You are on page 1of 8

Heart Failure

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
Liviu Klein, MD; Christopher M. O’Connor, MD; Jeffrey D. Leimberger, PhD;
Wendy Gattis-Stough, PharmD; Ileana L. Piña, MD; G. Michael Felker, MD; Kirkwood F. Adams, Jr, MD;
Robert M. Califf, MD; Mihai Gheorghiade, MD; for the OPTIME-CHF Investigators

Background—The prognostic value of serum sodium in patients hospitalized for worsening heart failure has not been well
Methods and Results—The Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart
Downloaded from by guest on November 26, 2017

Failure (OPTIME-CHF) study randomized 949 patients with systolic dysfunction hospitalized for worsening heart
failure to receive 48 to 72 hours of intravenous milrinone or placebo in addition to standard therapy. In a retrospective
analysis, we investigated the relationship between admission serum sodium and the primary end point of days
hospitalized for cardiovascular causes within 60 days of randomization, as well as the secondary end points of
in-hospital mortality, 60-day mortality, and 60-day mortality/rehospitalization. The number of days hospitalized for
cardiovascular causes was higher in the lowest sodium quartile: 8.0 (4.5, 18.5) versus 6 (4, 13) versus 6 (4, 11.5) versus
6 (4, 12) days (P⬍0.015 for comparison with the lowest quartile). Lower serum sodium was associated with higher
in-hospital and 60-day mortality: 5.9% versus 1% versus 2.3% versus 2.3% (P⬍0.015) and 15.9% versus 6.4% versus
7.8% versus 7% (P⫽0.002), respectively. There was a trend toward higher mortality/rehospitalization for patients who
were in the lowest sodium quartile. Multivariable-adjusted Cox proportional hazards analysis showed that serum sodium
on admission, when modeled linearly, predicted increased 60-day mortality: sodium (per 3-mEq/L decrease) had a
hazard ratio of 1.18 with a 95% CI of 1.03 to 1.36 (P⫽0.018).
Conclusions—In patients hospitalized for worsening heart failure, admission serum sodium is an independent predictor of
increased number of days hospitalized for cardiovascular causes and increased mortality within 60 days of discharge.
(Circulation. 2005;111:2454-2460.)
Key Words: heart failure 䡲 prognosis 䡲 sodium 䡲 risk factors

A lthough recent clinical trials1– 4 demonstrated that hos-

pitalized heart failure patients have relatively low in-
hospital mortality (3% to 4%), their readmission for cardio-
Serum sodium has been shown to be a prognostic factor in
outpatients with heart failure7; however, its significance in
hospitalized patients has not been well defined. In a retrospective
vascular causes and all-cause mortality rates within 60 days analysis of the Outcomes of a Prospective Trial of Intravenous
of discharge are as high as 25% and 10%, respectively. The Milrinone for Exacerbations of Chronic Heart Failure
mortality and morbidity appear to be significantly higher (OPTIME-CHF), we investigated the association between serum
during this postdischarge phase than during a comparable sodium and all-cause mortality and readmissions for cardiovas-
period for patients with severe disease that does not require cular causes in hospitalized patients with heart failure.
hospitalization.5 Despite the clinical significance of worsen-
ing heart failure that results in hospitalization, this phase of Methods
the syndrome has received little attention in the cardiovascu- Study Design
lar community,6 and risk stratification for these patients has The study design8 and primary results of OPTIME-CHF have been
not been well defined. published previously.1 The OPTIME-CHF study randomized 949

Received June 8, 2004; revision received January 26, 2005; accepted February 3, 2005.
From Northwestern University Feinberg School of Medicine (L.K., M.G.), Chicago, Ill; Duke Clinical Research Institute (C.M.O., J.D.L., W.G.-S.,
G.M.F., R.M.C.), Durham, NC; Case Western Reserve University (I.L.P.), Cleveland, Ohio; and University of North Carolina (K.F.A.), Chapel Hill, NC.
Correspondence to Mihai Gheorghiade, MD, Division of Cardiology, Northwestern University Feinberg School of Medicine, Galter 10-240, 201 E
Huron St, Chicago, IL 60611. E-mail
© 2005 American Heart Association, Inc.
Circulation is available at DOI: 10.1161/01.CIR.0000165065.82609.3D

Klein et al Hyponatremia in Hospitalized Heart Failure Patients 2455

patients with systolic dysfunction and worsening heart failure to serum sodium were more likely to have more severe heart
receive 48 to 72 hours of intravenous milrinone (0.5 ␮g · kg⫺1 · min⫺1 failure (higher number of admissions in the previous year)
without a loading dose) or placebo in a double-blinded fashion.
Patients requiring inotropic support and those with evidence of active and tended to have a longer duration of their disease. These
myocardial ischemia within the prior 3 months, serum creatinine patients also had lower systolic blood pressure and higher
⬎3.0 mg/dL, systolic blood pressure ⬍80 mm Hg, or unstable blood urea nitrogen (BUN). However, left ventricular ejec-
arrhythmias were excluded. Background therapy was left to the tion fraction, degree of congestion, symptoms (New York
discretion of the treating physician, but specific recommendations
for optimal medical therapy based on published guidelines were Heart Association [NYHA] functional class), and heart fail-
included with the study protocol.8 The primary end point was the ure score8 were similar across quartiles.
total number of days hospitalized for cardiovascular causes within 60
days of randomization.8 Days lost to follow-up and days deceased Outcomes by Serum Sodium Concentrations
were included prospectively in the primary end point to avoid bias
toward a therapy with increased mortality.1 For instance, a patient The primary end point of days hospitalized for cardiovascular
hospitalized initially for 7 days after randomization who then died on causes within 60 days of randomization was higher in the
day 45 of the 60-day follow-up would have 22 days as the primary lowest sodium quartile than in the other quartiles: 8.0 (4.5,
end point. Important secondary end points were 60-day mortality, the 18.5) versus 6 (4, 13) versus 6 (4, 11.5) versus 6 (4, 12) days
composite of death and rehospitalizations at 60-days, the ability to
reach target dosing of ACE inhibitors at discharge, and quality of life (P⬍0.001 overall; P⬍0.015 for any quartile compared with
(QOL). The latter was assessed with a visual analog scale from 0 first; Table 2). The in-hospital and 60-day mortality rates
(worst) to 100 (best) and a subjective health status questionnaire that were also increased in the lowest quartile of serum sodium:
assessed activity limitations, symptoms, and emotions as better,
Downloaded from by guest on November 26, 2017

5.9% versus 1% versus 2.3% versus 2.3% (P⫽0.015) and

worse, or the same.8 End points for the present analysis were the
same as those in the overall OPTIME-CHF study, as described 15.9% versus 6.4% versus 7.8% versus 7% (P⫽0.002),
previously. respectively (Figure 1). Patients in the lowest sodium quartile
trended toward higher rates of death or rehospitalization at 60
Data Analysis days: 41% versus 30.4% versus 33.5% versus 33.6%
Continuous variables are presented as median values with 25th and
(P⫽0.095). The primary end point had a moderate correlation
75th percentiles, whereas categorical variables are shown as percent-
ages of nonmissing values. The data are displayed in quartiles. All with the 60-day mortality and 60-day death/rehospitalization
analyses were performed on the basis of the intention-to-treat rates (r⫽0.48 and 0.64, respectively, by Spearman rank
principle. correlation).
Contingent on the assumptions of normality, ANOVA or Kruskal-
Wallis tests were used to explore the relationship between continu-
There were no differences observed across serum sodium
ous baseline and outcomes variables and serum sodium across quartiles in the rates of treatment failure (defined as sustained
quartiles. Because of the nonnormality of the primary end point, the hypotension for ⬎30 minutes that required intervention,
Kruskal-Wallis test was used for this outcome. Pearson ␹2 statistics myocardial ischemia and arrhythmias, worsening heart fail-
or Fisher exact test were used to examine the association between
serum sodium quartiles and baseline categorical variables. If the ure, and failure to achieve adequate clinical improvement at
overall test for differences among quartiles was significant at 48 hours after study-drug infusion) while patients were taking
the 0.05 level, we examined the differences between the first and the the study drug. However, significantly more patients with low
other quartiles. For dichotomous outcomes measures, logistic regres- serum sodium developed sustained hypotension that necessi-
sion analysis was used to examine the overall association of serum
sodium and outcome with indicator variables for the higher 3 tated intervention (Table 2). There was no association be-
quartiles. If the overall model was significant at the 0.05 level, we tween serum sodium concentration and the ability to reach
examined the significance of the higher 3 quartiles using the first target dosing of ACE inhibitors by discharge.
quartile as the referent group. A similar approach was used to assess Baseline QOL scores were comparable across sodium
the relationship between serum sodium and 60-day mortality with
Cox proportional hazards regression. Multivariable analysis was quartiles, and all patients had substantial and similar improve-
used to assess the independent risk of serum sodium on clinical end ment over baseline in the visual analog QOL by hospital
points. For the multivariable analysis, 41 candidate variables were discharge that was maintained at 60-day follow-up. There
considered that reflected demographics, cardiac history, comorbidi-
was no difference in the QOL by the subjective health status
ties, bedside clinical assessment, and laboratory studies. Within each
category, the most likely predictors were identified by backwards- questionnaire in the 4 quartiles, with an equal percentage of
variable selection, and variables were removed from the model at a patients feeling better or the same by 60 days (Table 2).
probability value ⬎0.05. The significant predictors from each of
these 5 groups were combined, and 6 prespecified covariates were Changes in Serum Sodium Concentration
added if they had not already been included: age, gender, ethnicity,
ejection fraction, etiology, and systolic blood pressure. These covari- Although on average, serum sodium increased by discharge
ates were included on the basis of the high theoretical likelihood that in the lowest admission quartile, it decreased in the other 3
they would be associated with outcomes. Backward stepwise vari- quartiles: ⫹1 (⫺2, 3) versus ⫺1 (⫺3, 1) versus ⫺2 (⫺3, 0)
able selection was again performed, and a final model was generated. versus ⫺3 (⫺6, ⫺2; P⬍0.001). Thirty-eight percent (93/244)
Two-sided values of P⬍0.05 were considered significant for all
analyses. Analyses were performed with SAS version 8.2 (SAS of the patients who were in the lowest serum sodium quartile
Institute Inc). at baseline were discharged with serum sodium concentration
⬎135 mEq/L. Their 60-day mortality rate was 10.75%
Results compared with 17.22% among patients who remained hy-
Baseline Characteristics ponatremic at discharge (P⫽0.19). The 60-day mortality rates
The baseline characteristics of the study patients across serum in the other 3 quartiles were 6.4% versus 7.8% versus 7%,
sodium quartiles are presented in Table 1. Patients with lower respectively.
2456 Circulation May 17, 2005

TABLE 1. Baseline Characteristics by Serum Sodium Quartiles

1st Quartile 2nd Quartile 3rd Quartile 4th Quartile
(n⫽256) (n⫽207) (n⫽220) (n⫽260) P
Age, y 68 (53–76) 65 (55–74) 68 (57–76) 69 (59–77) 0.06
Women, % 32 35 33 35 0.92
Ethnicity, %
White 72 66 64 58 0.041
Black 25 32 34 39
Medical history
Ischemic etiology, % 55 50 55 45 0.06
Myocardial infarction, % 45 51 50 47 0.59
Coronary artery bypass surgery, % 38 29 31 27 0.041
Hypertension, % 62 68 69 71 0.18
Atrial fibrillation, % 31 30 34 32 0.82
Ventricular tachycardia, % 11 10 11 8 0.65
Downloaded from by guest on November 26, 2017

Months since heart failure diagnosis 39.5 (17.5–75) 37 (11–69) 39 (12–70) 30.5 (9–65) 0.054
Hospitalizations in prior 12 months, n 2 (1–3) 1 (0–3) 1 (0–2) 1 (0–3) 0.003*
Clinical characteristics
Ejection fraction, % 21 (17.5–30) 22 (17–30) 22.5 (19.5–30) 24.5 (20–30) 0.21
NYHA class, %
III 47 45 49 42 0.12
IV 49 49 45 47
Systolic blood pressure, mm Hg 114 (100–130) 120 (105–136) 120 (107–132) 123 (110–138) ⬍0.001*
Diastolic blood pressure, mm Hg 70 (60–78) 70 (60–80) 70 (62–80) 70 (60–80) 0.11
Baseline heart rate, bpm 84 (72–96) 84 (72–97) 85 (76–95) 81 (70–94) 0.11
Jugular venous pressure ⬎6 cm, % 76 72 73 70 0.57
Pulmonary rales, % 83 79 80 82 0.67
Systolic murmur, % 52 47 43 51 0.24
Third heart sound, % 59 61 56 58 0.76
Heart failure score (4–10) 6 (5–7) 6 (5–7) 6 (5–7) 6 (5–7) 0.72
Laboratory values
Serum sodium, mEq/L 134 (132–135) 138 (137–138) 140 (139–140) 142 (141–144) ⬍0.001*
Serum potassium, mEq/L 4.2 (3.9–4.6) 4.1 (3.8–4.5) 4 (3.8–4.4) 4 (3.8–4.4) 0.012*
Serum BUN, mg/dL 33 (20–49) 24 (17–39) 23 (16–37) 24 (18–35) ⬍0.001*
Serum creatinine, mg/dL 1.4 (1.1–1.8) 1.4 (1–1.8) 1.3 (1–1.7) 1.4 (1.1–1.7) 0.069
Admission medications, %
Diuretics 92 93 89 88 0.27
ACE inhibitors 70 70 67 74 0.35
Angiotensin receptor blockers 13 14 17 8 0.022
␤-Blockers 21 20 25 23 0.53
Digoxin 77 82 71 63 ⬍0.001*
Calcium channel blockers 12 10 15 17 0.086
Amiodarone 16 15 16 15 0.98
Continuous variables are presented as median (interquartile range). ANOVA or Kruskal-Wallis test was used to test for overall
differences between continuous variables. Pearson ␹2 statistics or Fisher exact test was used to test differences between categorical
*All individual quartiles vs first quartile, P⬍0.05.

Effect of Milrinone Treatment The 60-day mortality rate was also similar across sodium
There was no difference observed in the number of days quartiles among patients treated with milrinone compared
hospitalized for cardiovascular causes within 60 days of with placebo (Table 3). The interaction between treatment
randomization regardless of the treatment assignment (mil- assignment and serum sodium was not significant for any
rinone or placebo) for any of the serum sodium quartiles. outcome (P⬎0.35), which indicates that the relationship
Klein et al Hyponatremia in Hospitalized Heart Failure Patients 2457

TABLE 2. Outcomes by Serum Sodium Quartiles (Unadjusted Analysis)

1st Quartile 2nd Quartile 3rd Quartile 4th Quartile
(n⫽256) (n⫽207) (n⫽220) (n⫽260) P
Primary end point, d 8 (4.5–18.5) 6 (4–13) 6 (4–11.5) 6 (4–12) 0.001*
Mortality, n (%)
In hospital 15 (5.9) 2 (1) 5 (2.3) 6 (2.3) 0.015*
OR (95% CI) Referent 0.16 (0.035–0.69) 0.37 (0.13–1.05) 0.38 (0.15–0.99)
60 Days† 40 (15.9) 13 (6.4) 17 (7.8) 18 (7) 0.002*
OR (95% CI) Referent 0.38 (0.2–0.72) 0.47 (0.27–0.82) 0.42 (0.24–0.74)
Rehospitalization/death within 60 days, n (%)† 103 (41) 62 (30.4) 73 (33.5) 87 (33.6) 0.095
OR (95% CI) Referent 0.63 (0.43–0.9) 0.72 (0.5–1.06) 0.73 (0.51–1.04)
Treatment failures (during infusion), % 17.9 13.2 13.8 13.1 0.4
In-hospital complications (any) 14.8 9.2 9.1 16.9 0.018
Sustained hypotension 10.5 3.9 5 6.9 0.022*
New atrial arrhythmias 4.3 3.4 0.9 3.5 0.11
Sustained ventricular tachycardia 0.8 1.5 1.8 3.8 0.09
Downloaded from by guest on November 26, 2017

Ventricular fibrillation 1.2 1.9 0.9 0.8 0.7

Reached target ACE dosing by discharge, % 39.1 41.1 42.3 46.9 0.32
Visual analog QOL score (0–100)
Baseline 40 (25–50) 40 (25–55) 40 (25–50) 50 (30–60) 0.053
Change at discharge 25 (10–40) 26.5 (10–50) 30 (15–45) 25 (10–40) 0.051
Change at 30 days 20 (2.5–40) 25 (5–40) 23.5 (5–40) 20 (0–38) 0.72
Change at 60 days 21 (5–45) 30 (7–45) 25 (5–40) 25 (5–40) 0.72
Subjective health questionnaire (better/same)
Change at discharge, % 99 99 100 99 0.41
Change at 30 days, % 85 88 90 88 0.5
Change at 60 days, % 87 84 88 88 0.68
Continuous variables are presented as median (interquartile range). ANOVA or Kruskal-Wallis test was used to test for overall
differences between continuous variables. Cox proportional hazards regression with indicator variables was used to analyze 60-day
mortality. Categorical variables were analyzed with logistic regression. P value in last column represents overall relationship with
serum sodium for regression models.
*All individual quartiles vs first quartile, P⬍0.05.
†Raw percentages of patients followed up to 60-day visit.

between serum sodium and end points did not differ 1.22 to 3.04, P⫽0.004), and elevated BUN (HR⫽1.33 per
between treatment groups (Table 3). 5-mg/dL increase, 95% CI 1.19 to 1.47, P⬍0.001).

Multivariable Analysis Discussion

The findings of the Cox proportional hazards model were Worsening heart failure that results in hospitalization repre-
consistent with those of the unadjusted analysis for the sents a major public health problem because of the high
primary end point and for the 60-day mortality rate. After postdischarge mortality rate, large number of hospital read-
adjustment for baseline differences, serum sodium on admis- missions, and significant associated costs. Several recent
studies have tried to identify predictors of mortality or
sion remained a significant predictor of the number of days
rehospitalization that could potentially aid clinical decision
hospitalized for cardiovascular causes within 60 days of
making in this population.9 –14 The present analysis, con-
randomization (P⫽0.03). Serum sodium, when modeled lin-
ducted in a sample derived from a large clinical trial,
early, remained a significant predictor of increased 60-day
identifies a substantial risk of short- and intermediate-term
mortality (hazard ratio [HR] 1.18 per 3-mEq/dL decrease, clinical events associated with decreasing serum sodium
95% CI 1.03 to 1.36, P⫽0.018). This translates into an 18% concentration in patients hospitalized for worsening heart
relative increase in the probability of death within 60 days of failure. Lower concentrations of serum sodium on admission
randomization for every 3-mEq/dL decrease in admission remained a predictor of increased number of days hospital-
sodium values (Figure 2). Other predictors of 60-day mortal- ized for cardiovascular causes and increased mortality within
ity were increasing age (HR⫽1.26 per 10-year increase, 95% 60 days of discharge after adjustment was made for a variety
CI 1.06 to 1.51, P⫽0.01), lower systolic blood pressure of baseline variables.
(HR⫽1.28 per 10-mm Hg decrease, 95% CI 1.12 to 1.46, In heart failure, decreased stimulation of mechanoreceptors
P⬍0.001), NYHA class IV symptoms (HR⫽1.93, 95% CI in the left ventricle, carotid sinus, aortic arch, and renal
2458 Circulation May 17, 2005

neurohormonal response to orthostasis, lower hepatic and

renal plasma flows, elevated liver enzymes, and prerenal
azotemia compared with normonatremic patients. These stud-
ies raised the hypothesis that low serum sodium may be a
marker of neurohormonal activation, reflecting the severity of
the disease. Indeed, the degree of neurohormonal activa-
tion23–25 and the prevalence of low serum sodium (21%
versus 7%)1,26 are markedly higher in hospitalized patients
with worsening heart failure than in outpatients with stable
Low serum sodium has also been correlated with ventric-
ular ectopy,27 an increase in sudden death28 and increased
in-hospital mortality.29 A clinical risk model derived from a
retrospective review of medical records has shown a signif-
icant 50% increase in 30-day all-cause mortality in patients
Figure 1. Kaplan-Meier survival curves to 60 days by serum with serum sodium below 136 mEq/L, risk that was also
sodium quartiles (unadjusted analysis). Probability value ⬍0.05 maintained at 1 year, compared with patients with normal
for first quartile vs each of the other quartiles from Cox propor-
tional hazards model. serum sodium.10
Downloaded from by guest on November 26, 2017

Hyponatremic patients have a greater immediate improve-

ment in the cardiac index and left ventricular filling pressures
afferent arterioles leads to increased sympathetic discharge,
in response to ACE inhibitors,30 and although they may
activation of the renin-angiotensin-aldosterone system, and
initially have more symptomatic hypotension in response to
nonosmotic release of vasopressin, among other neurohor-
ACE inhibitors, they have significant improvement in serum
mones.15 Increased sympathetic drive contributes to avid
sodium and survival compared with normonatremic
sodium and water retention through renal vasoconstriction,
patients.30 –32
stimulation of the renin-angiotensin-aldosterone system, and
Many prior reports examining the prognostic value of
a direct effect on the proximal convoluted tubule.15,16 In-
serum sodium in hospitalized heart failure patients were
creased angiotensin II and aldosterone levels in heart failure
either small or consisted of retrospective medical records
lead to decreased sodium and water delivery to the collecting
review. The present retrospective analysis is the first to
duct, which, combined with resistance to the action of
examine this relationship using data from a prospective,
natriuretic peptides, result in impairment of free-water excre-
randomized clinical trial that had an extensive standardized
tion and hyponatremia.15 Finally, the nonosmotic stimulation
assessment of baseline characteristics and outcomes and a
of vasopressin release leads to elevated vasopressin concen-
99% complete follow-up rate. In addition, we were able to
tration, which results in an increased number of aquaporin
analyze changes in serum sodium between admission and
water channels in the collecting duct of the kidney that
discharge. In the present analysis, lower serum sodium on
promote abnormal free water retention and contribute to the
admission was associated with more severe heart failure
development of hyponatremia.17–19
(longer duration of the disease and more hospitalizations in
In several studies from the early 1980s, Dzau et al20 –22
the previous year) but not with higher degree of congestion
observed that patients with heart failure and low serum
(similar prevalence of rales, jugular venous pressure, and
sodium had higher circulating levels of catecholamines,
renin, angiotensin II, aldosterone, and vasopressin than nor- edema across groups; Table 1). Lower serum sodium was also
monatremic patients. Hyponatremic patients had an impaired associated with a lower blood pressure and higher BUN
(Table 1). Reduction in renal perfusion, renin-angiotensin-
aldosterone, and sympathetic activation lead to increased
sodium and water reabsorption that is coupled with enhanced
urea reabsorption in the proximal tubules.13 Vasopressin, on
binding to V2 receptors in the inner medullary collecting
ducts, increases urea permeability through activation of urea
transporters, which enables its reabsorption.33 The marked
activation of neurohormonal systems, particularly vasopres-
sin, may be the cause of both low serum sodium and high
BUN in patients with decompensated heart failure. Use of
neurohormonal blockade with ACE inhibitors and ␤-blockers
may blunt some of these effects and may explain why
hyponatremic patients in the OPTIME-CHF study had much
lower BUN levels than in studies done in the 1980s, in which
the use of ACE inhibitors and ␤-blockers was significantly
Figure 2. Fourteen-day and 60-day mortality rates by serum
sodium levels (unadjusted analysis). Survival estimates are prod- Although the OPTIME-CHF study excluded patients with
uct-limit estimates from Cox proportional hazards model. active ischemia, renal failure, significant arrhythmias, or
Klein et al Hyponatremia in Hospitalized Heart Failure Patients 2459

TABLE 3. Outcomes by Serum Sodium Quartiles and Treatment Assignments

1st Quartile 2nd Quartile 3rd Quartile 4th Quartile

Milrinone Placebo Milrinone Placebo Milrinone Placebo Milrinone Placebo

(n⫽126) (n⫽129) (n⫽102) (n⫽105) (n⫽115) (n⫽105) (n⫽129) (n⫽131) P
Primary end point, d* 7 (4–19) 9 (5–18) 6 (4–10) 6 (4–14) 6 (4–9) 6 (4–13) 6 (4–13) 6 (4–10) 0.35
Mortality, %
In hospital† 6.3 5.4 1 1 3.5 1 3.1 1.5 0.53
60 Days‡ 18.3 13.6 5.9 6.8 5.3 10.6 9.3 4.7 0.91
Rehospitalization/death at 60 days§ 39.7 42.4 26.7 34 33.3 33.7 36.4 30.8 0.59
*Continuous variables are presented as median (interquartile range). P value is of interaction of treatment and serum sodium from regression of log-transformed
†P value is of interaction of treatment and serum sodium from logistic model.
‡Raw percentages of patients followed up to 60-day visit. P value is of interaction of treatment and serum sodium level from Cox model.
§Raw percentages of patients followed up to 60-day visit. P value is of interaction of treatment and serum sodium level from logistic model.

those who required inotropes,1,8 patients in the lowest serum the OPTIME-CHF study, however, do appear to have a
Downloaded from by guest on November 26, 2017

sodium quartile had an event rate (death/rehospitalizations) of clinical profile similar to that of unselected registry patients
41% within 60 days, which suggests that they are at partic- hospitalized for heart failure who have left ventricular dys-
ularly high risk (Table 2). Moreover, only 38% of these function: normotensive, with a high degree of congestion and
patients were able to normalize their serum sodium by the relatively preserved renal function.39 Finally, although lower
time of discharge. The 60-day mortality rate in this group was serum sodium is related to higher mortality, care must be
11% compared with 17% in patients who remained persis- observed in interpreting the exact shape of the relationship
tently hyponatremic at discharge; however, this difference did because of the relatively small number of deaths observed.
not achieve statistical significance, probably owing to the
small number of end points.
In this retrospective analysis, we found that in patients
Milrinone is known to improve hemodynamics in heart
hospitalized for worsening heart failure and systolic dysfunc-
failure patients,34 and it has been suggested that it might be
tion, serum sodium on admission is an important predictor of
useful especially in patients with more severe heart fail-
increased number of days hospitalized for cardiovascular
ure.35,36 In the present analysis, patients in the lowest serum
causes and increased mortality within 60 days of discharge.
sodium quartile (with more severe heart failure and presum-
The present study also raised the hypothesis that normaliza-
ably worse hemodynamics) experienced more sustained hy-
tion of serum sodium during hospitalization may improve
potension while using milrinone, despite having a similar
survival; however, this assumption needs to be tested further
improvement in QOL score.
in randomized clinical trials.
It has also been suggested that heart failure patients with
hyponatremia are more susceptible to the hypotensive and
azotemic effects of ACE inhibitors, possibly because they are Acknowledgment
Dr Klein is supported by a National Heart, Lung, and Blood Institute
more dependent on neurohormones to sustain their blood
training grant (No. T32 HL069771-O1A1).
pressure, and therefore initiation or uptitration of ACE
inhibitors is particularly difficult in these patients.30,31 Nev-
ertheless, in the present study, there were no significant
1. Cuffe MS, Califf RM, Adams KF Jr, Benza R, Bourge R, Colucci WS,
differences in the percentages of patients able to achieve Massie BM, O’Connor CM, Pina I, Quigg R, Silver MA, Gheorghiade M;
target doses of ACE inhibitors at discharge across serum Outcomes of a Prospective Trial of Intravenous Milrinone for Exacer-
sodium quartiles. bations of Chronic Heart Failure (OPTIME-CHF) Investigators.
Short-term intravenous milrinone for acute exacerbation of chronic heart
The high short-term mortality and morbidity rates in failure. JAMA. 2002;287:1541–1547.
patients hospitalized with worsening heart failure underline 2. Publication Committee for the VMAC Investigators (Vasodilatation in
the importance of identification of modifiable risk factors. Of the Management of Acute CHF). Intravenous nesiritide versus nitroglyc-
the predictors of mortality in the OPTIME-CHF study (age, erin for treatment of decompensated congestive heart failure: a ran-
domized controlled trial. JAMA. 2002;287:1531–1540.
NYHA class, low blood pressure, high BUN, and hyponatre- 3. Follath F, Cleland JG, Just H, Papp JG, Scholz H, Peuhkurinen K, Harjola
mia), hyponatremia is potentially modifiable by an available VP, Mitrovic V, Abdalla M, Sandell EP, Lehtonen L; Steering Committee
treatment (ie, vasopressin antagonists).37,38 and Investigators of the Levosimendan Infusion versus Dobutamine
(LIDO) Study. Efficacy and safety of intravenous levosimendan
The present analysis has several limitations. The study
compared with dobutamine in severe low-output heart failure (the LIDO
sample is derived from a randomized, controlled trial and study): a randomized double-blind trial. Lancet. 2002;360:196 –202.
consists solely of patients with impaired systolic function and 4. Gattis WA, O’Connor CM, Gallup DS, Hasselblad V, Gheorghiade M;
relatively preserved renal function. Whether serum sodium IMPACT Investigators. Pre-discharge initiation of carvedilol in patients
hospitalized for decompensated heart failure: results of the IMPACT-HF
concentration would be predictive of outcomes in patients
(Initiation Management Pre-discharge: process for Assessment of
hospitalized for heart failure and more advanced renal dys- Carvedilol Therapy in Heart Failure) Trial. J Am Coll Cardiol. 2004;43:
function deserves further investigation. Patients enrolled in 1534 –1541.
2460 Circulation May 17, 2005

5. Packer M, Fowler MB, Roecker EB, Coats AJ, Katus HA, Krum H, 23. Dzau VJ, Colucci WS, Hollenberg NK, Williams GH. Relation of the
Mohacsi P, Rouleau JL, Tendera M, Staiger C, Holcslaw TL, renin-angiotensin-aldosterone system to clinical state in congestive heart
Amann-Zalan I, DeMets DL; Carvedilol Prospective Randomized Cumu- failure. Circulation. 1981;63:645– 651.
lative Survival (COPERNICUS) Study Group. Effect of carvedilol on the 24. Chidsey CA, Braunwald E, Morrow AG. Catecholamine excretion and
morbidity of patients with severe chronic heart failure: results of the cardiac stores of norepinephrine in congestive heart failure. Am J Med.
Carvedilol Prospective Randomized Cumulative Survival 1965;39:442– 451.
(COPERNICUS) Study. Circulation. 2002;106:2194 –2199. 25. Levine TB, Franciosa JA, Vrobel T, Cohn JN. Hyponatremia as a marker
6. Felker GM, Adams KF Jr, Konstam MA, O’Connor CM, Gheorghiade for high renin heart failure. Br Heart J. 1982;47:161–166.
Ml. The problem of decompensated heart failure: nomenclature, classifi- 26. Pulignano G, Del Sindaco D, Tavazzi L, Lucci D, Gorini M, Leggio F,
cation, and risk stratification. Am Heart J. 2003;145:S18 –S25. Porcu M, Scherillo M, Opasich C, Di Lenarda A, Senni M, Maggioni AP;
7. Kearney MT, Fox KA, Lee AJ, Prescott RJ, Shah AM, Batin PD, Baig W, IN-CHF Investigators. Clinical features and outcomes of elderly outpa-
Lindsay S, Callahan TS, Shell WE, Eckberg DL, Zaman AG, Williams S, tients with heart failure followed up in hospital cardiology units: data
Neilson JM, Nolan J. Predicting death due to progressive heart failure in from a large nationwide cardiology database (IN-CHF Registry). Am
Heart J. 2002;143:45–55.
patients with mild-to-moderate chronic heart failure. J Am Coll Cardiol.
27. Dargie HJ, Cleland JG, Leckie BJ, Inglis CG, East BW, Ford I. Relation
of arrhythmias and electrolyte abnormalities to survival in patients with
8. Cuffe MS, Califf RM, Adams KF, Bourge RC, Colucci W, Massie B,
severe chronic heart failure. Circulation. 1987;75(suppl IV):98 –107.
O’Connor CM, Pina I, Quigg R, Silver M, Robinson LA, Leimberger JD,
28. Saxon LA, Stevenson WG, Middlekauff HR, Fonarow G, Woo M, Moser
Gheorghiade M. Rationale and design of the OPTIME-CHF trial:
D, Stevenson LW. Predicting death from progressive heart failure sec-
Outcomes of a Prospective Trial of Intravenous Milrinone for Exacer- ondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol.
bations of Chronic Heart Failure. Am Heart J. 2000;139:15–22. 1993;72:62– 65.
9. Felker GM, Gattis WA, Leimberger JD, Adams KF, Cuffe MS, Gheorghiade 29. Chin MH, Goldman L. Correlates of major complications or death in
M, O’Connor CM. Usefulness of anemia as a predictor of death and rehos- patients admitted to the hospital with congestive heart failure. Arch Intern
Downloaded from by guest on November 26, 2017

pitalization in patients with decompensated heart failure. Am J Cardiol. Med. 1996;156:1814 –1820.
2003;92:625–628. 30. Packer M, Medina N, Yushak M. Relation between serum sodium con-
10. Lee DS, Austin PC, Rouleau JL, Liu PP, Naimark D, Tu JV. Predicting centration and the hemodynamic and clinical responses to converting
mortality among patients hospitalized for heart failure: derivation and enzyme inhibition with captopril in severe heart failure. J Am Coll
validation of a clinical model. JAMA. 2003;290:2581–2587. Cardiol. 1984;3:1035–1043.
11. Aronson D, Mittleman MA, Burger AJ. Measures of heart period vari- 31. Packer M, Lee WH, Kessler PD, Medina N, Yushak M, Gottlieb SS.
ability as predictors of mortality in hospitalized patients with decom- Identification of hyponatremia as a risk factor for the development of
pensated congestive heart failure. Am J Cardiol. 2004;93:59 – 63. functional renal insufficiency during converting enzyme inhibition in
12. Aronson D, Burger AJ. Relation between pulse pressure and survival in severe chronic heart failure. J Am Coll Cardiol. 1987;10:837– 844.
patients with decompensated heart failure. Am J Cardiol. 2004;93: 32. Lee WH, Packer M. Prognostic importance of serum sodium concen-
785–788. tration and its modification by converting-enzyme inhibition in patients
13. Aronson D, Mittleman MA, Burger AJ. Elevated blood urea nitrogen with severe chronic heart failure. Circulation. 1986;73:257–267.
level as a predictor of mortality in patients admitted for decompensated 33. Bankir LT, Trinh-Trang-Tan MM. Renal urea transporters: direct and
heart failure. Am J Med. 2004;116:466 – 473. indirect regulation by vasopressin. Exp Physiol. 2000;85:243S–252S.
14. Felker GM, Leimberger JD, Califf RM, Cuffe MS, Massie BM, Adams 34. Anderson JL, Baim DS, Fein SA, Goldstein RA, LeJemtel TH, Likoff MJ.
KF Jr, Gheorghiade M, O’Connor CM. Risk stratification after hospital- Efficacy and safety of sustained (48 hour) intravenous infusions of mil-
ization for decompensated heart failure. J Card Fail. 2004;10:460 – 466. rinone in patients with severe congestive heart failure: a multicenter
15. Schrier RW, Abraham WT. Hormones and hemodynamics in heart study. J Am Coll Cardiol. 1987;9:711–722.
failure. N Engl J Med. 1999;341:577–585. 35. Mehra MR, Ventura HO, Kapoor C, Stapleton DD, Zimmerman D, Smart
16. Schrier RW, Berl T. Mechanism of effect of alpha-adrenergic stimulation FW. Safety and clinical utility of long-term intravenous milrinone in
with norepinephrine on renal water excretion. J Clin Invest. 1973;52: advanced heart failure. Am J Cardiol. 1997;80:61– 64.
36. Cesario D, Clark J, Maisel A. Beneficial effects of intermittent home
administration of the inotrope/vasodilator milrinone in patients with
17. Schrier RW, Berl T, Anderson RJ. Osmotic and non-osmotic control of
end-stage congestive heart failure: a preliminary study. Am Heart J.
vasopressin release. Am J Physiol. 1979;236:F321–F332.
18. Goldsmith SR, Francis GS, Cowley AW Jr, Levine TB, Cohn JN.
37. Gheorghiade M, Niazi I, Ouyang J, Czerwiec F, Kambayashi J, Zampino
Increased plasma arginine vasopressin levels in patients with congestive
M, Orlandi C; Tolvaptan Investigators. Vasopressin V2-receptor blockade
heart failure. J Am Coll Cardiol. 1983;1:1385–1390. with tolvaptan in patients with chronic heart failure: results from a
19. Goldsmith SR, Francis GS, Cowley AW Jr. Arginine vasopressin and the double-blind, randomized trial. Circulation. 2003;107:2690 –2696.
renal response to water loading in congestive heart failure. Am J Cardiol. 38. Gheorghiade M, Gattis WA, O’Connor CM, Adams KF Jr, Elkayam U,
1986;58:295–299. Barbagelata A, Ghali JK, Benza RL, McGrew FA, Klapholz M, Ouyang
20. Dzau VJ, Packer M, Lilly LS, Swartz SL, Hollenberg NK, Williams GH. J, Orlandi C; Acute and Chronic Therapeutic Impact of Vasopressin
Prostaglandins in severe congestive heart failure: relation to activation of Antagonism in Congestive Heart Failure (ACTIV in CHF) Investigators.
the renin-angiotensin system and hyponatremia. N Engl J Med. 1984;310: Acute and chronic therapeutic impact of a vasopressin 2 antagonist
347–352. (tolvaptan) in congestive heart failure. JAMA. 2004;291:1963–1971.
21. Lilly LS, Dzau VJ, Williams GH, Rydstedt L, Hollenberg NK. Hypona- 39. Adams KF, Fonarow GC, Emerman CL, LeJemtel TH, Costanzo MR,
tremia in congestive heart failure: implications for neurohormonal acti- Abraham WT, Berkowitz RL, Galvao M, Horton DP. Characteristics and
vation and responses to orthostasis. J Clin Endocrinol Metabol. 1984;59: outcomes of patients hospitalized for heart failure in the United States:
924 –930. rationale, design, and preliminary observations from the first 100,000
22. Dzau VJ. Renal and circulatory mechanisms in congestive heart failure. cases in the Acute Decompensated Heart Failure National Registry
Kidney Int. 1987;31:1402–1415. (ADHERE). Am Heart J. 2005;149:209 –216.
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
Liviu Klein, Christopher M. O'Connor, Jeffrey D. Leimberger, Wendy Gattis-Stough, Ileana L.
Piña, G. Michael Felker, Kirkwood F. Adams, Jr, Robert M. Califf and Mihai Gheorghiade
Downloaded from by guest on November 26, 2017

for the OPTIME-CHF Investigators

Circulation. 2005;111:2454-2460; originally published online May 2, 2005;

doi: 10.1161/01.CIR.0000165065.82609.3D
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2005 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539

The online version of this article, along with updated information and services, is located on the
World Wide Web at:

Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial
Office. Once the online version of the published article for which permission is being requested is located,
click Request Permissions in the middle column of the Web page under Services. Further information about
this process is available in the Permissions and Rights Question and Answer document.

Reprints: Information about reprints can be found online at:

Subscriptions: Information about subscribing to Circulation is online at: