The Economic Burden of Hyponatremia: Systematic Review and Meta-Analysis

Accepted Manuscript The Economic Burden of Hyponatremia: Systematic Review And Meta-Analysis Giovanni Corona, MD PhD, Corinna Giuliani, MD, Gabriele Parenti, MD PhD, Giorgio L. Colombo, MSc, Alessandra Sforza, MD, Mario Maggi, MD PhD, Gianni Forti, MD, Alessandro Peri, MD, PhD PII:

S0002-9343(16)30315-1

DOI:

10.1016/j.amjmed.2016.03.007

Reference:

AJM 13445

To appear in:

The American Journal of Medicine

Received Date: 15 January 2016 Revised Date:

10 March 2016

Accepted Date: 10 March 2016

Please cite this article as: Corona G, Giuliani C, Parenti G, Colombo GL, Sforza A, Maggi M, Forti G, Peri A, The Economic Burden of Hyponatremia: Systematic Review And Meta-Analysis, The American Journal of Medicine (2016), doi: 10.1016/j.amjmed.2016.03.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT THE ECONOMIC BURDEN OF HYPONATREMIA: SYSTEMATIC REVIEW AND META-ANALYSIS Running title: The cost of hyponatremia

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Giovanni Corona*, MD PhD, Corinna Giuliani*, MD, Gabriele Parenti*, MD PhD, Giorgio L. Colombo MSc, Alessandra Sforza, MD, Mario Maggi, MD PhD, Gianni Forti, MD and Alessandro

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Peri, MD, PhD

*Equally contributed to this article

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Endocrinology Unit, Maggiore-Bellaria Hospital, Bologna, Italy (GC, AS); Endocrine Unit (CG, GP, GF, AP) and Andrology Unit (MM), “Center for Research, Transfer and High Education on Chronic, Inflammatory, Degenerative and Neoplastic Disorders for the Development of Novel Therapies” (DENOThe), Dept. of Experimental and Clinical Biomedical Sciences “Mario Serio”,

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University of Florence, Careggi Hospital, 50139 Florence, Italy; Department of Drug Sciences, University of Pavia, Italy (GLC).

Address all correspondence and requests for reprints to:

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Alessandro Peri, MD PhD Endocrine Unit Department of Experimental and Clinical Biomedical Sciences”Mario Serio” University of Florence Viale Pieraccini, 6 50139 Florence Italy E mail: [email protected]

Keywords: hyponatremia, hospitalization, costs Funding: None All authors had access to the data Study concept and design: Giovanni Corona; Acquisition of data: Corinna Giuliani, Gabriele Parenti; Analysis and interpretation of data: Giovanni Corona, Alessandro Peri, Giorgio L Colombo; Drafting of the manuscript: Giovanni Corona, Alessandro Peri, Corinna Giuliani; Critical revision of the manuscript for important intellettual content: Gianni Forti, Mario Maggi, Alessandra Sforza, Giorgio L. Colombo; Statistical analysis: Giovanni Corona Study supervision: Alessandro Peri

ACCEPTED MANUSCRIPT ABSTRACT Background

Hyponatremia is the most common electrolyte abnormality observed in

clinical practice. Several studies have demonstrated that hyponatremia is associated with an increased length of hospital stay and of hospital resource utilization. To clarify the impact of

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hyponatremia on the length of hospitalization and costs, we performed a meta-analysis based on published studies that compared hospital length of stay and cost between patients with or without hyponatremia.

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Methods An extensive Medline, Embase and Cochrane search was performed to retrieve all studies published up to April 1st 2015, using the following words: "hyponatremia" or

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“hyponatraemia” AND "hospitalization" or “hospitalization”. A meta-analysis was performed including all studies comparing duration of hospitalization and hospital readmission rate in subjects with and without hyponatremia.

Results Out of 444 retrieved articles, 46 studies satisfied the inclusion criteria encompassing

hyponatremia

was

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a total of 3,940,042 patients; among these 757,763 (19·2%) were hyponatremic. Across all studies associated

with

a

significantly

longer

duration

of

hospitalization

(3·30[2·90;3·71] mean days; p<0·000). Similar results were obtained when patients with associated

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morbidities were analyzed separately. Furthermore, hyponatremic patients had a higher risk of readmission after the first hospitalization (OR=1·32[1·18;1·48]; p<0·000). A meta-regression

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analysis showed that the hyponatremia-related length of hospital stay was higher in males (S=0·09[0·05;0·12];p=0·000

and

I=-1·36[-3·03;0·32];

p=0·11)

and

in

elderly

patients

(S=0·002[0·001;0·003];p<0·000 and I=0·89[0·83;0·97]; p<0·001). A negative association between serum [Na+] cut-off and duration of hospitalization was detected. No association between duration of hospitalization, serum [Na+] and associated morbidities was observed. Finally, when only US studies (n=8) were considered, hyponatremia was associated with up to $3,000 higher hospital costs/patient when compared to the cost of normonatremic subjects.

ACCEPTED MANUSCRIPT Conclusions

This meta-analysis confirms that hyponatremia is associated with a prolonged

hospital length of stay, and higher risk of readmission. These observations suggest that

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hyponatremia may represent one important determinant of the hospitalization costs.

ACCEPTED MANUSCRIPT INTRODUCTION Hyponatremia, defined as a serum sodium concentration ([Na+]) <136 mEq/L, is the most common electrolyte abnormality observed in clinical practice and occurs in up to 30% of hospitalized patients in its mild form (serum [Na+] 130-134 mEq/L).1,2 Clinical and experimental

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evidence have demonstrated that hyponatremia represents a serious problem that is associated with significant morbidity and mortality. It is well known that acute severe hyponatremia may have severe neurological consequences, due to cerebral edema, and that it can be lethal if not diagnosed

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and effectively treated.3 Recent studies have demonstrated that chronic and mild hyponatremia also may negatively affect the health status, with deleterious effects that affect particularly the central

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nervous systems and the bone, causing gait instability, attention deficits, falls, osteoporosis and fractures.4-7

The association between hyponatremia and in-hospital mortality has been demonstrated in the elderly,8and in several clinical conditions, such as heart failure,9 pneumonia,10 acute myocardial

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infarction,11 cirrhosis,12 cancer.11 We have recently confirmed in an extensive meta-analysis that hyponatremia is significantly associated with an increased risk of overall mortality in hospitalized patients.13 We have observed also a rather small difference in serum [Na+] (mean 4·8 mEq/L) in

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patients who died compared to survivors, suggesting that mild hyponatremia may also lead to death. However, whether hyponatremia is a direct cause of death or is simply a marker of severity of an

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underlying pathological condition (such as heart failure, cancer, cirrhosis) that is associated to death is not clear, so far.14,15 Another critical point to clarify is whether the correction of hyponatremia could revert or reduce the increased risk of death associated with this electrolyte disorder. For this reason we recently performed a further meta-analysis that compared the mortality rate in patients with or without improvement of hyponatremia. As hypothesized, we found that any improvement of serum [Na+] was associated with a significant reduced risk of overall mortality.16 Taken together, these data suggest that hyponatremia, even when mild and chronic, represents also an economic and social burden because of the associated disability and mortality.

ACCEPTED MANUSCRIPT Therefore, it is not surprising that hyponatremia is associated with an increased length of hospital stay and in hospital resource utilization and costs.17 Several studies have demonstrated that hospitalacquired

hyponatremia was associated with higher costs of care in patients with cancer,18

cirrhosis19 and heart failure.20 In the US, the direct medical costs of hyponatremia were estimated to

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range between $1.6 billion and $3.6 billion21 and could be associated not only with the increased mortality and morbidity associated to this condition, but also with a prolonged length of stay in hospital.

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To clarify the impact of hyponatremia on length of hospital stay and costs, here we performed an original meta-analysis based on published studies that compared hospital length of

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stay, risk of hospital readmission and costs between patients with and without hyponatremia.

ACCEPTED MANUSCRIPT METHODS This meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist (see Supplementary file 1) (http://www.prismastatement.org/).

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Eligibility criteria

All studies specifically addressing the duration of hospitalization, cost and readmission risk

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Information source and Search strategy

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in subjects with and without hyponatremia were included in the analysis.

An extensive Medline, Embase, and Cochrane search was performed including the following words: ("hyponatraemia"[All Fields] OR "hyponatremia"[MeSH Terms] OR "hyponatremia"[All Fields])

AND

("hospitalisation"[All

Fields]

OR

"hospitalization"[MeSH

Terms]

OR

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"hospitalization"[All Fields]). The search (up to November 1st 2015) was restricted to Englishlanguage articles and human studies. A hand-searched bibliography of retrieved papers for additional references was performed. Details of the literature search process are outlined in the flow

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chart. The identification of relevant abstracts, the selection of studies based on the criteria described

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above, and the subsequent data extraction were performed independently by two of the authors (G.P., C.G.), and conflicts resolved by a third investigator (G.C). Full-text articles and meeting abstracts were included. The quality of studies was assessed using the Cochrane criteria.22

Study selection The meta-analysis was performed including all studies comparing duration of hospitalization and hospital readmission rate in subjects with and without hyponatremia (see Figure 1 and Table 1). Patients who died during hospitalization were not excluded and in this case length of hospitalization

ACCEPTED MANUSCRIPT was considered the time between admission and death. Studies that did not not specifically address the association between duration of hospitalization or hospitalization readmission rate in subjects with and without hyponatremia were excluded from the analysis (see Supplementary file 2 and

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Table 2).

Outcome and quality assessment

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The principal outcome of this analysis was to compare the duration of the hospitalization and costs in subjects with or without hyponatremia at admission. A secondary outcome included the

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risk of hospitalization readmission in patients with or without hyponatremia. The quality of the studies was assessed using the Cochrane criteria.22

Statistical analysis

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Heterogeneity on duration of hospitalization in patients with or without hyponatremia was assessed by using I2 statistics. Even when a low heterogeneity was detected, a random-effects model was applied, because the validity of tests of heterogeneity can be limited with a small number of

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component studies. To estimate possible publication or disclosure bias we used funnel plots, the Begg adjusted rank correlation test and Egger's test. A meta-regression analysis was performed to

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test the effect of age, serum [Na+] cut-off and several associated-morbidities at enrollment on duration of hospitalization. In addition, a linear regression analysis model, which weighted each study for the number of subjects enrolled, was performed to verify the independent effect of hyponatremia on duration of hospitalization after the adjustment for age and sex and serum [Na+] cut-off. All data were calculated using Comprehensive Meta-analysis Version 2, Biostat, and (Englewood, NJ, USA). Logistic multivariate analysis was performed on SPSS (Statistical Package for the Social Sciences; Chicago, USA) for Windows 20.1.

ACCEPTED MANUSCRIPT RESULTS Out of 444 retrieved articles, 358 articles were excluded for different reasons. The flow of the meta-analysis is summarized in Figure 1, and the characteristics of the studies included in the meta-analysis are summarized in Table 1 (see references 17, 19, 20, 23-65). 86 full-text articles

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were considered potentially eligible for the meta-analysis. However, 37 of them were excluded because they did not include information about serum [Na+] (n=4) or about duration of hospitalization (n=33) (see Supplementary file 2). Three additional studies were excluded, because

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they met inclusion criteria but did not provide data for meta-analysis (Table 2).66-68

The 46 selected studies were grouped according to different pathological conditions (Fig. 1

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and Table 1). Among them, 5 studies evaluated pediatric patients. Eleven studies reported data on the effect of hyponatremia for combined mixed diseases, which could not be grouped separately. Additional 9 studies retrospectively investigated the effect of hyponatremia in hospitalized series of subjects. In these studies, a major diagnosis was not specified.

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The risk of hospital readmission in subjects with and without hyponatremia was specified in 8 of the aforementioned studies.

Overall 3,940,042 patients and 757,763 hyponatremic subjects (19·2%) were included in the

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meta-analysis. Hyponatremia was defined according to varying cut-off definitions in the included studies (Table 1). When the same study reported data according to different serum [Na+] thresholds,

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a weighted arithmetic mean was considered. I2 in trials assessing the duration of hospitalization in subjects with and without hyponatremia was 99·4 (p<0·000). Funnel plot and Begg adjusted rank correlation test (Kendall’s τ: 0·18; p=0·09) suggested no major publication bias. When all 45 studies reporting data on duration of hospitalization were considered, hyponatremia was significantly associated with a significantly longer duration of hospitalization (3·30[2·90; 3·71] days; p<0·000). Similar results were obtained when patients with specific diseases or series of hospitalized patients were analyzed separately (Figure 2, panels A-G). Similarly, hyponatremic patients had a higher risk of hospitalization readmission (mean follow up

ACCEPTED MANUSCRIPT 72 days after first hospital discharge) when compared to those with normal [Na+] at the first hospital admission (Figure 3). Sub-analysis for risk of hospitalization readmission in specific diseases was not performed because of insufficient data. A meta-regression analysis showed that the hyponatremia-related duration of hospitalization

mild

association

between

age

and

longer

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was higher in males (S=0·09[0·05;0·12];p=0·000 and I=-13·6[-3·03;0·32]; p=0·11). In addition, a hospitalization

was

also

observed

(S=0·002[0·001;0·003];p<0·0001 and I=0·89[0·83;0·97]; p<0·000). Finally, a negative association

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between serum [Na+] cut-off and duration of hospitalization was detected (Figure 4). The latter association was confirmed in a multivariate regression model adjusting for age and sex (adj r = -

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0·210; p<0·000). Conversely, no association between duration of hospitalization, serum [Na+] and several associated morbidities such as history of heart failure, cardiovascular diseases, diabetes mellitus, hypertension, cirrhosis or chronic renal insufficiency at enrollment was observed (not shown).

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Finally, 9 studies reported differences in mean hospital cost between subjects with and without hyponatremia. Among them, 8 (see references 17, 19, 20, 25, 28, 29, 35, 47) included subjects living in the US and 1 was related to Spanish patients.30 When only studies from US were

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considered, hyponatremia was associated with a higher mean hospital cost (Figure 5).

ACCEPTED MANUSCRIPT DISCUSSION The present meta-analysis, which derives from the study of a large number of patients, confirms that hyponatremia represents a frequent condition observed in up to 20% of hospitalized patients. In addition, our data suggest that hyponatremia is associated with a prolonged hospital

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length of stay, and higher risk of readmission. The data were similar when European studies were compared to those performed in North America. Length of hospital stay is a strong determinant of the cost of hospital care.69 Hence, taken together these observations indicate that hyponatremia may

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represent one important determinant of the medical costs associated with hospitalization. Accordingly, our data showed that when only US studies were considered hyponatremia was

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associated with an increase of hospital costs of up to $3,000 when compared to normonatremia. A consensus panel of expert physicians suggested that the annual inpatient costs/patient directly attributable to hyponatremia (serum [Na+] <130 mEql/L) in the US ranges from $1528 to $3441.21 More recently, longitudinal data from a large managed care claim US database (Waltham, MA)

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indicated that an even higher 1-yr mean inpatient cost could be related to hyponatremic subjects ($10,636).70 Interestingly, similar costs (about $13,700 per year) have been estimated by the American Diabetes Association for the treatment of diabetic patients.71 Despite these data,

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hyponatremia is still underdiagnosed and often poorly considered if not ignored. Accordingly, we recently reported that an improvement of serum [Na+] of any degree was obtained in only 53·2% of

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hospitalized patients.16 In addition, among them about 1 out of 4 patients did not reach a serum [Na+] threshold of 130 mEq/L. 16 In agreement with these data, it has been shown that only a small percentage of patients with hyponatremia receive an ICD-9-CM diagnosis code for hyponatremia.72 In particular, among 2,134,363 admittances from all departments of internal medicine of the Spanish National Health System, only 1·5% coded hyponatremia as a primary or a secondary diagnosis.30 As reported above, such a percentage is very far from the true prevalence of this condition in hospitalized patients. An analysis of the reasons behind these data is beyond the aim of the present study. However, it is interesting to note that the vast majority of hyponatremia-related

ACCEPTED MANUSCRIPT ICD-9-CM was codified as a secondary diagnosis (81·7%).30 Hence, hyponatremia appears to be viewed as a secondary problem from the perspective of most physicians.30 Accordingly, whether hyponatremia represents an independent risk factor for mortality and morbidity or it is simply associated with other conditions that significantly raise these risks remains to be elucidated.

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Current data cannot clarify this point; however, it is interesting to note that hyponatremia-related increased length of hospital stay was confirmed even after the adjustment for age and gender and it was also independent of the type of related diseases. Similarly, a retrospective analysis of 1,046

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patients hospitalized for heart failure, who participated in the CHF Benchmark Project, a large collaborative quality improvement project coordinated by the University Health System Consortium

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in the US, confirmed that hyponatremia was an independent predictor of the duration of hospitalization.31 Similar results were reported in a series of 1402 patients admitted to 10 acute care community hospitals during 1995 in New York.73 In addition, more recently data from the Minimum Basic Data Set of discharged patients from all departments of internal medicine of the

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Spanish National Health System (NHS) between 2007 and 2010 showed that hyponatremia was independently associated with a longer hospitalization, higher costs and was considered a powerful

the Charlson index.30

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predictor of hospital readmission even after the adjustment of associated morbidities, as detected by

Another interesting finding of the present study derives from the meta-regression analysis,

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which indicates that the duration of hospitalization was even longer in patients with lower serum [Na+] at enrollment. Interestingly, in a recent meta-analysis we reported that the favorable effects of hyponatremia correction were inversely related to hyponatremia at enrollment.16 these findings suggest that patients with a more severe hyponatremia deserve an even more thoughtful work up, because the outcome of patients who were correctly treated for this condition may be more favorable compared to those who did not receive an appropriate treatment. The possible pathogenetic mechanisms underlying hyponatremia related morbidity and mortality are not completely understood. Hyponatremia-induced oxidative stress has been suggested

ACCEPTED MANUSCRIPT to play an important role.74,75 However, a growing body of evidence also indicates that several inflammatory mediators such as Il-1 and IL-6 can induce hyponatremia through excessive vasopressin release,76 thus confirming the presence of a bidirectional relationship between hyponatremia and inflammatory response.76,77 These data further confirm that a cause-effect

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relationship between hyponatremia, hospital length of stay and readmission rate cannot be extrapolated from the studies that have been analyzed here. Accordingly, it should be recognized that the data were adjusted only for age and gender, whereas the prevalence of associate morbidities

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was not considered as possible confounders, because they were not adequately reported in a sufficient number of studies. However, it should be recognized that a large survey regarding

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hospitalized patients confirmed an association between hyponatremia and longer hospitalization even after the adjustment of possible confounders including age, sex, race, admission service, and associated morbidities, as derived from the Deyo-Charlson Comorbidity Index score.27 A further limitation of the present study is represented by incomplete reports of the data on

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hospital duration and readmission rate in trials only marginally designed for the assessment of these endpoints. The prolonged hospital length of stay could be affected by the economic system of reimbursement in hospitals located in different countries. Admittedly, this issue may have an

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influence on the behavior of health professionals. In addition, the statistical analysis showed the presence of heterogeneity.78-79 Finally, even if statistical analyses did not suggest any relevant

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publication bias, the possibility of selective reporting cannot be excluded. In any case, the economic impact of hyponatremia in terms of prolonged hospitalization suggests that diagnostic and therapeutic algorithms used in clinical practice should be implemented. These considerations highlight the need for additional, well-designed studies of clinical outcomes with effective therapies in patients with hyponatremia.80-82

ACCEPTED MANUSCRIPT Conflicts of interest Alessandro Peri has served as a consultant and member of advisory boards for Otsuka. Giorgio L. Colombo has served as a consultant on advisory boards for Astellas, LEO Pharma, Sanofi, Merck Sharp and Dohme, DOC Generici, Takeda, UCB Pharma and MerckSerono, and has received

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research and educational grants from Bayer HealthCare, Takeda, Gilead Sciences, Merck Sharp and

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Dohme, Otsuka and LEO Pharma. The authors report no other conflicts of interest in this work.

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43. Hackworth WA, Heuman DM, Sanyal AJ, et al. Effect of hyponatraemia on outcomes following orthotopic liver transplantation. Liver Int 2009; 29:1071-7. 44. Yun BC, Kim WR, Benson JT, et al. Impact of pretransplant hyponatremia on outcome following liver transplantation. Hepatology 2009; 49:1610-5.

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45. Karapanagiotou A, Kydona C, Papadopoulos S, et al. The effect of hyponatremia on the outcome of patients after orthotopic liver transplantation. Transplant Proc 2012; 44:272426.

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46. Nair V, Niederman MS, Masani N, Fishbane S. Hyponatremia in community-acquired pneumonia. Am J Nephrol 2007; 27:184-90.

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47. Zilberberg MD, Exuzides A, Spalding J, Foreman A, Jones AG, Colby C, Shorr AF. Hyponatremia and hospital outcomes among patients with pneumonia: a retrospective cohort study. BMC Pulm Med 2008; 18: 8:16. 48. Scherz N, Labarère J, Méan M, Ibrahim SA, Fine MJ, Aujesky D. Prognostic importance of hyponatremia in patients with acute pulmonary embolism. Am J Respir Crit Care Med 2010; 182:1178-83. 49. Campo A, Mathai SC, Le Pavec J,et al. Outcomes of hospitalisation for right heart failure in pulmonary arterial hypertension. Eur Respir J 2011; 38:359-67.

ACCEPTED MANUSCRIPT 50. Dhawan A, Narang A, Singhi S. Hyponatraemia and the inappropriate ADH syndrome in pneumonia. Ann Trop Paediatr 1992; 12:455-62. 51. Al-Zahraa Omar F, Al Bunyan M. Severe hyponatremia as poor prognostic factor in childhood neurologic diseases. J Neurol Sci 1997; 151:213-16.

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52. Williams C, Simon TD, Riva-Cambrin J, Bratton SL. Hyponatremia with intracranial malignant tumor resection in children. J Neurosurg Pediatr 2012; 9:524-9.

53. Luu R, DeWitt PE, Reiter PD, Dobyns EL, Kaufman J. Hyponatremia in children with

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bronchiolitis admitted to the pediatric intensive care unit is associated with worse outcomes. J Pediatr 2013; 163:1652-56.

Med Biol 2013; 788:103-8.

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54. Wrotek A, Jackowska T. Hyponatremia in children hospitalized due to pneumonia. Adv Exp

55. Tang WW, Kaptein EM, Feinstein EI, Massry SG. Hyponatremia in hospitalized patients with the acquired immunodeficiency syndrome (AIDS) and the AIDS-related complex. Am J

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Med 1993; 94:169-74.

56. Sherlock M, O'Sullivan E, Agha A, et al. The incidence and pathophysiology of hyponatraemia after subarachnoid haemorrhage. Clin Endocrinol (Oxf) 2006; 64:250-4.

EP

57. Funk GC, Lindner G, Druml W, Metnitz B, Schwarz C, Bauer P, Metnitz PG. Incidence and prognosis of dysnatremias present on ICU admission. Intensive Care Med 2010; 36:304-11.

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58. Saifudheen K, Jose J, Gafoor VA, Musthafa M. Guillain-Barre syndrome and SIADH. Neurology 2011; 76:701-4. 59. Tada Y, Nakamura T, Funayama H, Sugawara Y, Ako J, Ishikawa SE, Momomura S. Early development of hyponatremia implicates short- and long-term outcomes in ST-elevation acute myocardial infarction. Circ J 2011; 75:1927-33. 60. Doshi SM, Shah P, Lei X, Lahoti A, Salahudeen AK. Hyponatremia in hospitalized cancer patients and its impact on clinical outcomes. Am J Kidney Dis 2012; 59:222-28.

ACCEPTED MANUSCRIPT 61. Hagino T, Ochiai S, Watanabe Y, et al. Hyponatremia at admission is associated with inhospital death in patients with hip fracture. Arch Orthop Trauma Surg 2013; 133:507-11. 62. Salahudeen AK, Doshi SM, Pawar T, Nowshad G, Lahoti A, Shah P. Incidence rate, clinical correlates, and outcomes of AKI in patients admitted to a comprehensive cancer center. Clin

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J Am Soc Nephrol 2013; 8:347-54.

63. Vandergheynst F, Sakr Y, Felleiter P,et al. Incidence and prognosis of dysnatraemia in critically ill patients: analysis of a large prevalence study. Eur J Clin Invest 2013; 43:933-

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48.

64. Causland FR, Wright J, Waikar SS. Association of serum sodium with morbidity and

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mortality in hospitalized patients undergoing major orthopedic surgery. J Hosp Med 2014; 9:297-302.

65. Cumming K, Hoyle GE, Hutchison JD, Soiza RL. Prevalence, incidence and etiology of hyponatremia in elderly patients with fragility fractures. PLoS One 2014; 9:e88272.

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66. Borenstein J, Aronow HU, Bolton LB, Choi J, Bresee C, Braunstein GD. Early recognition of risk factors for adverse outcomes during hospitalization among Medicare patients: a prospective cohort study. BMC Geriatr 2013; 13:72.

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67. Leung AA, McAlister FA, Rogers SO Jr, Pazo V, Wright A, Bates DW. Preoperative hyponatremia and perioperative complications. Arch Intern Med 2012; 172:1474-81.

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68. Dunlay SM, Gheorghiade M, Reid KJ, et al. Critical elements of clinical follow-up after hospital discharge for heart failure: insights from the EVEREST trial. Eur J Heart Fail 2010; 12:367-74.

69. Lave JR, Leinhardt S. The cost and length of a hospital stay. Inquiry 1976; 13:327-43. 70. Shea AM, Hammill BG, Curtis LH, Szczech LA, Schulman KA. Medical costs of abnormal serum sodium levels. J Am Soc Nephrol 2008; 19:764-70. 71. American Diabetes Association. Economic costs of diabetes in the U.S. in 2012. Diabetes Care 2013; 36:1033-46.

ACCEPTED MANUSCRIPT 72. Movig KL, Leufkens HG, Lenderink AW, Egberts AC. Validity of hospital discharge International Classification of Diseases (ICD) codes for identifying patients with hyponatremia. J Clin Epidemiol 2003; 56:530-5. 73. Philbin EF, Rocco TA Jr, Lynch LJ, Rogers VA, Jenkins P. Predictors and determinants of

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hospital length of stay in congestive heart failure in ten community hospitals. J Heart Lung Transplant 1997; 16:548-55.

74. Barsony J1, Sugimura Y, Verbalis JG. Osteoclast response to low extracellular sodium and

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the mechanism of hyponatremia-induced bone loss. J Biol Chem 2011286:10864-75. 75. Benvenuti S, Deledda C, Luciani P, et al. Low extracellular sodium causes neuronal distress

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independently of reduced osmolality in an experimental model of chronic hyponatremia.

76. Park SJ, Shin JI.Inflammation and hyponatremia: an underrecognized condition? Korean J Pediatr 2013; 56:519-22.

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77. Mastorakos G, Weber JS, Magiakou MA, Gunn H, Chrousos GP. Hypothalamic-pituitaryadrenal axis activation and stimulation of systemic vasopressin secretion by recombinant interleukin-6 in humans: potential implications for the syndrome of inappropriate

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vasopressin secretion. J Clin Endocrinol Metab 1994; 79:934-39. 78. Carande-Kulis VG, Maciosek MV, Briss PA, et al. Methods for systematic reviews of

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economic evaluations for the Guide to Community Preventive Services. Task Force on Community Preventive Services. Am J Prev Med. 2000;18(Suppl 1):75–91. 79. Drummond MF, O’Brien BJ, Stoddart GL, et al. Methods for the Economic Evaluation of Health Care Programmes. 3rd ed. New York: Oxford University Press; 2006. 80. Peri A. Clinical review: the use of vaptans in clinical endocrinology. J Clin Endocrinol Metab 2013; 98: 1321–1332. 81. Verbalis JG, Goldsmith SR, Greenberg A, et al. Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations. Am J Med 2013; 12:S1-42.

ACCEPTED MANUSCRIPT 82. Konstam MA, Udelson JE. Hyponatraemia and vasopressin in heart failure: markers or

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mediators? Eur J Heart Fail 2009; 13: 242–44.

ACCEPTED MANUSCRIPT FIGURE LEGENDS

Figure 1. Trial flow diagram.

RI PT

Figure 2. Mean duration of hospitalization (95% CI; days) in patients with or without (no) hyponatremia in hospitalized series of subjects (A) or according to the presence of heart failure (B), heart surgery (C), liver diseases (D), pulmonary diseases (E), pediatric patients (F) or combined

SC

disease (G).

Figure 3. Odds ratio (95% CI) for hospital readmission in patients with or without (no)

M AN U

hyponatremia.

Figure 4. Weighted relationship between serum [Na+] cut-off definition and duration of hospitalization.

AC C

EP

hyponatremia.

TE D

Figure 5. Mean hospitalization cost (95% CI; Us dollar) in patients with or without (no)

ACCEPTED MANUSCRIPT

Type

Age

Male

Na+

Patients

H

NH

HF

DM

HT

CD

RF

CH

of disease

(years,

(%)

cut-off

(n)

(n)

(n)

(%)

(%)

(%)

(%)

(%)

(%)

mean) Lim et al, 200123

(mEq/L)

Hospitalized

NA

40.5

130

407

55

Hospitalized

65.1

47.5

135

204

104

Zilbeberg, Exuzides et al, 200817 (USA)

Hospitalized

61.8

45.5

135

198281

Callahan et al,

Hospitalized

59.5

53.5

134

Whyte et al, 200926 (UK)

Hospitalized

69

39.7

135

Wald et al, 201027 (Canada)

Hospitalized

55.2

48.2

Amin et al, 201228

Hospitalized

NA

42.9

Gill et al, 200624 (UK)

Deitelzweig, Amin

NA

NA

NA

100

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

9620

2047

7573

44.6

NA

NA

NA

0.8

7.9

226

113

113

NA

NA

NA

NA

NA

NA

M AN U

187382

138

53236

20181

33055

16.9

14.8

NA

9.3

2.6

1.6

117630

55881

558815

4.1

NA

NA

NA

NA

4.2

135

5

71.6

24.23

135

36048

18024

18024

12

NA

NA

NA

NA

4.12

Hospitalized

71.6

53.2

136

2134363

31933

2102430

21.9

23.2

NA

NA

4.7

2.1

et al, 2013 (USA)

(Spain)

NA

Hospitalized

29

Marco et al, 201330

NA

EP

(USA)

NA

10899

TE D

(USA)

AC C

2009

25

352

SC

(Japan)

RI PT

Source

ACCEPTED MANUSCRIPT

Krumholz et al,

Heart failure

NA

41

135

1046

171

875

100

40

NA

52

20

NA

Heart failure

73.2

48.3

135

47647

7882

32572

100

41.6

23

45.7

NA

NA

Heart failure

56.2

NA

135

398

71

327

100

NA

NA

NA

NA

NA

Heart failure

NA

NA

NA

2005

1789

100

NA

NA

NA

NA

NA

Heart failure

77

46.3

135

1.3

Heart failure

75.3

44.17

135

Heart failure

77.2

46.25

31

Gheorghiade et al, 32

2007 (USA) Gheorghiade et al, 33

Cyr et al, 201134

Shorr et al, 201135 (USA) Amin et al, 201320

Arèvalo Lorido et al, 36

2013 (Spain) Heart failure

73

57.9

Heart failure

75.9

Heart failure

Heart surgery

al, 2013 (USA) Hamaguchi et al, 39

2014 (Japan) Crestanello et al, 40

2013 (USA)

87682

100

NA

NA

NA

3.8

51710

25855

25855

100

NA

NA

NA

NA

NA

147

826

100

44.5

84.0

20.7

36.1

NA

6

6

7

973

4837

561

4276

100

33.8

69.3

31.1

NA

NA

46.5

135

5347

2341

3006

100

4.2

NA

25.8

6.1

1.4

70.7

59.3

135

1659

176

1483

100

30

52.1

28.2

NA

NA

61.8

66.2

135

4370

931

3439

100

40

77.7

38.2

13.1

NA

AC C

38

24562

135

(Japan) Shchekochikhin et

135

EP

Sato et al, 2013

37

112244

TE D

(USA)

216

M AN U

(USA)

SC

2007 (USA)

RI PT

1999 (USA)

ACCEPTED MANUSCRIPT

Crestanello et al,

Heart surgery

61.4

66.4

135

4850

2875

1975

NA

35.5

77.3

NA

13.5

NA

Heart surgery

62.2

66.6

135

2247

527

1720

NA

38.9

83.5

44.7

9.5

NA

Liver diseases

51

78

130

213

90

123

NA

NA

NA

NA

NA

100

Liver diseases

50.1

55.7

135

2175

1495

NA

NA

NA

NA

NA

100

Liver diseases

51.6

65.21

135

Liver diseases

55.3

64.1

135

Pulmonary diseases

73.5

50

Pulmonary diseases

68.4

45

Pulmonary diseases

67

Pulmonary diseases Pediatric series

41

Crestanello, Phillips 42

et al, 2013 (USA) Hackworth et al, 43

Yun et al, 200944

Karapangiotou et al, 45

2012 (Greece) Deitelzweig et al, 19

Zilbeberg et al, 47

2008 (USA) Scherz et al, 201048 (Switzerland) Campo et al, 201149 (USA) Dhawan et al, 199250 (India)

52

NA

NA

NA

NA

NA

100

21864

10932

10932

NA

NA

NA

NA

NA

100

342

95

247

22

20

50.5

NA

NA

0.6

135

7965

649

7316

NA

NA

NA

NA

NA

NA

40.2

135

13728

2907

10821

16.5

NA

NA

NA

NA

NA

55

8

136

115

52

63

NA

6.6

27.9

5.1

NA

NA

3.1

73

131

727

217

510

NA

NA

NA

NA

NA

NA

EP

(USA)

23

135

AC C

Nair et al, 200746

75

TE D

2013 (USA)

680

M AN U

(USA)

SC

2009 (USA)

RI PT

2013 (USA)

ACCEPTED MANUSCRIPT

Al-Zaharaa et al,

NA

56.9

130

72

37

35

NA

NA

NA

NA

NA

NA

Williams et al,

Pediatric series

NA

NA

135

2343

205

2138

NA

NA

NA

NA

NA

NA

Pediatric series

0.8

54

135

102

23

79

NA

NA

NA

NA

NA

NA

Pediatric series

NA

52.8

136

312

208

NA

NA

NA

NA

NA

NA

Combined diseases

34.2

NA

135

Combined diseases

50

52.9

135

Combined diseases

63.2

58.4

Combined diseases

42

72

Combined diseases

64.4

Combined diseases Combined diseases

52

2012 (USA) Luu et al, 201353

Wrotek et al, 201354

56

2006 (Ireland) Funk et al, 201057 (Austria) Saifudheen et al, 58

2011 (India) Tada et al, 201159 (Japan) Doshi et al, 201260 (USA) Hagino et al, 201361 (Japan)

210

83

127

NA

NA

NA

NA

NA

NA

316

179

137

NA

NA

NA

NA

NA

NA

TE D

Sherlock et al,

135

140952

26782

14170

NA

NA

NA

NA

NA

NA

135

50

24

26

NA

NA

NA

NA

NA

NA

84.8

136

140

29

111

NA

41.2

64.7

100

NA

NA

56

52

135

3357

1596

1761

NA

NA

NA

NA

NA

NA

82.6

21.5

135

512

49

463

NA

NA

NA

NA

NA

NA

EP

(USA)

AC C

Tang et al, 199355

104

M AN U

(Poland)

SC

(USA)

RI PT

1997

Pediatric series

51

ACCEPTED MANUSCRIPT

Vandergheynst et al, 63

2013 (Europe) Causland et al, 64

2014 (USA) Cumming et al, 65

2014 (UK)

55.8

51.8

135

3356

1571

1785

NA

NA

NA

NA

NA

NA

Combined diseases

60.6

62.3

135

11174

1703

9461

9.6

NA

NA

NA

9.2

3.2

Combined diseases

62.5

44.8

135

15797

1234

14563

10

12.4

NA

NA

NA

0.65

Combined diseases

79

22

135

127

NA

NA

NA

NA

NA

NA

Table 1. Observational studies included in the meta-analysis.

RI PT

2013 (India)

Combined diseases

SC

62

33

M AN U

Salahudeen et al,

94

H: patients with hyponatremia; NH: patients without hyponatremia; HF: heart failure; DM: diabetes mellitus; HT: hypertension; CD: cardiovascular

AC C

EP

TE D

disease; RF: renal failure; CH: cirrhosis; NA: not available

ACCEPTED MANUSCRIPT

Dunlay et al, 201068

RI PT

Leung et al, 201267

SC

Borenstein et al, 201366

Brief description of the study and main conclusions Prospective cohort study in a sample of Medicare patients to identify patient characteristics associated with adverse events that are present early in a hospital state. Hyponatremia was an independent risk factor of readmission within 30 days but there were no data about rate of readmission in patients with hyponatremia vs patients without hyponatremia. Retrospective cohort of 964263 adults undergoing major surgery and observed for 30-day to determine whether preoperative hyponatremia is a predictor of 30-day perioperative morbidity and mortality. Hyponatremia was associated with prolonged median lengths of stay by approximately 1 day but there were no specific data available for meta-analysis. Retrospective analysis of data from the EVEREST trial to identify risk factors predicting cardiovascular rehospitalization and mortality. Hyponatremia was an independent risk factors for re-hospitalization and mortality but there were no data about rate of readmission in patients with hyponatremia vs patients without hyponatremia.

M AN U

First author, year

AC C

EP

TE D

Table 2. Studies that met inclusion criteria but did not provide data for meta-analysis

ACCEPTED MANUSCRIPT

Records identified through different sources N=444

SC

RI PT

Records removed: Review or Editorials N= 48 Case report N=47 Comment/Editorial N= 11 Does not meet inclusion criteria N= 252

M AN U

Full-text article assessed for eligibility N= 86

Full-text articles excluded: No serum sodium data N= 4 No LOS data N= 33

Studies excluded (see table 2) N= 3

AC C

EP

TE D

Studies included in qualitative synthesis N= 49

Studies included in quantitative synthesis (meta-analysis) N= 46

HOSPITALIZED SERIES N= 9

HEART FAILURE N=10

HEART SURGERY N=3

LIVER DISEASES N=4

PULMONARY DISEASES N=4

PEDIATRIC SERIES N=5

COMBINED DISEASES N=11

ACCEPTED MANUSCRIPT

A

Statistics for each study

EP

Meta Analysis

AC C

Overall

0,90 3,00 1,40 2,00 5,00 0,70 1,10 0,24 1,80 1,19

-0,04 -0,16 1,24 0,81 1,63 0,58 1,06 0,17 1,67 0,76

TE D

Lim et al, 2001 Gill et al, 2006 Zilbeberg, Exuzides et al, 2008 Callahan et al, 2009 Whyyte et al, 2009 Wald et al, 2010 Amin et al, 2012 Deitelzweig, Amin et al, 2013 Marco et al, 2013

Lower limit

Upper limit 1,84 6,16 1,56 3,19 8,37 0,82 1,14 0,31 1,93 1,63

SC

Difference in means

Difference in means and 95% CI

M AN U

Study name

RI PT

Hospitalized series Meta Analysis

-8,00

-4,00

0,00

No Hyponatremia Favours A

4,00

8,00

Hyponatremia Favours B

ACCEPTED MANUSCRIPT

Heart Meta failure Analysis

AC C

Meta Analysis

-0,08 0,53 0,77 0,51 0,82 1,26 0,66 6,51 0,99 5,08 1,01

TE D

2,00 1,06 0,90 2,11 0,90 1,40 1,50 10,00 2,00 10,50 1,33

EP

Gheorghiade et al, 1998 Krumholz et al, 1999 Gheorghiade et al, 2007 Cyr et al, 2011 Shorr et al, 2011 Amin et al, 2013 Arévalo Lorido et al, 2013 Sato et al, 2013 Shchekochikhin et al, 2013 Hamaguchi et al, 2014 Overall

Lower limit

Upper limit 4,08 1,59 1,03 3,71 0,98 1,54 2,34 13,49 3,01 15,92 1,65

Difference in means and 95%CI

SC

Difference in means

RI PT

Statistics for each study

M AN U

Study name

B

-8,00

-4,00

0,00

No Hyponatremia Favours A

4,00

8,00

Hyponatremia Favours B

ACCEPTED MANUSCRIPT

C

Statistics for each study Difference in means

Lower limit

4,40

1,78

Crestanello et al, 2013

3,70

1,50

Crestanello, Phillips et al, 2013

5,46

2,21

Overall

4,30

2,81

7,02 5,90

8,71

M AN U

Crestanello et al, 2012

Upper limit

Difference in means and 95% CI

SC

Study name

RI PT

HeartAnalysis surgery Meta

5,80

-8,00

-4,00

0,00

AC C

EP

Meta Analysis

TE D

No Hyponatremia Favours A

4,00

8,00

Hyponatremia Favours B

ACCEPTED MANUSCRIPT

LiverAnalysis diseases Meta

Difference in means

Karapangiotou et al, 2012 Deitelzweig et al, 2013 Overall

11,20 1,20

6,04 -0,14

16,36 2,54

5,64 1,74

2,79 1,56

8,49 1,92

1,38

EP

TE D

3,50

AC C

Meta Analysis

Upper limit

Difference in means and 95%CI

SC

Hackworth et al, 2009 Yun et al, 2009

Lower limit

RI PT

Statistics for each study

M AN U

Study name

D

5,62

-8,00

-4,00

0,00

No Hyponatremia Favours A

4,00

8,00

Hyponatremia Favours B

ACCEPTED MANUSCRIPT

E

Statistics for each study Difference in means

Lower limit

Upper limit

Nair et al, 2007

2,30

1,35

Zilbeberg et al, 2008

0,60

0,18

Campo et al, 2011

3,00

0,51

5,49

Overall

1,72

0,21

3,23

3,25

1,02

M AN U

TE D

AC C

EP

Meta Analysis

Difference in means and 95% CI

SC

Study name

RI PT

Pulmonary diseases Meta Analysis

-8,00 -4,00

0,00

No Hyponatremia Favours A

4,00

8,00

Hyponatremia Favours B

ACCEPTED MANUSCRIPT

F

Statistics for each study

0,60 31,10 14,40 4,81 1,00 10,14

0,53 28,71 10,80 3,82 0,23 5,03

AC C

Meta Analysis

EP

TE D

Singhi et al, 1992 Al-Zaharaa et al, 1997 Williams et al, 2012 Luu et al, 2013 Wrotek et al, 2013 Overall

Lower limit

Upper limit

Difference in means and 95%CI

SC

Difference in means

0,67 33,49 18,00 5,80 1,77 15,25

M AN U

Study name

RI PT

Pediatric series Meta Analysis

-20,00 -10,00

0,00

No Hyponatremia Favours A

10,00 20,00

Hyponatremia Favours B

ACCEPTED MANUSCRIPT

Combined diseases Meta Analysis Difference in means

TE D

AC C

Meta Analysis

7,72 11,75 0,99 8,19 4,03 4,06 -6,32 4,18 1,21 0,44 1,10 3,27

Upper limit

Difference in means and 95%CI

8,28 12,65 3,01 28,97 14,77 5,14 13,92 5,22 4,75 1,76 5,90 8,13

M AN U

8,00 12,20 2,00 18,58 9,40 4,60 3,80 4,70 2,98 1,10 3,50 5,70

EP

Tang et al, 1993 Sherlock et al, 2006 Funk et al, 2010 Saifudheen et al, 2011 Tada et al, 2011 Doshi et al, 2012 Hagino et al, 2013 Salahudeen et al,2013 Vandergheynst et al, 2013 Causland et al, 2014 Cumming et al, 2014 Overall

Lower limit

RI PT

Statistics for each study

SC

Study name

G

-20,00 -10,00

0,00

No Hyponatremia Favours A

10,00 20,00

Hyponatremia Favours B

ACCEPTED MANUSCRIPT

RI PT

Risk of readmission Meta Analysis Study name

Odds ratio and 95% CI

Meta Analysis

AC C

EP

Overall

1,25 3,60 1,27 1,60 1,11 1,14 1,14 1,24 0,84 2,21 1,29 1,45 0,42 269,21 1,37 1,46 1,18 1,48

M AN U

2,12 1,42 1,12 1,19 1,37 1,37 10,60 1,42 1,32

TE D

Gheorghiade et al, 1998 Scherz et al, 2010 Amin et al, 2012 Amin et al, 2013 Arévalo Lorido et al, 2013 Deitelzweig et al, 2013 Luu et al, 2013 Marco et al, 2013

SC

Odds Lower Upper ratio limit limit

0,1 0,2 0,5 1 No Hyponatremia Favours A

2

5 10

Hyponatremia Favours B

RI PT

Regression of sodio cut off on Difference in means 31,10

SC

S=-1.00[-1.30;-0.70];p<0.000 I=138.39[97.81;178.90]; p<0.000

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24,88 21,77 18,66

D

15,55

TE

12,44 9,33

EP

6,22 3,11 0,00 129,20

130,16

AC C

Differences in (days) means inmeans Difference

27,99

131,12

132,08

133,04

134,00

134,96

off Sodium sodio cut off cut (mmol/L)

135,92

136,88

137,84

138,80

ACCEPTED MANUSCRIPT

Hyponatremia cost ($) Meta Analysis Difference in means

2463,16 547,80 738,30 952,33 2799,71 1443,03 2155,04 286,34 881,66

3424,84 2160,20 2911,70 1353,67 2928,29 2240,97 3248,96 547,66 2892,59

TE D EP AC C

Meta Analysis

2944,00 1354,00 1825,00 1153,00 2864,00 1842,00 2702,00 417,00 1887,13

Upper limit

M AN U

Zilbeberg, Exuzides et al, 2008 Zilbeberg et al, 2008 Callahan et al, 2009 Shorr et al, 2011 Amin et al, 2012 Amin et al, 2013 Deitelzweig et al, 2013 Deitelzweig, Amin et al, 2013 Overall

Lower limit

Difference in means and 95% CI

RI PT

Statistics for each study

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Study name

-4000,00 -2000,00 0,00

No Hyponatremia Favours A

2000,00 4000,00

Hyponatremia Favours B

ACCEPTED MANUSCRIPT

Highlights • Patients with hyponatremia have an increased length of stay in the hospital compared to patients without hyponatremia.

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• Patients with hyponatremia have a higher risk of readmission in the hospital.

AC C

EP

TE D

M AN U

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• Hyponatremia may represent one important determinant of the hospitalization costs.

ACCEPTED MANUSCRIPT Full-text articles excluded:

1) No serum sodium data

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Albert NM, Nutter B, Forney J, Slifcak E, Tang WH. A randomized controlled pilot study of outcomes of strict allowance of fluid therapy in hyponatremic heart failure (SALT-HF). J Card Fail

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2013; 19:1-9.

Dasta JF, Chiong JR, Christian R, Lin J. Evaluation of costs associated with tolvaptan-mediated

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hospital length of stay reduction among US patients with the syndrome of inappropriate antidiuretic hormone secretion, based on SALT-1 and SALT-2 trials. Hosp Pract 2012; 40:7-14.

Chiong JR, Kim S, Lin J, Christian R, Dasta JF. Evaluation of costs associated with tolvaptan-

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mediated length-of-stay reduction among heart failure patients with hyponatremia in the US, based on the EVEREST trial. J Med Econ 2012; 15:276-84.

EP

Stelfox HT, Ahmed SB, Zygun D, Khandwala F, Laupland K. Characterization of intensive care

57:650-8

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unit acquired hyponatremia and hypernatremia following cardiac surgery. Can J Anaesth 2010;

2) No length of hospital stay data Stelfox HT, Ahmed SB, Zygun D, Khandwala F, Laupland K. Characterization of intensive care unit acquired hyponatremia and hypernatremia following cardiac surgery. Can J Anaesth 2010; 57:650-8

ACCEPTED MANUSCRIPT Malabu UH, Porter D, Vangaveti VN, Kazi M, Kennedy RL. Prevalence of hyponatremia in acute medical admissions in tropical Asia Pacific Australia. Asian Pac J Trop Med 2014; 7:40-3.

Mandai S, Kuwahara M, Kasagi Y, et al. Lower serum sodium level predicts higher risk of

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infection-related hospitalization in maintenance hemodialysis patients: an observational cohort study. BMC Nephrol 2013; 14:276.

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Korkmaz I, Güven FM, Eren SH, Beydilli I, Yildirim B, Aktas C, Alagozlu H. Baseline

Pak Med Assoc 2013; 63:331-5.

M AN U

characteristics and the association between hyponatraemia and pulmonary embolism prognosis. J

Ng AC, Chow V, Yong AS, Chung T, Kritharides L. Fluctuation of serum sodium and its impact on

TE D

short and long-term mortality following acute pulmonary embolism. PLoS One 2013; 8:e61966.

Lee SE, Choi DJ, Yoon CH, et al. Improvement of hyponatraemia during hospitalisation for acute heart failure is not associated with improvement of prognosis: an analysis from the Korean Heart

EP

Failure (KorHF) registry. Heart 2012; 98:1798-804.

AC C

Arampatzis S, Frauchiger B, Fiedler GM,et al. Characteristics, symptoms, and outcome of severe dysnatremias present on hospital admission. Am J Med 2012; 125:1125.e1-1125.e7.

Abraham WT, Hensen J, Gross PA, et al. Lixivaptan safely and effectively corrects serum sodium concentrations in hospitalized patients with euvolemic hyponatremia. Kidney Int 2012; 82:1223-30.

ACCEPTED MANUSCRIPT Konishi M, Haraguchi G, Ohigashi H, et al. Progression of hyponatremia is associated with increased cardiac mortality in patients hospitalized for acute decompensated heart failure. J Card Fail 2012; 18:620-5.

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Miyashita J, Shimada T, Hunter AJ, Kamiya T. Impact of hyponatremia and the syndrome of inappropriate antidiuresis on mortality in elderly patients with aspiration pneumonia. J Hosp Med.

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2012; 7:464-9.

Manu P, Ray K, Rein JL, De Hert M, Kane JM, Correll CU. Medical outcome of psychiatric

M AN U

inpatients with admission hyponatremia. Psychiatry Res 2012; 198:24-7.

Kang SH, Kim HW, Lee SY, et al. Is the sodium level per se related to mortality in hospitalized

TE D

patients with severe hyponatremia? Clin Nephrol 2012; 77:182-7.

Rastogi D, Pelter MA, Deamer RL. Evaluations of hospitalizations associated with thiazide-

EP

associated hyponatremia. J Clin Hypertens (Greenwich) 2012; 14:158-64.

Bettari L, Fiuzat M, Shaw LK, et al. Hyponatremia and long-term outcomes in chronic heart failure-

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-an observational study from the Duke Databank for Cardiovascular Diseases. J Card Fail 2012; 18: 74-81

Tolouian R, Alhamad T, Farazmand M, Mulla ZD. The correlation of hip fracture and hyponatremia in the elderly. J Nephrol. 2012; 25:789-93.

ACCEPTED MANUSCRIPT Lohani S, Devkota UP. Hyponatremia in patients with traumatic brain injury: etiology, incidence, and severity correlation. World Neurosurg 2011; 76:355-60.

Haddad F, Peterson T, Fuh E, et al. Characteristics and outcome after hospitalization for acute right

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heart failure in patients with pulmonary arterial hypertension. Circ Heart Fail 2011; 4:692-9.

Balling L, Schou M, Videbæk L, et al. Prevalence and prognostic significance of hyponatraemia in

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outpatients with chronic heart failure. Eur J Heart Fail 2011; 13:968-73

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Rao MY, Sudhir U, Anil Kumar T, Saravanan S, Mahesh E, Punith K. Hospital-based descriptive study of symptomatic hyponatremia in elderly patients. J Assoc Physicians India 2010; 58:667-9.

Havránek Š, Bělohlávek J, Škulec R, Kovárník T, Dytrych V, Linhart A. Long-term prognostic

71:38-44.

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impact of hyponatremia in the ST-elevation myocardial infarction. Scand J Clin Lab Invest 2011;

EP

Frenkel WN, van den Born BJ, van Munster BC, Korevaar JC, Levi M, de Rooij SE. The association between serum sodium levels at time of admission and mortality and morbidity in

AC C

acutely admitted elderly patients: a prospective cohort study. J Am Geriatr Soc 2010; 58:2227-8.

Novack V, Pencina M, Zahger D, Fuchs L, Nevzorov R, Jotkowitz A, Porath A. Routine laboratory results and thirty day and one-year mortality risk following hospitalization with acute decompensated heart failure. PLoS One 201; 5:e12184.

ACCEPTED MANUSCRIPT Mohammed AA, van Kimmenade RR, Richards M, Bayes-Genis A, Pinto Y, Moore SA, Januzzi JL. Hyponatremia, natriuretic peptides, and outcomes in acutely decompensated heart failure: results from the International Collaborative of NT-proBNP Study. Jr Circ Heart Fail 2013; 3:354-

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61.

Shapiro DS, Sonnenblick M, Galperin I, Melkonyan L, Munter G. Severe hyponatraemia in elderly

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hospitalized patients: prevalence, aetiology and outcome. Intern Med J 2010; 40:574-80

Klopotowski M, Kruk M, Przyluski J,et al. Sodium level on admission and in-hospital outcomes of

Sci Monit 2009;15:CR477-83.

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STEMI patients treated with primary angioplasty: the ANIN Myocardial Infarction Registry. Med

Waikar SS, Mount DB, Curhan GC. Mortality after hospitalization with mild, moderate, and severe

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hyponatremia. Am J Med 2009;122:857-65.

Rusinaru D, Buiciuc O, Leborgne L, Slama M, Massy Z, Tribouilloy C. Relation of serum sodium

EP

level to long-term outcome after a first hospitalization for heart failure with preserved ejection

AC C

fraction. Am J Cardiol 2009

Yawar A, Jabbar A, Haque NU, Zuberi LM, Islam N, Akhtar J. Hyponatraemia: etiology, management and outcome. J Coll Physicians Surg Pak 2008; 18:467-71.

Olotu AI, Mithwani S, Newton CR. Haemolytic uraemic syndrome in children admitted to a rural district hospital in Kenya. Trop Doct 2008; 38:165-7.

ACCEPTED MANUSCRIPT

Forfia PR, Mathai SC, Fisher MR, et al. Hyponatremia predicts right heart failure and poor survival in pulmonary arterial hypertension. Am J Respir Crit Care Med 2008;177:1364-9.

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Tribouilloy C, Rusinaru D, Mahjoub H, Soulière V, Lévy F, Peltier M, Slama M, Massy Z.Prognosis of heart failure with preserved ejection fraction: a 5 year prospective population-based

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study. Eur Heart J 2008;29:339-47.

Mahjoub H, Rusinaru D, Soulière V, Durier C, Peltier M, Tribouilloy C. Long-term survival in

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patients older than 80 years hospitalised for heart failure. A 5-year prospective study. Eur J Heart Fail 2008; 10:78-84.

Chua M, Hoyle GE, Soiza RL.Prognostic implications of hyponatremia in elderly hospitalized

AC C

EP

TE D

patients. Arch Gerontol Geriatr 2007; 45:253-8.