams GH. Prostaglandins in severe congestive heart failure: relation to activation of the reninangiotensin system and hyponatremia. N Engl J Med. 1984; 310:347-352.
20. Lilly LS, Dzau VJ, Williams GH, Rydstedt L, Hollenberg NK. Hyponatremia in congestive heart failure: implications for neurohormonal activation and responses to orthostasis. J Clin Endocrinol Metab. 1984; 59:924-930.
21. Dzau VJ. Renal and circulatory mechanisms in congestive heart failure. Kidney Int. 1987; 31:1402-1415.
aggggggggioioioioioioioninininininini AAAAAAAP,P,PPPPP SSSSSSSweweweweweweweddlandidiiiiii CCCCCCC;;;;;; EfEfEfEfEfEfEffifififififificacacacacacacaccccycy, , , y g , , ; y
n Antagonism in Heart Failure Outcome Study With Tolvaptan (t
pitalized for heart failure: the EVEREST clinical status trials. J M3J, Madias NE. Hyponatremia. N En J Med. 2000; 342:1581-1 8’Connor CM, Sopko G, Hasselblad V, Califf RM, Stevenson W.ngestive Heart Failure and Pulmonary Artery Catheterization Eff
, , , y g , , ; yn AnAnAnAnAntttttagogogogogonininiinismsmsmsmsm in Heart Failure OuOuOuOuOuttcome Studuuuu y WWiWWW th Tolvaptan (
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by guest on June 28, 2018http://circheartfailure.ahajournals.org/
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nloaded from
22. Pulignano G, Del Sindaco D, Tavazzi L, Lucci D, Gorini M, Leggio F, Porcu M, Scherillo M, Opasich C, Di Lenarda A, Senni M, Maggioni AP; IN-CHFInvestigators. Clinical features and outcomes of elderly outpatients with heart failure followed up in hospital cardiology units: data from a large nationwide cardiology database (IN-CHF Registry). Am Heart J. 2002; 143:45-55.
23. Gheorghiade M, Rossi JS, Cotts W, Shin DD, Hellkamp AS, Piña IL, Fonarow GC, DeMarco T, Pauly DF, Rogers J, DiSalvo TG, Butler J, Hare JM, Francis GS,Stough WG, O'Connor CM.Characterization and Prognostic Value of Persistent Hyponatremia in Patients With Severe Heart Failure in the ESCAPE Trial. Arch Intern Med. 2007; 167:1998-2005.
24. Lee WH, Packer M. Prognostic importance of serum sodium concentration and its modification by converting-enzyme inhibition in patients with severe chronic heart failure. Circulation. 1986; 73:257–267.
25. Krumholz HM, Chen YT, Bradford WD, Cerese J. Variations in and correlates of length of stay in academic hospitals among patients with heart failure resulting from systolic dysfunction. AmJ Manag Care. 2006; 5:715–723.
26. Kearney MT, Fox KA, Lee AJ, Prescott RJ, Shah AM, Batin PD, Baig W, Lindsay S, Callahan TS, Shell WE, Eckberg DL, Zaman AG, Williams S, Neilson JM,Nolan J.Predicting death due to progressive heart failure in patients with mild-to-moderate chronic heart failure. J Am Coll Cardiol. 2002; 50:1801–1808.
27. Rich MW, Beckham V, Wittenberg, Leven CL, Freedland KE, Carney RM. A multidisciplinary intervention to prevent the readmission of elderly patients with congestive heart failure. N Engl J Med. 1995; 333:1190–1195.
28. Lee DS, Austin PC, Rouleau JL, Liu PP, Naimark D, Tu JV. Predicting mortality among patients hospitalized for heart failure: derivation and validation of a clinical model. JAMA. 2003; 290:2581–2587.
29. Klein L, O'Connor CM, Leimberger JD, Gattis-Stough W, Piña IL, Felker GM, Adams KF Jr, Califf RM, Gheorghiade M; OPTIME-CHF Investigators. Lower serum sodium is associated with increased short-term mortality in hospitalized patients with worsening heart failure: results from the outcomes of a prospective trial of intravenous milrinone for exacerbations of chronic heart failure (OPTIME-CHF) study. Circulation. 2005; 111:2454–2460.
30. Wald R, Jaber BL, Price LL, Upadhyay Y, Madias NE. Impact of Hospital-Associated Hyponatremia on Selected Outcomes. Arch Intern Med. 2010; 170:294-302.
31. Katz MA. Hyperglycemia-induced hyponatremia: calculation of expected serum sodium depression. N Engl J Med. 1973; 289:843-844.
32. Hillier TA, Abbott RD, Barrett EJ. Hyponatremia: evaluating the correction factor for hyperglycemia. Am J Med. 1999; 106:399-403.
33. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987; 40:373-383.
34. Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol. 1992; 45:613-619.
35. Broce JC, Price LL, Liangos O, Uhlig K, Jaber BL. Hospital-acquired acute kidney injury: an analysis of nadir-to-peak serum creatinine increments stratified by baseline estimated GFR. Clin J Am Soc Nephrol. 2011; 6:1556-65.
36. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, Coresh J; CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009; 150:604-12.
ss wiwiwiwiwiwiwiththththththth mmmmmmmililililililild-d-d-d-d-d-d-tototototototo-m-m-m-m-m-m-mooooooo08. E Caaaaaaarnrnrnrnrnrnrneyeyeyeyeyeyey RRRRRRRMMMMMMM AAAA, g, , , y
nary intervention to prevent the readmission of elderly patients wetin PC, Rouleau JL, Liu PP, Naimark D, Tu JV. Predicting morta
p m
onnor CM, Leimberger JD, Gattis-Stough W, Piña IL, Felker MLower serumRM Gheorghiade M; OPTIME-CHF Investigators
, g, , , ynarararararyyyy y iiiiinteteteteterrrvenenenenention to prevent the rrrerereaadmission nnnn offfff eeeeelderly patients weeae rrrtr failureeee... N N NN EnEnEnEnEnglglglglgl JJJJJ MMMMMededededed. 199999995; 3333:3:3:3:3:11111111119090909090–1–1–119919191955. tininininin PC, RRRRRouuulleauuu JLLL,L LLLiuuuu PPPPP, NNaaimammarkkkkk DDDDD,,,,, TuTTu JJJV. PPreeeeeddiddd ctininininnggg momorttta
pitalililililizezzzezed dddd fooorr hehehehh ararttt t failililiilururure: ddddderererere iiiiivavvv titiiitionnon aaaaandndndndd vvvvvalalalllidididddatatatioionnn ofofofofof aaa clililililininiicaccall lll m; 290:2581–2587... onononnononorrr CMCMCMC ,,,, LeLeLeimimbebergrgrgggererer JJJD,D,D, GGGatatattitisss-StStStouououoo ghghggg WWW,,,,, PiPiñañaña IIIL,L,L,,, FFFelelkekerrr GMGMGM
LLowowerer ssererumumRMRM GhGhGhhheoeorgrghihihihiadadaddee M;M; OOOPTPTIMMIMEE-CHCHFF InInveveststigigigi atatororss
by guest on June 28, 2018http://circheartfailure.ahajournals.org/
Dow
nloaded from
37. Schrier RW: Body fluid regulation in health and disease: A unifying hypothesis. Ann Int Med. 1990; 113:155-159.
38. Leier CV, Dei Cas L, Metra M. Clinical relevance and management of the major electrolyte abnormalities in congestive heart failure: hyponatremia, hypokalemia, and hypomagnesemia. Am Heart J. 1994; 128:564-74.
39. Gottlieb SS, Abraham W, Butler J, Forman DE, Loh E, Massie BM, O'connor CM, Rich MW, Stevenson LW, Young J, Krumholz HM. The prognostic importance of different definitions of worsening renal function in congestive heart failure.. J. Card. Fail. 2002; 8:136-141.
40. Gankam Kengne F, Andres C, Sattar L, Melot C, Decaux G : Mild hyponatremia and risk of fracture in the ambulatory elderly. QJM 2008; 101:583–588.
41. Verbalis JG, Barsony J, Sugimura Y, Tian Y, Adams DJ, Carter EA, Resnick HE. Hyponatremia-induced osteoporosis. Journal of Bone and Mineral Research. 2010; 25:554–563.
42. Yanagi N, Maruyama T, Arita M, Kaji Y, Niho Y. Alterations in electrical and mechanical activity in Langendorff-perfused guinea pig hearts exposed to decreased external sodium concentration with or without hypotonic insult. Pathophysiology. 2001; 7:251-261.
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Table 1. Profile of hospitalized patients with heart failure according to presence or absence of hyponatremia
Variable
Normonatremia
(n = 3006)
Community-acquired hyponatremia
(n = 1039)
Hospital- acquired
hyponatremia
(n = 1302)
P-value
(Overall)
P-value (Community- vs. hospital-acquired
hyponatremia)
Age, years 76.5 ± 12.2 75.9 ± 12.4 74.6 ± 12.0 <0.0001 0.01
Female, % 55.2 55.3 48.0 <0.0001 0.0005
Race, % 0.0006 0.36
White 89.3 88.3 87.9
Black 4.6 2.7 3.7
Other 6.1 9.0 8.4
Medical Service, % 96.4 94.4 86.6 <0.0001 <0.0001
Deyo-Charlson comorbidity index score
2.1 ± 1.3 2.3 ± 1.6 2.4 ± 1.5 <0.0001 0.03
Deyo-Charlson comorbidity index category, %
<0.0001 0.004
0 0.0 0.0 0.0
1 37.8 33.8 28.3
2 37.9 37.3 37.2
3 24.3 28.9 34.5
Selected comorbidities, %
Myocardial infarction 21.6 23.8 37.1 <0.0001 <0.0001
Peripheral vascular disease
7.6 10.9 10.2 0.0007 0.60
Cerebrovascular disease 6.2 5.6 7.6 0.10 -
3..777777
0
0
m
6.6.6.6.6.11111 9.99.0 8....44444
9696969696.444 949494949 .444 866666 6.6666 <<<0.0000 00000000
momomorbrbididitityyy 222.111 ±±± 111.333 222.333 ±±± 111.666 222.444 ±±± 111.555 <0<0<0 00.0000
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Chronic pulmonary disease
29.9 30.0 29.0 0.83 -
Chronic kidney disease 5.6 5.6 7.8 0.01 0.03
Rheumatic disease 0.0 0.0 0.0 - -
Liver disease 1.0 1.5 1.3 0.28 -
Diabetes mellitus 3.7 4.0 5.4 0.04 0.11
Malignancy 4.8 7.9 7.0 0.0003 0.41
HIV 0.0 0.0 0.0 - -
Dementia 3.0 1.1 1.2 <0.0001 0.83
Psychosis 22.2 17.0 13.8 <0.0001 0.03
Non-psychosis mental disorder
15.4 20.2 16.0 0.001 0.008
Acute respiratory infection
1.1 1.8 1.5 0.21
Pneumonia or influenza 15.9 19.9 19.7 0.001 0.87
Malignant neoplasm of respiratory or intra-thoracic organs
0.9 1.5 1.3 0.23
eGFR, mL/min/1.73 m2 <0.0001 0.12
<30 10.7 13.6 14.9
30-59 40.2 30.3 33.3
60 49.1 56.2 51.8
Continuous variables are displayed as mean ± standard deviation
13.8 <0.0.000000000
166.0.0.0.000 00000 0000.00000
1.5 1.3 0.230.9
y 1
n
lasm of
yyy 1....11111 1..8 1.1.1.1.1.55555 0.0.0.00 21
nfluenza 15.999 1119.9.9..99 99 9 19.7 0.001
lalalasmsm oofff 0.0.0.0 9999 1.1.1.11 55555 1.1.1.11 33333 0.0.0.232323
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Table 2. Outcomes of hospitalized patients with a diagnosis of heart failure according to presence or absence of hyponatremia
Hospital outcome
Normonatremia
(n = 3006)
Community-acquired hyponatremia
(n = 1039)
Hospital- acquired
hyponatremia
(n = 1302)
P-value
(Overall)
P-value (Community- vs. hospital-acquired
hyponatremia)
In-hospital mortality % 5.7 9.7 9.1 <0.0001 0.58
Hospital length of stay, days
4 ( 3, 7) 6 ( 4, 10) 9 ( 5, 14) <0.0001 <0.0001
Discharge to short-/long-term care facility, %
40.4 48.6 54.7 <0.0001 0.005
In-hospital worsening kidney function, %
30.0 41.4 55.4 <0.0001 <0.0001
Continuous variables are displayed as median (with 25th and 75th percentile). Patients who died in-hospital
were excluded from the analysis for hospital length of stay or discharge disposition. The analysis of worsening
kidney function was restricted to 89% of the cohort (n =4764) where patients had baseline-to-peak serum
creatinine could be calculated (normonatremia [n = 2564]; community-acquired hyponatremia [n = 938];
hospital- acquired hyponatremia [n = 1262])
). Paatitiiiiiienentsts whohohohohohoo ddddddiiieieieieied d
m the analysis for hospital length of stay or discharge disposition. The analysis
s restricted to 89% of the cohort (n =4764) where patients had baseline-to-p a
calculated (normonatremia [n = 2564]; community-acquired hyponatremia n
y
m theeeee aaaaanananananalylylylylysissss s fofofofofor hospital length of stay yyyy ororororo discharge dispopopopoposition. The analysis
s rererereestricted tooooo 898888 % % %%% ofofofofof ttttthehehehehe cccohohohohohorrrrrt (nn =====474 64664) whwhwhwhwherererrreeeee papapatiiiienennenntstststst hadadddd bbbbbasasasasaselelelelelinnnnne-----tototototo-p-p-p-p-pea
caaaaalccclcculuuu ated (((((nooorrmonoonatreeeemmmimm a [n[n[n[n[n == 22566644]; coccommmmmmmmmmunnnnnittty--accquqqq iriirededddd hhhhhypyyyy onnonnaaataa rerremiaa [n
yponatremia [n = 126662]2]22]))))
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Table 3. Multivariable analyses examining the association between hyponatremia subtypes in hospitalized patients with a diagnosis of heart
failure and hospital-based outcomes
Adjusted odds ratio (95% confidence interval) Adjusted relative prolongation in hospital length of stay
(95% confidence interval) Predictor In-hospital mortality Discharge to short-/long-term care facility
In-hospital worsening kidney function
Patients with a diagnosis of heart failure
Community-acquired hyponatremia (vs. normonatremia)
Basic model 1.73 (1.33, 2.25) 1.43 (1.22, 1.67) 1.58 (1.35, 1.86) 1.40 (1.32, 1.48)
Expanded model 1.69 (1.29,2.21) 1.51 (1.29, 1.78) 1.54 (1.31, 1.80)
1.39 (1.32,1.47)
Hospital-acquired hyponatremia (vs. normonatremia)
Basic model 1.64 (1.27, 2.11) 1.80 (1.55, 2.09) 2.69 (2.32, 3.11) 1.90 (1.80, 2.00)
Expanded model 1.55 (1.19, 2.01) 2.07 (1.77, 2.42) 2.61 (2.26, 3.03) 1.91 (1.82,2.01)
Patients with a primary diagnosis of heart failure*
Community-acquired hyponatremia (vs. normonatermia)
6.77 (2.24, 20.47) 1.39 (1.21, 1.62) 1.48 (1.01, 2.17) 1.41 (1.33, 1.49)
73 (1.33, 2.25) 1.43 (1.22, 1.67) 1.58
6
337333 ((((1.33, 2.22.22 255255) )))) 1.43434 (((1.1 2222222222,,,, 1.1111 6777) 111.11 58555
69 (1.29,2.21) 11111.5.5.5.551 (1(1(1(1.2.2.2.2.29,9999 1111.7.7.7.78)8)8)8)) 1.54
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Hospital-acquired hyponatremia (vs. normonatremia)
7.61 (2.57, 22.58) 1.79 (1.56, 2.05) 3.98 (2.75 ,5.75) 2.02 (1.92, 2.12)
The basic model for the entire cohort was adjusted for age, sex, race, hospital service, and Deyo-Charlson comorbidity index. The expanded model for the entire cohort was
adjusted for age, sex, race, hospital service, Deyo-Charlson comorbidity index, psychosis, mental illness and pneumonia/influenza
* The model for patients with a primary diagnosis of HF (n=984) was adjusted for age, sex and Deyo-Charlson comorbidity index.
Patients who died in-hospital were excluded from the analysis of hospital length of stay and discharge disposition.
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Table 4. Characteristics of hospitalized patients with a primary diagnosis of heart failure
Variable
Non-primary diagnosis of heart
failure (n = 4363)
Primary diagnosis of heart failure
(n = 984)
P-value
Age, years 75.9 ± 1.2 76.0 ± 12.1 0.86 Female, % 53.9 51.6 0.20 Race, % 0.43 White 88.7 89.1 Black 3.9 4.5 Other 7.4 6.4 Medical Service, % 92.3 99.4 <0.0001 Deyo-Charlson comorbidity index score 2.3 ± 1.5 1.9 ± 1.2 <0.0001 Deyo-Charlson comorbidity index category, %
<0.0001
0 0.0 0.0 1 31.8 47.5 2 38.5 33.6 3 29.6 18.9 Selected comorbidities, %
Myocardial infarction 28.0 15.9 <0.0001 Peripheral vascular disease 9.3 7.0 0.02 Cerebrovascular disease 7.3 2.3 <0.0001 Chronic pulmonary disease 30.3 27.1 0.05 Chronic kidney disease 6.1 6.1 0.96 Rheumatic disease 0.0 0.0 - Liver disease 1.3 0.5 0.03 Diabetes mellitus 4.1 4.6 0.48 Malignancy 6.5 3.4 <0.0001 HIV 0.0 0.0 - Dementia 2.5 0.8 0.001 Psychosis 21.0 11.2 <0.0001 Non-psychosis mental disorder 17.2 13.1 0.002 Acute respiratory infection 1.2 2.1 0.02 Pneumonia or influenza 20.0 6.7 <0.0001 Malignant neoplasm of respiratory or
intra-thoracic organs 1.3 0.5 0.04
eGFR, mL/min/1.73 m2 0.02 <30 11.9 14.0 30-59 36.1 38.7 60 52.0 47.3 In-hospital mortality 7.3 2.4 Continuous variables are displayed as mean ± standard deviation
474777777.5.5 3.6 8 9
tr <
u<
adisease 6 1 6 1
tieeseee ,, ,, %%rccctiioiioi n 282828.0 1155.99999 <
ular rrr dididididisesesess asasasasse eeee 9.9.9.9 33333 7.7.7.7.000disease 7.777 3 2.3 <
arararyyy dididiseseseasasaseee 303030 33.3 272727 11.1 ddisiseaeasese 666 111 666 111
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Figure Legend
Figure. Restrictive cubic spline depicting the unadjusted relationship between the hospital
admission serum sodium concentration and in-hospital mortality in patients with a diagnosis
of heart failure. The dashed lines represent the 95% confidence interval.
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and Nicolaos E. MadiasDmitry Y. Shchekochikhin, Robert W. Schrier, JoAnn Lindenfeld, Lori Lyn Price, Bertrand L. Jaber
a Diagnosis of Heart FailureOutcome Differences in Community- versus Hospital-Acquired Hyponatremia in Patients with
Print ISSN: 1941-3289. Online ISSN: 1941-3297 Copyright © 2013 American Heart Association, Inc. All rights reserved.
is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation: Heart Failure published online March 19, 2013;Circ Heart Fail.
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