Active management of severe hyponatraemia is associated with improved mortality

in European Journal of Endocrinology
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  • 1 Academic Department of Endocrinology, Beaumont Hospital and RCSI Medical School, Dublin, Ireland
  • | 2 Department of Chemical Pathology, Beaumont Hospital, Dublin, Ireland

Correspondence should be addressed to A Garrahy; Email: draoifegarrahy@gmail.com
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Objective

Severe hyponatraemia (plasma sodium concentration, pNa <120 mmol/L) is reported to be associated with mortality rates as high as 50%. Although there are several international guidelines for the management of severe hyponatraemia, there are few data on the impact of treatment.

Design and methods

We have longitudinally reviewed rates of specialist input, active management of hyponatraemia, treatment outcomes and mortality rates in patients with severe hyponatraemia (pNa <120 mmol/L) in 2005, 2010 and 2015, and compared the recent mortality rate with that of patients with pNa 120–125 mmol/L.

Results

Between 2005 and 2010 there was a doubling in the rate of specialist referral (32 to 68%, P = 0.003) and an increase in the use of active management of hyponatraemia in patients with pNa <120 mmol/L (63 to 88%, P = 0.02), associated with a reduction in mortality from 51 to 15% (P < 0.001). The improved rates of intervention were maintained between 2010 and 2015, but there was no further reduction in mortality. When data from all three reviews were pooled, specialist consultation in patients with pNa <120 mmol/L was associated with a 91% reduction in mortality risk, RR 0.09 (95% CI: 0.03–0.26), P < 0.001. Log-rank testing on in-hospital survival in 2015 found no significant difference between patients with pNa <120 mmol/L and pNa 120–125 mmol/L (P = 0.56).

Conclusion

Dedicated specialist input and active management of severe hyponatraemia are associated with a reduction in mortality, to rates comparable with moderate hyponatraemia.

Abstract

Objective

Severe hyponatraemia (plasma sodium concentration, pNa <120 mmol/L) is reported to be associated with mortality rates as high as 50%. Although there are several international guidelines for the management of severe hyponatraemia, there are few data on the impact of treatment.

Design and methods

We have longitudinally reviewed rates of specialist input, active management of hyponatraemia, treatment outcomes and mortality rates in patients with severe hyponatraemia (pNa <120 mmol/L) in 2005, 2010 and 2015, and compared the recent mortality rate with that of patients with pNa 120–125 mmol/L.

Results

Between 2005 and 2010 there was a doubling in the rate of specialist referral (32 to 68%, P = 0.003) and an increase in the use of active management of hyponatraemia in patients with pNa <120 mmol/L (63 to 88%, P = 0.02), associated with a reduction in mortality from 51 to 15% (P < 0.001). The improved rates of intervention were maintained between 2010 and 2015, but there was no further reduction in mortality. When data from all three reviews were pooled, specialist consultation in patients with pNa <120 mmol/L was associated with a 91% reduction in mortality risk, RR 0.09 (95% CI: 0.03–0.26), P < 0.001. Log-rank testing on in-hospital survival in 2015 found no significant difference between patients with pNa <120 mmol/L and pNa 120–125 mmol/L (P = 0.56).

Conclusion

Dedicated specialist input and active management of severe hyponatraemia are associated with a reduction in mortality, to rates comparable with moderate hyponatraemia.

Introduction

Hyponatraemia is the commonest electrolyte disturbance in clinical practice (1) and has consistently been shown to be associated with increased mortality (2, 3, 4, 5, 6). In acute severe hyponatraemia, the osmotic movement of water into the brain results in cerebral oedema, which manifests as nausea, vomiting, headache and irritability, and can rapidly progress to seizures, coma and death in up to 50% of patients (7, 8). In this emergency scenario, rapid increase in plasma sodium concentration (pNa) by 4–6 mmol/L with hypertonic saline can reduce brain swelling, reverse neurological symptoms (9) and prevent fatal brain herniation (8). A large meta-analysis and population studies have demonstrated a linear relationship between pNa and mortality risk in hyponatraemia (2, 10). Some studies have suggested that this linear relationship is not maintained at pNa <120 mmol/L (5, 11).

Hyponatraemia occurs secondary to disparate medical conditions which can present to many different specialties (12); delay in seeking specialist input can delay emergency therapy (13). Some experts have therefore recommended specialist management of hyponatraemia, in order to improve clinical outcomes. In a small, prospective interventional study, which compared the outcome of intensive specialist input with routine care of hospitalised patients with hyponatraemia, Tzoulis et al. reported that prompt endocrine consultation led to faster attainment of pNa targets, and reduced length of hospital stay (14). In addition, a 2015 meta-analysis showed, for the first time, that improvement in pNa in hyponatraemic patients is associated with a reduction in overall mortality (OR: 0.57, P = 0.002); the reduction in mortality was greatest in patients with lowest pNa at baseline (15). However, hyponatraemia remains under-investigated and uncorrected; half of all patients enrolled in the multinational observational Hyponatraemia Registry were discharged from hospital with pNa <130 mmol/L (16).

We present the clinical and biochemical outcomes of treatment of severe hyponatraemia at three timepoints over a 10-year period, in our hospital. The data were generated by prospective audit of the effects of change in hospital policy for management of severe hyponatraemia (pNa <120 mmol/L). We also examined outcomes in a group of patients with pNa 120–125 mmol/L. Our secondary aim was to compare the most recent mortality data using these two pNa cut-offs.

Methods

Study design

This is an observational single-centre study performed in Beaumont Hospital, a 600 bed acute hospital which is the national centre for neurosurgery and renal transplant in Ireland. We included consecutive patients who were admitted with, or who developed severe hyponatraemia (pNa <120 mmol/L), during three review periods over 10 years. We chose this pNa cut-off, as some studies have failed to demonstrate any further increase in mortality risk as pNa falls below this threshold (5, 11). Patients with moderate hyponatraemia (pNa 120–125 mmol/L) admitted during the same time served as a comparator group, chosen because this range of hyponatraemia has been shown to be associated with the highest risk of mortality (11).

The three review periods were as follows:

  • 2005, 6 months: This audit was conducted prior to the development of hospital policy for the endocrine service to offer consultation service and offer take over care of patients with pNa <120 mmol/L, in order to facilitate active management.

  • 2010, 6 months: A prospective review of the impact of the 2005 intervention, prior to a further change in hospital policy, to recommend that all patients with pNa <125 mmol/L should be referred to an Endocrinologist.

  • 2015, 9 months: A prospective observational study to assess the impact of an education package on the approach to investigation and management of hyponatraemia, based on 2013 guidelines for bolus hypertonic saline treatment of patients with hyponatraemia and clinical signs and symptoms of cerebral encephalopathy (9, 17).

The study was approved by Beaumont Hospital Ethics Committee.

Specific laboratory-designed computer software was used to search for hospital in-patients with severe hyponatraemia (pNa <120 mmol/L) and moderate hyponatraemia (pNa 120–125 mmol/L). Patients were clinically classified as hypovolaemic, euvolaemic or hypervolaemic based on standard guidelines (17). Clinical information was derived from case notes and computerised laboratory records, and used to calculate the Charlson Comorbidity Index (CCI) in the 2015 review (18). In-hospital death was defined as death occurring during the hospital stay. Cause of death was derived from the death certificate and review of the patient’s clinical notes. Specialist referral was defined as formal endocrinology or nephrology consultation. Information on the treatment of hyponatraemia was collected within 48 h of admission or onset of hyponatraemia from case notes and prescription charts. Active treatment of hyponatraemia was aetiology-dependent and included; intravenous 0.9 or 3% saline, fluid restriction, tolvaptan, demeclocycline, diuresis or discontinuation of medications that had caused hyponatraemia.

Laboratory methods

PNa was measured using ion selective electrode (Olympus AU2700), normal reference range 133–146 mmol/L. Plasma and urine osmolality were measured using depression of freezing point method (2400 osmometer; Fiske, Norwood, MA).

Statistical analysis

Clinical and biochemical outcomes were compared across three timepoints, 2005, 2010 and 2015. Categorical variables are presented as number (%) and continuous variables as median (interquartile range) (as they were non-parametric). The Fishers Exact test and Chi Square test were used to compare categorical variables between groups when there were ≤5 and >5 cases in one or more groups, respectively, the Mann–Whitney to compare continuous variables between two groups, and the Kruskal–Wallis test to compare continuous variables between three groups. The log rank test was used to compare curves for overall survival across groups which are represented as Kaplan–Meier curves. The predictors of survival were analysed by multivariate Cox proportional hazards regression. The 2015 data were analysed for differences in clinical outcomes between patients with severe and moderate hyponatraemia. Data from all three review periods were not pooled for this analysis, due to the potential impact of differences in rates of active intervention in each timepoint. A P value of <0.05 was considered as statistically significant in all tests. Statistical analysis was performed using Prism GraphPad 8.0 and cox regression analysis was performed using SPSS Version 25.0.

Results

Patient demographics are outlined in Tables 1 and 2.

Table 1

Demographics and outcomes in patients with pNa <120 mmol/L. Ascertainment of Urine osmolality (UOsm), Urinary sodium concentration (UNa) and serum cortisol was recorded in patients with euvolaemic hyponatraemia. Data are presented as median (IQR) for continuous and number (percentage) for categorical variables. A P-value of <0.05 was considered as statistically significant.

200520102015P values
2005 vs 20102010 vs 2015
n414179
Age (years)55 (43–70)63 (46–78)72 (59–81)0.160.05
Nadir pNa (mmol/L)116 (114–118)116 (114–118)117 (114–119)0.80.4
Chronic HNN/AN/A39 (49%)
Volume category
 Euvolaemic21 (51%)19 (46%)43 (54%)
 Hypovolaemic9 (22%)11 (27%)22 (28%)
 Hypervolaemic9 (22%)11 (27%)14 (18%)
 Undocumented2 (5%)
Ascertainment of:
 UOsm10 (48%)14 (74%)43 (100%)0.120.002
 UNa6 (29%)15 (79%)43 (100%)0.0020.007
 Serum cortisol*6 (29%)11 (58%)33 (97%)0.11<0.001
Specialist consultation13 (32%)25 (68%)37 (47%)0.0030.05
Active treatment26 (63%)36 (88%)61 (77%)0.020.22
 3% saline4 (10%)10 (24%)7 (9%)0.140.03
 Tolvaptan004 (5%)
Length of stay (days)**17 (11–24)11 (6–16)12 (7–22)0.040.38
pNa on discharge** (mmol/L)129 (117–136)134 (131–136)132 (130–137)0.010.54
Mortality21 (51%)6 (15%)11 (14%)<0.001>0.99

*Patients on glucocorticoid therapy excluded. **Patients who died excluded.

N/A, not available; HN, hyponatraemia.

Table 2

Demographics and outcomes in patients with pNa 120–125 mmol/L. Ascertainment of Urine osmolality (UOsm), Urinary sodium concentration (UNa) and serum cortisol was recorded in patients with euvolaemic hyponatraemia. Data are presented as median (IQR) for continuous and number (percentage) for categorical variables. A P-value of <0.05 was considered as statistically significant.

200520102015P values
2005 vs 20102010 vs 2015
n8480287
Age (years)61 (45–70)66 (56–73)71 (61–80)0.0060.008
Nadir pNa (mmol/L)123 (122–124)123 (121–124)123 (121–125)0.010.007
Chronic HNN/AN/A168 (58.5%)
Volume Category
 Euvolaemic43 (51%)33 (41%)154 (54%)
 Hypovolaemic15 (18%)18 (23%)77 (27%)
 Hypervolaemic12 (14%)20 (25%)55 (19%)
 Undocumented14 (17%)9 (11%)1
Ascertainment of:
 UOsm17 (40%)16 (48%)143 (93%)0.03<0.001
 UNa15 (35%)15 (45%)143 (93%)0.002<0.001
 Serum cortisol*14 (33%)13 (39%)112 (91%)0.09<0.001
Specialist consultation22 (26%)20 (25%)92 (32%)>0.990.27
Active treatment29 (35%)38 (48%)202 (70%)0.11<0.001
Length of stay (days)**9 (6–13)8 (4–21)10 (5–19)0.830.35
pNa on discharge ** (mmol/L)130 (128–134)133 (130–136)133 (130–136)0.0040.84
Mortality24 (29%)26 (33%)27 (9%)0.61<0.001

*Patients on glucocorticoid therapy excluded. **Patients who died excluded.

N/A, not available. HN, hyponatraemia.

Specialist referral and management of severe hyponatraemia, pNa <120 mmol/L

2005 vs 2010

There was a significant rise in the rate of specialist referral between 2005 and 2010 (32 to 68%, P = 0.003). This was reflected in an increase in the ascertainment of some of the key diagnostic parameters for the diagnosis of SIAD; for instance, the rate of measurement of urinary sodium concentration (UNa) increased from 29 to 79% (P = 0.002). The improvements in specialist referral from 2005 to 2010 led to an increase in active management of severe hyponatraemia (63 to 88%, P = 0.02). Ten percent (4/41) of patients with severe hyponatraemia were treated with hypertonic saline in 2005, compared with 25% (10/41) in 2010, although the difference was not statistically significant (P = 0.14). Length of stay in patients with severe hyponatraemia fell from 17 to 11 days between 2005 and 2010 (P = 0.04). There was a significant increase in pNa on discharge from hospital during the same interval, 129 to 134 mmol/L (P = 0.01).

2010 vs 2015

There was no further significant change in referral or active management of severe hyponatraemia between 2010 and 2015, 68 to 47% (P = 0.05) and 88 to 77% (P = 0.22), respectively. Median length of stay and pNa on discharge were also similar in 2010 and 2015 (Table 1).

Mortality in patients with severe hyponatraemia, pNa <120 mmol/L

2005 vs 2010

The increase in specialist referral and active management of severe hyponatraemia from 2005 to 2010 was associated with a reduction in overall mortality from 51 to 15% (P < 0.001). The Kaplan–Meier curve for 30-day in-hospital survival is displayed in Fig. 1A; the log rank test showed that the 30-day in-hospital mortality in patients with severe hyponatraemia was significantly lower in 2010 compared with 2005 (P = 0.03).

Figure 1
Figure 1

(A) Kaplan–Meier curve for in-hospital mortality in patients with pNa <120 mmol/L in 2005, 2010 and 2015; (B) Kaplan–Meier curve for in-hospital mortality in patients with pNa <120 mmol/L in 2005, 2010 and 2015. A full colour version of this figure is available at https://doi.org/10.1530/EJE-20-0577.

Citation: European Journal of Endocrinology 184, 1; 10.1530/EJE-20-0577

2010 vs 2015

The lower mortality rates in patients with pNa <120 mmol/L were sustained (15% in 2010 to 14% in 2015, P > 0.99). There was no difference between 30-day in-hospital survival between 2010 and 2015 on the log rank test (P = 0.75) (Fig. 1A).

Outcomes in patients with severe hyponatraemia, pNa <120 mmol/L, pooled results from 2005, 2010 and 2015

When the results for the three review periods were pooled, overall mortality rates were 4% in patients with severe hyponatraemia with specialist referral compared with 42% in those without specialist referral, RR = 0.09 (95% CI: 0.03–0.26), P < 0.001. Pooled mortality rates were 17% in patients with severe hyponatraemia who received active treatment (21/123) compared with 45% in those who did not (17/38), RR = 0.38 (95% CI: 0.23–0.65), P < 0.001. A cox proportional hazards regression model was performed to determine independent risk factors for mortality, incorporating age, nadir pNa, hypervolemic hyponatraemia, specialist referral and hyponatraemia treatment; only specialist referral was associated with a significant reduction in mortality, HR = 0.12 (95% CI: 0.04–0.4), P < 0.001. There was no significant association between age, nadir pNa, hypervolemic hyponatraemia and treatment of hyponatraemia and mortality risk, P = 0.99, P = 0.31, P = 0.22 and P = 0.86, respectively.

Clinical information regarding those patients with pNa <120 mmol/L who died, is presented in Table 3.

Table 3

Outline of deaths among patients with severe hyponatraemia (pNa <120 mmol/L).

200520102015P values
2005 vs 20102010 vs 2015
n21611
Age, years63 (49–74)71 (56–75)81 (44–87)0.520.19
Nadir pNa, mmol/L 114 (113–117) 116 (112–117) 117 (112–118)0.740.44
Volume status, n (%)
 Euvolaemic9 (43%)1 (17%) 4 (36.5%)
 Hypovolaemic3 (14%)03 (27%)
 Hypervolaemic7 (33%)5 (83%) 4 (36.5%)
Underlying causes of hyponatraemia, n*
 Liver/heart failure654
 Malignancy51
 CNS41
 Sepsis/hypovolemia33
 Pulmonary fibrosis1
 Unknown2
pNa <120 mmol/L at death, n (%)17 (81%)5 (83%)5 (45%)>0.990.3

*In patients with pNa <120 mmol/L who died.

Management and outcomes in patients with pNa 120–125 mmol/L

Specialist referral rate in patients with pNa 120–125 mmol/L did not change significantly across the three time periods. There was, however, an increase in active management of hyponatraemia in this cohort, 48 to 70%, from 2010 to 2015 (P < 0.001). This was accompanied by a decrease in mortality, from 34 to 9% (P < 0.001). The Kaplan–Meier curve for 30-day in-hospital survival is displayed in Fig. 1B; the log rank test showed no significant difference between 2005 and 2010, but 30-day survival rate was significantly higher in 2015 compared with 2010 (P < 0.001).

Mortality in patients with pNa <120 mmol/L compared with those with pNa 120–125 mmol/L

In-hospital mortality in 2015 was compared in patients with pNa <120 mmol/L with those with pNa 120–125 mmol/L. Median age, median CCI and distribution of volume status were similar between the two groups. The relative risk for in-hospital death in patients with pNa <120 mmol/L compared with the comparator group was 1.55 (95% CI: 0.8– 2.92; P = 0.2). The Kaplan–Meier curve for in-hospital survival in patients with pNa <120 mmol/L and the comparator group in 2015 are displayed in Fig. 2; the log rank test showed no significant difference between mortality rates in the two groups (P = 0.56).

Figure 2
Figure 2

Kaplan–Meier curve for in-hospital mortality in patients with pNa <120 mmol/L (severe) and pNa 120–125 mmol/L (moderate) in 2015. A full colour version of this figure is available at https://doi.org/10.1530/EJE-20-0577.

Citation: European Journal of Endocrinology 184, 1; 10.1530/EJE-20-0577

Discussion

Hyponatraemia has been shown to be associated with increased mortality in almost every published series in the literature, throughout a wide spectrum of medical conditions (2, 3, 4, 5, 6, 19, 20). In patients with hyponatraemia, there is a linear relationship between pNa and mortality risk; this has been proven in population studies such as the NHANES database (10), audits of hospitalised patients (11), and in a 2013 meta-analysis of 81 studies (2). In response to this association between hyponatraemia and mortality, consensus recommendations by expert groups have proposed a more aggressive management strategy for severe hyponatraemia. In acute hyponatraemia with neurological symptoms, bolus infusions of 3% saline rather than slow intravenous infusion, have been recommended, in order to produce a significant early rise in pNa, to reduce cerebral oedema and prevent deaths (9, 17, 21). Bolus intravenous hypertonic saline has been shown to be more effective than slow intravenous infusion in producing an acute elevation in pNa, and in restoring cognitive function (9). There have, however, been very few published data on the impact of treatment on mortality in hyponatraemia.

In this paper, we have reported clinical outcomes for patients with severe hyponatraemia (pNa <120 mmol/L) and for those with pNa 120–125 mmol/L, using data gathered during three prospective reviews over a 10-year period. Our data demonstrate that increased specialist input and active management of severe hyponatraemia are associated with improvements in mortality, to such a degree that mortality rates were similar to patients with hyponatraemia of moderate severity.

Our results illustrate the clinical benefits of structured specialist input to the care of patients hospitalised with hyponatraemia. Following the initial audit, the introduction of a policy of specialist referral for all patients with pNa <120 mmol/L led to a doubling in the rate of specialist consultation, and 40% increase in active management of patients with severe hyponatraemia, between 2005 and 2010. The increase in specialist input was associated with a number of positive outcomes in patients with severe hyponatraemia; a 5 mmol/L increase in median pNa on discharge, 129 vs 134 mmol/L (P < 0.001), a reduction in length of stay, 17 vs 11 days (P = 0.04), and fall in mortality rate, 51% vs 15% (P < 0.001). The initial improvements in these three key outcomes were maintained in 2015, despite a non-statistically significant drop in rates of specialist consultation and active management during that time. There are two potential reasons for this; first, at the time of the 2015 review, a hospital-wide observational, but not interventional, study in hyponatraemia outcomes was being conducted by the Endocrine Department. The reduction in specialist referral in 2015 may have reflected a perception that the endocrine supervision of collection of key diagnostic data, as part of the studies by Cuesta et al., entailed formal consultation regarding hyponatraemia management. Secondly, with the establishment of hospital protocols for active management of hyponatraemia, physicians may have become more confident about managing hyponatraemia, without specialist intervention. Patients with severe hyponatraemia were significantly older in the 2015 analysis, 72 years vs 63 years (P = 0.05), reflecting an older local catchment area population, but our own (unpublished) data actually shows significantly higher rates of specialist referral and hyponatraemia-targeted treatment in older patients compared with younger controls.

We were surprised to note that the rate of active management of hyponatraemia exceeded the rate of specialist referral in 2015 by almost 2:1. We consider that the hospital-wide education has encouraged confidence in the initiation of treatment for hyponatraemia by non-specialists. Increasingly, specialist referral was sought only when protocol-driven treatment failed or in cases of complex hyponatraemia. This may explain why endocrinology intervention was not associated with reduced duration of hospital stay, as specialist opinion was only sought in difficult or complex cases, in whom standard treatment had not reached targets. In contrast, a previous prospective interventional study showed that prompt specialist input in patients with hyponatraemia significantly reduces time to correction of hyponatraemia and shortens length of hospital stay, by a median of four days (14). Our data supports the findings of Tzoulis et al., but we have additionally demonstrated a significant reduction in mortality in patients with severe hyponatraemia associated with specialist input. Indeed, when cox regression analysis was applied to pooled data from all three review periods, only specialist referral was independently associated with improvements in in-hospital survival.

In the most recent review period, the mortality in patients with pNa <120 mmol/L was reduced to levels which are similar to those in patients with moderate hyponatraemia (pNa 120–125 mmol/L) (Fig. 2). This contrasts with historical data, which showed higher death rates, of up to 50%, in patients with severe hyponatraemia (22) and mortality rates of 80% in patients with neurological symptoms who are not actively managed (23). In addition, large meta-analysis and population studies have demonstrated a linear relationship between plasma sodium and risk of death (10, 15). However, more recent interventional data suggests that this relationship is less robust at pNa <120 mmol/L, suggesting that the impact of active management of hyponatraemia is reducing the high mortality from severe hyponatraemia (5, 11). Sterns and colleagues reported a mortality rate of only 8% in a series of 64 patients with pNa <110 mmol/L (24), which is much lower than the historical figures quoted by Gill and colleagues. When the authors carefully analysed each fatal case, they found that the majority of deaths were caused by the underlying causative illness rather hyponatraemia per se (24). These figures are similar to the mortality rate in patients with pNa <120 mmol/L of 14% that we have reported; in all but two fatal cases in our series, there were comorbidities which directly contributed to death of the patients (25). Although our data and that of Sterns and colleagues could be interpreted to support the concept that patients die ‘with’ rather than ‘from’ hyponatraemia, both of our data sets were derived from an environment where there was rapidly instituted, active management of acute hyponatraemia, which was accompanied by neurological manifestations of cerebral oedema. In other words, both data sets were derived from a patient population in whom potentially fatal hyponatraemia was dealt with, and the residual mortality was due to underlying causative disease, which was unaffected by intervention for hyponatraemia. We would therefore argue that the reduced mortality in these two papers, one sequential over time and one in comparison to historical data, argue strongly for the benefits of active management of severe hyponatraemia.

This is a single-centre study, and the data reflect altered clinical practice at a local level. However, our results concur with those of a study from another Irish centre, which recently reported improvements in mortality in over 100 000 patients presenting to an emergency department with hyponatraemia over a 15-year period (26). As no information was provided regarding aetiology or subsequent management of hyponatraemia, it is unclear what contributed to the improvements in outcome in that study. However, their results suggest that improvements in mortality in patients with hyponatraemia are not just limited to our centre.

The observational design of our study is less robust than a prospective interventional study, but our data reflect changes in real-life practice. Specialist input may not have been sought on patients receiving end-of-life care and this may have contributed to higher mortality in those without consultation, but this would be the case across all three review periods. Our analysis does not account for overall improvements in the standard of hospital-delivered care in our institution over this 10-year period, for example, improvements in stroke and cancer care. This highlights the complexity in interpreting outcomes in hyponatraemia management, as they are inherently influenced by treatment of the underlying condition. We did not capture data on rates of overcorrection, an important adverse endpoint when assessing the efficacy of intervention in hyponatraemia which could potentially be lessened by earlier specialist supervision, but this will be recorded on further reviews. Finally, it is possible that better-decision making regarding choice of treatment played a role in improvements in mortality. As the spectrum of hyponatraemia encompassed the full range of hyper-, hypo- and eu-volaemic hyponatraemia, the range of treatments utilised in the management of patients was disparate. As a result, the effects of individual treatment regimens could not be analysed to identify the pharmacological influences on the change in mortality, though the increase in the use of hypertonic saline in severe hyponatraemia is likely to have had a major influence in reduced mortality in that category.

Conclusion

We have demonstrated that the rates of active intervention for both severe and moderate hyponatraemia have increased over a 10-year period. Increased specialist management of severe hyponatraemia has been associated with a sustained reduction in mortality in severe hyponatraemia, to a rate similar to that in patients with moderate hyponatraemia. This study adds to a growing body of evidence supporting active sodium-directed intervention in patients with severe hyponatraemia, to achieve clinically important outcomes.

Declaration of interest

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

Funding

A G received an unrestricted educational grant from Pfizer and the Charitable Infirmary Charitable Trust.

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  • 12

    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. (https://doi.org/10.1016/j.ejim.2015.10.020)

    • Search Google Scholar
    • Export Citation
  • 13

    Tzoulis P & Bouloux PM Inpatient hyponatraemia: adequacy of investigation and prevalence of endocrine causes. Clinical Medicine 2015 15 2024. (https://doi.org/10.7861/clinmedicine.15-1-20)

    • Search Google Scholar
    • Export Citation
  • 14

    Tzoulis P, Carr H, Bagkeris E & Bouloux PM Improving care and outcomes of inpatients with syndrome of inappropriate antidiuresis (SIAD): a prospective intervention study of intensive endocrine input vs. routine care. Endocrine 2017 55 539546. (https://doi.org/10.1007/s12020-016-1161-9)

    • Search Google Scholar
    • Export Citation
  • 15

    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. (https://doi.org/10.1371/journal.pone.0124105)

    • Search Google Scholar
    • Export Citation
  • 16

    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. (https://doi.org/10.1038/ki.2015.4)

    • Search Google Scholar
    • Export Citation
  • 17

    Verbalis JG, Goldsmith SR, Greenberg A, Korzelius C, Schrier RW, Sterns RH & Thompson CJ Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations. American Journal of Medicine 2013 126 (Supplement 1) S1S42. (https://doi.org/10.1016/j.amjmed.2013.07.006)

    • Search Google Scholar
    • Export Citation
  • 18

    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. (https://doi.org/10.1016/0021-9681(8790171-8)

    • Search Google Scholar
    • Export Citation
  • 19

    Gheorghiade M, Abraham WT, Albert NM, Gattis Stough W, Greenberg BH, O’Connor CM, She L, Yancy CW, Young J & Fonarow GC et al. 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. (https://doi.org/10.1093/eurheartj/ehl542)

    • Search Google Scholar
    • Export Citation
  • 20

    Mannheimer B, Skov J, Falhammar H, Calissendorff J, Lindh JD & Nathanson D Sex-specific risks of death in patients hospitalized for hyponatremia: a population-based study. Endocrine 2019 66 660665. (https://doi.org/10.1007/s12020-019-02073-x)

    • Search Google Scholar
    • Export Citation
  • 21

    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. European Journal of Endocrinology 2014 170 G1G47. (https://doi.org/10.1530/EJE-13-1020)

    • Search Google Scholar
    • Export Citation
  • 22

    Gill G, Huda B, Boyd A, Skagen K, Wile D, Watson I & van Heyningen C Characteristics and mortality of severe hyponatraemia – a hospital-based study. Clinical Endocrinology 2006 65 246249. (https://doi.org/10.1111/j.1365-2265.2006.02583.x)

    • Search Google Scholar
    • Export Citation
  • 23

    Ayus JC & Arieff AI Chronic hyponatremic encephalopathy in postmenopausal women: association of therapies with morbidity and mortality. JAMA 1999 281 22992304. (https://doi.org/10.1001/jama.281.24.2299)

    • Search Google Scholar
    • Export Citation
  • 24

    Sterns RH Severe symptomatic hyponatremia: treatment and outcome. A study of 64 cases. Annals of Internal Medicine 1987 107 656664. (https://doi.org/10.7326/0003-4819-107-5-656)

    • Search Google Scholar
    • Export Citation
  • 25

    Cuesta M, Garrahy A, Slattery D, Gupta S, Hannon AM, McGurren K, Sherlock M, Tormey W & Thompson CJ Mortality rates are lower in SIAD, than in hypervolaemic or hypovolaemic hyponatraemia: results of a prospective observational study. Clinical Endocrinology 2017 87 400406. (https://doi.org/10.1111/cen.13388)

    • Search Google Scholar
    • Export Citation
  • 26

    McCarthy K, Conway R, Byrne D, Cournane S, O’Riordan D & Silke B Hyponatraemia during an emergency medical admission as a marker of illness severity and case complexity. European Journal of Internal Medicine 2019 59 6064. (https://doi.org/10.1016/j.ejim.2018.08.002)

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    • Export Citation

 

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  • View in gallery

    (A) Kaplan–Meier curve for in-hospital mortality in patients with pNa <120 mmol/L in 2005, 2010 and 2015; (B) Kaplan–Meier curve for in-hospital mortality in patients with pNa <120 mmol/L in 2005, 2010 and 2015. A full colour version of this figure is available at https://doi.org/10.1530/EJE-20-0577.

  • View in gallery

    Kaplan–Meier curve for in-hospital mortality in patients with pNa <120 mmol/L (severe) and pNa 120–125 mmol/L (moderate) in 2015. A full colour version of this figure is available at https://doi.org/10.1530/EJE-20-0577.

  • 1

    Upadhyay A, Jaber BL & Madias NE Incidence and prevalence of hyponatremia. American Journal of Medicine 2006 119 (Supplement 1) S30S35. (https://doi.org/10.1016/j.amjmed.2006.05.005)

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    • Export Citation
  • 2

    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. (https://doi.org/10.1371/journal.pone.0080451)

    • Search Google Scholar
    • Export Citation
  • 3

    Lombardi G, Ferraro PM, Calvaruso L, Naticchia A, D'Alonzo S & Gambaro G Sodium fluctuations and mortality in a general hospitalized population. Kidney and Blood Pressure Research 2019 44 604614. (https://doi.org/10.1159/000500916)

    • Search Google Scholar
    • Export Citation
  • 4

    Sturdik I, Adamcova M, Kollerova J, Koller T, Zelinkova Z & Payer J Hyponatraemia is an independent predictor of in-hospital mortality. European Journal of Internal Medicine 2014 25 379382. (https://doi.org/10.1016/j.ejim.2014.02.002)

    • 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. (https://doi.org/10.1016/j.amjmed.2009.01.027)

    • Search Google Scholar
    • Export Citation
  • 6

    Al Mawed S, Pankratz VS, Chong K, Sandoval M, Roumelioti ME & Unruh M Low serum sodium levels at hospital admission: outcomes among 2.3 million hospitalized patients. PLoS ONE 2018 13 e0194379. (https://doi.org/10.1371/journal.pone.0194379)

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    • Export Citation
  • 7

    Crook MA, Velauthar U, Moran L & Griffiths W Review of investigation and management of severe hyponatraemia in a hospital population. Annals of Clinical Biochemistry 1999 36 158162. (https://doi.org/10.1177/000456329903600204)

    • Search Google Scholar
    • Export Citation
  • 8

    Sterns RH Treatment of severe hyponatremia. Clinical Journal of the American Society of Nephrology 2018 13 641649. (https://doi.org/10.2215/CJN.10440917)

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    • Export Citation
  • 9

    Garrahy A, Dineen R, Hannon AM, Cuesta M, Tormey W, Sherlock M & Thompson CJ Continuous versus bolus infusion of hypertonic saline in the treatment of symptomatic hyponatremia due to SIAD. Journal of Clinical Endocrinology and Metabolism 2019 104 35953602. (https://doi.org/10.1210/jc.2019-00044)

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    • Export Citation
  • 10

    Mohan S, Gu S, Parikh A & Radhakrishnan J Prevalence of hyponatremia and association with mortality: results from NHANES. American Journal of Medicine 2013 126 1127 .e1113 7 .e1. (https://doi.org/10.1016/j.amjmed.2013.07.021)

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    • Export Citation
  • 11

    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. (https://doi.org/10.2215/CJN.10101110)

    • Search Google Scholar
    • Export Citation
  • 12

    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. (https://doi.org/10.1016/j.ejim.2015.10.020)

    • Search Google Scholar
    • Export Citation
  • 13

    Tzoulis P & Bouloux PM Inpatient hyponatraemia: adequacy of investigation and prevalence of endocrine causes. Clinical Medicine 2015 15 2024. (https://doi.org/10.7861/clinmedicine.15-1-20)

    • Search Google Scholar
    • Export Citation
  • 14

    Tzoulis P, Carr H, Bagkeris E & Bouloux PM Improving care and outcomes of inpatients with syndrome of inappropriate antidiuresis (SIAD): a prospective intervention study of intensive endocrine input vs. routine care. Endocrine 2017 55 539546. (https://doi.org/10.1007/s12020-016-1161-9)

    • Search Google Scholar
    • Export Citation
  • 15

    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. (https://doi.org/10.1371/journal.pone.0124105)

    • Search Google Scholar
    • Export Citation
  • 16

    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. (https://doi.org/10.1038/ki.2015.4)

    • Search Google Scholar
    • Export Citation
  • 17

    Verbalis JG, Goldsmith SR, Greenberg A, Korzelius C, Schrier RW, Sterns RH & Thompson CJ Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations. American Journal of Medicine 2013 126 (Supplement 1) S1S42. (https://doi.org/10.1016/j.amjmed.2013.07.006)

    • Search Google Scholar
    • Export Citation
  • 18

    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. (https://doi.org/10.1016/0021-9681(8790171-8)

    • Search Google Scholar
    • Export Citation
  • 19

    Gheorghiade M, Abraham WT, Albert NM, Gattis Stough W, Greenberg BH, O’Connor CM, She L, Yancy CW, Young J & Fonarow GC et al. 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. (https://doi.org/10.1093/eurheartj/ehl542)

    • Search Google Scholar
    • Export Citation
  • 20

    Mannheimer B, Skov J, Falhammar H, Calissendorff J, Lindh JD & Nathanson D Sex-specific risks of death in patients hospitalized for hyponatremia: a population-based study. Endocrine 2019 66 660665. (https://doi.org/10.1007/s12020-019-02073-x)

    • Search Google Scholar
    • Export Citation
  • 21

    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. European Journal of Endocrinology 2014 170 G1G47. (https://doi.org/10.1530/EJE-13-1020)

    • Search Google Scholar
    • Export Citation
  • 22

    Gill G, Huda B, Boyd A, Skagen K, Wile D, Watson I & van Heyningen C Characteristics and mortality of severe hyponatraemia – a hospital-based study. Clinical Endocrinology 2006 65 246249. (https://doi.org/10.1111/j.1365-2265.2006.02583.x)

    • Search Google Scholar
    • Export Citation
  • 23

    Ayus JC & Arieff AI Chronic hyponatremic encephalopathy in postmenopausal women: association of therapies with morbidity and mortality. JAMA 1999 281 22992304. (https://doi.org/10.1001/jama.281.24.2299)

    • Search Google Scholar
    • Export Citation
  • 24

    Sterns RH Severe symptomatic hyponatremia: treatment and outcome. A study of 64 cases. Annals of Internal Medicine 1987 107 656664. (https://doi.org/10.7326/0003-4819-107-5-656)

    • Search Google Scholar
    • Export Citation
  • 25

    Cuesta M, Garrahy A, Slattery D, Gupta S, Hannon AM, McGurren K, Sherlock M, Tormey W & Thompson CJ Mortality rates are lower in SIAD, than in hypervolaemic or hypovolaemic hyponatraemia: results of a prospective observational study. Clinical Endocrinology 2017 87 400406. (https://doi.org/10.1111/cen.13388)

    • Search Google Scholar
    • Export Citation
  • 26

    McCarthy K, Conway R, Byrne D, Cournane S, O’Riordan D & Silke B Hyponatraemia during an emergency medical admission as a marker of illness severity and case complexity. European Journal of Internal Medicine 2019 59 6064. (https://doi.org/10.1016/j.ejim.2018.08.002)

    • Search Google Scholar
    • Export Citation