European Journal of Internal Medicine 25 (2014) 379–382
Contents lists available at ScienceDirect
European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Original Article
Hyponatraemia is an independent predictor of in-hospital mortality Igor Sturdik ⁎, Monika Adamcova, Jana Kollerova, Tomas Koller, Zuzana Zelinkova, Juraj Payer 5th Department of Internal Medicine, Medical Faculty of Comenius University, University Hospital Bratislava, Slovakia
a r t i c l e
i n f o
Article history: Received 21 November 2013 Received in revised form 13 January 2014 Accepted 6 February 2014 Available online 26 February 2014 Keywords: Hyponatraemia In-hospital mortality Hospitalised patients Internal department
a b s t r a c t Background: Hyponatraemia increases morbidity and mortality, but the extent to which this condition influences mortality independently of other contributing factors is unclear. Materials and methods: All hyponatremic patients admitted to the internal medicine department during a six month period were included. Medical records were reviewed and patients' demographics, underlying disease, cause of hyponatremia and in-hospital deaths were noted. Control group consisted of patients with normonatremia admitted to the same department during the same period matched 1:1 by sex, age and underlying disease. Difference in in-hospital mortality rate between the study and control groups was tested by chisquare test. Baseline demographics, underlying diseases, cause of hyponatremia and state of hyponatremia correction as possible risk factors for mortality were tested in a multivariate analysis. Results: The baseline cohort of all admitted patients consisted of 2171 patients. Hyponatraemia was found in 278 (13%) patients (160 females and 118 males). The three most common causes of hyponatremia included gastrointestinal loss (52 patients), decreased oral intake (47 patients), and dilution hyponatremia (45 patients). The in-hospital mortality rate in the hyponatremic group was significantly higher compared with the control group (22% vs 7%, respectively; OR 3.75, 95% CI 2.17–6.48, p b 0.0001). In a multivariate analysis age above 65 years, dilution hyponatremia, decreased oral intake as etiologic factors of hyponatremia, and unsuccessful hyponatremia correction were independent factors associated with increased mortality. Conclusion: Hyponatraemia represents independent factor associated with in-hospital mortality. Age above 65 years, failure to correct hyponatremia and some specific etiologic factors of hyponatremia are related to increased mortality. © 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction Hyponatraemia is defined as the change in the amount of sodium in the extracellular fluid and the size of the extracellular fluid to the detriment of sodium. It is the most common electrolyte abnormality in hospitalised patients, its prevalence is 15 to 20% [1]. Although the majority of patients have mild, usually asymptomatic decrease in sodium, hyponatremia remains clinically significant for two main reasons. First, acute severe hyponatremia has unfavourable prognosis. The probability of mortality as 50% or more has been reported for patients with serum sodium concentrations below 120 mmol/L independently of underlying disease [2–4]. Second, adverse outcomes, including mortality, are higher in hyponatremic patients with a wide range of underlying diseases [5–14].
During the last three decades several studies were published, focusing on hyponatremia-associated in-hospital morbidity and mortality. The data published thus far differ substantially in reported prevalence of hyponatremia in hospitalised patients and hyponatremia-associated mortality due to various reasons, mostly differences in methodology used and study designs. Different inclusion criteria were used across studies, particularly the different cut-off values for sodium level to categorize the degree of hyponatremia and most data available concern severe hyponatremia. Moreover, most studies had a small number of patients and control groups were absent [4,15–18]. Therefore, we investigated the rate of in-hospital mortality related to hyponatremia in a consecutive cohort of patients matched 1:1 by sex, age and underlying disease. 2. Material and methods
⁎ Corresponding author at: 5th Department of Internal Medicine, Medical Faculty of Comenius University and University Hospital, Ruzinovska 6, 826 06 Bratislava, Slovakia. Tel.: +421 248234108; fax +421 248234110. E-mail addresses: [email protected] (I. Sturdik), [email protected] (M. Adamcova), [email protected] (J. Kollerova), [email protected] (T. Koller), [email protected] (Z. Zelinkova), [email protected] (J. Payer).
A retrospective analysis of medical data was performed. All admissions from 1st January 2012 to 31st August 2012 to the 5th Department of Internal Medicine Comenius University and University Hospital in Bratislava were analysed and the medical records of hyponatremic patients were identified based on the laboratory results at admission.
http://dx.doi.org/10.1016/j.ejim.2014.02.002 0953-6205/© 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
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I. Sturdik et al. / European Journal of Internal Medicine 25 (2014) 379–382
Hyponatraemia was defined as plasma sodium levels below 135 mmol/L at admission to the hospital and categorized as mild (130–135 mmol/L), moderate (125–130 mmol/L) and severe (below 125 mmol/L). When applicable, natrium levels were corrected for hyperglycaemia (glycaemia above 5.5 mmol/L) by the means of Katz formula (measured sodium + 0.016 x (serum glucose − 100)) [19]. In case of repeated admissions during the study period, the admission with the lowest sodium level was analysed. Medical records of all hyponatremic patients were reviewed and age, sex, date and primary reason for admission to hospital, comorbidity, drug history, severity of hyponatremia, success in correcting hyponatremia, the cause of hyponatremia, and possible death and its cause were noted. Determination of hyponatremia cause was based on a patient's clinical condition at admission (clinical symptoms of hydration, skin turgor, presence of edema, blood pressure) and laboratory parameters (serum osmolality, creatinine, urea, urine osmolality, sodium in the urine when applicable). Controls were patients with normonatremia admitted to the hospital during the same time period matched by sex, age (+/− 2 years) and underlying disease 1:1 with the study group. Ischemic heart disease, arterial hypertension, diabetes mellitus, chronic kidney disease, liver cirrhosis, chronic obstructive pulmonary disease, any endocrinological and psychiatric disease were the matching underlying diseases. In hospital mortality was defined as death during the same hospitalisation. Statistical analysis was performed using the IBM SPSS version 18 software. Difference in in-hospital mortality rate between the study and control groups was tested by a chi-square test. Baseline demographics, underlying disease, degree and cause of hyponatremia and success of correcting hyponatremia as possible risk factors for mortality were tested in a multivariate analysis. 3. Results Between January and August 2012, 2171 patients (males/females 1022/1149, 47% were males; average age 70 years, range 22–97) were admitted. After correction for pseudohyponatremia (32 cases), the true hyponatremia was present in 278 (13%) patients. From all hyponatremic patients, 103 (37%) had mild, 129 (46%) moderate and 46 (17%) severe hyponatremia. From all patients with hyponatremia, the majority (187 admissions; 67%) of admissions were not due to hyponatremia. In 24 patients (9%) the primary cause of hyponatremia was not identified and in 56 patients (20%) it was due to the combination of several causes. The respective causes of hyponatremia comprised gastrointestinal loss (52 patients, 19%), decreased oral intake (47 patients, 17%), dilution reasons (45 patients, 16%), clear water intake (25 patients, 9%), diuretics therapy (15 patients, 5%), SIADH (13 patients, 5%) and Addison's disease (1 patient, 0%). [Table 1]. The overall all cause of mortality in hyponatremic patients' group was significantly higher compared with control group (22% vs 7%, respectively; pb0,0001). Hyponatraemia was associated with increased mortality rate (OR 3.75, 95% CI 2.17–6.48) [Fig. 1]. In a multivariate analysis age over 65 years, specific etiologies of hyponatremia, dilution and decreased oral intake, and unsuccessful hyponatremia correction were independent factors associated with increased mortality [Table 2]. The mortality did not depend on severity of hyponatremia [Table 3]. There was no significant difference in the level of natremia between in hospital deaths of hyponatremic patients compared and hyponatremic patients who survived (127.33 vs 125.88 mmol/L respectively, p = 0.129). In the control group, there were no factors associated with mortality determined in the multivariate analysis including age, sex and the underlying condition. 4. Discussion In this retrospective study of hospitalised patients we analysed the influence of hyponatremia on in-hospital mortality and found that
Table 1 Basic demographic characteristics.
N M/F (% males) Age (yrs; range) Underlying disease – Ischemic heart disease – Arterial hypertension – Liver cirrhosis – Chronic renal failure – Diabetes mellitus 1 – Diabetes mellitus 2 – COPDa – Endocrinological disease – Psychiatric disease Reason for admission – Hyponatraemia – Others Aetiology of hyponatremia – Gastrointestinal loss – Decreased oral intake – Dilution reasons – Clear water intake – Diuretics therapy – SIADH b – Addison's disease – Cerebral salt wasting syndrome – Unknown – Combination of causes c
Hyponatraemia
Controls
278 118/160 (42%) 70 (22–97) 145 (52%) 179 (64%) 27 (10%) 82 (30%) 5 (2%) 70 (25%) 25 (9%) 33 (12%) 22 (8%)
278 118/160 (42%) 70 (22–97) 168 (60%) 210 (75%) 23 (8%) 90 (32%) 4 (1%) 71 (26%) 18 (7%) 24 (9%) 11 (4%)
91 (33%) 187 (67%)
N/A
52 (19%) 47 (17%) 45 (16%) 25 (9%) 15 (5%) 13 (5%) 1 (0%) 0 24 (9%) 56 (20%)
N/A
a
Chronic obstructive pulmonary disease. Syndrome of inappropriate antidiuretic hormone secretion. c Combination: dilution + diuretics + clear water intake, diuretics + gastrointestinal loss, diuretics + clear water intake. b
hyponatremia was an independent factor associated with mortality. Furthermore, we analysed the predictive factors of hyponatremiaassociated mortality and found that age and dilution and decreased oral intake as causes of hyponatremia as well as failure to correct hyponatremia were risk factors for hyponatremia-associated mortality. The phenomenon of hyponatremia increasing the death risk has been shown previously in several specific conditions and clinical settings, such as heart failure [20,21], liver cirrhosis [22–24], acute myocardial infarction [12,25], renal failure [26,27], pulmonary embolism [28–30], elderly patients [31–33] and intensive care unit patients [34–36]. Few studies have also shown increased mortality in hyponatremic patients with mixed underlying in general internal medicine departments [37,38]. The frequency of hyponatremia in these respective mainly retrospective cohorts varied from 5% to 20% with mortality risk of 1.5 to 3. In our study,
Fig. 1. In hospital mortality in hyponatremia and control groups. The percentage of inhospital deaths was significantly higher in hyponatremic group compared with control group (22% vs 7%, respectively; OR 3.75, 95% CI 2.17–6.48, p b 0.0001). Grey bars — no in-hospital deaths, black bars — in-hospital deaths.
I. Sturdik et al. / European Journal of Internal Medicine 25 (2014) 379–382 Table 2 The results show (in bold) that age above 65 years, dilution hyponatremia and decreased oral intake as etiologic factors of hyponatremia, and unsuccessful hyponatremia correction were independent factors associated with increased mortality. Predictive factors of hyponatremia-related mortality — age, sex, aetiology, clinical symptoms, severity of hyponatremia, and aetiology of hyponatremia. Variables
OR
95% CI
P
Age above 65 years Sex Severity of hyponatremia Correction of hyponatremia Clear water intake Gastrointestinal loss Diuretics therapy Dilution reasons SIADH a Decreased oral intake
0.24 1.80 1.08 3.18 1.08 1.25 0.88 3.82 0.00 3.53
0.11–0.54 0.94–3.47 0.66–1.74 1.65–6.15 0.40–2.91 0.52–3.01 0.31–2.51 1.47–9.91 0.00 1.54–8.1
0.001 0.08 0.768 0.001 0.884 0.619 0.808 0.006 0.999 0.003
a
Syndrome of inappropriate antidiuretic hormone secretion.
we found the frequency of hyponatremia of 13% in general internal medicine in patients which is in line with previously published observations. Hyponatraemia in our controlled cohort increased the risk of death 3 fold, irrespectively of underlying condition. Thus, the results of our study corroborate the previously reported disease-specific mortality risk in hyponatremic patients extending it with the finding of increased mortality in general, i.e. not related to a specific underlying condition. In this study, we found that age, failure to correct hyponatremia and dilution and decreased oral intake as causes of hyponatremia were predictors of increased hyponatremia-associated mortality. In previously published studies the most common reason of hyponatremia was also dilution of patients with liver cirrhosis and heart failure, other reasons were diuretic therapy and gastrointestinal loss. Death risk due to hyponatremia increased especially in elderly patients and in group without successful hyponatremia correction. In this population, the majority of hyponatremic patients suffered from mild and moderate hyponatremia, thus the correction of even mild hyponatremia represents an important part of clinical management and should not be underestimated. Dilution hyponatremia as one of the risk factors for mortality detected in the multivariate analysis can reflect the underlying conditions, congestive heart failure and liver cirrhosis which would be in line with the findings of the above mentioned studies. Accordingly, decreased oral intake may accompany end-stage of various conditions and increased mortality in these patients might thus rather reflect the bad clinical condition in general. Results of studies about dependence of mortality and hyponatremia severity are not uniform. Some studies showed mutual dependence on these factors [4,6,15], paradoxically some others did not prove it [2,39,40]. In our study, mortality was unrelated to severity of hyponatremia. Although we observed the lowest mortality in the group of severe hyponatremia, this difference compared with mild hyponatremia group and moderate hyponatremia group was not statistically significant. On the other hand, although not statistically significant, this observed low mortality rate in the group with potentially the worst prognosis could be explained by the fact that these patients more often present with neurological symptoms or impaired consciousness. Therefore, they are more likely to be admitted and monitored at metabolic intensive care unit. Considering that in our study failure to correct hyponatremia represented a negative prognostic factor and Table 3 Comparison of mortality mild, moderate and severe hyponatremia. Severity of hyponatremia
Prevalence N (%)
Mortality N (%)
P
MILD MODERATE SEVERE
103 (37%) 129 (46%) 46 (17%)
22 (8%) 31 (11%) 7 (3%)
0.46
381
that intensive management of patients with severe hyponatremia might result in higher success rate of hyponatremia correction and thus influence the prognosis. Despite the identification of patient comorbidities, the limit of this study is a disability to incorporate the severity of these comorbidities. Thus, the question remains whether hyponatremia represents a surrogate marker of the severity of the underlying conditions that led to its development or whether it directly contributes to observed adverse outcomes. Whether the relationship between hyponatremia and adverse results is causal or associative, hyponatremia is still convincing prognosis indicator for adverse outcomes. 5. Conclusion In this exhaustive, retrospective case–controlled study, we showed that hyponatremia at admission is associated with in-hospital mortality independently of underlying condition. Age, dilution and decreased oral intake as causes of hyponatraemia are risk factors for hyponatraemiaassociated mortality.Furthermore, failure to correct natremia increased the risk of death in hyponatremic patients. Thus, admission sodium should be used to stratify patients who need more intensive monitoring and therapy irrespective of the degree of hyponatremia. Conflict of interests All the authors disclose themselves from any conflict of interest. Learning points • Hyponatraemia is independent factor of in-hospital mortality • Age above 65 years, failure to correct hyponatraemia and some specific etiologic factors of hyponatraemia are related to increased mortality References [1] Whelan B, Bennett K, O'Riordan D, Silke B. Serum sodium as a risk factor for in-hospital mortality in acute unselected general medical patients. QJM monthly journal of the Association of Physicians 2009;102:175–82. [2] Saeed BO, Beaumont D, Handley GH, Weaver JU. Severe hyponatraemia: investigation and management in a district general hospital. J Clin Pathol 2002;55:893–6. [3] Baran D, Hutchinson TA. The outcome of hyponatremia in a general hospital population. Clin Nephrol 1984;22:72–6. [4] Gill G, Huda B, Boyd A, Skagen K, Wile D, Watson I, et al. Characteristics and mortality of severe hyponatraemia–a hospital-based study. Clin Endocrinol 2006;65:246–9. [5] Verbalis JG, Goldsmith SR, Greenberg A, Korzelius C, Schrier RW, Sterns RH, et al. Diagnosis, Evaluation, and Treatment of Hyponatremia: Expert Panel Recommendations. The Am J Med 2013;126:S1–S42. [6] Wald R, Jaber BL, Price LL, Upadhyay A, Madias NE. Impact of hospital-associated hyponatremia on selected outcomes. Arch Intern Med 2010;170:294–302. [7] Angeli P, Wong F, Watson H, Gines P. Hyponatremia in cirrhosis: Results of a patient population survey. Hepatology 2006;44:1535–42. [8] Serste T, Gustot T, Rautou PE, Francoz C, Njimi H, Durand F, et al. Severe hyponatremia is a better predictor of mortality than MELDNa in patients with cirrhosis and refractory ascites. J Hepatol 2012;57:274–80. [9] Dimopoulos K, Diller GP, Petraco R, Koltsida E, Giannakoulas G, Tay EL, et al. Hyponatraemia: A strong predictor of mortality in adults with congenital heart disease. Eur Heart J 2010;31:595–601. [10] Bettari L, Fiuzat M, Felker G, O’Connor C. Significance of hyponatremia in heart failure. Heart Fail Rev 2012;17:17–26. [11] Cardenas A, Gines P. Management of patients with cirrhosis awaiting liver transplantation. Gut 2011;60:412–21. [12] Goldberg A, Hammerman H, Petcherski S, Nassar M, Zdorovyak A, Yalonetsky S, et al. Hyponatremia and long-term mortality in survivors of acute ST-elevation myocardial infarction. Arch Intern Med 2006;166:781–6. [13] Asadollahi K, Beeching N, Gill G. Hyponatraemia as a risk factor for hospital mortality. Q JM: monthly journal of the Association of Physicians 2006;99:877–80. [14] Chawla A, Sterns RH, Nigwekar SU, Cappuccio JD. Mortality and serum sodium: do patients die from or with hyponatremia? Clin J Am Soc Nephrol 2011;6:960–5. [15] Erasmus RT, Matsha TE. The frequency, aetiology and outcome of severe hyponatraemia in adult hospitalised patients. The Cent Afr J Med 1998;44:154–8. [16] Nzerue CM, Baffoe-Bonnie H, You W, Falana B, Dai S. Predictors of outcome in hospitalized patients with severe hyponatremia. J Natl Med Assoc 2003;95:335–43. [17] Lee CT, Guo HR, Chen JB. Hyponatremia in the emergency department. The Am J Emerg Med 2000;18:264–8.
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[18] Crook MA, Velauthar U, Moran L, Griffiths W. Review of investigation and management of severe hyponatraemia in a hospital population. Ann Clin Biochem 1999; 36(Pt 2):158–62. [19] Katz MA. Hyperglycemia-induced hyponatremia–calculation of expected serum sodium depression. The N Engl J Med 1973;289:843–4. [20] Bettari L, Fiuzat M, Shaw LK, Wojdyla DM, Metra M, Felker GM, et al. Hyponatremia and long-term outcomes in chronic heart failure–an observational study from the Duke Databank for Cardiovascular Diseases. J Card Fail 2012;18:74–81. [21] Milo-Cotter O, Cotter G, Weatherley BD, Adams KF, Kaluski E, Uriel N, et al. Hyponatraemia in acute heart failure is a marker of increased mortality but not when associated with hyperglycaemia. Eur J Heart Fail 2008;10:196–200. [22] Kim JH, Lee JS, Lee SH, Bae WK, Kim NH, Kim KA, et al. The association between the serum sodium level and the severity of complications in liver cirrhosis. Korean J Intern Med 2009;24:106–12. [23] Vaa BE, Asrani SK, Dunn W, Kamath PS, Shah VH. Influence of serum sodium on MELD-based survival prediction in alcoholic hepatitis. Mayo Clin Proc 2011;86: 37–42. [24] Yun BC, Kim WR, Benson JT, Biggins SW, Therneau TM, Kremers WK, et al. Impact of pretransplant hyponatremia on outcome following liver transplantation. Hepatology 2009;49:1610–5. [25] Qureshi W, Hassan S, Khalid F, Almahmoud MF, Shah B, Tashman R, et al. Outcomes of correcting hyponatremia in patients with myocardial infarction. Clin Res Cardiol official journal of the German Cardiac Society 2013;102:637–44. [26] Kovesdy CP, Lott EH, Lu JL, Malakauskas SM, Ma JZ, Molnar MZ, et al. Hyponatremia, hypernatremia, and mortality in patients with chronic kidney disease with and without congestive heart failure. Circulation 2012;125:677–84. [27] Waikar SS, Curhan GC, Brunelli SM. Mortality associated with low serum sodium concentration in maintenance hemodialysis. The Am J Med 2011;124: 77–84. [28] Scherz N, Labarere J, Mean 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.
[29] Korkmaz I, Guven FM, Eren SH, Beydilli I, Yildirim B, Aktas C, et al. Baseline characteristics and the association between hyponatraemia and pulmonary embolism prognosis. The J Pak Med Assoc 2013;63:331–5. [30] Ng AC, Chow V, Yong AS, Chung T, Kritharides L. Fluctuation of serum sodium and its impact on short and long-term mortality following acute pulmonary embolism. PLoS One 2013;8:e61966. [31] Schrier RW, Sharma S, Shchekochikhin D. Hyponatraemia: more than just a marker of disease severity? Nat Rev Nephrol 2013;9:37–50. [32] Shapiro DS, Sonnenblick M, Galperin I, Melkonyan L, Munter G. Severe hyponatraemia in elderly hospitalized patients: prevalence, aetiology and outcome. Intern Med J 2010;40:574–80. [33] Turgutalp K, Ozhan O, Gok Oguz E, Horoz M, Camsari A, Yilmaz A, et al. Clinical features, outcome and cost of hyponatremia-associated admission and hospitalization in elderly and very elderly patients: a single-center experience in Turkey. Int Urol Nephrol 2013;45:265–73. [34] Palmer BF. Hyponatremia in the intensive care unit. Semin Nephrol 2009;29:257–70. [35] Rosner MH, Ronco C. Dysnatremias in the intensive care unit. Contrib Nephrol 2010;165:292–8. [36] 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. [37] Hoorn EJ, Zietse R. Hyponatremia and mortality: moving beyond associations. Am J Kidney Dis: the official journal of the National Kidney Foundation 2013;62:139–49. [38] Marco J, Barba R, Matia P, Plaza S, Mendez M, Canora J, et al. Low prevalence of hyponatremia codification in departments of internal medicine and its prognostic implications. Curr Med Res Opin 2013;12:1757–62. [39] Clayton JA, Le Jeune IR, Hall IP. Severe hyponatraemia in medical in-patients: aetiology, assessment and outcome. QJM: monthly journal of the Association of Physicians 2006;99:505–11. [40] Vu T, Wong R, Hamblin PS, Zajac J, Grossmann M. Patients presenting with severe hypotonic hyponatremia: etiological factors, assessment, and outcomes. Hosp Pract 1995;2009(37):128–36.
Contents lists available at ScienceDirect
European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Original Article
Hyponatraemia is an independent predictor of in-hospital mortality Igor Sturdik ⁎, Monika Adamcova, Jana Kollerova, Tomas Koller, Zuzana Zelinkova, Juraj Payer 5th Department of Internal Medicine, Medical Faculty of Comenius University, University Hospital Bratislava, Slovakia
a r t i c l e
i n f o
Article history: Received 21 November 2013 Received in revised form 13 January 2014 Accepted 6 February 2014 Available online 26 February 2014 Keywords: Hyponatraemia In-hospital mortality Hospitalised patients Internal department
a b s t r a c t Background: Hyponatraemia increases morbidity and mortality, but the extent to which this condition influences mortality independently of other contributing factors is unclear. Materials and methods: All hyponatremic patients admitted to the internal medicine department during a six month period were included. Medical records were reviewed and patients' demographics, underlying disease, cause of hyponatremia and in-hospital deaths were noted. Control group consisted of patients with normonatremia admitted to the same department during the same period matched 1:1 by sex, age and underlying disease. Difference in in-hospital mortality rate between the study and control groups was tested by chisquare test. Baseline demographics, underlying diseases, cause of hyponatremia and state of hyponatremia correction as possible risk factors for mortality were tested in a multivariate analysis. Results: The baseline cohort of all admitted patients consisted of 2171 patients. Hyponatraemia was found in 278 (13%) patients (160 females and 118 males). The three most common causes of hyponatremia included gastrointestinal loss (52 patients), decreased oral intake (47 patients), and dilution hyponatremia (45 patients). The in-hospital mortality rate in the hyponatremic group was significantly higher compared with the control group (22% vs 7%, respectively; OR 3.75, 95% CI 2.17–6.48, p b 0.0001). In a multivariate analysis age above 65 years, dilution hyponatremia, decreased oral intake as etiologic factors of hyponatremia, and unsuccessful hyponatremia correction were independent factors associated with increased mortality. Conclusion: Hyponatraemia represents independent factor associated with in-hospital mortality. Age above 65 years, failure to correct hyponatremia and some specific etiologic factors of hyponatremia are related to increased mortality. © 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction Hyponatraemia is defined as the change in the amount of sodium in the extracellular fluid and the size of the extracellular fluid to the detriment of sodium. It is the most common electrolyte abnormality in hospitalised patients, its prevalence is 15 to 20% [1]. Although the majority of patients have mild, usually asymptomatic decrease in sodium, hyponatremia remains clinically significant for two main reasons. First, acute severe hyponatremia has unfavourable prognosis. The probability of mortality as 50% or more has been reported for patients with serum sodium concentrations below 120 mmol/L independently of underlying disease [2–4]. Second, adverse outcomes, including mortality, are higher in hyponatremic patients with a wide range of underlying diseases [5–14].
During the last three decades several studies were published, focusing on hyponatremia-associated in-hospital morbidity and mortality. The data published thus far differ substantially in reported prevalence of hyponatremia in hospitalised patients and hyponatremia-associated mortality due to various reasons, mostly differences in methodology used and study designs. Different inclusion criteria were used across studies, particularly the different cut-off values for sodium level to categorize the degree of hyponatremia and most data available concern severe hyponatremia. Moreover, most studies had a small number of patients and control groups were absent [4,15–18]. Therefore, we investigated the rate of in-hospital mortality related to hyponatremia in a consecutive cohort of patients matched 1:1 by sex, age and underlying disease. 2. Material and methods
⁎ Corresponding author at: 5th Department of Internal Medicine, Medical Faculty of Comenius University and University Hospital, Ruzinovska 6, 826 06 Bratislava, Slovakia. Tel.: +421 248234108; fax +421 248234110. E-mail addresses: [email protected] (I. Sturdik), [email protected] (M. Adamcova), [email protected] (J. Kollerova), [email protected] (T. Koller), [email protected] (Z. Zelinkova), [email protected] (J. Payer).
A retrospective analysis of medical data was performed. All admissions from 1st January 2012 to 31st August 2012 to the 5th Department of Internal Medicine Comenius University and University Hospital in Bratislava were analysed and the medical records of hyponatremic patients were identified based on the laboratory results at admission.
http://dx.doi.org/10.1016/j.ejim.2014.02.002 0953-6205/© 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
380
I. Sturdik et al. / European Journal of Internal Medicine 25 (2014) 379–382
Hyponatraemia was defined as plasma sodium levels below 135 mmol/L at admission to the hospital and categorized as mild (130–135 mmol/L), moderate (125–130 mmol/L) and severe (below 125 mmol/L). When applicable, natrium levels were corrected for hyperglycaemia (glycaemia above 5.5 mmol/L) by the means of Katz formula (measured sodium + 0.016 x (serum glucose − 100)) [19]. In case of repeated admissions during the study period, the admission with the lowest sodium level was analysed. Medical records of all hyponatremic patients were reviewed and age, sex, date and primary reason for admission to hospital, comorbidity, drug history, severity of hyponatremia, success in correcting hyponatremia, the cause of hyponatremia, and possible death and its cause were noted. Determination of hyponatremia cause was based on a patient's clinical condition at admission (clinical symptoms of hydration, skin turgor, presence of edema, blood pressure) and laboratory parameters (serum osmolality, creatinine, urea, urine osmolality, sodium in the urine when applicable). Controls were patients with normonatremia admitted to the hospital during the same time period matched by sex, age (+/− 2 years) and underlying disease 1:1 with the study group. Ischemic heart disease, arterial hypertension, diabetes mellitus, chronic kidney disease, liver cirrhosis, chronic obstructive pulmonary disease, any endocrinological and psychiatric disease were the matching underlying diseases. In hospital mortality was defined as death during the same hospitalisation. Statistical analysis was performed using the IBM SPSS version 18 software. Difference in in-hospital mortality rate between the study and control groups was tested by a chi-square test. Baseline demographics, underlying disease, degree and cause of hyponatremia and success of correcting hyponatremia as possible risk factors for mortality were tested in a multivariate analysis. 3. Results Between January and August 2012, 2171 patients (males/females 1022/1149, 47% were males; average age 70 years, range 22–97) were admitted. After correction for pseudohyponatremia (32 cases), the true hyponatremia was present in 278 (13%) patients. From all hyponatremic patients, 103 (37%) had mild, 129 (46%) moderate and 46 (17%) severe hyponatremia. From all patients with hyponatremia, the majority (187 admissions; 67%) of admissions were not due to hyponatremia. In 24 patients (9%) the primary cause of hyponatremia was not identified and in 56 patients (20%) it was due to the combination of several causes. The respective causes of hyponatremia comprised gastrointestinal loss (52 patients, 19%), decreased oral intake (47 patients, 17%), dilution reasons (45 patients, 16%), clear water intake (25 patients, 9%), diuretics therapy (15 patients, 5%), SIADH (13 patients, 5%) and Addison's disease (1 patient, 0%). [Table 1]. The overall all cause of mortality in hyponatremic patients' group was significantly higher compared with control group (22% vs 7%, respectively; pb0,0001). Hyponatraemia was associated with increased mortality rate (OR 3.75, 95% CI 2.17–6.48) [Fig. 1]. In a multivariate analysis age over 65 years, specific etiologies of hyponatremia, dilution and decreased oral intake, and unsuccessful hyponatremia correction were independent factors associated with increased mortality [Table 2]. The mortality did not depend on severity of hyponatremia [Table 3]. There was no significant difference in the level of natremia between in hospital deaths of hyponatremic patients compared and hyponatremic patients who survived (127.33 vs 125.88 mmol/L respectively, p = 0.129). In the control group, there were no factors associated with mortality determined in the multivariate analysis including age, sex and the underlying condition. 4. Discussion In this retrospective study of hospitalised patients we analysed the influence of hyponatremia on in-hospital mortality and found that
Table 1 Basic demographic characteristics.
N M/F (% males) Age (yrs; range) Underlying disease – Ischemic heart disease – Arterial hypertension – Liver cirrhosis – Chronic renal failure – Diabetes mellitus 1 – Diabetes mellitus 2 – COPDa – Endocrinological disease – Psychiatric disease Reason for admission – Hyponatraemia – Others Aetiology of hyponatremia – Gastrointestinal loss – Decreased oral intake – Dilution reasons – Clear water intake – Diuretics therapy – SIADH b – Addison's disease – Cerebral salt wasting syndrome – Unknown – Combination of causes c
Hyponatraemia
Controls
278 118/160 (42%) 70 (22–97) 145 (52%) 179 (64%) 27 (10%) 82 (30%) 5 (2%) 70 (25%) 25 (9%) 33 (12%) 22 (8%)
278 118/160 (42%) 70 (22–97) 168 (60%) 210 (75%) 23 (8%) 90 (32%) 4 (1%) 71 (26%) 18 (7%) 24 (9%) 11 (4%)
91 (33%) 187 (67%)
N/A
52 (19%) 47 (17%) 45 (16%) 25 (9%) 15 (5%) 13 (5%) 1 (0%) 0 24 (9%) 56 (20%)
N/A
a
Chronic obstructive pulmonary disease. Syndrome of inappropriate antidiuretic hormone secretion. c Combination: dilution + diuretics + clear water intake, diuretics + gastrointestinal loss, diuretics + clear water intake. b
hyponatremia was an independent factor associated with mortality. Furthermore, we analysed the predictive factors of hyponatremiaassociated mortality and found that age and dilution and decreased oral intake as causes of hyponatremia as well as failure to correct hyponatremia were risk factors for hyponatremia-associated mortality. The phenomenon of hyponatremia increasing the death risk has been shown previously in several specific conditions and clinical settings, such as heart failure [20,21], liver cirrhosis [22–24], acute myocardial infarction [12,25], renal failure [26,27], pulmonary embolism [28–30], elderly patients [31–33] and intensive care unit patients [34–36]. Few studies have also shown increased mortality in hyponatremic patients with mixed underlying in general internal medicine departments [37,38]. The frequency of hyponatremia in these respective mainly retrospective cohorts varied from 5% to 20% with mortality risk of 1.5 to 3. In our study,
Fig. 1. In hospital mortality in hyponatremia and control groups. The percentage of inhospital deaths was significantly higher in hyponatremic group compared with control group (22% vs 7%, respectively; OR 3.75, 95% CI 2.17–6.48, p b 0.0001). Grey bars — no in-hospital deaths, black bars — in-hospital deaths.
I. Sturdik et al. / European Journal of Internal Medicine 25 (2014) 379–382 Table 2 The results show (in bold) that age above 65 years, dilution hyponatremia and decreased oral intake as etiologic factors of hyponatremia, and unsuccessful hyponatremia correction were independent factors associated with increased mortality. Predictive factors of hyponatremia-related mortality — age, sex, aetiology, clinical symptoms, severity of hyponatremia, and aetiology of hyponatremia. Variables
OR
95% CI
P
Age above 65 years Sex Severity of hyponatremia Correction of hyponatremia Clear water intake Gastrointestinal loss Diuretics therapy Dilution reasons SIADH a Decreased oral intake
0.24 1.80 1.08 3.18 1.08 1.25 0.88 3.82 0.00 3.53
0.11–0.54 0.94–3.47 0.66–1.74 1.65–6.15 0.40–2.91 0.52–3.01 0.31–2.51 1.47–9.91 0.00 1.54–8.1
0.001 0.08 0.768 0.001 0.884 0.619 0.808 0.006 0.999 0.003
a
Syndrome of inappropriate antidiuretic hormone secretion.
we found the frequency of hyponatremia of 13% in general internal medicine in patients which is in line with previously published observations. Hyponatraemia in our controlled cohort increased the risk of death 3 fold, irrespectively of underlying condition. Thus, the results of our study corroborate the previously reported disease-specific mortality risk in hyponatremic patients extending it with the finding of increased mortality in general, i.e. not related to a specific underlying condition. In this study, we found that age, failure to correct hyponatremia and dilution and decreased oral intake as causes of hyponatremia were predictors of increased hyponatremia-associated mortality. In previously published studies the most common reason of hyponatremia was also dilution of patients with liver cirrhosis and heart failure, other reasons were diuretic therapy and gastrointestinal loss. Death risk due to hyponatremia increased especially in elderly patients and in group without successful hyponatremia correction. In this population, the majority of hyponatremic patients suffered from mild and moderate hyponatremia, thus the correction of even mild hyponatremia represents an important part of clinical management and should not be underestimated. Dilution hyponatremia as one of the risk factors for mortality detected in the multivariate analysis can reflect the underlying conditions, congestive heart failure and liver cirrhosis which would be in line with the findings of the above mentioned studies. Accordingly, decreased oral intake may accompany end-stage of various conditions and increased mortality in these patients might thus rather reflect the bad clinical condition in general. Results of studies about dependence of mortality and hyponatremia severity are not uniform. Some studies showed mutual dependence on these factors [4,6,15], paradoxically some others did not prove it [2,39,40]. In our study, mortality was unrelated to severity of hyponatremia. Although we observed the lowest mortality in the group of severe hyponatremia, this difference compared with mild hyponatremia group and moderate hyponatremia group was not statistically significant. On the other hand, although not statistically significant, this observed low mortality rate in the group with potentially the worst prognosis could be explained by the fact that these patients more often present with neurological symptoms or impaired consciousness. Therefore, they are more likely to be admitted and monitored at metabolic intensive care unit. Considering that in our study failure to correct hyponatremia represented a negative prognostic factor and Table 3 Comparison of mortality mild, moderate and severe hyponatremia. Severity of hyponatremia
Prevalence N (%)
Mortality N (%)
P
MILD MODERATE SEVERE
103 (37%) 129 (46%) 46 (17%)
22 (8%) 31 (11%) 7 (3%)
0.46
381
that intensive management of patients with severe hyponatremia might result in higher success rate of hyponatremia correction and thus influence the prognosis. Despite the identification of patient comorbidities, the limit of this study is a disability to incorporate the severity of these comorbidities. Thus, the question remains whether hyponatremia represents a surrogate marker of the severity of the underlying conditions that led to its development or whether it directly contributes to observed adverse outcomes. Whether the relationship between hyponatremia and adverse results is causal or associative, hyponatremia is still convincing prognosis indicator for adverse outcomes. 5. Conclusion In this exhaustive, retrospective case–controlled study, we showed that hyponatremia at admission is associated with in-hospital mortality independently of underlying condition. Age, dilution and decreased oral intake as causes of hyponatraemia are risk factors for hyponatraemiaassociated mortality.Furthermore, failure to correct natremia increased the risk of death in hyponatremic patients. Thus, admission sodium should be used to stratify patients who need more intensive monitoring and therapy irrespective of the degree of hyponatremia. Conflict of interests All the authors disclose themselves from any conflict of interest. Learning points • Hyponatraemia is independent factor of in-hospital mortality • Age above 65 years, failure to correct hyponatraemia and some specific etiologic factors of hyponatraemia are related to increased mortality References [1] Whelan B, Bennett K, O'Riordan D, Silke B. Serum sodium as a risk factor for in-hospital mortality in acute unselected general medical patients. QJM monthly journal of the Association of Physicians 2009;102:175–82. [2] Saeed BO, Beaumont D, Handley GH, Weaver JU. Severe hyponatraemia: investigation and management in a district general hospital. J Clin Pathol 2002;55:893–6. [3] Baran D, Hutchinson TA. The outcome of hyponatremia in a general hospital population. Clin Nephrol 1984;22:72–6. [4] Gill G, Huda B, Boyd A, Skagen K, Wile D, Watson I, et al. Characteristics and mortality of severe hyponatraemia–a hospital-based study. Clin Endocrinol 2006;65:246–9. [5] Verbalis JG, Goldsmith SR, Greenberg A, Korzelius C, Schrier RW, Sterns RH, et al. Diagnosis, Evaluation, and Treatment of Hyponatremia: Expert Panel Recommendations. The Am J Med 2013;126:S1–S42. [6] Wald R, Jaber BL, Price LL, Upadhyay A, Madias NE. Impact of hospital-associated hyponatremia on selected outcomes. Arch Intern Med 2010;170:294–302. [7] Angeli P, Wong F, Watson H, Gines P. Hyponatremia in cirrhosis: Results of a patient population survey. Hepatology 2006;44:1535–42. [8] Serste T, Gustot T, Rautou PE, Francoz C, Njimi H, Durand F, et al. Severe hyponatremia is a better predictor of mortality than MELDNa in patients with cirrhosis and refractory ascites. J Hepatol 2012;57:274–80. [9] Dimopoulos K, Diller GP, Petraco R, Koltsida E, Giannakoulas G, Tay EL, et al. Hyponatraemia: A strong predictor of mortality in adults with congenital heart disease. Eur Heart J 2010;31:595–601. [10] Bettari L, Fiuzat M, Felker G, O’Connor C. Significance of hyponatremia in heart failure. Heart Fail Rev 2012;17:17–26. [11] Cardenas A, Gines P. Management of patients with cirrhosis awaiting liver transplantation. Gut 2011;60:412–21. [12] Goldberg A, Hammerman H, Petcherski S, Nassar M, Zdorovyak A, Yalonetsky S, et al. Hyponatremia and long-term mortality in survivors of acute ST-elevation myocardial infarction. Arch Intern Med 2006;166:781–6. [13] Asadollahi K, Beeching N, Gill G. Hyponatraemia as a risk factor for hospital mortality. Q JM: monthly journal of the Association of Physicians 2006;99:877–80. [14] Chawla A, Sterns RH, Nigwekar SU, Cappuccio JD. Mortality and serum sodium: do patients die from or with hyponatremia? Clin J Am Soc Nephrol 2011;6:960–5. [15] Erasmus RT, Matsha TE. The frequency, aetiology and outcome of severe hyponatraemia in adult hospitalised patients. The Cent Afr J Med 1998;44:154–8. [16] Nzerue CM, Baffoe-Bonnie H, You W, Falana B, Dai S. Predictors of outcome in hospitalized patients with severe hyponatremia. J Natl Med Assoc 2003;95:335–43. [17] Lee CT, Guo HR, Chen JB. Hyponatremia in the emergency department. The Am J Emerg Med 2000;18:264–8.
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