Advertisement

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

  • Author Footnotes
    1 These authors contributed equally to this article.
    Giovanni Corona
    Footnotes
    1 These authors contributed equally to this article.
    Affiliations
    Endocrinology Unit, Maggiore-Bellaria Hospital, Bologna, Italy
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this article.
    Corinna Giuliani
    Footnotes
    1 These authors contributed equally to this article.
    Affiliations
    Endocrine Unit, “Center for Research, Transfer and High Education on Chronic, Inflammatory, Degenerative and Neoplastic Disorders for the Development of Novel Therapies” (DENOThe), Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Careggi Hospital, Italy
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this article.
    Gabriele Parenti
    Footnotes
    1 These authors contributed equally to this article.
    Affiliations
    Department of Medicine and Geriatrics, Careggi Hospital, Italy
    Search for articles by this author
  • Giorgio L. Colombo
    Affiliations
    Department of Drug Sciences, University of Pavia, Italy
    Search for articles by this author
  • Alessandra Sforza
    Affiliations
    Endocrinology Unit, Maggiore-Bellaria Hospital, Bologna, Italy
    Search for articles by this author
  • Mario Maggi
    Affiliations
    Andrology Unit, “Center for Research, Transfer and High Education on Chronic, Inflammatory, Degenerative and Neoplastic Disorders for the Development of Novel Therapies” (DENOThe), Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Careggi Hospital, Italy
    Search for articles by this author
  • Gianni Forti
    Affiliations
    Endocrine Unit, “Center for Research, Transfer and High Education on Chronic, Inflammatory, Degenerative and Neoplastic Disorders for the Development of Novel Therapies” (DENOThe), Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Careggi Hospital, Italy
    Search for articles by this author
  • Alessandro Peri
    Correspondence
    Requests for reprints should be addressed to Alessandro Peri, MD, PhD, Endocrine Unit, Department of Experimental and Clinical Biomedical Sciences, “Mario Serio”, University of Florence, Viale Pieraccini, 6, Florence 50139, Italy.
    Affiliations
    Endocrine Unit, “Center for Research, Transfer and High Education on Chronic, Inflammatory, Degenerative and Neoplastic Disorders for the Development of Novel Therapies” (DENOThe), Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Careggi Hospital, Italy
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this article.

      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 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 and without hyponatremia.

      Methods

      An extensive Medline, Embase, and Cochrane search was performed to retrieve all studies published up to April 1, 2015 using the following words: “hyponatremia” or “hyponatraemia” AND “hospitalization” or “hospitalisation.” A meta-analysis was performed including all studies comparing duration of hospitalization and hospital readmission rate in subjects with and without hyponatremia.

      Results

      Of 444 retrieved articles, 46 studies satisfied the inclusion criteria, encompassing a total of 3,940,042 patients; among these, 757,763 (19.2%) were hyponatremic. Across all studies, hyponatremia was associated with a significantly longer duration of hospitalization (3.30 [2.90-3.71; 95% CIs] mean days; P < .000). Similar results were obtained when patients with associated morbidities were analyzed separately. Furthermore, hyponatremic patients had a higher risk of readmission after the first hospitalization (odds ratio 1.32 [1.18-1.48; 95% CIs]; P < .000). A meta-regression analysis showed that the hyponatremia-related length of hospital stay was higher in males (Slope = 0.09 [0.05-0.12; 95% CIs]; P = .000 and Intercept = −1.36 [−3.03-0.32; 95% CIs]; P = .11) and in elderly patients (Slope = 0.002 [0.001-0.003; 95% CIs]; P < .000 and Intercept = 0.89 [0.83-0.97; 95% CIs]; P < .001). A negative association between serum [Na+] cutoff 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 around $3000 higher hospital costs/patient when compared with the cost of normonatremic subjects.

      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 hyponatremia may represent one important determinant of the hospitalization costs.

      Keywords

      Clinical Significance
      • Patients with hyponatremia have an increased length of stay in the hospital compared with patients without hyponatremia.
      • Patients with hyponatremia have a higher risk of readmission to the hospital.
      • Hyponatremia may represent one important determinant of the hospitalization costs.
      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+] 130-135 mEq/L).
      • Upadhyay A.
      • Jaber B.L.
      • Madias N.E.
      Incidence and prevalence of hyponatremia.
      • Hoorn E.J.
      • Lindemans J.
      • Zietse R.
      Development of severe hyponatremia in hospitalized patients: treatment-related risk factors and inadequate management.
      Clinical and experimental 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 and effectively treated.
      • Gill G.
      • Huda B.
      • Boyd A.
      • et al.
      Characteristics and mortality of severe hyponatremia – a hospital-based study.
      Recent studies have demonstrated that chronic and mild hyponatremia also may negatively affect health status, with deleterious effects that affect, particularly, the central nervous system and the bone, causing gait instability, attention deficits, falls, osteoporosis, and fractures.
      • Renneboog B.
      • Musch W.
      • Vandemergel X.
      • Manto M.U.
      • Decaux G.
      Mild chronic hyponatremia is associated with falls, unsteadiness and attention deficits.
      • Gankam K.F.
      • Andres C.
      • Sattar L.
      • Decaux G.
      Mild hyponatremia and risk of fracture in the ambulatory elderly.
      • Kinsella S.
      • Moran S.
      • Sullivan M.O.
      • Molloy M.G.
      • Eustace J.A.
      Hyponatremia independent of osteoporosis is associated with fracture occurrence.
      • Verbalis J.G.
      • Barsony J.
      • Sugimura Y.
      • et al.
      Hyponatremia-induced osteoporosis.
      The association between hyponatremia and in-hospital mortality has been demonstrated in the elderly,
      • Terzian C.
      • Frye E.B.
      • Piotrowski Z.H.
      Admission hyponatremia in the elderly: factors influencing prognosis.
      and in several clinical conditions, such as heart failure,
      • 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.
      pneumonia,
      • Zilberberg M.D.
      • Exuzides A.
      • Spalding J.
      • et al.
      Hyponatremia and hospital outcomes among patients with pneumonia: a retrospective cohort study.
      acute myocardial infarction,
      • Waikar S.S.
      • Mount D.B.
      • Curhan G.C.
      Mortality after hospitalization with mild, moderate, and severe hyponatremia.
      cirrhosis,
      • Kim W.R.
      • Biggins S.W.
      • Kremers W.K.
      • et al.
      Hyponatremia and mortality among patients on the liver-transplant waiting list.
      and cancer.
      • Waikar S.S.
      • Mount D.B.
      • Curhan G.C.
      Mortality after hospitalization with mild, moderate, and severe hyponatremia.
      We have recently confirmed in an extensive meta-analysis that hyponatremia is significantly associated with an increased risk of overall mortality in hospitalized patients.
      • Corona G.
      • Giuliani C.
      • Parenti G.
      • et al.
      Moderate hyponatremia is associated with increased risk of mortality: evidence from a meta-analysis.
      We have also observed a rather small difference in serum [Na+] (mean 4.8 mEq/L) in patients who died, compared with 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 underlying pathological condition (such as heart failure, cancer, cirrhosis) that is associated with death, is not clear, so far.
      • Konstam M.A.
      • Udelson J.E.
      Hyponatraemia and vasopressin in heart failure: markers or mediators?.
      • Chawla A.
      • Sterns R.H.
      • Nigwekar S.U.
      • Cappuccio J.D.
      Mortality and the serum sodium: Do patients die with or from hyponatremia?.
      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.
      • Corona G.
      • Giuliani C.
      • Verbalis J.G.
      • et al.
      Hyponatremia improvement is associated with a reduced risk of mortality: evidence from a meta-analysis.
      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. Therefore, it is not surprising that hyponatremia is associated with an increased length of hospital stay and in hospital resource utilization and costs.
      • Zilberberg M.D.
      • Exuzides A.
      • Spalding J.
      • et al.
      Epidemiology, clinical and economic outcomes of admission hyponatremia among hospitalized patients.
      Several studies have demonstrated that hospital-acquired hyponatremia was associated with higher costs of care in patients with cancer,
      • Adrogué H.J.
      Consequences of inadequate management of hyponatremia.
      cirrhosis,
      • Deitelzweig S.
      • Amin A.
      • Christian R.
      • Friend K.
      • Lin J.
      • Lowe T.J.
      Hyponatremia-associated healthcare burden among US patients hospitalized for cirrhosis.
      and heart failure.
      • Amin A.
      • Deitelzweig S.
      • Christian R.
      • Friend K.
      • Lin J.
      • Lowe T.J.
      Healthcare resource burden associated with hyponatremia among patients hospitalized for heart failure in the US.
      In the US, the direct medical costs of hyponatremia were estimated to range between $1.6 billion and $3.6 billion
      • Boscoe A.
      • Paramore C.
      • Verbalis J.G.
      Cost of illness of hyponatremia in the United States.
      and could be associated not only with the increased mortality and morbidity associated with this condition, but also with a prolonged length of stay in the hospital.
      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 stay, risk of hospital readmission, and costs between patients with and without hyponatremia.

      Methods

      This meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist (see Appendix 1, available online) (http://www.prisma-statement.org/).

      Eligibility Criteria

      All studies specifically addressing the duration of hospitalization, cost, and readmission risk in subjects with and without hyponatremia were included in the analysis.

      Information Source and Search Strategy

      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 “hospitalization”[All Fields]). The search (up to November 1, 2015) was restricted to English-language 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 chart. The identification of relevant abstracts, the selection of studies based on the criteria described above, and the subsequent data extraction were performed independently by 2 of the authors (GP, CG), and conflicts resolved by a third investigator (GC). Full-text articles and meeting abstracts were included. The quality of studies was assessed using the Cochrane criteria.

      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 was considered the time between admission and death. Studies that did 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 Appendix 2, available online, and Table 2).
      Figure thumbnail gr1
      Figure 1Trial flow diagram. LOS = length of stay.
      Table 1Observational Studies Included in the Meta-analysis
      SourceType of DiseaseAge (Years, Mean)Male (%)Na+ Cutoff (mEq/L)Patients (n)H (n)NH (n)HF (%)DM (%)HT (%)CD (%)RF (%)CH (%)
      Lim & Yap, 2001
      • Lim J.K.
      • Yap K.B.
      Hyponatraemia in hospitalised elderly patients.
      (Japan)
      HospitalizedNA40.513040755352NANANANANANA
      Gill et al, 2006
      • Gill G.
      • Huda B.
      • Boyd A.
      • et al.
      Characteristics and mortality of severe hyponatremia – a hospital-based study.
      (UK)
      Hospitalized65.147.5135204104100NANANANANANA
      Zilberberg et al, 2008
      • Zilberberg M.D.
      • Exuzides A.
      • Spalding J.
      • et al.
      Epidemiology, clinical and economic outcomes of admission hyponatremia among hospitalized patients.
      (USA)
      Hospitalized61.845.5135198,28110,899187,382NANANANANANA
      Callahan et al, 2009
      • Callahan M.A.
      • Do H.T.
      • Caplan D.W.
      • Yoon-Flannery K.
      Economic impact of hyponatremia in hospitalized patients: a retrospective cohort study.
      (USA)
      Hospitalized59.553.513496202047757344.6NANANA0.87.9
      Whyte et al, 2009
      • Whyte M.
      • Down C.
      • Miell J.
      • Crook M.
      Lack of laboratory assessment of severe hyponatraemia is associated with detrimental clinical outcomes in hospitalised patients.
      (UK)
      Hospitalized6939.7135226113113NANANANANANA
      Wald et al, 2010
      • Wald R.
      • Jaber B.L.
      • Price L.L.
      • Upadhyay A.
      • Madias N.E.
      Impact of hospital-associated hyponatremia on selected outcomes.
      (Canada)
      Hospitalized55.248.213853,23620,18133,05516.914.8NA9.32.61.6
      Amin et al, 2012
      • Amin A.
      • Deitelzweig S.
      • Christian R.
      • et al.
      Evaluation of incremental healthcare resource burden and readmission rates associated with hospitalized hyponatremic patients in the US.
      (USA)
      HospitalizedNA42.9135117,630558,815558,8154.1NANANANA4.2
      Deitelzweig et al, 2013
      • Deitelzweig S.
      • Amin A.
      • Christian R.
      • Friend K.
      • Lin J.
      • Lowe T.J.
      Hyponatremia-associated healthcare burden among US patients hospitalized for cirrhosis.
      (USA)
      Hospitalized71.624.2313536,04818,02418,02412NANANANA4.12
      Marco et al, 2013
      • Marco J.
      • Barba R.
      • Matía P.
      • et al.
      A. Low prevalence of hyponatremia codification in departments of internal medicine and its prognostic implications.
      (Spain)
      Hospitalized71.653.21362,134,36331,9332,102,43021.923.2NANA4.72.1
      Krumholz et al, 1999
      • Krumholz H.M.
      • Chen Y.T.
      • Bradford W.D.
      • Cerese J.
      Variations in and correlates of length of stay in academic hospitals among patients with heart failure resulting from systolic dysfunction.
      (USA)
      Heart failureNA41135104617187510040NA5220NA
      Gheorghiade et al, 2007
      • Gheorghiade M.
      • Rossi J.S.
      • Cotts W.
      • et al.
      Characterization and prognostic value of persistent hyponatremia in patients with severe heart failure in the ESCAPE Trial.
      (USA)
      Heart failure73.248.313547,647788232,57210041.62345.7NANA
      Gheorghiade et al, 2007
      • Gheorghiade M.
      • Abraham W.T.
      • Albert N.M.
      • et al.
      OPTIMIZE-HF Investigators and Coordinators
      Relationship between admission serum sodium concentration and clinical outcomes in patients hospitalized for heart failure: an analysis from the OPTIMIZE-HF registry.
      (USA)
      Heart failure56.2NA13539871327100NANANANANA
      Cyr et al, 2011
      • Cyr P.L.
      • Slawsky K.A.
      • Olchanski N.
      • et al.
      Effect of serum sodium concentration and tolvaptan treatment on length of hospitalization in patients with heart failure.
      (USA)
      Heart failureNANANA20052161789100NANANANANA
      Shorr et al, 2011
      • Shorr A.F.
      • Tabak Y.P.
      • Johannes R.S.
      • Gupta V.
      • Saltzberg M.T.
      • Costanzo M.R.
      Burden of sodium abnormalities in patients hospitalized for heart failure.
      (USA)
      Heart failure7746.3135112,24424,56287,682100NANANA3.81.3
      Amin et al, 2013
      • Amin A.
      • Deitelzweig S.
      • Christian R.
      • Friend K.
      • Lin J.
      • Lowe T.J.
      Healthcare resource burden associated with hyponatremia among patients hospitalized for heart failure in the US.
      (USA)
      Heart failure75.344.1713551,71025,85525,855100NANANANANA
      Arèvalo Lorido et al, 2013
      • Arévalo Lorido J.C.
      • Carretero Gómez J.
      • Formiga F.
      • et al.
      RICA Investigators
      Hyponatremia as predictor of worse outcome in real world patients admitted with acute heart failure.
      (Spain)
      Heart failure77.246.2513597314782610044.584.0620.7636.17NA
      Sato et al, 2013
      • Sato N.
      • Gheorghiade M.
      • Kajimoto K.
      • et al.
      ATTEND Investigators
      Hyponatremia and in-hospital mortality in patients admitted for heart failure (from the ATTEND registry).
      (Japan)
      Heart failure7357.91354837561427610033.869.331.1NANA
      Shchekochikhin et al, 2013
      • Shchekochikhin D.Y.
      • Schrier R.W.
      • Lindenfeld J.
      • Price L.L.
      • Jaber B.L.
      • Madias N.E.
      Outcome differences in community- versus hospital-acquired hyponatremia in patients with a diagnosis of heart failure.
      (USA)
      Heart failure75.946.51355347234130061004.2NA25.86.11.4
      Hamaguchi et al, 2014
      • Hamaguchi S.
      • Kinugawa S.
      • Tsuchihashi-Makaya M.
      • et al.
      Hyponatremia is an independent predictor of adverse clinical outcomes in hospitalized patients due to worsening heart failure.
      (Japan)
      Heart failure70.759.3135165917614831003052.128.2NANA
      Crestanello et al, 2013
      • Crestanello J.A.
      • Phillips G.
      • Firstenberg M.S.
      • et al.
      Preoperative hyponatremia predicts outcomes after cardiac surgery.
      (USA)
      Heart surgery61.866.2135437093134391004077.738.213.1NA
      Crestanello et al, 2013
      • Crestanello J.A.
      • Phillips G.
      • Firstenberg M.S.
      • et al.
      Postoperative hyponatremia predicts an increase in mortality and in-hospital complications after cardiac surgery.
      (USA)
      Heart surgery61.466.4135485028751975NA35.577.3NA13.5NA
      Crestanello et al, 2013
      • Crestanello J.A.
      • Phillips G.
      • Firstenberg M.S.
      • et al.
      Does preoperative hyponatremia potentiate the effects of left ventricular dysfunction on mortality after cardiac surgery?.
      (USA)
      Heart surgery62.266.613522475271720NA38.983.544.79.5NA
      Hackworth et al, 2009
      • Hackworth W.A.
      • Heuman D.M.
      • Sanyal A.J.
      • et al.
      Effect of hyponatraemia on outcomes following orthotopic liver transplantation.
      (USA)
      Liver diseases517813021390123NANANANANA100
      Yun et al, 2009
      • Yun B.C.
      • Kim W.R.
      • Benson J.T.
      • et al.
      Impact of pretransplant hyponatremia on outcome following liver transplantation.
      (USA)
      Liver diseases50.155.713521756801495NANANANANA100
      Karapanagiotou et al, 2012
      • Karapanagiotou A.
      • Kydona C.
      • Papadopoulos S.
      • et al.
      The effect of hyponatremia on the outcome of patients after orthotopic liver transplantation.
      (Greece)
      Liver diseases51.665.21135752352NANANANANA100
      Deitelzweig et al, 2013
      • Deitelzweig S.
      • Amin A.
      • Christian R.
      • Friend K.
      • Lin J.
      • Lowe T.J.
      Hyponatremia-associated healthcare burden among US patients hospitalized for cirrhosis.
      (USA)
      Liver diseases55.364.113521,86410,93210,932NANANANANA100
      Nair et al, 2007
      • Nair V.
      • Niederman M.S.
      • Masani N.
      • Fishbane S.
      Hyponatremia in community-acquired pneumonia.
      (USA)
      Pulmonary diseases73.55013534295247222050.5NANA0.6
      Zilberberg et al, 2008
      • Zilberberg M.D.
      • Exuzides A.
      • Spalding J.
      • et al.
      Hyponatremia and hospital outcomes among patients with pneumonia: a retrospective cohort study.
      (USA)
      Pulmonary diseases68.44513579656497316NANANANANANA
      Scherz et al, 2010
      • Scherz N.
      • Labarère J.
      • Méan M.
      • Ibrahim S.A.
      • Fine M.J.
      • Aujesky D.
      Prognostic importance of hyponatremia in patients with acute pulmonary embolism.
      (Switzerland)
      Pulmonary diseases6740.213513,728290710,82116.5NANANANANA
      Campo et al, 2011
      • Campo A.
      • Mathai S.C.
      • Le Pavec J.
      • et al.
      Outcomes of hospitalisation for right heart failure in pulmonary arterial hypertension.
      (USA)
      Pulmonary diseases5581361155263NA6.627.95.1NANA
      Dhawan et al, 1992
      • Dhawan A.
      • Narang A.
      • Singhi S.
      Hyponatraemia and the inappropriate ADH syndrome in pneumonia.
      (India)
      Pediatric series3.173131727217510NANANANANANA
      Al-Zahraa et al, 1997
      • Al-Zahraa Omar F.
      • Al Bunyan M.
      Severe hyponatremia as poor prognostic factor in childhood neurologic diseases.
      Pediatric seriesNA56.9130723735NANANANANANA
      Williams et al, 2012
      • Williams C.
      • Simon T.D.
      • Riva-Cambrin J.
      • Bratton S.L.
      Hyponatremia with intracranial malignant tumor resection in children.
      (USA)
      Pediatric seriesNANA13523432052138NANANANANANA
      Luu et al, 2013
      • Luu R.
      • DeWitt P.E.
      • Reiter P.D.
      • Dobyns E.L.
      • Kaufman J.
      Hyponatremia in children with bronchiolitis admitted to the pediatric intensive care unit is associated with worse outcomes.
      (USA)
      Pediatric series0.8541351022379NANANANANANA
      Wrotek et al, 2013
      • Wrotek A.
      • Jackowska T.
      Hyponatremia in children hospitalized due to pneumonia.
      (Poland)
      Pediatric seriesNA52.8136312104208NANANANANANA
      Tang et al, 1993
      • Tang W.W.
      • Kaptein E.M.
      • Feinstein E.I.
      • Massry S.G.
      Hyponatremia in hospitalized patients with the acquired immunodeficiency syndrome (AIDS) and the AIDS-related complex.
      (USA)
      Combined diseases34.2NA13521083127NANANANANANA
      Sherlock et al, 2006
      • Sherlock M.
      • O'Sullivan E.
      • Agha A.
      • et al.
      The incidence and pathophysiology of hyponatraemia after subarachnoid haemorrhage.
      (Ireland)
      Combined diseases5052.9135316179137NANANANANANA
      Funk et al, 2010
      • Funk G.C.
      • Lindner G.
      • Druml W.
      • et al.
      Incidence and prognosis of dysnatremias present on ICU admission.
      (Austria)
      Combined diseases63.258.4135140,95226,78214,170NANANANANANA
      Saifudheen et al, 2011
      • Saifudheen K.
      • Jose J.
      • Gafoor V.A.
      • Musthafa M.
      Guillain-Barre syndrome and SIADH.
      (India)
      Combined diseases4272135502426NANANANANANA
      Tada et al, 2011
      • Tada Y.
      • Nakamura T.
      • Funayama H.
      • et al.
      Early development of hyponatremia implicates short- and long-term outcomes in ST-elevation acute myocardial infarction.
      (Japan)
      Combined diseases64.484.813614029111NA41.264.7100NANA
      Doshi et al, 2012
      • Doshi S.M.
      • Shah P.
      • Lei X.
      • Lahoti A.
      • Salahudeen A.K.
      Hyponatremia in hospitalized cancer patients and its impact on clinical outcomes.
      (USA)
      Combined diseases5652135335715961761NANANANANANA
      Hagino et al, 2013
      • Hagino T.
      • Ochiai S.
      • Watanabe Y.
      • et al.
      Hyponatremia at admission is associated with in-hospital death in patients with hip fracture.
      (Japan)
      Combined diseases82.621.513551249463NANANANANANA
      Salahudeen et al, 2013
      • Salahudeen A.K.
      • Doshi S.M.
      • Pawar T.
      • Nowshad G.
      • Lahoti A.
      • Shah P.
      Incidence rate, clinical correlates, and outcomes of AKI in patients admitted to a comprehensive cancer center.
      (India)
      Combined diseases55.851.8135335615711785NANANANANANA
      Vandergheynst et al, 2013
      • Vandergheynst F.
      • Sakr Y.
      • Felleiter P.
      • et al.
      Incidence and prognosis of dysnatraemia in critically ill patients: analysis of a large prevalence study.
      (Europe)
      Combined diseases60.662.313511,174170394619.6NANANA9.23.2
      Causland et al, 2014
      • Causland F.R.
      • Wright J.
      • Waikar S.S.
      Association of serum sodium with morbidity and mortality in hospitalized patients undergoing major orthopedic surgery.
      (USA)
      Combined diseases62.544.813515,797123414,5631012.4NANANA0.65
      Cumming et al, 2014
      • Cumming K.
      • Hoyle G.E.
      • Hutchison J.D.
      • Soiza R.L.
      Prevalence, incidence and etiology of hyponatremia in elderly patients with fragility fractures.
      (UK)
      Combined diseases79221351273394NANANANANANA
      CD = cardiovascular disease; CH = cirrhosis; DM = diabetes mellitus; H = patients with hyponatremia; HF = heart failure; HT = hypertension; NA = not available; NH = patients without hyponatremia; RF = renal failure.
      Table 2Studies That Met Inclusion Criteria But Did Not Provide Data for Meta-analysis
      First Author, YearBrief Description of the Study and Main Conclusions
      Borenstein et al, 2013
      • Borenstein J.
      • Aronow H.U.
      • Bolton L.B.
      • Choi J.
      • Bresee C.
      • Braunstein G.D.
      Early recognition of risk factors for adverse outcomes during hospitalization among Medicare patients: a prospective cohort study.
      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.
      Leung et al, 2012
      • Leung A.A.
      • McAlister F.A.
      • Rogers Jr., S.O.
      • Pazo V.
      • Wright A.
      • Bates D.W.
      Preoperative hyponatremia and perioperative complications.
      Retrospective cohort of 964,263 adults undergoing major surgery and observed for 30 days 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.
      Dunlay et al, 2010
      • Dunlay S.M.
      • Gheorghiade M.
      • Reid K.J.
      • et al.
      Critical elements of clinical follow-up after hospital discharge for heart failure: insights from the EVEREST trial.
      Retrospective analysis of data from the EVEREST trial to identify risk factors predicting cardiovascular rehospitalization and mortality. Hyponatremia was an independent risk factor for re-hospitalization and mortality but there were no data about rate of readmission in patients with hyponatremia vs patients without hyponatremia.

      Outcome and Quality Assessment

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

      Statistical Analysis

      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 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 test the effect of age, serum [Na+] cutoff, 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+] cutoff.
      All data were calculated using Comprehensive Meta-analysis Version 2 (Biostat, Englewood, NJ). Logistic multivariate analysis was performed on SPSS (Statistical Package for the Social Sciences; Chicago, Ill.) for Windows 20.1.

      Results

      Of 444 retrieved articles, 358 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
      • Gill G.
      • Huda B.
      • Boyd A.
      • et al.
      Characteristics and mortality of severe hyponatremia – a hospital-based study.
      • Zilberberg M.D.
      • Exuzides A.
      • Spalding J.
      • et al.
      Hyponatremia and hospital outcomes among patients with pneumonia: a retrospective cohort study.
      • Zilberberg M.D.
      • Exuzides A.
      • Spalding J.
      • et al.
      Epidemiology, clinical and economic outcomes of admission hyponatremia among hospitalized patients.
      • Deitelzweig S.
      • Amin A.
      • Christian R.
      • Friend K.
      • Lin J.
      • Lowe T.J.
      Hyponatremia-associated healthcare burden among US patients hospitalized for cirrhosis.
      • Amin A.
      • Deitelzweig S.
      • Christian R.
      • Friend K.
      • Lin J.
      • Lowe T.J.
      Healthcare resource burden associated with hyponatremia among patients hospitalized for heart failure in the US.
      • Lim J.K.
      • Yap K.B.
      Hyponatraemia in hospitalised elderly patients.
      • Callahan M.A.
      • Do H.T.
      • Caplan D.W.
      • Yoon-Flannery K.
      Economic impact of hyponatremia in hospitalized patients: a retrospective cohort study.
      • Whyte M.
      • Down C.
      • Miell J.
      • Crook M.
      Lack of laboratory assessment of severe hyponatraemia is associated with detrimental clinical outcomes in hospitalised patients.
      • Wald R.
      • Jaber B.L.
      • Price L.L.
      • Upadhyay A.
      • Madias N.E.
      Impact of hospital-associated hyponatremia on selected outcomes.
      • Amin A.
      • Deitelzweig S.
      • Christian R.
      • et al.
      Evaluation of incremental healthcare resource burden and readmission rates associated with hospitalized hyponatremic patients in the US.
      • Marco J.
      • Barba R.
      • Matía P.
      • et al.
      A. Low prevalence of hyponatremia codification in departments of internal medicine and its prognostic implications.
      • Krumholz H.M.
      • Chen Y.T.
      • Bradford W.D.
      • Cerese J.
      Variations in and correlates of length of stay in academic hospitals among patients with heart failure resulting from systolic dysfunction.
      • Gheorghiade M.
      • Rossi J.S.
      • Cotts W.
      • et al.
      Characterization and prognostic value of persistent hyponatremia in patients with severe heart failure in the ESCAPE Trial.
      • Gheorghiade M.
      • Abraham W.T.
      • Albert N.M.
      • et al.
      OPTIMIZE-HF Investigators and Coordinators
      Relationship between admission serum sodium concentration and clinical outcomes in patients hospitalized for heart failure: an analysis from the OPTIMIZE-HF registry.
      • Cyr P.L.
      • Slawsky K.A.
      • Olchanski N.
      • et al.
      Effect of serum sodium concentration and tolvaptan treatment on length of hospitalization in patients with heart failure.
      • Shorr A.F.
      • Tabak Y.P.
      • Johannes R.S.
      • Gupta V.
      • Saltzberg M.T.
      • Costanzo M.R.
      Burden of sodium abnormalities in patients hospitalized for heart failure.
      • Arévalo Lorido J.C.
      • Carretero Gómez J.
      • Formiga F.
      • et al.
      RICA Investigators
      Hyponatremia as predictor of worse outcome in real world patients admitted with acute heart failure.
      • Sato N.
      • Gheorghiade M.
      • Kajimoto K.
      • et al.
      ATTEND Investigators
      Hyponatremia and in-hospital mortality in patients admitted for heart failure (from the ATTEND registry).
      • Shchekochikhin D.Y.
      • Schrier R.W.
      • Lindenfeld J.
      • Price L.L.
      • Jaber B.L.
      • Madias N.E.
      Outcome differences in community- versus hospital-acquired hyponatremia in patients with a diagnosis of heart failure.
      • Hamaguchi S.
      • Kinugawa S.
      • Tsuchihashi-Makaya M.
      • et al.
      Hyponatremia is an independent predictor of adverse clinical outcomes in hospitalized patients due to worsening heart failure.
      • Crestanello J.A.
      • Phillips G.
      • Firstenberg M.S.
      • et al.
      Preoperative hyponatremia predicts outcomes after cardiac surgery.
      • Crestanello J.A.
      • Phillips G.
      • Firstenberg M.S.
      • et al.
      Postoperative hyponatremia predicts an increase in mortality and in-hospital complications after cardiac surgery.
      • Crestanello J.A.
      • Phillips G.
      • Firstenberg M.S.
      • et al.
      Does preoperative hyponatremia potentiate the effects of left ventricular dysfunction on mortality after cardiac surgery?.
      • Hackworth W.A.
      • Heuman D.M.
      • Sanyal A.J.
      • et al.
      Effect of hyponatraemia on outcomes following orthotopic liver transplantation.
      • Yun B.C.
      • Kim W.R.
      • Benson J.T.
      • et al.
      Impact of pretransplant hyponatremia on outcome following liver transplantation.
      • Karapanagiotou A.
      • Kydona C.
      • Papadopoulos S.
      • et al.
      The effect of hyponatremia on the outcome of patients after orthotopic liver transplantation.
      • Nair V.
      • Niederman M.S.
      • Masani N.
      • Fishbane S.
      Hyponatremia in community-acquired pneumonia.
      • Scherz N.
      • Labarère J.
      • Méan M.
      • Ibrahim S.A.
      • Fine M.J.
      • Aujesky D.
      Prognostic importance of hyponatremia in patients with acute pulmonary embolism.
      • Campo A.
      • Mathai S.C.
      • Le Pavec J.
      • et al.
      Outcomes of hospitalisation for right heart failure in pulmonary arterial hypertension.
      • Dhawan A.
      • Narang A.
      • Singhi S.
      Hyponatraemia and the inappropriate ADH syndrome in pneumonia.
      • Al-Zahraa Omar F.
      • Al Bunyan M.
      Severe hyponatremia as poor prognostic factor in childhood neurologic diseases.
      • Williams C.
      • Simon T.D.
      • Riva-Cambrin J.
      • Bratton S.L.
      Hyponatremia with intracranial malignant tumor resection in children.
      • Luu R.
      • DeWitt P.E.
      • Reiter P.D.
      • Dobyns E.L.
      • Kaufman J.
      Hyponatremia in children with bronchiolitis admitted to the pediatric intensive care unit is associated with worse outcomes.
      • Wrotek A.
      • Jackowska T.
      Hyponatremia in children hospitalized due to pneumonia.
      • Tang W.W.
      • Kaptein E.M.
      • Feinstein E.I.
      • Massry S.G.
      Hyponatremia in hospitalized patients with the acquired immunodeficiency syndrome (AIDS) and the AIDS-related complex.
      • Sherlock M.
      • O'Sullivan E.
      • Agha A.
      • et al.
      The incidence and pathophysiology of hyponatraemia after subarachnoid haemorrhage.
      • Funk G.C.
      • Lindner G.
      • Druml W.
      • et al.
      Incidence and prognosis of dysnatremias present on ICU admission.
      • Saifudheen K.
      • Jose J.
      • Gafoor V.A.
      • Musthafa M.
      Guillain-Barre syndrome and SIADH.
      • Tada Y.
      • Nakamura T.
      • Funayama H.
      • et al.
      Early development of hyponatremia implicates short- and long-term outcomes in ST-elevation acute myocardial infarction.
      • Doshi S.M.
      • Shah P.
      • Lei X.
      • Lahoti A.
      • Salahudeen A.K.
      Hyponatremia in hospitalized cancer patients and its impact on clinical outcomes.
      • Hagino T.
      • Ochiai S.
      • Watanabe Y.
      • et al.
      Hyponatremia at admission is associated with in-hospital death in patients with hip fracture.
      • Salahudeen A.K.
      • Doshi S.M.
      • Pawar T.
      • Nowshad G.
      • Lahoti A.
      • Shah P.
      Incidence rate, clinical correlates, and outcomes of AKI in patients admitted to a comprehensive cancer center.
      • Vandergheynst F.
      • Sakr Y.
      • Felleiter P.
      • et al.
      Incidence and prognosis of dysnatraemia in critically ill patients: analysis of a large prevalence study.
      • Causland F.R.
      • Wright J.
      • Waikar S.S.
      Association of serum sodium with morbidity and mortality in hospitalized patients undergoing major orthopedic surgery.
      • Cumming K.
      • Hoyle G.E.
      • Hutchison J.D.
      • Soiza R.L.
      Prevalence, incidence and etiology of hyponatremia in elderly patients with fragility fractures.
      ). Eighty-six full-text articles 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 Appendix 2, available online). Three additional studies were excluded because they met inclusion criteria but did not provide data for meta-analysis (Table 2).
      • Borenstein J.
      • Aronow H.U.
      • Bolton L.B.
      • Choi J.
      • Bresee C.
      • Braunstein G.D.
      Early recognition of risk factors for adverse outcomes during hospitalization among Medicare patients: a prospective cohort study.
      • Leung A.A.
      • McAlister F.A.
      • Rogers Jr., S.O.
      • Pazo V.
      • Wright A.
      • Bates D.W.
      Preoperative hyponatremia and perioperative complications.
      • Dunlay S.M.
      • Gheorghiade M.
      • Reid K.J.
      • et al.
      Critical elements of clinical follow-up after hospital discharge for heart failure: insights from the EVEREST trial.
      The 46 selected studies were grouped according to different pathological conditions (Figure 1 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. An additional 9 studies retrospectively investigated the effect of hyponatremia in hospitalized series of subjects. In these studies, a major diagnosis was not specified.
      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 meta-analysis. Hyponatremia was defined according to varying cutoff definitions in the included studies (Table 1). When the same study reported data according to different serum [Na+] thresholds, a weighted arithmetic mean was considered. I2 in trials assessing the duration of hospitalization in subjects with and without hyponatremia was 99.4 (P < .000). Funnel plot and Begg-adjusted rank correlation test (Kendall's τ: 0.18; P = .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; 95% CIs] days; P < .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 72 days after first hospital discharge) when compared with 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.
      Figure thumbnail gr2ab
      Figure 2Mean duration of hospitalization (95% confidence interval; 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 disease (G). CI = confidence interval.
      Figure thumbnail gr2cd
      Figure 2Mean duration of hospitalization (95% confidence interval; 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 disease (G). CI = confidence interval.
      Figure thumbnail gr2ef
      Figure 2Mean duration of hospitalization (95% confidence interval; 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 disease (G). CI = confidence interval.
      Figure thumbnail gr2g
      Figure 2Mean duration of hospitalization (95% confidence interval; 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 disease (G). CI = confidence interval.
      Figure thumbnail gr3
      Figure 3Odds ratio (95% confidence interval) for hospital readmission in patients with or without (no) hyponatremia. CI = confidence interval.
      A meta-regression analysis showed that the hyponatremia-related duration of hospitalization was higher in males (Slope = 0.09 [0.05-0.12; 95% CIs]; P = .000 and Intercept = −13.6 [−3.03-0.32; 95% CIs]; P = .11). In addition, a mild association between age and longer hospitalization was also observed (Slope = 0.002 [0.001-0.003; 95% CIs]; P < .0001 and Intercept = 0.89 [0.83-0.97; 95% CIs]; P < .000). Finally, a negative association between serum [Na+] cutoff 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 = −0.210; P < .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).
      Figure thumbnail gr4
      Figure 4Weighted relationship between serum [Na+] cutoff definition and duration of hospitalization.
      Finally, 9 studies reported differences in mean hospital cost between subjects with and without hyponatremia. Among them, 8 (see references
      • Zilberberg M.D.
      • Exuzides A.
      • Spalding J.
      • et al.
      Hyponatremia and hospital outcomes among patients with pneumonia: a retrospective cohort study.
      • Zilberberg M.D.
      • Exuzides A.
      • Spalding J.
      • et al.
      Epidemiology, clinical and economic outcomes of admission hyponatremia among hospitalized patients.
      • Deitelzweig S.
      • Amin A.
      • Christian R.
      • Friend K.
      • Lin J.
      • Lowe T.J.
      Hyponatremia-associated healthcare burden among US patients hospitalized for cirrhosis.
      • Amin A.
      • Deitelzweig S.
      • Christian R.
      • Friend K.
      • Lin J.
      • Lowe T.J.
      Healthcare resource burden associated with hyponatremia among patients hospitalized for heart failure in the US.
      • Callahan M.A.
      • Do H.T.
      • Caplan D.W.
      • Yoon-Flannery K.
      Economic impact of hyponatremia in hospitalized patients: a retrospective cohort study.
      • Amin A.
      • Deitelzweig S.
      • Christian R.
      • et al.
      Evaluation of incremental healthcare resource burden and readmission rates associated with hospitalized hyponatremic patients in the US.
      • Shorr A.F.
      • Tabak Y.P.
      • Johannes R.S.
      • Gupta V.
      • Saltzberg M.T.
      • Costanzo M.R.
      Burden of sodium abnormalities in patients hospitalized for heart failure.
      ) included subjects living in the US, and one was related to Spanish patients.
      • Marco J.
      • Barba R.
      • Matía P.
      • et al.
      A. Low prevalence of hyponatremia codification in departments of internal medicine and its prognostic implications.
      When only studies from US were considered, hyponatremia was associated with a higher mean hospital cost (Figure 5).
      Figure thumbnail gr5
      Figure 5Mean hospitalization cost (95% confidence interval [CI]; US dollars) in patients with or without (no) hyponatremia.

      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 length of stay, and higher risk of readmission. The data were similar when European studies were compared with those performed in North America. Length of hospital stay is a strong determinant of the cost of hospital care.
      • Lave J.R.
      • Leinhardt S.
      The cost and length of a hospital stay.
      Hence, taken together, these observations indicate that hyponatremia may represent one important determinant of the medical costs associated with hospitalization. Accordingly, our data showed that when only US studies were considered, hyponatremia was associated with an increase of hospital costs of up to $3000 when compared with normonatremia. A consensus panel of expert physicians suggested that the annual costs/hospitalized patient directly attributable to hyponatremia (cut off for serum [Na+] < 130 mEql/L) in the US ranges from $1528 to $3441.
      • Boscoe A.
      • Paramore C.
      • Verbalis J.G.
      Cost of illness of hyponatremia in the United States.
      More recently, longitudinal data from a large US managed care claim database (Waltham, Mass.) indicated that an even higher 1-year mean inpatient cost could be related to hyponatremic subjects ($10,636).
      • Shea A.M.
      • Hammill B.G.
      • Curtis L.H.
      • Szczech L.A.
      • Schulman K.A.
      Medical costs of abnormal serum sodium levels.
      Interestingly, similar costs (about $13,700 per year) have been estimated by the American Diabetes Association for the treatment of diabetic patients.
      • American Diabetes Association
      Economic costs of diabetes in the U.S. in 2012.
      Despite these data, 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 hospitalized patients.
      • Corona G.
      • Giuliani C.
      • Verbalis J.G.
      • et al.
      Hyponatremia improvement is associated with a reduced risk of mortality: evidence from a meta-analysis.
      In addition, among them, about 1 of 4 patients did not reach a serum [Na+] threshold of 130 mEq/L.
      • Corona G.
      • Giuliani C.
      • Verbalis J.G.
      • et al.
      Hyponatremia improvement is associated with a reduced risk of mortality: evidence from a meta-analysis.
      In agreement with these data, it has been shown that only a small percentage of patients with hyponatremia receive an International Classification of Diseases, 9th Revision, Clinical Modification diagnosis code for hyponatremia.
      • Movig K.L.
      • Leufkens H.G.
      • Lenderink A.W.
      • Egberts A.C.
      Validity of hospital discharge International Classification of Diseases (ICD) codes for identifying patients with hyponatremia.
      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.
      • Marco J.
      • Barba R.
      • Matía P.
      • et al.
      A. Low prevalence of hyponatremia codification in departments of internal medicine and its prognostic implications.
      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 in the vast majority of cases (81.7%) hyponatremia was codified as a secondary diagnosis according to the International Classification of Diseases, 9th Revision, Clinical Modification.
      • Marco J.
      • Barba R.
      • Matía P.
      • et al.
      A. Low prevalence of hyponatremia codification in departments of internal medicine and its prognostic implications.
      Hence, hyponatremia appears to be viewed as a secondary problem from the perspective of most physicians.
      • Marco J.
      • Barba R.
      • Matía P.
      • et al.
      A. Low prevalence of hyponatremia codification in departments of internal medicine and its prognostic implications.
      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. 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 sex, and it was also independent of the type of related diseases. Similarly, a retrospective analysis of 1046 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 in the US, confirmed that hyponatremia was an independent predictor of the duration of hospitalization.
      • Krumholz H.M.
      • Chen Y.T.
      • Bradford W.D.
      • Cerese J.
      Variations in and correlates of length of stay in academic hospitals among patients with heart failure resulting from systolic dysfunction.
      Similar results were reported in a series of 1402 patients admitted to 10 acute care community hospitals during 1995 in New York.
      • Philbin E.F.
      • Rocco Jr., T.A.
      • Lynch L.J.
      • Rogers V.A.
      • Jenkins P.
      Predictors and determinants of hospital length of stay in congestive heart failure in ten community hospitals.
      In addition, more recently, data from the Minimum Basic Data Set of discharged patients from all departments of internal medicine of the 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 predictor of hospital readmission even after the adjustment of associated morbidities, as detected by the Charlson index.
      • Marco J.
      • Barba R.
      • Matía P.
      • et al.
      A. Low prevalence of hyponatremia codification in departments of internal medicine and its prognostic implications.
      Another interesting finding of the present study derives from the meta-regression analysis, 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.
      • Corona G.
      • Giuliani C.
      • Verbalis J.G.
      • et al.
      Hyponatremia improvement is associated with a reduced risk of mortality: evidence from a meta-analysis.
      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 with 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 to play an important role.
      • Barsony J.
      • Sugimura Y.
      • Verbalis J.G.
      Osteoclast response to low extracellular sodium and the mechanism of hyponatremia-induced bone loss.
      • Benvenuti S.
      • Deledda C.
      • Luciani P.
      • et al.
      Low extracellular sodium causes neuronal distress independently of reduced osmolality in an experimental model of chronic hyponatremia.
      However, a growing body of evidence also indicates that several inflammatory mediators such as interleukin-1 and interleukin-6 can induce hyponatremia through excessive vasopressin release,
      • Park S.J.
      • Shin J.I.
      Inflammation and hyponatremia: an underrecognized condition?.
      thus confirming the presence of a bidirectional relationship between hyponatremia and inflammatory response.
      • Park S.J.
      • Shin J.I.
      Inflammation and hyponatremia: an underrecognized condition?.
      • Mastorakos G.
      • Weber J.S.
      • Magiakou M.A.
      • Gunn H.
      • Chrousos G.P.
      Hypothalamic-pituitary-adrenal axis activation and stimulation of systemic vasopressin secretion by recombinant interleukin-6 in humans: potential implications for the syndrome of inappropriate vasopressin secretion.
      These data further confirm that a cause–effect 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 sex, whereas the prevalence of associated morbidities was not considered as a possible confounder, because they were not adequately reported in a sufficient number of studies. However, it should be recognized that a large survey about 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.
      • Wald R.
      • Jaber B.L.
      • Price L.L.
      • Upadhyay A.
      • Madias N.E.
      Impact of hospital-associated hyponatremia on selected outcomes.
      A further limitation of the present study is represented by incomplete reports of the data on 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 influence on the behavior of health professionals. In addition, the statistical analysis showed the presence of heterogeneity.
      • Carande-Kulis V.G.
      • Maciosek M.V.
      • Briss P.A.
      • et al.
      Methods for systematic reviews of economic evaluations for the Guide to Community Preventive Services. Task Force on Community Preventive Services.
      • Drummond M.F.
      • O'Brien B.J.
      • Stoddart G.L.
      • et al.
      Methods for the Economic Evaluation of Health Care Programmes.
      Finally, even if statistical analyses did not suggest any relevant 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.
      • Konstam M.A.
      • Udelson J.E.
      Hyponatraemia and vasopressin in heart failure: markers or mediators?.
      • Peri A.
      Clinical review: the use of vaptans in clinical endocrinology.
      • Verbalis J.G.
      • Goldsmith S.R.
      • Greenberg A.
      • et al.
      Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations.

      Appendix 1

      Supplementary Table 1PRISMA 2009 Checklist
      Section/Topic#Checklist ItemReported on Page #
      Title
       Title1THE ECONOMIC BURDEN OF HYPONATREMIA: SYSTEMATIC REVIEW AND META-ANALYSIS1
      Abstract
       Structured summary2Background: 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 hyponatremia on the length of hospitalization and costs, we performed a meta-analysis based on published studies that compared hospital length of stay between patients with or without hyponatremia.

      Methods: An extensive Medline, Embase, and Cochrane search was performed to retrieve all studies published up to April 1, 2015, using the following words: “hyponatremia” or “hyponatraemia” AND “hospitalization.” A meta-analysis was performed including all studies comparing duration of hospitalization and hospital readmission rate in subjects with or without hyponatremia.

      Findings: Of 444 retrieved articles, 46 studies satisfied inclusion criteria, encompassing a total of 3,940,042 patients, of whom 757,763 (19.2%) were hyponatremic. Across all studies, hyponatremia was associated with a significantly longer duration of hospitalization (3.30 [2.90-3.71; 95% CIs] mean days; P < .0001). Similar results were obtained when patients with associated morbidities were analyzed separately. Furthermore, hyponatremic patients had a higher risk of hospitalization at the first hospital admission (OR = 1.32 [1.18; 1.48; 95% CIs]; P < .0001). A meta-regression analysis showed that the hyponatremia-related length of hospital stay was higher in males (Slope [S] = 0.09 [0.05-0.12; 95% CIs]; P = .0001 and Intercept [I] = −1.36 [−3.03-0.32; 95% CIs]; P = .11) and in elderly patients (S = 0.002 [0.001-0.003; 95% CIs]; P < .0001 and I = 0.89 [0.83-0.97; 95% CIs]; P < .001). A negative association between serum [Na+] cutoff 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 $3000 higher hospital costs/patients when compared with the cost of normonatremic subjects.

      Interpretation: This meta-analysis confirms that hyponatremia is associated with a prolonged hospital length of stay and higher risk of readmission. These observations indicate that hyponatremia represents one important determinant of the hospitalization costs.
      2
      Introduction
       Rationale3In the US, the direct medical costs of hyponatremia were estimated to range between $1.6 billion and $3.6 billion and could be associated not only with the increased mortality and morbidity, but also with a prolonged length of stay in hospital.4-5
       Objectives4To clarify the impact of hyponatremia on length of hospital stay 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.5
      Methods
       Protocol and registration5All studies specifically addressing the duration of hospitalization, cost and readmission risk in subjects with or without hyponatremia were included in the analysis.6
       Eligibility criteria6Studies not including information about serum [Na+] or about duration of hospitalization were excluded from the analysis (see Table 2).6
       Information sources7PubMed from 1965 – November 1, 2015

      EMBASE from 1974 – November 1, 2015

      Cochrane from 1967 – November 1, 2015.

      The principal source of information was derived from published articles.
      6
       Search8An 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 “hospitalization” [All Fields].6
       Study selection9We did not employ a search software. We hand-searched bibliographies of retrieved papers for additional references

      Details of the literature search process are outlined in the flow chart (Figure 1).
      6
       Data collection process10Data extraction were performed independently by 2 of the authors (GP, CG), and conflicts resolved by a third investigator (GC). The credentials of all investigators are indicated in the author list.6
       Data items11The principal outcome of this analysis was to compare the duration of the hospitalization and cost in subjects with or without hyponatremia at admission. A secondary outcome included the risk of hospitalization readmission in patients with or without hyponatremia.7
       Risk of bias in individual studies12Quality of the studies was assessed using the Cochrane criteria.7
       Summary measures13The identification of relevant studies was performed independently by 2 of the authors (GP, CG), and conflicts resolved by a third investigator (GC). Mean duration of hospitalization and cost with 95% confidence interval (CI) was calculated for in subjects with or without hyponatremia at admission. In addition, odds ratios (95% CI) of hospitalization readmission in patients with or without hyponatremia were also evaluated.6-7
       Synthesis of results14Heterogeneity on duration of hospitalization in patients with or without hyponatremia was assessed by using I2 statistics. For a more conservative approach, results of random effect models were presented.7
       Risk of bias across studies15The Begg-adjusted rank correlation test was used to test the presence of possible bias across studies.7
       Additional analyses16A meta-regression analysis was performed to test the effect of age, serum [Na+] cutoff and several associated morbidities at enrollment on duration of hospitalization. In addition, a linear regression analysis model, weighting 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+] cutoff.7
      Results
       Study selection17Of 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 trials included in the meta-analysis are summarized in Table 1.

      Among the 46 selected studies, 3, 10, 4, 4, 5 studies evaluated the effect of hyponatremia in subjects undergoing heart surgery, in those with heart failure (HF), end-stage liver diseases, pulmonary diseases, and in pediatric patients, respectively. In addition, another 11 studies reported data on the effect of hyponatremia for combined mixed diseases, which could not be grouped separately (Table 1). In addition, 9 studies retrospectively investigated the effect of hyponatremia in a hospitalized series of subjects. In these studies, a major diagnosis was not specified.
      7-8
       Study characteristics18Overall 3,940,042 patients and 757,763 hyponatremic subjects (19.2%) were included in the meta-analysis. Hyponatremia was defined according to varying cutoff definitions in the included studies (Table 1). When the same study reported data according to different serum [Na+] thresholds, a pondered mean was considered. I2 in trials assessing the duration of hospitalization in subjects with or without hyponatremia was 99.4 (P < .0001).7-8
       Risk of bias within studies19For a more conservative approach, results of random effect models were presented.7-8
       Results of individual studies20We included 7 forest plots evaluating duration of hospitalization on patients with specific diseases or series of hospitalized patients. In addition, one plot on risk of hospitalization readmission and one on hospitalization cost were also included. Finally, a forest plot to examine effect age and [Na+] in predicting duration of hospitalization (meta-regression analysis) was also evaluated.7-8
       Synthesis of results21Present results of each meta-analysis were done, including confidence intervals and measures of consistency.7-9
       Risk of bias across studies22Funnel plot and Begg-adjusted rank correlation test (Kendall's τ: 0.18; P = .09) suggested no major publication bias.8
       Additional analysis23A meta-regression analysis showed that the hyponatremia-related duration of hospitalization was higher in males (S = 0.09 [0.05; 0.12; 95% CIs]; P = .0001 and I = −13.6 [−3.03; 0.32; 95% CIs]; P = .11). In addition, a mild association between age and longer hospitalization was also observed (S = 0.002 [0.001; 0.003; 95% CIs]; P < .0001 and I = 0.89 [0.83; 0.97; 95% CIs]; P < .0001). Finally, a negative association 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 = −0.210; P < .0001). 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 enrolment was observed (not shown).9
      Discussion
       Summary of evidence24The present meta-analysis, deriving from the study of a huge number of patients, confirms that hyponatremia represents a frequent condition observed in up to 20% of hospitalized patients. In addition, our data show that hyponatremia is associated with a prolonged hospital length of stay, and higher risk of readmission. The data were similar when European studies were compared with those performed in North America.9-10
       Limitations25Several limitations should be recognized. First of all, it should be recognized that the data were adjusted only for age and sex, whereas the prevalence of associated morbidities was not considered as possible confounders, because they were not reported adequately in a sufficient number of studies. Hence, potential unmeasured confounders may have caused residual confounding effects, but the measured factors that are correlated with such confounders should have mitigated this bias. However, meta-analysis is particularly useful when there is a variety of reports with low statistical power; in this situation, pooling of data can improve power and provide a more convincing result.

      A further limitation of the present study is represented by incomplete reporting of the data on hospital duration and readmission rate in trials only marginally designed for the assessment of these endpoints. In particular, all the reviewed studies analyzed were observational surveys and none of them was originally designed to address hyponatremia-related hospitalization outcome or medical burden. In addition, the statistical analysis showed the presence of heterogeneity.
      • Konstam M.A.
      • Udelson J.E.
      Hyponatraemia and vasopressin in heart failure: markers or mediators?.
      • Verbalis J.G.
      • Goldsmith S.R.
      • Greenberg A.
      • et al.
      Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations.
      Finally, even if statistical analyses did not suggest any relevant publication bias, the possibility of selective reporting cannot be excluded.
      11-12
       Conclusions26Taken together, present data indicate that hyponatremia represents one important determinant of the hospitalization medical costs. The economic impact of hyponatremia in terms of prolonged hospitalization suggests new therapeutic options with the need to develop and implement new diagnostic and therapeutic algorithms in clinical practice.12-13
      Funding
       Funding27No separate funding was necessary for the undertaking of this systematic review and meta-analysis.

      Appendix 2

      Full-text articles excluded:

      References

        • Upadhyay A.
        • Jaber B.L.
        • Madias N.E.
        Incidence and prevalence of hyponatremia.
        Am J Med. 2006; 119: 30-35
        • Hoorn E.J.
        • Lindemans J.
        • Zietse R.
        Development of severe hyponatremia in hospitalized patients: treatment-related risk factors and inadequate management.
        Nephrol Dial Transplant. 2006; 28: 70-76
        • Gill G.
        • Huda B.
        • Boyd A.
        • et al.
        Characteristics and mortality of severe hyponatremia – a hospital-based study.
        Clin Endocrinol (Oxf). 2006; 65: 246-249
        • Renneboog B.
        • Musch W.
        • Vandemergel X.
        • Manto M.U.
        • Decaux G.
        Mild chronic hyponatremia is associated with falls, unsteadiness and attention deficits.
        Am J Med. 2006; 119: 71.e1-71.e8
        • Gankam K.F.
        • Andres C.
        • Sattar L.
        • Decaux G.
        Mild hyponatremia and risk of fracture in the ambulatory elderly.
        QJM. 2008; 101: 583-588
        • Kinsella S.
        • Moran S.
        • Sullivan M.O.
        • Molloy M.G.
        • Eustace J.A.
        Hyponatremia independent of osteoporosis is associated with fracture occurrence.
        Clin J Am Soc Nephrol. 2010; 5: 275-280
        • Verbalis J.G.
        • Barsony J.
        • Sugimura Y.
        • et al.
        Hyponatremia-induced osteoporosis.
        J Bone Miner Res. 2010; 25: 554-563
        • Terzian C.
        • Frye E.B.
        • Piotrowski Z.H.
        Admission hyponatremia in the elderly: factors influencing prognosis.
        J Gen Intern Med. 1994; 9: 89-91
        • 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: 2454-2460
        • Zilberberg M.D.
        • Exuzides A.
        • Spalding J.
        • et al.
        Hyponatremia and hospital outcomes among patients with pneumonia: a retrospective cohort study.
        BMC Pulm Med. 2008; 8: 16
        • Waikar S.S.
        • Mount D.B.
        • Curhan G.C.
        Mortality after hospitalization with mild, moderate, and severe hyponatremia.
        Am J Med. 2009; 122: 857-865
        • Kim W.R.
        • Biggins S.W.
        • Kremers W.K.
        • et al.
        Hyponatremia and mortality among patients on the liver-transplant waiting list.
        N Engl J Med. 2008; 359: 1018-1026
        • Corona G.
        • Giuliani C.
        • Parenti G.
        • et al.
        Moderate hyponatremia is associated with increased risk of mortality: evidence from a meta-analysis.
        PLoS One. 2013; 8: e80451
        • Konstam M.A.
        • Udelson J.E.
        Hyponatraemia and vasopressin in heart failure: markers or mediators?.
        Eur J Heart Fail. 2009; 13: 242-244
        • Chawla A.
        • Sterns R.H.
        • Nigwekar S.U.
        • Cappuccio J.D.
        Mortality and the serum sodium: Do patients die with or from hyponatremia?.
        Clin J Am Soc Nephrol. 2011; 6: 960-965
        • Corona G.
        • Giuliani C.
        • Verbalis J.G.
        • et al.
        Hyponatremia improvement is associated with a reduced risk of mortality: evidence from a meta-analysis.
        PLoS One. 2015; 10: e0124105
        • Zilberberg M.D.
        • Exuzides A.
        • Spalding J.
        • et al.
        Epidemiology, clinical and economic outcomes of admission hyponatremia among hospitalized patients.
        Curr Med Res Opin. 2008; 24: 1601-1608
        • Adrogué H.J.
        Consequences of inadequate management of hyponatremia.
        Am J Nephrol. 2005; 25: 240-249
        • Deitelzweig S.
        • Amin A.
        • Christian R.
        • Friend K.
        • Lin J.
        • Lowe T.J.
        Hyponatremia-associated healthcare burden among US patients hospitalized for cirrhosis.
        Adv Ther. 2013; 30: 71-80
        • Amin A.
        • Deitelzweig S.
        • Christian R.
        • Friend K.
        • Lin J.
        • Lowe T.J.
        Healthcare resource burden associated with hyponatremia among patients hospitalized for heart failure in the US.
        J Med Econ. 2013; 16: 415-420
        • Boscoe A.
        • Paramore C.
        • Verbalis J.G.
        Cost of illness of hyponatremia in the United States.
        Cost Eff Resour Alloc. 2006; 31: 4-10
      1. (Version 5.0.1 [updated September 2008])Higgins J.P.T. Green S. Cochrane Handbook for Systematic Reviews of Interventions. The Cochrane Collaboration, London2008 (Available at:) (Accessed January 11, 2016)
        • Lim J.K.
        • Yap K.B.
        Hyponatraemia in hospitalised elderly patients.
        Med J Malaysia. 2001; 56: 232-235
        • Callahan M.A.
        • Do H.T.
        • Caplan D.W.
        • Yoon-Flannery K.
        Economic impact of hyponatremia in hospitalized patients: a retrospective cohort study.
        Postgrad Med. 2009; 121: 186-191
        • Whyte M.
        • Down C.
        • Miell J.
        • Crook M.
        Lack of laboratory assessment of severe hyponatraemia is associated with detrimental clinical outcomes in hospitalised patients.
        Int J Clin Pract. 2009; 63: 1451-1455
        • Wald R.
        • Jaber B.L.
        • Price L.L.
        • Upadhyay A.
        • Madias N.E.
        Impact of hospital-associated hyponatremia on selected outcomes.
        Arch Intern Med. 2010; 8: 294-302
        • Amin A.
        • Deitelzweig S.
        • Christian R.
        • et al.
        Evaluation of incremental healthcare resource burden and readmission rates associated with hospitalized hyponatremic patients in the US.
        J Hosp Med. 2012; 7: 634-639
        • Marco J.
        • Barba R.
        • Matía P.
        • et al.
        A. Low prevalence of hyponatremia codification in departments of internal medicine and its prognostic implications.
        Curr Med Res Opin. 2013; 29: 1757-1762
        • Krumholz H.M.
        • Chen Y.T.
        • Bradford W.D.
        • Cerese J.
        Variations in and correlates of length of stay in academic hospitals among patients with heart failure resulting from systolic dysfunction.
        Am J Manag Care. 1999; 5: 715-723
        • Gheorghiade M.
        • Rossi J.S.
        • Cotts W.
        • et al.
        Characterization and prognostic value of persistent hyponatremia in patients with severe heart failure in the ESCAPE Trial.
        Arch Intern Med. 2007; 167: 1998-2005
        • Gheorghiade M.
        • Abraham W.T.
        • Albert N.M.
        • et al.
        • OPTIMIZE-HF Investigators and Coordinators
        Relationship between admission serum sodium concentration and clinical outcomes in patients hospitalized for heart failure: an analysis from the OPTIMIZE-HF registry.
        Eur Heart J. 2007; 28: 980-988
        • Cyr P.L.
        • Slawsky K.A.
        • Olchanski N.
        • et al.
        Effect of serum sodium concentration and tolvaptan treatment on length of hospitalization in patients with heart failure.
        Am J Health Syst Pharm. 2011; 68: 328-333
        • Shorr A.F.
        • Tabak Y.P.
        • Johannes R.S.
        • Gupta V.
        • Saltzberg M.T.
        • Costanzo M.R.
        Burden of sodium abnormalities in patients hospitalized for heart failure.
        Congest Heart Fail. 2011; 17: 1-7
        • Arévalo Lorido J.C.
        • Carretero Gómez J.
        • Formiga F.
        • et al.
        • RICA Investigators
        Hyponatremia as predictor of worse outcome in real world patients admitted with acute heart failure.
        Cardiol J. 2013; 20: 506-512
        • Sato N.
        • Gheorghiade M.
        • Kajimoto K.
        • et al.
        • ATTEND Investigators
        Hyponatremia and in-hospital mortality in patients admitted for heart failure (from the ATTEND registry).
        Am J Cardiol. 2013; 111: 1019-1025
        • Shchekochikhin D.Y.
        • Schrier R.W.
        • Lindenfeld J.
        • Price L.L.
        • Jaber B.L.
        • Madias N.E.
        Outcome differences in community- versus hospital-acquired hyponatremia in patients with a diagnosis of heart failure.
        Circ Heart Fail. 2013; 6: 379-386
        • Hamaguchi S.
        • Kinugawa S.
        • Tsuchihashi-Makaya M.
        • et al.
        Hyponatremia is an independent predictor of adverse clinical outcomes in hospitalized patients due to worsening heart failure.
        J Cardiol. 2014; 63: 182-188
        • Crestanello J.A.
        • Phillips G.
        • Firstenberg M.S.
        • et al.
        Preoperative hyponatremia predicts outcomes after cardiac surgery.
        J Surg Res. 2013; 181: 60-66
        • Crestanello J.A.
        • Phillips G.
        • Firstenberg M.S.
        • et al.
        Postoperative hyponatremia predicts an increase in mortality and in-hospital complications after cardiac surgery.
        J Am Coll Surg. 2013; 216: 1135-1143
        • Crestanello J.A.
        • Phillips G.
        • Firstenberg M.S.
        • et al.
        Does preoperative hyponatremia potentiate the effects of left ventricular dysfunction on mortality after cardiac surgery?.
        J Thorac Cardiovasc Surg. 2013; 145: 1589-1594
        • Hackworth W.A.
        • Heuman D.M.
        • Sanyal A.J.
        • et al.
        Effect of hyponatraemia on outcomes following orthotopic liver transplantation.
        Liver Int. 2009; 29: 1071-1077
        • Yun B.C.
        • Kim W.R.
        • Benson J.T.
        • et al.
        Impact of pretransplant hyponatremia on outcome following liver transplantation.
        Hepatology. 2009; 49: 1610-1615
        • 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: 2724-2726
        • Nair V.
        • Niederman M.S.
        • Masani N.
        • Fishbane S.
        Hyponatremia in community-acquired pneumonia.
        Am J Nephrol. 2007; 27: 184-190
        • Scherz N.
        • Labarère J.
        • Méan M.
        • Ibrahim S.A.
        • Fine M.J.
        • Aujesky D.
        Prognostic importance of hyponatremia in patients with acute pulmonary embolism.
        Am J Respir Crit Care Med. 2010; 182: 1178-1183
        • Campo A.
        • Mathai S.C.
        • Le Pavec J.
        • et al.
        Outcomes of hospitalisation for right heart failure in pulmonary arterial hypertension.
        Eur Respir J. 2011; 38: 359-367
        • Dhawan A.
        • Narang A.
        • Singhi S.
        Hyponatraemia and the inappropriate ADH syndrome in pneumonia.
        Ann Trop Paediatr. 1992; 12: 455-462
        • Al-Zahraa Omar F.
        • Al Bunyan M.
        Severe hyponatremia as poor prognostic factor in childhood neurologic diseases.
        J Neurol Sci. 1997; 151: 213-216
        • Williams C.
        • Simon T.D.
        • Riva-Cambrin J.
        • Bratton S.L.
        Hyponatremia with intracranial malignant tumor resection in children.
        J Neurosurg Pediatr. 2012; 9: 524-529
        • Luu R.
        • DeWitt P.E.
        • Reiter P.D.
        • Dobyns E.L.
        • Kaufman J.
        Hyponatremia in children with bronchiolitis admitted to the pediatric intensive care unit is associated with worse outcomes.
        J Pediatr. 2013; 163: 1652-1656
        • Wrotek A.
        • Jackowska T.
        Hyponatremia in children hospitalized due to pneumonia.
        Adv Exp Med Biol. 2013; 788: 103-108
        • Tang W.W.
        • Kaptein E.M.
        • Feinstein E.I.
        • Massry S.G.
        Hyponatremia in hospitalized patients with the acquired immunodeficiency syndrome (AIDS) and the AIDS-related complex.
        Am J Med. 1993; 94: 169-174
        • Sherlock M.
        • O'Sullivan E.
        • Agha A.
        • et al.
        The incidence and pathophysiology of hyponatraemia after subarachnoid haemorrhage.
        Clin Endocrinol (Oxf). 2006; 64: 250-254
        • Funk G.C.
        • Lindner G.
        • Druml W.
        • et al.
        Incidence and prognosis of dysnatremias present on ICU admission.
        Intensive Care Med. 2010; 36: 304-311
        • Saifudheen K.
        • Jose J.
        • Gafoor V.A.
        • Musthafa M.
        Guillain-Barre syndrome and SIADH.
        Neurology. 2011; 76: 701-704
        • Tada Y.
        • Nakamura T.
        • Funayama H.
        • et al.
        Early development of hyponatremia implicates short- and long-term outcomes in ST-elevation acute myocardial infarction.
        Circ J. 2011; 75: 1927-1933
        • Doshi S.M.
        • Shah P.
        • Lei X.
        • Lahoti A.
        • Salahudeen A.K.
        Hyponatremia in hospitalized cancer patients and its impact on clinical outcomes.
        Am J Kidney Dis. 2012; 59: 222-228
        • Hagino T.
        • Ochiai S.
        • Watanabe Y.
        • et al.
        Hyponatremia at admission is associated with in-hospital death in patients with hip fracture.
        Arch Orthop Trauma Surg. 2013; 133: 507-511
        • Salahudeen A.K.
        • Doshi S.M.
        • 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 J Am Soc Nephrol. 2013; 8: 347-354
        • 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: 933-948
        • Causland F.R.
        • Wright J.
        • Waikar S.S.
        Association of serum sodium with morbidity and mortality in hospitalized patients undergoing major orthopedic surgery.
        J Hosp Med. 2014; 9: 297-302
        • Cumming K.
        • Hoyle G.E.
        • Hutchison J.D.
        • Soiza R.L.
        Prevalence, incidence and etiology of hyponatremia in elderly patients with fragility fractures.
        PLoS One. 2014; 9: e88272
        • Borenstein J.
        • Aronow H.U.
        • Bolton L.B.
        • Choi J.
        • Bresee C.
        • Braunstein G.D.
        Early recognition of risk factors for adverse outcomes during hospitalization among Medicare patients: a prospective cohort study.
        BMC Geriatr. 2013; 13: 72
        • Leung A.A.
        • McAlister F.A.
        • Rogers Jr., S.O.
        • Pazo V.
        • Wright A.
        • Bates D.W.
        Preoperative hyponatremia and perioperative complications.
        Arch Intern Med. 2012; 172: 1474-1481
        • Dunlay S.M.
        • Gheorghiade M.
        • Reid K.J.
        • 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: 367-374
        • Lave J.R.
        • Leinhardt S.
        The cost and length of a hospital stay.
        Inquiry. 1976; 13: 327-343
        • Shea A.M.
        • Hammill B.G.
        • Curtis L.H.
        • Szczech L.A.
        • Schulman K.A.
        Medical costs of abnormal serum sodium levels.
        J Am Soc Nephrol. 2008; 19: 764-770
        • American Diabetes Association
        Economic costs of diabetes in the U.S. in 2012.
        Diabetes Care. 2013; 36: 1033-1046
        • Movig K.L.
        • Leufkens H.G.
        • Lenderink A.W.
        • Egberts A.C.
        Validity of hospital discharge International Classification of Diseases (ICD) codes for identifying patients with hyponatremia.
        J Clin Epidemiol. 2003; 56: 530-535
        • Philbin E.F.
        • Rocco Jr., T.A.
        • Lynch L.J.
        • Rogers V.A.
        • Jenkins P.
        Predictors and determinants of hospital length of stay in congestive heart failure in ten community hospitals.
        J Heart Lung Transplant. 1997; 16: 548-555
        • Barsony J.
        • Sugimura Y.
        • Verbalis J.G.
        Osteoclast response to low extracellular sodium and the mechanism of hyponatremia-induced bone loss.
        J Biol Chem. 2011; 286: 10864-10875
        • Benvenuti S.
        • Deledda C.
        • Luciani P.
        • et al.
        Low extracellular sodium causes neuronal distress independently of reduced osmolality in an experimental model of chronic hyponatremia.
        Neuromolecular Med. 2013; 15: 493-503
        • Park S.J.
        • Shin J.I.
        Inflammation and hyponatremia: an underrecognized condition?.
        Korean J Pediatr. 2013; 56: 519-522
        • Mastorakos G.
        • Weber J.S.
        • Magiakou M.A.
        • Gunn H.
        • Chrousos G.P.
        Hypothalamic-pituitary-adrenal axis activation and stimulation of systemic vasopressin secretion by recombinant interleukin-6 in humans: potential implications for the syndrome of inappropriate vasopressin secretion.
        J Clin Endocrinol Metab. 1994; 79: 934-939
        • Carande-Kulis V.G.
        • Maciosek M.V.
        • Briss P.A.
        • et al.
        Methods for systematic reviews of economic evaluations for the Guide to Community Preventive Services. Task Force on Community Preventive Services.
        Am J Prev Med. 2000; 18: 75-91
        • Drummond M.F.
        • O'Brien B.J.
        • Stoddart G.L.
        • et al.
        Methods for the Economic Evaluation of Health Care Programmes.
        3rd ed. Oxford University Press, New York2006
        • Peri A.
        Clinical review: the use of vaptans in clinical endocrinology.
        J Clin Endocrinol Metab. 2013; 98: 1321-1332
        • Verbalis J.G.
        • Goldsmith S.R.
        • Greenberg A.
        • et al.
        Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations.
        Am J Med. 2013; 12(10 suppl 1): S1-S42