outcome differences in community- versus hospital...

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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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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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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(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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care facility, while negative binomial regression was used to e a

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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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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

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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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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

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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

t

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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

m t

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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


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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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

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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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