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European Journal of Heart Failure 2008 10(2):196-200; doi:10.1016/j.ejheart.2008.01.008
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© 2008 European Society of Cardiology

Hyponatraemia in acute heart failure is a marker of increased mortality but not when associated with hyperglycaemia

Olga Milo-Cotterb,*, Gad Cotterb, Beth D. Weatherleyb, Kirkwood F. Adamsc, Edo Kaluskid, Nir Uriele, Christopher M. O'Connora and G. Michael Felkera

a Duke University Medical Center and the Duke Clinical Research Institute USA
b Momentum Research, Inc Durham, USA
c University of North Carolina Chapel Hill, USA
d Cardiac Catheterization Laboratories, Department of Cardiology, University of Medicine and Dentistry Newark, New Jersey, USA
e Assaf Harofeh Medical Center Zerifin, Israel

* Corresponding author. Momentum-Research Inc. (MRI); Suite 802, 3100 Tower Boulevard, Durham, NC, 27707, USA. E-mail address: olgacotter{at}momentum-research.com (O. Milo-Cotter).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Limitations
 6. Conclusions
 References
 
Previous studies suggest that hyponatraemia is a marker of neurohormonal activation and increased mortality in patients with acute heart failure (AHF). Although diabetes is a common co-morbidity in heart failure, no prior study has considered the impact of serum glucose on this relationship.

Methods: Over four consecutive months we prospectively registered all patients admitted due to AHF. Sodium and glucose levels were determined immediately upon admission. Patients were followed through admission and for the next 6 months. Of 342 patients enrolled, complete data were available for 331 patients.

Results: Hyponatraemia (sodium <135 mmol/L) was detected in 22% of patients. However, 47% of patients with hyponatraemia had concomitant hyperglycaemia (glucose level <11 mmol/L). Hyponatraemia was associated with increased 6-month mortality (21 vs. 8%, p=0.002). This association was restricted to patients who had hyponatraemia without concomitant hyperglycaemia. The 6-month mortality of patients with and without hyponatraemia was 11% versus 10% (p=0.87) when hyperglycaemia was present versus 29% and 7% (p=0.001) when hyperglycaemia was absent.

Conclusions: In this preliminary study, hyperglycaemia-associated hyponatraemia was present in a significant proportion of patients admitted with AHF. In patients with hyperglycaemia, hyponatraemia had no prognostic significance, whereas in patients without hyperglycaemia, hyponatraemia remained a powerful predictor of mortality. These results need confirmation in a larger study.

Key Words: Hyponatraemia • Heart failure

Received October 3, 2007; Revised January 9, 2008; Accepted January 16, 2008


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Limitations
 6. Conclusions
 References
 
Hyponatraemia, traditionally defined as a serum sodium <135 mmol/L, is a common clinical finding in patients with acute heart failure [1,2]. A variety of previous studies have demonstrated that the presence of hyponatraemia in patients with heart failure is a marker of greater disease severity and is a powerful predictor of worse prognosis [1,3-5]. As a result of these data, serum sodium has been included as an important component of published risk prediction models in both acute and chronic heart failure [4,6,7].

The development of hyponatraemia in patients with heart failure may result from a variety of mechanisms, including activation of the renin-angiotensin-aldosterone axis, non-osmotic release of arginine vasopressin (AVP), the effects of the sympathetic nervous system on renal vasoconstriction, or the direct effects of diuretic therapy [8,9]. One well-known cause of hyponatraemia that has not previously been evaluated in heart failure patients is hyperglycaemia, sometimes termed "hyperosmolar hyponatraemia". In the presence hyperglycaemia, free water shifts from the intracellular to the extracellular space, while total body sodium and total body water are unchanged [10]. Since this phenomenon reflects the osmotic load of hyperglycaemia rather than heart-failure-mediated activation of the neurohormonal axes and sympathetic nervous system, it may not be associated with the same adverse prognosis seen in other forms of hyponatraemia. Given the high proportion of heart failure patients with diabetes mellitus, the interaction between hyponatraemia and hyperglycaemia would be clinically relevant to predicting prognosis in a substantial proportion of patients with heart failure. To investigate the impact of this relationship, we evaluated the prognostic interactions of serum sodium and serum glucose in a large, well-characterized cohort of acute heart failure patients at a single community hospital.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Limitations
 6. Conclusions
 References
 
2.1. Setting
The study was performed in the Assaf-Harofeh Medical Center, a community hospital in the south eastern part of the Tel-Aviv metropolitan area. Assaf-Harofeh is the only hospital serving a geographical area that includes three cities and approximately 500,000 people.

2.2. Patients and methods
The study was approved by the ethics review board of the Assaf-Harofeh Medical Center. During the study period (December 2003 to March 2004) emergency room records were screened for all hospital admissions due to dyspnoea. AHF was diagnosed by the presence of signs of pulmonary congestion on physical examination and chest X-ray. Patients were identified the day after admission and were followed prospectively. All medical data were obtained from patient files. These data included clinical, laboratory and echocardiographic parameters. For all patients, the first laboratory data recorded in the emergency department (including serum glucose and sodium levels) were obtained. Echocardiographic measures of ejection fraction (EF) were collected from the patients' charts when available. Patients were followed throughout their period of hospitalisation, for episodes of worsening heart failure and death. In-hospital worsening heart failure (WHF) was defined as persistent or recurrent symptoms and signs of heart failure that required an increase or initiation of heart-failure-specific therapy (either intravenous therapy, or mechanical ventilatory or circulatory support). After discharge, all patients were followed up by telephone at three and six months for information related to heart failure admissions and death. If patients could not be contacted directly, additional relevant medical data were obtained from patients' relatives, computerized records from our outpatient clinics, and emergency room records, where possible.

2.3. Statistical analysis
Means with associated standard deviations are presented for continuous variables and the percentage of non-missing values is presented for categorical variables. Groups defined by the cross-classification of hyponatraemia and hyperglycaemia were compared using analysis of variance (ANOVA) for continuous measures and chi-square test for dichotomous measures. Kaplan-Meier curves were constructed for both survival and survival free of worsening heart failure at 6 months, and groups compared using the log rank test. Cox regression was used to estimate hazard ratios for hyponatraemia in the presence or absence of hyperglycaemia, and to test for the interaction of these effects. Analyses were performed using SAS release 9.1 (SAS Institute, Cary, NC).


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Limitations
 6. Conclusions
 References
 
During the study period, 14,144 patients were admitted to the emergency room, of which 6,852 were hospitalised and reviewed for AHF. From this cohort, 355 patients were prospectively identified as being admitted to the hospital with possible signs of AHF; of these, 15 patients did not meet the inclusion criteria and were excluded. Both serum sodium and glucose levels at admission were available for 331 of these patients. The mean serum sodium on admission was 136±11 mmol/L, and 22% of patients had hyponatraemia on admission, defined as a serum sodium <135 mmol/L. Of the patients with hyponatraemia, 47% had co-existing hyperglycaemia (defined as a serum glucose >11 mmol/L). Baseline characteristics stratified by the presence of hyponatraemia and/or hyperglycaemia are presented in Table 1. In general, patients with hyponatraemia without hyperglycaemia had evidence of the greater disease severity, including lower systolic and diastolic blood pressure, lower oxygen saturation on admission, and more renal impairment compared to the remainder of the cohort.


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  		Table 1 Patient characteristics at presentation according to the presence of hyponatraemia and/or hyperglycaemia

 
Six-month mortality for the entire cohort was 10.6%. Patients with hyponatraemia had a higher 6-month mortality than those without hyponatraemia (21% versus 8.0%, p=0.002). However, when patients with hyponatraemia were subdivided according to serum glucose, this risk was confined to those with hyponatraemia without hyperglycaemia (29% 6-month mortality for patients with hyponatraemia vs. 7.0% for those without, p<0.001, Table 2). In patients with hyperglycaemia, 6-month mortality was similar whether hyponatraemia was present (11.4% mortality) or absent (10.3% mortality, p=0.87). Kaplan-Meier survival curves for the various groups are shown in Fig. 1. In Cox regression modelling, the hazard ratio (HR) for hyponatraemia was 4.5 (95% confidence interval (CI) 2.0-9.8) in patients without hyperglycaemia. Conversely, the mortality hazard for patients with hyponatraemia and concomitant hyperglycaemia was not increased (HR 1.1 95% CI 0.3-3.9, p=0.07 for interaction in Cox model).


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  		Table 2 Six month outcomes stratified by presence of hyponatraemia and hyperglycaemia

 


Figure 01
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  		Fig. 1 Kaplan-Meier survival curves by presence of hyponatraemia and/or hyperglycaemia. The p value for the log rank test of equality over the strata was <0.001.

 
For the composite endpoint of death or WHF, hyponatraemia was again associated with adverse outcomes (6-month event rate 55% vs. 41% for those without hyponatraemia, p=0.036). Notably, the risk for the composite endpoint associated with hyponatraemia was similar whether or not concomitant hyperglycaemia was present (57.1%) or absent (52.6%) (Table 2).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Limitations
 6. Conclusions
 References
 
Despite advancements in the treatment of AHF, the morbidity and mortality associated with this clinical syndrome remain high. Clinical variables that accurately risk-stratify patients with AHF are of significant interest, in order to optimize selection of level of care and specific therapies. Hyponatraemia has been one of the most consistent predictors of risk in previous AHF studies. In the recent Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial, 21% of patients had hyponatraemia on admission, of which 87% had persistent hyponatraemia at the time of hospital discharge [11]. Discharge hyponatraemia was associated with a significantly increased risk for early mortality and rehospitalisation for recurrent heart failure events. In the Acute and Chronic Therapeutic Impact of Vasopressin Antagonist in Chronic Heart Failure Trial (ACTIV in CHF), hyponatraemia was observed in 22% of patients at the time of admission for AHF, and predicted mortality at 60 days after discharge [12]. In the Outcomes of Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure Study (OPTIME-CHF), patients in the lowest plasma sodium quartile had longer hospital stay and higher mortality compared to other plasma sodium quartiles [1]. Hyponatraemia on admission has been identified as one of the most important overall prognostic markers in acute heart failure risk prediction models published by Lee et al. [4] and by Felker et al. [7].

Previous published studies have failed to adjust for the effects of hyperglycaemia on serum sodium. Seldin and Tarail described the acute effect of hyperglycaemia in lowering sodium concentration nearly 50 years ago [13]. Through its osmotic load, hyperglycaemia results in the movement of free water from the intracellular to the extracellular space, resulting in a decrease in the serum sodium even though total body water and total body sodium may be unchanged. Subsequently, a correction factor of a 1.6 mmol/L (meq/L) decrease in serum sodium concentration for every 5.5 mmol/L increase in glucose concentration was proposed [14]. Others have suggested amended correction factors ranging from 2.4 to 4.0 mmol/L [15].

Despite these well-known data on the effect of serum glucose on serum sodium concentration (committed to memory by interns everywhere), previous studies evaluating the effect of hyponatraemia in heart failure have failed to adjust for the effect of glucose concentration on serum sodium levels. Our study is therefore the first to evaluate the prognostic effect of hyponatraemia due to hyperglycaemia in heart failure. We found that hyponatraemia in the absence of hyperglycaemia confers a poor short-term prognosis in AHF patients, with a hazard ratio for 6-month mortality of 4.5. Conversely, in AHF patients with presumed "hyperosmolar" hyponatraemia (which was approximately half the hyponatraemia patients in this cohort), there was little if any adverse prognosis associated with the presence of hyponatraemia (hazard ratio for 6-month mortality=1.1). Our study examined a well-characterized cohort from a large community hospital, with similar baseline characteristics to other broadly based studies of AHF [16,17]. Given the high proportion of AHF patients with diabetes mellitus (~45% in our study as well as in the ADHERE Study) [16], our findings are likely to be broadly relevant to a significant number of patients hospitalised with AHF.


   5. Limitations
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Limitations
6. Conclusions
 References
 
The present study is relatively small and the conclusions are based on a relatively limited number of events. Although statistically significant, these results will clearly need to be confirmed in larger studies. Although we collected study data prospectively, the specific analysis of the association between hyperglycaemia and hyponatraemia was retrospective and therefore susceptible to the biases inherent in this type of analysis. Of note, these findings were not seen with the composite endpoint of death or WHF, for which event rates for hyponatraemic patients were similar whether hyperglycaemia was present or absent.


   6. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Limitations
 6. Conclusions
References
 
In summary, we found that the prognostic value of hyponatraemia for predicting mortality was limited to those patients with hyponatraemia without co-existing hyperglycaemia, who had an extremely poor short-term prognosis (29% mortality rate at 6 months). While based on a small number of events, these data suggest the importance of incorporating blood glucose into the analysis of hyponatraemia in acute heart failure. Accurate assessment of the impact of hyponatraemia will allow for better risk stratification and potentially better targeting of therapies in AHF.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Limitations
 6. Conclusions
 References
 

  1. Klein L., O'Connor C.M., Leimberger J.D., et al. 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(19):2454–2460.[Abstract/Free Full Text]
  2. Lee W.H., 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(2):257–267.[Abstract/Free Full Text]
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  4. Lee D.S., Austin P.C., Rouleau J.L., Liu P.P., Naimark D., Tu J.V. Predicting mortality among patients hospitalized for heart failure: derivation and validation of a clinical model. JAMA: J Am Med Assoc (2003) 290(19):2581–2587.[Abstract/Free Full Text]
  5. Chin M.H., Goldman L. Correlates of major complications or death in patients admitted to the hospital with congestive heart failure. Arch Intern Med (1996) 156(16):1814–1820.[Abstract/Free Full Text]
  6. Levy W.C., Mozaffarian D., Linker D.T., et al. The Seattle Heart Failure Model: Prediction of Survival in Heart Failure. Circulation (2006) 113(11):1424–1433.[Abstract/Free Full Text]
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  8. Goldsmith S.R., Gheorghiade M. Vasopressin antagonism in heart failure. J Am Coll Cardiol (2005) 46(10):1785–1791.[Abstract/Free Full Text]
  9. Dzau V.J., Colucci W.S., Hollenberg N.K., Williams G.H. Relation of the renin-angiotensin-aldosterone system to clinical state in congestive heart failure. Circulation (1981) 63(3):645–651.[Free Full Text]
  10. Katz M.A. Hyperglycemia-induced hyponatremia-calculation of expected serum sodium depression. N Engl J Med (1973) 289(16):843–844.[Web of Science][Medline]
  11. Gheorghiade M., Hellkamp A.S., Pina I., et al. Hemodynamic characterization and prognostic value of persistent hyponatremia in patients with severe heart failure in the ESCAPE Trial. J Am Coll Cardiol (2005) 45:145A.
  12. Gheorghiade M., Adams K.F., O'Connor C.M., et al. Improvement in hyponatremia during hospitalization for worsening heart failure is associated with improved outcomes: Insights from the Acute and Chronic Therapeutic Impact of a Vasopressin antagonist in chronic heart failure (ACTIV-CHF) Study. J Am Coll Cardiol (2005) 45:145A.
  13. Seldin D.W., Tarail R. Effect of hypertonic solutions on metabolism and excretion of electrolytes. Am J Physiol (1949) 159(1):160–174.[Free Full Text]
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  15. Hillier T.A., Abbott R.D., Barrett E.J. Hyponatremia: evaluating the correction factor for hyperglycemia. Am J Med (1999) 106(4):399–403.[CrossRef][Web of Science][Medline]
  16. Yancy C.W., Lopatin M., Stevenson L.W., De Marco T., Fonarow G.C. Clinical presentation, management, and in-hospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function: a report from the acute decompensated heart failure national registry (ADHERE) database. J Am Coll Cardiol (2006) 47(1):76–84.[Abstract/Free Full Text]
  17. Cleland J.G.F., Swedberg K., Follath F., et al. The EuroHeart failure survey programme—a survey on the quality of care among patients with heart failure in Europe: Part 1: patient characteristics and diagnosis. Eur Heart J (2003) 24(5):442–463.[Abstract/Free Full Text]

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