Long-term outcome of profound hyponatremia: a prospective 12 months follow-up study

in European Journal of Endocrinology
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  • 1 Endocrinology, Diabetology and Metabolism, University Hospital Basel, Basel, Switzerland
  • | 2 Division of Endocrinology, Diabetology and Metabolism, Medical University Clinic, Kantonsspital Aarau, Aarau, Switzerland
  • | 3 Department of Clinical Research, University Hospital Basel, Basel, Switzerland
  • | 4 Nephrology, Dialysis & Transplantation, Kantonsspital Aarau, Aarau, Switzerland
  • | 5 Institute of Laboratory Medicine, Kantonsspital Aarau, Aarau, Switzerland

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Background

Hyponatremia is the most common electrolyte abnormality in hospitalized patients and given its impact on mortality and morbidity, a relevant medical condition. Nevertheless, little is known about factors influencing long-term outcome.

Methods

This is a prospective observational 12-month follow-up study of patients with profound hyponatremia (≤125 mmol/L) admitted to the emergency department of two tertiary care centers between 2011 and 2013. We analyzed the predictive value of clinical and laboratory parameters regarding the following outcomes: 1-year mortality, rehospitalization and recurrent profound hyponatremia.

Results

Median (IQR) initial serum sodium (s-sodium) level of 281 included patients was 120 mmol/L (116–123). During the follow-up period, 58 (20.6%) patients died. The majority (56.2%) were rehospitalized at least once. Recurrent hyponatremia was observed in 42.7%, being profound in 16%. Underlying comorbidities, assessed by the Charlson Comorbidity Index, predicted 1-year mortality (odds ratio (OR) 1.43, 95% confidence interval (CI) 1.25–1.64, P < 0.001). Furthermore, ‘s-sodium level at admission’ (OR 1.14, 95% CI 1.01–1.29, P = 0.036) and ‘correction of hyponatremia’ defined as s-sodium ≥135 mmol/L at discharge were associated with mortality (OR 0.47, 95% CI 0.23–0.94, P = 0.034). Mortality rate fell with decreasing baseline s-sodium levels and was lower in the hyponatremia category ≤120 mmol/L vs >120 mmol/L (14.8% and 27.8%, P < 0.01). Patients with s-sodium level ≤120 mmol/L were more likely to have drug-induced hyponatremia, whereas hypervolemic hyponatremia was more common in patients with s-sodium >120 mmol/L.

Conclusion

Hyponatremia is associated with a substantial 1-year mortality, recurrence and rehospitalization rate. The positive correlation of s-sodium and mortality emphasizes the importance of the underlying disease, which determines the outcome besides hyponatremia itself.

Abstract

Background

Hyponatremia is the most common electrolyte abnormality in hospitalized patients and given its impact on mortality and morbidity, a relevant medical condition. Nevertheless, little is known about factors influencing long-term outcome.

Methods

This is a prospective observational 12-month follow-up study of patients with profound hyponatremia (≤125 mmol/L) admitted to the emergency department of two tertiary care centers between 2011 and 2013. We analyzed the predictive value of clinical and laboratory parameters regarding the following outcomes: 1-year mortality, rehospitalization and recurrent profound hyponatremia.

Results

Median (IQR) initial serum sodium (s-sodium) level of 281 included patients was 120 mmol/L (116–123). During the follow-up period, 58 (20.6%) patients died. The majority (56.2%) were rehospitalized at least once. Recurrent hyponatremia was observed in 42.7%, being profound in 16%. Underlying comorbidities, assessed by the Charlson Comorbidity Index, predicted 1-year mortality (odds ratio (OR) 1.43, 95% confidence interval (CI) 1.25–1.64, P < 0.001). Furthermore, ‘s-sodium level at admission’ (OR 1.14, 95% CI 1.01–1.29, P = 0.036) and ‘correction of hyponatremia’ defined as s-sodium ≥135 mmol/L at discharge were associated with mortality (OR 0.47, 95% CI 0.23–0.94, P = 0.034). Mortality rate fell with decreasing baseline s-sodium levels and was lower in the hyponatremia category ≤120 mmol/L vs >120 mmol/L (14.8% and 27.8%, P < 0.01). Patients with s-sodium level ≤120 mmol/L were more likely to have drug-induced hyponatremia, whereas hypervolemic hyponatremia was more common in patients with s-sodium >120 mmol/L.

Conclusion

Hyponatremia is associated with a substantial 1-year mortality, recurrence and rehospitalization rate. The positive correlation of s-sodium and mortality emphasizes the importance of the underlying disease, which determines the outcome besides hyponatremia itself.

Introduction

Hyponatremia is the most common electrolyte abnormality in hospitalized patients (1). Prevalence for mild hyponatremia is up to 30–42%, depending on the health care setting and the patient population studied (2). Profound hyponatremia, defined as a serum sodium (s-sodium) level <125 mmol/L, is less common with a prevalence of 2–3% (3, 4).

Hyponatremia is associated with an increased in-hospital, short-, and long-term mortality both in hospitalized (5, 6, 7) and ambulatory patients (8, 9). An increased morbidity and mortality…’convey the intended meaning. increased morbidity and mortality rate was shown especially in hyponatremic patients with medical conditions such as heart failure (10), myocardial infarction (11), liver cirrhosis (12), cancer (13), pneumonia (14) and stroke (15, 16).

Given the poor prognosis linked to hyponatremia, identification of modifiable factors in this context is of great interest. As highlighted by previous studies, hyponatremia per se may contribute to adverse outcome, which is reflected by a positive correlation of mortality and severity of hyponatremia (17, 18, 19, 20). Conversely, other studies observed a paradoxical fall in mortality rate as s-sodium values decreased below a certain level (e.g. <120 mmol/L) (5, 19, 21). This indicates the presence of factors other than hyponatremia itself affecting mortality, e.g. etiology of hyponatremia, comorbidities or therapeutic issues. So far, in previous publications, these possible outcome parameters have not been precisely assessed and studied in a prospective manner, and especially in profound hyponatremia, data are scarce and controversial (7, 19, 21, 22).

The aim of this study was to prospectively explore the predictive value of different clinical, laboratory and therapeutic parameters regarding outcome in a broad, well-defined cohort of hospitalized patients with profound hyponatremia.

Methods

Study design

From June 2011 to August 2013, 298 patients with profound hyponatremia presenting to the medical emergency department of the University Hospital Basel and the University Medical Clinic Aarau in Switzerland were included in a prospective observational study, which as a primary endpoint aimed to evaluate plasma copeptin as a diagnostic marker in the differential diagnosis of profound hyponatremia. As a predefined secondary endpoint, we aimed to explore clinical outcome and outcome predictors of patients with profound hyponatremia after 12 months of study entry. Inclusion criteria were full legal age, initial s-sodium level ≤125 mmol/L and a serum osmolality below 280 mmol/kg. Patients with hyponatremia due to hyperglycemia or with age <18 years were excluded from the analysis. Study protocol was approved by the Ethics Committee of Basel and Aarau, and informed consent was obtained from all patients or in case of impaired mental state from their relatives.

Baseline data collection

Collected baseline data contained medical history, clinical examination (especially volume status) and specific laboratory testing including plasma and urine electrolytes, creatinine, osmolality, urea and uric acid. Furthermore blood glucose, as well…’ and correct if necessary., blood glucose, as well as thyroid-stimulating hormone and cortisol levels in unclear cases, were routinely measured.

Diagnostic and therapeutic approach

Initial diagnostic adjudication and treatment decisions were completely up to the attending physician and not influenced by the study team. Symptomatic hyponatremia was treated with hypertonic sodium chloride (3% NaCl) infusion irrespective of the underlining cause. Oligo- or asymptomatic patients were treated with either fluid restriction or fluid administration (0.9% NaCl infusion) according to the cause of hyponatremia. Vaptans were not used, as they are not approved in Switzerland.

The final classification of hyponatremia was done by experienced board-certified endocrinologists (not involved in patients’ treatment and care) in a standardized fashion using the above-mentioned data collected at admission. Moreover, information regarding management during hospitalization and treatment response was also included in the final diagnosis.

Follow-up

Follow-up was done by a structured telephone interview 12 months after study entry. Interviews were performed by study doctors, study nurses or students. Patients and/or their respective family doctors were asked regarding rehospitalization and recurrent hyponatremia. Clinical report including laboratory findings was requested from every single rehospitalization to objectify information from phone interview and to get detailed information about circumstances of rehospitalization or eventually death.

Outcome measures and analyzed outcome predictors

We analyzed the influence of different laboratory and clinical parameters on three main outcomes: overall mortality, rehospitalization and recurrent profound hyponatremia. Besides ‘s-sodium level at admission’, the following therapy-associated predictors were evaluated: ‘ICU admission’, ‘s-sodium correction rate’ defined as delta s-sodium from admission to 24 h later, ‘correction of hyponatremia’ defined as s-sodium level ≥135 mmol/L at discharge, ‘hospital aggravated hyponatremia’ defined as decrease in s-sodium level ≥2 mmol/L during the first 48 h after hospital admission, and ‘overly rapid correction’ as a s-sodium increment >12 mmol/L during first 24 h respectively >18 mmol/L during first 48 h. Furthermore, we analyzed whether etiology of hyponatremia or comorbidities assessed by the Charlson Comorbidity Index (CCI) were outcome predictors. The CCI is a comorbidity scoring system counting from 0 to 37 points, which allows to weigh disease severity according to the ICD-9-CM system (23, 24).

Because of controversial data regarding mortality according to hyponatremia severity, patients were divided in two categories (initial s-sodium level ≤ and >120 mmol/L) and were characterized in view of hyponatremia cause, therapy and outcome.

Statistics

For statistical analysis, all relevant clinical and laboratory parameters obtained by interview, clinical testing and reviewing of medical records were entered into an Excel database. Data were analyzed using STATA (12.1, Texas 77845, USA) and GraphPad Prism 6.00 for Windows (San Diego, California, USA). Discrete variables are expressed as frequency (percentage), continuous variables as mean with standard deviation (s.d.) and non-continuous variables as medians with interquartile range (IQR). For data not normally distributed, Mann–Whitney U test was used for two-group comparison. Univariate and multivariate logistic regression analyses with two different models were performed. Both models were adjusted for age, CCI and s-sodium level at hospital admission. Model 1 was calculated for s-sodium ≥135 mmol/L at discharge, Delta s-sodium 24 h and ICU admission and Model 2 for s-sodium ≥135 mmol/L, Delta s-sodium 24 h, ICU admission, hypervolemic hyponatremia and malignant SIAD. All tests were two-tailed, and P values less than 0.05 were considered to indicate statistical significance.

Results

From the initial 298 patients, complete follow-up data were available for 281 patients. Seventeen patients were excluded because of loss of follow-up (n = 8), withdrawal of informed consent (n = 3) or insufficient data (n = 6).

Baseline characteristics and follow-up data

Median age of the 281 analyzed patients (66.5% females) was 72 (IQR 61–80). SIAD was the most common cause of hyponatremia (61.2%), especially drug-induced SIAD was very frequent (40.2%). Other etiologies of hyponatremia were as follows: hypovolemic hyponatremia (gastrointestinal losses and loss in the third space) 19.9%, hypervolemic hyponatremia (liver, heart and kidney failure) 11.4% and primary polydipsia 7.5%.

Median s-sodium level at hospital admission was 120 mmol/L (IQR 116–123) and was raised by a median of 5 mmol/L (IQR 2–8) during the first 24 h. Half of the patients (49.1%) reached normal s-sodium levels (≥135 mmol/L) at discharge. During hospitalization, 36.7% of patients were admitted to the intensive care unit (ICU) and 8.5% were treated with 3% NaCl infusion. Hospital aggravated hyponatremia occurred in 8.5% of patients. Overly rapid correction was seen in 20 (7.1%) patients, whereby nine of them received 0.9% NaCl infusion, six 3% NaCl infusion and five patients were treated with fluid restriction. No patient developed osmotic demyelination syndrome (ODS) during the observation phase. Detailed baseline characteristics are shown in Table 1 and follow-up data in Table 2.

Table 1

Baseline characteristics of 281 patients. Data are presented as % (n) and median (IQR: 25th–75th).

CharacteristicsValues
 Age (years)72 (61–80)
 Female66.5% (187)
 Systolic blood pressure (mmHg)136 (119–155)
 Heart rate (per minute)80 (68–90)
 Body temperature (°C)37 (36.5–37.5)
 GCS (Glasgow Coma Score)15 (15–15)
 BMI (kg/m2)23.8 (20.8–27.4)
 Charlson Comorbidity Index2 (1–5)
Etiology of hyponatremia
 Malignant SIAD7.1% (20)
 Non-malignant SIAD54.1% (152)
  SIAD drugs/diuretics40.2% (113)
  SIAD idiopathic4.6% (13)
  SIAD lung3.2% (9)
  SIAD cns6% (17)
 Hypervolemic hyponatremia11.4% (32)
  Heart failure5.3% (15)
  Liver failure4.3% (12)
  Kidney failure1.8% (5)
 Hypovolemic hyponatremia19.9% (56)
 Primary polydipsia7.5% (21)
Laboratory findings
 S-sodium at hospital admission (mmol/L)120 (116–123)
 Plasma glucose (mmol/L)6.6 (5.7–8.1)

BMI, body mass index.

Table 2

Follow-up and outcome data. Data are presented as % (n) and median (IQR: 25th–75th).

Therapeutic findings during initial hospitalization
 Delta s-sodium 24 h (mmol/L)5 (2–8)
 Overly rapid correction7.1% (20)
 Hospital aggravated hyponatremia8.5% (24)
 ICU admission36.7% (103)
Laboratory findings at discharge
 S-sodium (mmol/L)134 (130–137)
 S-sodium ≥135 mmol/L49.1% (138)
Outcome
 Overall mortality20.6% (58)
 In-hospital-mortality3.9% (11)
 30-day-mortality rate31% (18)
 Time to rehospitalization (days)75 (21–206)
 30-day-rehospitalization rate18.5% (52)
 Rehospitalization rate56.2% (158)
  - with hyponatremia during first rehospitalization60.8% (96)
 Recurrent rehospitalization28.5% (80)
 Recurrent hyponatremia42.7% (120)
 Recurrent profound hyponatremia (Na ≤125 mmol/L)16% (45)
Cause of Mortality (n = 58)
 Malignant disease32.8% (19)
 Unknown24.1% (14)
 Respiratory insufficiency12.1% (7)
 Heart failure10.3% (6)
 Septic shock8.6% (5)
 Liver failure8.6% (5)
 Renal failure3.4% (2)
Cause of first rehospitalization (n = 158)
 Infectious18.4% (29)
 Orthopedic/surgery17.7% (28)
 Hematological/oncological11.4% (18)
 Others10.8% (17)
 Neurologic10.1% (16)
 Gastrointestinal9.5% (15)
 Cardiovascular7.6% (12)
 Hyponatremia6.3% (10)
 Psychiatric5.7% (9)
 Pulmonary2.5% (4)

BMI, body mass index.

Outcome measures

Mortality

Overall mortality was 20.6%, whereof 3.9% died during the initial hospital stay and 31% within the first 30 days after discharge. Leading causes of death were malignant disease (32.8%), respiratory (12.1%) respectively cardiac arrest (10.3%), or unspecified polymorbidity (24.1%) (Table 2). In none of these patients, death could directly be attributed to hyponatremia, as suggestive hyponatremia complications (e.g. brain edema, epileptic seizure) were not recorded.

Mortality risk was significantly higher in patients with multiple comorbidities expressed by a high CCI both in univariate and multivariate analysis (OR 1.49, 95% CI 1.33–1.68, P < 0.001 and OR 1.45, 95% CI 1.27–1.65, P < 0.001).

A significant correlation with mortality was shown for ‘s-sodium level at admission’, whereby higher values were associated with a higher mortality rate (OR 1.17, 95% CI 1.1–1.3, P = 0.005). This association was also present in multivariate analysis (OR 1.14, 95% CI 1.01–1.29, P = 0.036).

Single therapeutic factors, such as ‘correction rate’, ‘ICU admission’ or ‘hospital aggravated hyponatremia’, were not associated with mortality. However, correction of hyponatremia (s-sodium level ≥135 mmol/L) was significantly associated with a lower mortality rate (OR 1.09, 95% CI 1.01–1.18, P = 0.02 and OR 0.46, 95% CI 0.3–0.8, P = 0.011), even after multivariate adjustment (OR 0.47, 95% CI 0.23–0.95, P = 0.034).

Concerning etiology of hyponatremia, higher mortality rates were found for hypervolemic hyponatremia and malignant SIAD (OR 3.07, 95% CI 1.4–6.7, P = 0.005 and OR 4.4, 95% CI 1.7–11.2, P = 0.002 respectively). On the contrary, non-malignant SIAD was associated with a lower mortality rate (OR 0.45, 95% CI 0.24–0.77, P = 0.005). However, after multivariate analysis, etiologies of hyponatremia lost significance as outcome markers (data not shown). Detailed results for univariate and multivariate analyses are shown in Tables 3 and 4.

Table 3

Univariate analysis.

Outcome 1 MortalityOutcome 2 RehospitalizationOutcome 3 Recurrent profound hyponatremia
PredictorsODDS (95% CI)P valueODDS (95% CI)P valueODDS (95% CI)P value
Laboratory parameters
 S-sodium at admission1.17 (1.05–1.3)0.0050.98 (0.90–1.07)0.6940.83 (0.73–0.95)0.005
Etiology of hyponatremia
 Malignant SIAD4.4 (1.73–11.15)0.0024.89 (1.4–17.1)0.0135.07 (1.96–13.1)0.001
 Non-malignant SIAD0.43 (0.24–0.77)0.0051.00 (0.62–1.61)0.9980.95 (0.5–1.79)0.866
 Hypervolemic hyponatremia3.07 (1.41–6.67)0.0050.58 (0.27–1.21)0.1440.5 (0.15–1.73)0.278
 Hypovolemic hyponatremia0.79 (0.37–1.69)0.5460.74 (0.41–1.34)0.3200.45 (0.17–1.2)0.109
 Primary polydipsia0.7 (0.2–2.48)0.5801.38 (0.53–3.62)0.5121.42 (0.45–4.51)0.547
Therapeutic parameters
 S-sodium correction rate first 24 h0.93 (0.87–1.00)0.0581.04 (0.98–1.09)0.2220.98 (0.91–1.06)0.646
 Hospital-aggravated hyponatremia1.65 (0.65–4.18)0.2940.53 (0.23–1.25)0.1461.41 (0.5–4.01)0.514
 Correction of hyponatremia (≥135 mmol/L)0.46 (0.25–0.84)0.0110.59 (0.36–0.94)0.0280.4 (0.2–0.79)0.009
Comorbidities
 Charlson Comorbidity Index1.49 (1.33–1.68)<0.00011.07 (0.98–1.16)0.1571.1 (0.99–1.22)0.087

Bold values indicate statistically significant values.

Table 4

Multivariate analysis

Model 1*Model 2**
ODDS (95% CI)P valueODDS (95% CI)P value
Outcome 1: Mortality
 S-sodium at admission1.15 (1.01–1.32)0.041.15 (0.10–1.32)0.05
 Correction of hyponatremia (≥135 mmol/L)0.48 (0.24–0.97)0.0390.47 (0.23–0.94)0.034
 Charlson Comorbidity Index1.48 (1.31–1.68)<0.00011.44 (1.27–1.65)<0.0001
Outcome 2: Rehospitalization
 S-sodium at admission0.94 (0.85–1.04)0.2160.95 (0.86–1.06)0.368
 Correction of hyponatremia (≥135 mmol/L)0.56 (0.34–0.92)0.0220.57 (0.35–0.95)0.030
 Charlson Comorbidity Index1.07 (0.98–1.18)0.1481.05 (0.94–1.16)0.391
Outcome 3: Recurrent profound hyponatremia
 S-sodium at admission0.74 (0.63–0.87)<0.00010.75 (0.64–0.89)0.001
 Correction of hyponatremia (≥135 mmol/L)0.38 (0.18–0.79)0.0100.39 (0.19–0.81)0.012
 Charlson Comorbiditiy Index1.1 (0.98–1.24)0.1041.06 (0.93–1.22)0.364

Model 1 adjusted for age, Charlson Comorbidity Index, s-sodium at hospital admission, s-sodium ≥135 mmol/L at discharge, Delta s-sodium 24 h, ICU admission. **Model 2 adjusted for age, Charlson Comorbidity Index, s-sodium at hospital admission, s-sodium ≥135 mmol/L at discharge, Delta s-sodium 24 h, ICU admission, hypervolemic hyponatremia, malignant SIAD.

Rehospitalization and recurrent hyponatremia

Thirty-day rehospitalization rate was 18.5%, but 56.2% of patients were rehospitalization at least once in 12 months, 28.5% repeatedly. During follow-up, recurrent hyponatremia was observed in 42.7% of patients, being profound (s-sodium level ≤125 mmol/L) again in 16% (Table 2).

‘S-sodium level at admission’ was not linked to an increased rehospitalization rate, but showed a significant association with recurrent profound hyponatremia, after multivariate adjustment (OR 0.75, 95% CI 0.64–0.89, P = 0.001) also.

The risk of rehospitalization and recurrent profound hyponatremia was lower in patients who reached eunatremia at discharge (‘correction of hyponatremia’), both in univariate and multivariate analysis (OR 0.57, 95% CI 0.35–0.95, P = 0.03 and OR 0.39, 95% CI 0.19–0.81, P = 0.012 respectively).

‘Malignant SIAD’ was a risk factor for rehospitalization (OR 4.89, 95% CI 1.4–17.1, P = 0.013) and recurrent profound hyponatremia (OR 5.07, 95% CI 1.96–13.1, P = 0.001) in univariate but not in multivariate analysis.

All other variables were not significantly associated with the outcomes of rehospitalization and recurrent profound hyponatremia (Tables 3 and 4).

Patients characteristics according to hyponatremia categories: s-sodium ≤ and >120 mmol/L

Characteristics of patients with initial s-sodium level ≤ vs >120 mmol/L revealed several differences (Table 5).

Table 5

Characteristics of patients with initial s-sodium level of ≤120 mmol/L and >120 mmol/L. Data are presented as % (n) and median (IQR: 25th–75th).

CharacteristicsS-sodium ≤120mmol/L (n = 155)S-sodium >120mmol/L (n = 126)P value
 Age (years)73 (62–81)70 (58–79.3)0.0769
 Female65.8% (102)67.5% (85)0.7712
 Systolic blood pressure (mmHg)139 (120–159)135 (114–153)0.0811
 Heart rate (per minute)76 (65.8–88)84 (70–97)0.0008
 Charlson Comorbidity Index2 (1–4)2 (1–5.3)0.0436
Etiology of hyponatremia
 Malignant SIAD7.7% (12)6.3% (8)0.6533
 Non-malignant SIAD62.6% (97)43.7% (55)0.0016
  SIAD drugs/diuretics49% (76)29.4% (37)0.0008
  SIAD idiopathic5.2% (8)4% (5)0.6379
  SIAD lung3.2% (5)3.2% (4)0.9826
  SIAD cns5.2% (8)7.1% (9)0.4903
 Hypervolemic hyponatremia7.7% (12)15.9% (20)0.0333
  Heart failure3.9% (6)7.1% (9)0.2265
  Liver failure1.9% (3)7.1% (9)0.0323
  Kidney failure1.9% (3)1.6% (2)0.8290
 Hypovolemic hyponatremia15.5% (24)25.4% (32)0.0390
 Primary polydipsia6.5% (10)8.7% (11)0.4718
Medication
 Diuretics64.5% (100)54% (68)0.0736
  Thiazide diuretics50.3% (78)37.3% (47)0.0293
  Loop-diuretics16.1%% (25)19.8% (25)0.4199
  Potassium-sparing diuretics12.3% (19)11.9% (15)0.9292
 Antihypertensives54.2% (84)45.2% (57)0.1363
 NSAID11% (17)15.1% (19)0.3068
 Neuroleptics10.3% (16)7.9% (10)0.4941
 Opioids7.7% (12)11.9% (15)0.2404
Laboratory findings
 S-sodium at hospital admission (mmol/L)117 (113–120)123 (122–124)<0.0001
 S-sodium at discharge (mmol/L)135 (131–137)134 (129–137)0.2306
 S-sodium ≥135 mmol/L at discharge52.3% (81)45.2% (57)0.2429
Therapeutic findings
 Delta s-sodium 24 h (mmol/L)5 (2–9)4.5 (1–6)0.0163
 Delta s-sodium 48 h (mmol/L)11 (7–15)8 (3.5–11)<0.0001
 Overly rapid correction11.6% (18)1.6% (2)0.0012
 ICU admission48.4% (75)22.2% (28)<0.0001
 3% NaCl infusion12.3% (19) 4% (5)0.0136
Outcome
 Overall mortality14.8% (23)27.8% (35)0.0078
 In-hospital mortality1.3% (2)7.1% (9)0.0121
 Rehospitalization rate56.1% (87)56.3% (71)0.9712
 Recurrent hyponatremia45.8% (71)38.9% (49)0.2449
 Recurrent profound hyponatremia21.3% (33)9.5% (12)0.0076

BMI, body mass index.

In-hospital and overall mortality was higher in patients with initial s-sodium levels >120 mmol/L (7.1% vs 1.3%, P = 0.0121 vs 27.8% vs 14.8%, P = 0.0078). Figure 1 shows Kaplan–Meier survival curves for both subgroups. Concerning etiology of hyponatremia patients with a s-sodium level >120 mmol/L more often suffered from hypervolemic or hypovolemic hyponatremia (15.9% vs 7.7%, P = 0.0333 and 25.4% vs 15.5%, P = 0.039 respectively). With 62.6%, non-malignant SIAD – especially due to drugs/diuretics – was the most frequent etiology in the lower s-sodium subgroup (49% vs 29.4%, P = 0.0008).

Figure 1
Figure 1

Kaplan–Meier curve. Survival rate in patients with initial s-sodium level ≤120 mmol/L and >120 mmol/L.

Citation: European Journal of Endocrinology 175, 6; 10.1530/EJE-16-0500

Initial s-sodium correction rate was higher when hyponatremia was more pronounced: 5 mmol/L during the first 24 h compared with 4.5 mmol/L (P = 0.0163) in the subgroup with initial s-sodium level >120 mmol/L. Furthermore, ICU admission and treatment with 3% NaCl infusion was more common in patients with initial s-sodium ≤120 mmol/L (48.4% vs 22.2%, P < 0.0001 and 12.3% vs 4%, P = 0.0136 respectively).

During follow-up, patients in the lower hyponatremia category recurred more often with profound hyponatremia (21.3% vs 9.5%, P = 0.0076). On the contrary, rehospitalization rate was comparable between the two groups (56.1% vs 56.3%, P = 0.97).

Discussion

We herein confirm the adverse outcomes linked to hyponatremia. As a key finding, we observed a highly significant association of the CCI and death, meaning that mortality in hyponatremia is mainly influenced by comorbidities. Besides CCI, we identified two other important predictors of long-term survival: ‘s-sodium level at admission’ and ‘correction of hyponatremia’.

The mortality rate in our cohort of hyponatremic patients was 20.6%, which is well within the published range of 5–50% (5, 19, 2). Supposing that hyponatremia itself is causing death, an inverse relationship between s-sodium and mortality would be expected. In contrast, we found a strong, positive association between initial s-sodium concentration and mortality; thus, mortality rate was lower in patients with lower s-sodium levels. This is in contrast with a recently published meta-analysis indicating that hyponatremia-related risk augments with decreasing s-sodium level (6). In this meta-analysis, only 5 of 81 analyzed studies used a s-sodium cutoff of <125 mmol/L as was used in our study, thus supporting an inverse correlation of hyponatremia level and death in mild but not in profound hyponatremia. Indeed, similar to our data, other studies observed a paradoxical fall in mortality rate in profound hyponatremia (5, 19, 21, 25). In two large prospective studies, one-year mortality rate was highest in patients with a s-sodium between 120 and 129 mmol/L and lower in patients with a s-sodium >130 mmol/L or <120 mmol/L respectively (5, 19). As a possible explanation for the lower mortality rate in patients with lower s-sodium levels, we found a lower CCI and in line with a previous study, significantly more cases with non-malignant (mainly drug induced) SIAD in the lower hyponatremia category (19, 21). Thus, etiologies of hyponatremia may vary according to its degree and notably drug-induced SIAD seems to predispose to very low s-sodium levels (26). We assume that hyponatremia – being a marker of disease severity and outcome in heart failure or liver cirrhosis – might not be similarly linked to mortality in other conditions like drug-induced SIAD.

An alternative rational for the lower mortality in patients with s-sodium <120 mmol/L may be a different therapeutic approach in very profound vs milder hyponatremia. Indeed, we observed a higher percentage of ICU admission and of hypertonic saline administration as well as a more rapid initial sodium correction rate in patients with s-sodium of ≤120 vs >120 mmol/L. Furthermore, in patients with s-sodium levels >120 mmol/L, hospital-aggravated hyponatremia tended to be more frequent suggesting a delayed or inadequate management of hyponatremia. This is in accordance with the recently published Hyponatremia Registry showing that active treatment significantly depends on hyponatremia severity (27). However, the hypothesis that modality and velocity of hyponatremia treatment influences outcome could not be strengthened by our data: besides hyponatremia correction, we did not find a significant association of single therapeutic factors and mortality – probably because of insufficient power.

Hyponatremia correction was reached in 49.1% of our patients and strongly correlated with a lower mortality rate. This is in agreement with a recent meta-analysis, finding a reduced risk of death for any degree of hyponatremia improvement (28). One might postulate that patients who reach normonatremia are generally healthier, and their condition is more often attributable to a transient etiology of hyponatremia (e.g. drug-induced SIAD, pulmonary infection) (26). However, when looking at patients in the hyponatremia category ≤120 mmol/L – harboring a lower CCI and often a transient hyponatremia cause – we did not find a higher percentage of hyponatremia correction. This is probably explained by an ‘earlier’ hospital discharge of healthier patients (before reaching an s-sodium level of ≥135 mmol/L).

In the aforementioned meta-analysis, comorbidities were not considered as confounders due to insufficient data. In our study, data were adjusted for age, comorbidities (CCI) and cause of hyponatremia, but ‘correction of hyponatremia’ remained significantly associated with a reduced mortality rate. This underscores the significance of hyponatremia correction across different clinical conditions, which could play an important role in preventing mortality.

The 1-year readmission rate in our study was very high (56.2%). Not surprisingly, malignant SIAD turned out to be a predictor of both rehospitalization and rehyponatremia. Reasons for rehospitalization were various, but hyponatremia itself was only rarely indicated as the main cause. However, many patients presented with accompanying hyponatremia, and it is tempting to speculate that it was a contributing factor for rehospitalization. ThisPlease clarify if ‘also after multivariate adjustment‘ could read ‘even after multivariate adjustment‘ in the sentence ‘This is supported by the…‘ is supported by the fact that CCI was not a predictor of readmission, whereas correction of hyponatremia was significantly associated with a lower rehospitalization rate even after multivariate adjustment.

Interestingly, there was a significant association of hyponatremia severity and recurrent profound hyponatremia; patients with initial s-sodium level ≤120 mmol/L recurred more often compared with those with initial levels above 120 mmol/L. In these patients with mainly drug-induced SIAD, this may be explained by a restart of predisposing drugs after normalization of hyponatremia.

Our study has the following strengths. Aside from large-scale epidemiologic studies, it is the largest reported series of prospectively enrolled patients with profound hyponatremia. The prospective study design with specific testing allowed us to carefully categorize patients into diagnostic groups. Excluding patient with hyperglycemia-induced hyponatremia eliminated an important and frequent confounder in hyponatremia studies. However, some limitations should be considered. First, this is a predefined secondary analysis of a prospective study. Thus, there was no power calculation specific to this paper, what may weaken our findings. Secondly, when focusing on the subgroups on initial s-sodium level ≤ or >120 mmol/L, the primary endpoint death was reached in ‘only’ 23 and 35 patients respectively. Thus, caution is needed when interpreting results according to these hyponatremia categories. Furthermore, although in line with previous studies, the division into these two categories at a cutoff of 120 mmol/L is somehow arbitrary.

In conclusion, we confirm the impact of profound hyponatremia in daily clinical practice, with a high 1-year mortality, recurrence and rehospitalization rate. The positive correlation of the CCI and initial s-sodium level with mortality emphasizes the importance of the underlying disease, which seems to particularly impact on prognosis. But still, hyponatremia of any degree is associated with poor outcome, and our data suggest that a particular attention should be paid to hyponatremia itself as a therapeutic target – irrespective of etiology and severity.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

The study was investigator initiated and primarily supported by the University Hospital Basel, Basel University, Medical University Clinic Aarau and the Swiss National Foundation research funds. M C-C was supported by a grant from the Swiss National Foundation (PP00P3-123346), Switzerland.

Acknowledgments

The authors thank the staff of the clinics and departments of emergency medicine, internal medicine, and the department of endocrinology, diabetology and metabolism for most helpful support during study. Furthermore, the authors thank the many supporters, study and laboratory personnel at both participating centers, especially Cemile Bathelt, Kathrin Ulrich, Merih Guglielmetti, Sonja Schwenne, Kristina Schumacher, Renate Hunziker and Ursina Minder. They also thank the members of the OPTIMA study team for their support for patient enrolment and data collection.

References

  • 1

    Spasovski G, Vanholder R, Allolio B, Annane D, Ball S, Bichet D, Decaux G, Fenske W, Hoorn EJ & Ichai C et al. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Nephrology Dialysis Transplantation 2014 29 (Supplement 2) i1i39. (doi:10.1093/ndt/gfu040)

    • Search Google Scholar
    • Export Citation
  • 2

    Upadhyay A, Jaber BL & Madias NE. Incidence and prevalence of hyponatremia. American Journal of Medicine 2006 119 S30S35. (doi:10.1016/j.amjmed.2006.05.005)

    • Search Google Scholar
    • Export Citation
  • 3

    Upadhyay A, Jaber BL & Madias NE. Epidemiology of hyponatremia. Seminars in Nephrology 2009 29 227238. (doi:10.1016/j.semnephrol.2009.03.004)

  • 4

    Hawkins RC. Age and gender as risk factors for hyponatremia and hypernatremia. Clinica Chimia Acta 2003 337 169172. (doi:10.1016/j.cccn.2003.08.001)

    • Search Google Scholar
    • Export Citation
  • 5

    Waikar SS, Mount DB & Curhan GC. Mortality after hospitalization with mild, moderate, and severe hyponatremia. American Journal of Medicine 2009 122 857865. (doi:10.1016/j.amjmed.2009.01.027)

    • Search Google Scholar
    • Export Citation
  • 6

    Corona G, Giuliani C, Parenti G, Norello D, Verbalis JG, Forti G, Maggi M & Peri A. Moderate hyponatremia is associated with increased risk of mortality: evidence from a meta-analysis. PLoS ONE 2013 8 e80451. (doi:10.1371/journal.pone.0080451)

    • Search Google Scholar
    • Export Citation
  • 7

    Balling L, Gustafsson F, Goetze JP, Dalsgaard M, Nielsen H, Boesgaard S, Bay M, Kirk V, Nielsen OW & Kober L et al. Hyponatraemia at hospital admission is a predictor of overall mortality. Internal Medicine Journal 2015 45 195202. (doi:10.1111/imj.12623)

    • Search Google Scholar
    • Export Citation
  • 8

    Gankam-Kengne F, Ayers C, Khera A, de Lemos J & Maalouf NM. Mild hyponatremia is associated with an increased risk of death in an ambulatory setting. Kidney International 2013 83 700706. (doi:10.1038/ki.2012.459)

    • Search Google Scholar
    • Export Citation
  • 9

    Sajadieh A, Binici Z, Mouridsen MR, Nielsen OW, Hansen JF & Haugaard SB. Mild hyponatremia carries a poor prognosis in community subjects. American Journal of Medicine 2009 122 679686. (doi:10.1016/j.amjmed.2008.11.033)

    • Search Google Scholar
    • Export Citation
  • 10

    Gheorghiade M, Abraham WT, Albert NM, Gattis Stough W, Greenberg BH, O’Connor CM, She L, Yancy CW, Young J & Fonarow GC. Relationship between admission serum sodium concentration and clinical outcomes in patients hospitalized for heart failure: an analysis from the OPTIMIZE-HF registry. European Heart Journal 2007 28 980988. (doi:10.1093/eurheartj/ehl542)

    • Search Google Scholar
    • Export Citation
  • 11

    Singla I, Zahid M, Good CB, Macioce A, Sonel AF. Effect of hyponatremia (<135 mEq/L) on outcome in patients with non-ST-elevation acute coronary syndrome. American Journal of Cardiology 2007 100 406408. (doi:10.1016/j.amjcard.2007.03.039)

    • Search Google Scholar
    • Export Citation
  • 12

    Yu C, Sharma N & Saab S. Hyponatremia: clinical associations, prognosis, and treatment in cirrhosis. Experimental and Clinical Transplantation 2013 11 311. (doi:10.6002/ect.2012.0147)

    • Search Google Scholar
    • Export Citation
  • 13

    Doshi SM, Shah P, Lei X, Lahoti A & Salahudeen AK. Hyponatremia in hospitalized cancer patients and its impact on clinical outcomes. American Journal of Kidney Diseases 2012 59 222228. (doi:10.1053/j.ajkd.2011.08.029)

    • Search Google Scholar
    • Export Citation
  • 14

    Nair V, Niederman MS, Masani N & Fishbane S. Hyponatremia in community-acquired pneumonia. American Journal of Nephrology 2007 27 184190. (doi:10.1159/000100866)

    • Search Google Scholar
    • Export Citation
  • 15

    Huang WY, Weng WC, Peng TI, Chien YY, Wu CL, Lee M, Hung CC & Chen KH. Association of hyponatremia in acute stroke stage with three-year mortality in patients with first-ever ischemic stroke. Cerebrovascular Diseases 2012 34 5562. (doi:10.1159/000338906)

    • Search Google Scholar
    • Export Citation
  • 16

    Rodrigues B, Staff I, Fortunato G & McCullough LD. Hyponatremia in the prognosis of acute ischemic stroke. Journal of Stroke and Cerebrovascular Diseases 2014 23 850854. (doi:10.1016/j.jstrokecerebrovasdis.2013.07.011)

    • Search Google Scholar
    • Export Citation
  • 17

    Wald R, Jaber BL, Price LL, Upadhyay A & Madias NE. Impact of hospital-associated hyponatremia on selected outcomes. Archives of Internal Medicine 2010 170 294302. (doi:10.1001/archinternmed.2009.513)

    • Search Google Scholar
    • Export Citation
  • 18

    Bennani SL, Abouqal R, Zeggwagh AA, Madani N, Abidi K, Zekraoui A & Kerkeb O. Incidence, causes and prognostic factors of hyponatremia in intensive care. Revue de Médecine Interne 2003 24 224229.

    • Search Google Scholar
    • Export Citation
  • 19

    Holland-Bill L, Christiansen CF, Heide-Jorgensen U, Ulrichsen SP, Ring T, Jorgensen JO & Sorensen HT. Hyponatremia and mortality risk: a Danish cohort study of 279 508 acutely hospitalized patients. European Journal of Endocrinology 2015 173 7181. (doi:10.1530/EJE-15-0111)

    • Search Google Scholar
    • Export Citation
  • 20

    Asadollahi K, Hastings IM, Beeching NJ & Gill GV. Laboratory risk factors for hospital mortality in acutely admitted patients. QJM 2007 100 501507. (doi:10.1093/qjmed/hcm055)

    • Search Google Scholar
    • Export Citation
  • 21

    Chawla A, Sterns RH, Nigwekar SU & Cappuccio JD. Mortality and serum sodium: do patients die from or with hyponatremia? Clinical Journal of the American Society of Nephrology 2011 6 960965. (doi:10.2215/CJN.10101110)

    • Search Google Scholar
    • Export Citation
  • 22

    Baran D & Hutchinson TA. The outcome of hyponatremia in a general hospital population. Clinical Nephrology 1984 22 7276.

  • 23

    Charlson ME, Pompei P, Ales KL & MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. Journal of Chronic Diseases 1987 40 373383. (doi:10.1016/0021-9681(87)90171-8)

    • Search Google Scholar
    • Export Citation
  • 24

    Deyo RA, Cherkin DC & Ciol MA. Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. Journal of Clinical Epidemiology 1992 45 613619. (doi:10.1016/0895-4356(92)90133-8)

    • Search Google Scholar
    • Export Citation
  • 25

    Clayton JA, Le Jeune IR & Hall IP. Severe hyponatraemia in medical in-patients: aetiology, assessment and outcome. QJM 2006 99 505511. (doi:10.1093/qjmed/hcl071)

    • Search Google Scholar
    • Export Citation
  • 26

    Shepshelovich D, Leibovitch C, Klein A, Zoldan S, Milo G, Shochat T, Rozen-Zvi B, Gafter-Gvili A & Lahav M. The syndrome of inappropriate antidiuretic hormone secretion: Distribution and characterization according to etiologies. European Journal of Internal Medicine 2015 26 819824. (doi:10.1016/j.ejim.2015.10.020)

    • Search Google Scholar
    • Export Citation
  • 27

    Greenberg A, Verbalis JG, Amin AN, Burst VR, Chiodo JA 3rd, Chiong JR, Dasta JF, Friend KE, Hauptman PJ & Peri A et al. Current treatment practice and outcomes. Report of the hyponatremia registry. Kidney International 2015 88 167177. (doi:10.1038/ki.2015.4)

    • Search Google Scholar
    • Export Citation
  • 28

    Corona G, Giuliani C, Verbalis JG, Forti G, Maggi M & Peri A. Hyponatremia improvement is associated with a reduced risk of mortality: evidence from a meta-analysis. PLoS ONE 2015 10 e0124105. (doi:10.1371/journal.pone.0124105)

    • Search Google Scholar
    • Export Citation

 

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    Kaplan–Meier curve. Survival rate in patients with initial s-sodium level ≤120 mmol/L and >120 mmol/L.

  • 1

    Spasovski G, Vanholder R, Allolio B, Annane D, Ball S, Bichet D, Decaux G, Fenske W, Hoorn EJ & Ichai C et al. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Nephrology Dialysis Transplantation 2014 29 (Supplement 2) i1i39. (doi:10.1093/ndt/gfu040)

    • Search Google Scholar
    • Export Citation
  • 2

    Upadhyay A, Jaber BL & Madias NE. Incidence and prevalence of hyponatremia. American Journal of Medicine 2006 119 S30S35. (doi:10.1016/j.amjmed.2006.05.005)

    • Search Google Scholar
    • Export Citation
  • 3

    Upadhyay A, Jaber BL & Madias NE. Epidemiology of hyponatremia. Seminars in Nephrology 2009 29 227238. (doi:10.1016/j.semnephrol.2009.03.004)

  • 4

    Hawkins RC. Age and gender as risk factors for hyponatremia and hypernatremia. Clinica Chimia Acta 2003 337 169172. (doi:10.1016/j.cccn.2003.08.001)

    • Search Google Scholar
    • Export Citation
  • 5

    Waikar SS, Mount DB & Curhan GC. Mortality after hospitalization with mild, moderate, and severe hyponatremia. American Journal of Medicine 2009 122 857865. (doi:10.1016/j.amjmed.2009.01.027)

    • Search Google Scholar
    • Export Citation
  • 6

    Corona G, Giuliani C, Parenti G, Norello D, Verbalis JG, Forti G, Maggi M & Peri A. Moderate hyponatremia is associated with increased risk of mortality: evidence from a meta-analysis. PLoS ONE 2013 8 e80451. (doi:10.1371/journal.pone.0080451)

    • Search Google Scholar
    • Export Citation
  • 7

    Balling L, Gustafsson F, Goetze JP, Dalsgaard M, Nielsen H, Boesgaard S, Bay M, Kirk V, Nielsen OW & Kober L et al. Hyponatraemia at hospital admission is a predictor of overall mortality. Internal Medicine Journal 2015 45 195202. (doi:10.1111/imj.12623)

    • Search Google Scholar
    • Export Citation
  • 8

    Gankam-Kengne F, Ayers C, Khera A, de Lemos J & Maalouf NM. Mild hyponatremia is associated with an increased risk of death in an ambulatory setting. Kidney International 2013 83 700706. (doi:10.1038/ki.2012.459)

    • Search Google Scholar
    • Export Citation
  • 9

    Sajadieh A, Binici Z, Mouridsen MR, Nielsen OW, Hansen JF & Haugaard SB. Mild hyponatremia carries a poor prognosis in community subjects. American Journal of Medicine 2009 122 679686. (doi:10.1016/j.amjmed.2008.11.033)

    • Search Google Scholar
    • Export Citation
  • 10

    Gheorghiade M, Abraham WT, Albert NM, Gattis Stough W, Greenberg BH, O’Connor CM, She L, Yancy CW, Young J & Fonarow GC. Relationship between admission serum sodium concentration and clinical outcomes in patients hospitalized for heart failure: an analysis from the OPTIMIZE-HF registry. European Heart Journal 2007 28 980988. (doi:10.1093/eurheartj/ehl542)

    • Search Google Scholar
    • Export Citation
  • 11

    Singla I, Zahid M, Good CB, Macioce A, Sonel AF. Effect of hyponatremia (<135 mEq/L) on outcome in patients with non-ST-elevation acute coronary syndrome. American Journal of Cardiology 2007 100 406408. (doi:10.1016/j.amjcard.2007.03.039)

    • Search Google Scholar
    • Export Citation
  • 12

    Yu C, Sharma N & Saab S. Hyponatremia: clinical associations, prognosis, and treatment in cirrhosis. Experimental and Clinical Transplantation 2013 11 311. (doi:10.6002/ect.2012.0147)

    • Search Google Scholar
    • Export Citation
  • 13

    Doshi SM, Shah P, Lei X, Lahoti A & Salahudeen AK. Hyponatremia in hospitalized cancer patients and its impact on clinical outcomes. American Journal of Kidney Diseases 2012 59 222228. (doi:10.1053/j.ajkd.2011.08.029)

    • Search Google Scholar
    • Export Citation
  • 14

    Nair V, Niederman MS, Masani N & Fishbane S. Hyponatremia in community-acquired pneumonia. American Journal of Nephrology 2007 27 184190. (doi:10.1159/000100866)

    • Search Google Scholar
    • Export Citation
  • 15

    Huang WY, Weng WC, Peng TI, Chien YY, Wu CL, Lee M, Hung CC & Chen KH. Association of hyponatremia in acute stroke stage with three-year mortality in patients with first-ever ischemic stroke. Cerebrovascular Diseases 2012 34 5562. (doi:10.1159/000338906)

    • Search Google Scholar
    • Export Citation
  • 16

    Rodrigues B, Staff I, Fortunato G & McCullough LD. Hyponatremia in the prognosis of acute ischemic stroke. Journal of Stroke and Cerebrovascular Diseases 2014 23 850854. (doi:10.1016/j.jstrokecerebrovasdis.2013.07.011)

    • Search Google Scholar
    • Export Citation
  • 17

    Wald R, Jaber BL, Price LL, Upadhyay A & Madias NE. Impact of hospital-associated hyponatremia on selected outcomes. Archives of Internal Medicine 2010 170 294302. (doi:10.1001/archinternmed.2009.513)

    • Search Google Scholar
    • Export Citation
  • 18

    Bennani SL, Abouqal R, Zeggwagh AA, Madani N, Abidi K, Zekraoui A & Kerkeb O. Incidence, causes and prognostic factors of hyponatremia in intensive care. Revue de Médecine Interne 2003 24 224229.

    • Search Google Scholar
    • Export Citation
  • 19

    Holland-Bill L, Christiansen CF, Heide-Jorgensen U, Ulrichsen SP, Ring T, Jorgensen JO & Sorensen HT. Hyponatremia and mortality risk: a Danish cohort study of 279 508 acutely hospitalized patients. European Journal of Endocrinology 2015 173 7181. (doi:10.1530/EJE-15-0111)

    • Search Google Scholar
    • Export Citation
  • 20

    Asadollahi K, Hastings IM, Beeching NJ & Gill GV. Laboratory risk factors for hospital mortality in acutely admitted patients. QJM 2007 100 501507. (doi:10.1093/qjmed/hcm055)

    • Search Google Scholar
    • Export Citation
  • 21

    Chawla A, Sterns RH, Nigwekar SU & Cappuccio JD. Mortality and serum sodium: do patients die from or with hyponatremia? Clinical Journal of the American Society of Nephrology 2011 6 960965. (doi:10.2215/CJN.10101110)

    • Search Google Scholar
    • Export Citation
  • 22

    Baran D & Hutchinson TA. The outcome of hyponatremia in a general hospital population. Clinical Nephrology 1984 22 7276.

  • 23

    Charlson ME, Pompei P, Ales KL & MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. Journal of Chronic Diseases 1987 40 373383. (doi:10.1016/0021-9681(87)90171-8)

    • Search Google Scholar
    • Export Citation
  • 24

    Deyo RA, Cherkin DC & Ciol MA. Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. Journal of Clinical Epidemiology 1992 45 613619. (doi:10.1016/0895-4356(92)90133-8)

    • Search Google Scholar
    • Export Citation
  • 25

    Clayton JA, Le Jeune IR & Hall IP. Severe hyponatraemia in medical in-patients: aetiology, assessment and outcome. QJM 2006 99 505511. (doi:10.1093/qjmed/hcl071)

    • Search Google Scholar
    • Export Citation
  • 26

    Shepshelovich D, Leibovitch C, Klein A, Zoldan S, Milo G, Shochat T, Rozen-Zvi B, Gafter-Gvili A & Lahav M. The syndrome of inappropriate antidiuretic hormone secretion: Distribution and characterization according to etiologies. European Journal of Internal Medicine 2015 26 819824. (doi:10.1016/j.ejim.2015.10.020)

    • Search Google Scholar
    • Export Citation
  • 27

    Greenberg A, Verbalis JG, Amin AN, Burst VR, Chiodo JA 3rd, Chiong JR, Dasta JF, Friend KE, Hauptman PJ & Peri A et al. Current treatment practice and outcomes. Report of the hyponatremia registry. Kidney International 2015 88 167177. (doi:10.1038/ki.2015.4)

    • Search Google Scholar
    • Export Citation
  • 28

    Corona G, Giuliani C, Verbalis JG, Forti G, Maggi M & Peri A. Hyponatremia improvement is associated with a reduced risk of mortality: evidence from a meta-analysis. PLoS ONE 2015 10 e0124105. (doi:10.1371/journal.pone.0124105)

    • Search Google Scholar
    • Export Citation