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Nephrology Dialysis Transplantation 2006 21(1):70-76; doi:10.1093/ndt/gfi082
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© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Original Articles: Clinical Nephrology

Development of severe hyponatraemia in hospitalized patients: treatment-related risk factors and inadequate management

Ewout J. Hoorn1, Jan Lindemans2 and Robert Zietse1

Departments of 1 Internal Medicine and 2 Clinical Chemistry, Erasmus Medical Center, Rotterdam, The Netherlands

Correspondence and offprint requests to: Robert Zietse, MD, Dr Molewaterplein 40, 3015 GD Rotterdam, The Netherlands. Email: r.zietse{at}erasmusmc.nl



   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Although hyponatraemia [plasma sodium (PNa) <136 mmol/l] frequently develops in hospital, risk factors for hospital-acquired hyponatraemia remain unclear.

Methods. Patients who presented with severe hyponatraemia (PNa ≤ 125 mmol/l) were compared with patients with hospital-acquired severe hyponatraemia in a 3 month hospital-wide cohort study.

Results. Thirty-eight patients had severe hyponatraemia on admission (PNa 121±4 mmol/l), whereas 36 patients had hospital-acquired severe hyponatraemia (PNa 133±5 -> 122±4 mmol/l). In hospital-acquired hyponatraemia, treatment started significantly later (1.0±2.6 vs 9.8±10.6 days, P<0.001) and the duration of hospitalization was longer (18.2±11.5 vs 30.7±23.4 days, P = 0.01). The correction of PNa in hospital-acquired hyponatraemia was slower after both 24 h (6±4 vs 4±4 mmol/l, P = 0.009) and 48 h (10±6 mmol/l vs 6±5 mmol/l, P = 0.001) of treatment. Nineteen patients (26%) from both groups were not treated for hyponatraemia and this was associated with a higher mortality rate (seven out of 19 vs seven out of 55, P = 0.04). Factors that contributed to hospital-acquired hyponatraemia included: thiazide diuretics (none out of 38 vs eight out of 36, P = 0.002), drugs stimulating antidiuretic hormone (two out of 38 vs eight out of 36, P = 0.04), surgery (none out of 38 vs 10 out of 36, P<0.001) and hypotonic intravenous fluids (one out of 38 vs eight out of 36, P = 0.01). Symptomatic hyponatraemia was present in 27 patients (36%), and 14 patients died (19%).

Conclusions. The development of severe hyponatraemia in hospitalized patients was associated with treatment-related factors and inadequate management. Early recognition of risk factors and expedited therapy may make hospital-acquired severe hyponatraemia more preventable.

Keywords: antidiuretic hormone; hypotonic intravenous fluids; post-operative hyponatraemia; syndrome of inappropriate antidiuretic hormone secretion; thiazide diuretics; water–sodium balance



   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 References
 
Hyponatraemia is the most common electrolyte disorder in hospitalized patients, and is generally defined as a plasma sodium concentration (PNa) of <136 mmol/l [1–3]. Although different definitions of severe hyponatraemia have been used, ranging from 110 to 125 mmol/l [3–7], several studies have established an association between severe hyponatraemia and increased morbidity and mortality rates [3,8–10]. This adverse outcome may be the result of the underlying disease and/or direct complications of hyponatraemia, including cerebral oedema in acute hyponatraemia [8,9] and the osmotic demyelination syndrome (ODS) after overly rapid correction of chronic hyponatraemia [10].

Hyponatraemia is frequently acquired or aggravated in hospital [3]. Although several predisposing factors have been identified in selected patient populations [1,8,11], no studies have directly investigated which factors contribute to hospital-acquired hyponatraemia in a general hospital population. Therefore, we conducted the present hospital-wide cohort study in which we compared patients who were admitted with severe hyponatraemia with patients with hospital-acquired severe hyponatraemia, analysing factors related not only to the underlying disorder but also to the treatment and management during hospitalization.



   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 References
 
Study group
In a study period of 3 months (August–October 2003), all PNa levels measured in adult hospitalized patients in the Erasmus Medical Center, an 831-bed urban university hospital in Rotterdam, The Netherlands, were reviewed. Hyponatraemia was defined as PNa <136 mmol/l and severe hyponatraemia as PNa ≤125 mmol/l. Patients with severe hyponatraemia were studied in further detail. Patients entered the study either when they were admitted with a PNa ≤125 mmol/l (admission hyponatraemia) or when they were already hospitalized and the level decreased in hospital to PNa ≤125 mmol/l (hospital-acquired hyponatraemia). Patients were identified from determined PNa values of hospitalized patients, which were sent electronically twice daily from the clinical chemistry department to one of the investigators (E.J.H.). PNa values were determined with ion-selective electrodes (Hitachi 917, Roche, according to the manufacturer's instructions) and in all of these samples plasma osmolality and plasma glucose concentration were determined simultaneously. Because pseudo-hyponatraemia may still be a problem despite the use of ion-selective electrodes [12], in all patients the first step consisted of the exclusion of pseudo-hyponatraemia, through analysis of plasma osmolality, total protein, triglyceride and cholesterol concentrations.

Evaluation
After inclusion, we analysed which factors may have contributed to the development of hyponatraemia (underlying disorders, medication and in-hospital procedures) and which symptoms of hyponatraemia the patient had developed. Subsequently, the patient cohort was followed-up prospectively until discharge or death, to evaluate if further symptoms developed, if and how PNa was restored and if patients developed ODS [7,10]. Clinical data were collected by way of chart review and interview, observation and (neurological) examination of patients. The definition of symptomatic hyponatraemia was based on a clinical assessment of symptomatology, including the presence of sensorium changes, seizures, and/or respiratory depression, applying previously established criteria [8,9,13]. Sensorium changes comprised acute confusional states, stupor, delirium and/or coma in the absence of dementia, psychiatric illness and substance abuse. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) was defined by the criteria described by Verbalis [14]. Drugs that can increase the non-osmotic release of antidiuretic hormone (ADH) or potentiate its renal action (ADH-stimulating drugs) were recorded, with the exception of commonly prescribed drugs that rarely produce hyponatraemia, including acetaminophen and non-steroidal anti-inflammatory drugs [15]. Patients were screened for ODS based on clinical grounds (i.e. the development of confusion, agitation, or flaccid or spastic paralysis during or after correction of hyponatraemia), but no magnetic resonance imaging scans (the golden standard for ODS) were performed [7,10].

In order to study the clinical management of hyponatraemia, all medical charts and discharge letters were reviewed to evaluate whether severe hyponatraemia was documented, which diagnoses for hyponatraemia were established, if therapy was instituted and if so which therapy. Treatment of hyponatraemia was defined as the institution of any of the described therapeutic modalities for hyponatraemia [1,2,15] and/or the discontinuation of a potential causative factor (e.g. diuretics). During the study period, the treating physicians remained responsible for the care of the patients reported in this study and the investigators did not intervene at any point. Informed consent was received from all patients.

Statistical analysis
Data were analysed using SPSS (version 12.0, Chicago, IL). Nominal data were analysed using Fisher's exact test and ordinal data using the Mann–Whitney rank sum test. A P-value of 0.05 was considered significant. All data are expressed as mean±SD.



   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 References
 
Incidence and department distribution of hyponatraemia
During the 3 month study period, PNa was determined in 2907 out of 5437 (54%) hospitalized patients. In those patients, 30% (880 out of 2907) had at least one episode of hyponatraemia (PNa<136 mmol/l) (Table 1).


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  		Table 1. Incidences and department distribution of hyponatraemia and severe hyponatraemia

 
PNa was determined significantly less often in the departments of surgery (39%), gynaecology (13%) and ear, nose and throat (38%) (all P<0.001, compared with all other departments). The incidence of hyponatraemia was significantly higher in the departments of internal medicine (36%), surgery (32%) and intensive care (38%) (all P<0.05, compared with all other departments). Severe hyponatraemia (PNa ≤ 125 mmol/l) was present in 76 patients (3%), and 74 of those patients were studied in more detail, excluding two patients with mannitol-induced hyponatraemia. In this study group, there were no patients with pseudo-hyponatraemia (average plasma osmolality 254±10 mOsm/kg) or hyperglycaemia-induced hyponatraemia (average plasma glucose 6.0±1.5 mmol/l, range 3.4–9.5 mmol/l).

Outcome, course and management of severe hyponatraemia
Thirty-eight patients (51%) were admitted with severe hyponatraemia, whereas 36 patients (49%) had hospital-acquired severe hyponatraemia. The demographic and outcome characteristics of these patients are shown in Table 2. Twenty-seven patients (36%) had symptoms that were attributed to hyponatraemia and, because these patients also lacked alternative explanations for these symptoms, they were judged to have symptomatic hyponatraemia. These symptoms always developed when PNa was ≤125 mmol/l. No patients were directly admitted for analysis of severe hyponatraemia, although in some patients symptoms attributable to severe hyponatraemia (e.g. vertigo with falls, lethargy and nausea) were the main reason for admission. Fourteen patients (19%) died (seven with symptomatic hyponatraemia), and these patients were more often female (11 out of 14 vs 28 out of 60, P = 0.02).


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  		Table 2. Demographic and outcome characteristics of 74 patients with admission and hospital-acquired severe hyponatraemia

 
The primary causes of death were respiratory arrest (seven patients), cardiac arrest (two patients), multi-organ failure (two patients) or unknown (three patients), and especially in patients with respiratory arrest and unknown causes of death severe hyponatraemia may have contributed to this outcome [8,13]. Eleven patients (15%) were admitted to the intensive care unit, and for five patients this was directly related to the complications of symptomatic hyponatraemia (three patients with respiratory insufficiency and two patients with seizures).

The course and management of patients with admission and hospital-acquired hyponatraemia are shown in Table 3. By definition, all patients with hospital-acquired hyponatraemia had a fall in PNa, which averaged 11±6 mmol/l, and was more rapid compared with the few patients with admission hyponatraemia, who also had a fall in PNa (eight patients). The PNa decrease rates in symptomatic patients and patients who died were 0.9±1.0 and 0.7±0.9 mmol/l/day, respectively.


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  		Table 3. Time course in plasma sodium concentration and observed management in admission and hospital-acquired severe hyponatraemia

 
Fifty-five patients (74%) were treated for severe hyponatraemia. In hospital-acquired hyponatraemia, the time until therapy was started after the first PNa value <136 mmol/l was recorded was significantly longer (1.0±2.6 vs 9.8±10.6 days, P<0.001).

An overview of how severe hyponatraemia was treated in each aetiological category is shown in Table 4. Of the 19 patients in whom treatment was lacking, seven died, resulting in a higher mortality rate in untreated patients (seven out of 19 vs seven out of 55, P = 0.04); this mortality rate did not differ between admission and hospital-acquired hyponatraemia. During the first 24 and 48 h of treatment, PNa was corrected more rapidly in admission hyponatraemia compared with hospital-acquired hyponatraemia (Figure 1). This also appeared to be the case in patients who died, although this difference was not statistically significant, perhaps because of the small number of patients (eight vs three patients). However, patients with symptomatic hyponatraemia were corrected with similar correction rates in the two groups. Finally, untreated patients (not shown in Figure 1) did have a minor rise in PNa (4±4 mmol/l for both 24 and 48 h), possibly because the stimulus for ADH abated, or because ‘escape’ from the effects of ADH occurred [16].


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  		Table 4. Observed treatment of severe hyponatraemia in major aetiological groupsa

 


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  		Fig. 1. Correction rates of severe hyponatraemia in the first 24 and 48 h of therapy are shown in admission and hospital-acquired severe hyponatraemia (38 vs 36 patients). In addition, correction rates of two subgroups are shown, including patients who had symptomatic hyponatraemia prior to their correction (15 vs 12 patients), and patients who died during the correction of hyponatraemia (eight vs three patients).

 

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  		Table 5. Analysis of factors contributing to the development of severe hyponatraemia during hospitalization

 
Factors contributing to hospital-acquired hyponatraemia
To evaluate which factors that may have contributed to hyponatraemia were present on admission and which were introduced during hospitalization, those underlying disorders, drugs and in-hospital procedures that may affect water and sodium balance were compared (Table 5). This analysis identified two hospital-associated factors that were more often present in patients with hospital-acquired hyponatraemia, namely surgery (none out of 38 vs 10 out of 36, P<0.001) and hypotonic intravenous (i.v.) fluids (one out of 38 vs eight out of 36, P = 0.01). Secondly, during hospitalization, but not on admission, the hospital-acquired group received significantly more thiazide diuretics (none out of 38 vs eight out of 36, P = 0.002) and ADH-stimulating drugs (two out of 38 vs eight out of 36, P = 0.04), either because these drugs were started in hospital, or because they were discontinued in patients with admission hyponatraemia. ADH-stimulating drugs included haloperidol (four patients), hypoglycaemic medication (three patients), chemotherapeutics (bortezomib and thalidomide), sodium valproate (two patients), carbamazepine, serotonin re-uptake inhibitors and 1-desamino-8-D-arginine vasopressine (dDAVP).

Underlying disorders that may have affected water and sodium homeostasis were approximately equally distributed in the two groups (Table 5). Most underlying disorders were already present on admission, although gastrointestinal losses and renal insufficiency often developed in hospital, but not significantly more so in hospital-acquired hyponatraemia. The exception were four patients, three of whom developed severe hyponatraemia as a result of SIADH due to stroke, and another patient who developed severe hyponatraemia as a result of a myocardial infarction [17]. Additional diseases in which patients had the clinical and biochemical characteristics of SIADH included pneumonia (two patients), lung carcinoma (two patients), oesophageal carcinoma, hydrocephalus, neurotrauma, Guillain–Barré syndrome and encephalitis [14,15].

The 34 patients with symptomatic hyponatraemia and/or hyponatraemia-associated mortality often had advanced medical conditions, such as liver failure (five deaths, two symptomatic patients), heart failure (one death, one symptomatic patient) and SIADH due to stroke (two deaths, one symptomatic patient), and it is possible that hyponatraemia was predominantly a secondary feature in these patients. However, in patients with post-operative hyponatraemia (one death, four symptomatic patients), diuretic-induced hyponatraemia (two deaths, two symptomatic patients), drug-induced hyponatraemia (five symptomatic patients) and in some patients with SIADH (five symptomatic patients), it is likely that hyponatraemia contributed significantly, or caused the observed morbidity and mortality.

In particular, hospital-acquired hyponatraemia appeared multi-factorial, because in this group the total number of possible causative factors during hospitalization was significantly higher than in patients with hyponatraemia on admission. Common combinations of causative factors included: diuretics and ADH-stimulating drugs (10 patients), heart failure and renal insufficiency (nine patients), surgery and hypotonic i.v. fluids (eight patients), liver failure and renal insufficiency (eight patients) and, finally, SIADH and ADH-stimulating drugs (four patients). Less common factors (not shown in Table 5) that may have contributed to hyponatraemia included Addison's disease (two patients) and hypothyroidism (two patients). There were no patients with apparent polydipsia, although most patients continued their habitual fluid intake, which may have contributed to hyponatraemia in some cases.



   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
References
 
In the present study, we sought to identify differences between patients who were admitted with severe hyponatraemia and those who developed severe hyponatraemia in hospital. The principal results demonstrate that hospital-acquired severe hyponatraemia was associated with treatment-related factors and inadequate or delayed management, thereby allowing a further decrease in PNa, and exposing these patients to the dangers of severe hyponatraemia [8,9].

Overall, the following picture of severe hyponatraemia in hospitalized patients emerged. Half of the patients presented with severe hyponatraemia, whereas the other half developed severe hyponatraemia in hospital (Table 2). In both groups, severe hyponatraemia was associated with substantial symptomatology and mortality (Table 2). When severe hyponatraemia was already present on admission, the time until treatment was initiated was significantly shorter than when severe hyponatraemia was hospital acquired (Table 3). Thus, there appeared to be a low recognition of deteriorating hyponatraemia, an assumption that was substantiated further by the observations that hospital-acquired hyponatraemia was less often documented and PNa less often determined prior to the lowest PNa (Table 3). Although severe hyponatraemia was also corrected significantly more slowly in hospital-acquired hyponatraemia, patients with symptomatic hyponatraemia were corrected equally rapidly in both groups (Figure 1). In addition, no cases of ODS were observed during the correction phase (Table 2). Finally, there appeared to be no relationship between the rate of correction and mortality (Figure 1), although few extreme correction rates were observed, and patients with hospital-acquired hyponatraemia appeared to die earlier (Table 2). However, untreated patients did have a higher mortality rate. Furthermore, a number of patients received inappropriate and potentially hazardous treatment for severe hyponatraemia, for example isotonic saline for SIADH (Table 4) [18]. In summary, in this study, permitting severe hyponatraemia and the associated symptomatology and mortality to develop in hospital was of greater clinical impact than how severe hyponatraemia was corrected.

A difficult question remains as to whether symptomatology and mortality in hyponatraemic patients are caused directly by severe hyponatraemia, the underlying disorder, or both [19]. Factoring in co-morbidity, we believe that symptomatic hyponatraemia and hyponatraemia-associated mortality could have been more preventable in patients with hospital-acquired hyponatraemia who lacked a severe underlying disorder associated with hyponatraemia, for example in post-operative, diuretic- or drug-induced severe hyponatraemia. We emphasize that although the decrease rates of PNa appeared to be relatively slow for the development of symptomatic hyponatraemia [20], hyponatraemia may have been more acute in many patients because of infrequent PNa measurements. Except for adverse patient outcomes, the duration of hospitalization in hospital-acquired hyponatraemia was also significantly longer (Table 3), thus increasing health care costs [19].

The awareness of severe hyponatraemia has been addressed previously by Arieff, who almost 20 years ago described that even in hyponatraemic patients with severe neurological symptoms, hyponatraemia was often not recognized [8]. More recently, Movig et al. evaluated the discharge diagnosis ‘hyponatraemia’ in 2632 cases of hyponatraemia and identified a similar low recognition rate, with only 30% of patients in whom severe hyponatraemia was classified [21]. A possible explanation as to why severe hyponatraemia is not readily recognized may be that the underlying disorder diverts attention from hyponatraemia and/or may give the impression that the cause of hyponatraemia and the associated symptoms are solely a result of that underlying disorder.

Previously, Palevsky et al. in a study on hypernatraemia in hospitalized patients showed results that were very similar to ours, namely an association between inadequate or delayed treatment and hospital-acquired hypernatraemia [22]. They suggested that better management may be achieved by physician education and development of preventive hospital systems, and our results suggest that these recommendations can also be extrapolated to hyponatraemia [22]. Indeed, Paltiel et al. showed that the implementation of a hospital warning system improved the management of electrolyte disorders, in their case hypokalaemia [23].

The optimal treatment for severe hyponatraemia remains controversial, because the importance of slow correction to prevent ODS [7,10] must be weighed against a significantly improved survival rate associated with more rapid correction [19,24,25]. The latter was demonstrated by Ayus and Arieff who showed that patients with chronic hyponatraemia whose PNa was restored by 22 mmol/l in 35 h with intravenous NaCl had a better neurological outcome than those whose PNa was restored by 3 mmol/l in 41 h with water restriction [24]. In a recent review, Martin showed that the recommended correction rates for hyponatraemia have steadily declined over the years to ~8 mmol/l/day [26]. The question is if this decreasing trend has overstepped its goals and if part of the poor outcome could have been prevented by more aggressive therapy [11,27], provided that risk factors for ODS are taken into account [28].

In the second part of this study, we assessed which factors were associated with hospital-acquired hyponatraemia. In principle, hyponatraemia can develop in hospital when there is a deterioration of the underlying disease, or when factors are being introduced in the hospital that can potentially disturb sodium and water balance. In this study, it appeared that most of the factors that contributed to hospital-acquired hyponatraemia were either maintained or introduced in hospital, and included thiazide diuretics, ADH-stimulating drugs, hypotonic i.v. fluids and surgery (Table 5). Nevertheless, because the average admission PNa of patients with hospital-acquired hyponatraemia was already in the hyponatraemic range (PNa 133±5 mmol/l), it is conceivable that underlying disorders or medication already led to moderate hyponatraemia at the time of admission in some patients, which was then aggravated further by factors introduced in the hospital.

The post-operative state and thiazides are well-established causes of hyponatraemia, but have chiefly been described in selected patient populations [8,29–31]. Hypotonic i.v. fluids as a cause of hospital-acquired hyponatraemia have mainly been described in hospitalized children, often with adverse outcome [32,33]. The ADH-stimulating capacity of some of the drugs identified in this study has long been known [15,34,35], whereas we also identified novel chemotherapeutic [36], antiepileptic [37] and antidepressant [38] drugs that probably contributed to hyponatraemia. The mechanisms by which the above factors can cause hyponatraemia are through the non-osmotic release of ADH followed by reabsorption of electrolyte-free water that was orally ingested or provided in hypotonic i.v. fluids, and/or by the promotion of renal sodium loss [39]. In particular, the development of hospital-acquired hyponatraemia appeared to depend on a combination of these factors, because the total number of possible causes of hyponatraemia during hospitalization was significantly higher, once more illustrating the multi-factorial nature of this condition (Table 3) [4,40,41].

This is one of the largest reported series of patients with severe hyponatraemia. The majority of the previous cohort studies were retrospective chart reviews, and usually reviewed a similar number of patients, but with lower PNa levels using a longer study period [3–7]. In the present study, by choosing a relatively short study period, and a PNa level in which the likelihood of symptomatic hyponatraemia is increased [20], we sought to investigate the frequently encountered cases of hyponatraemia. Indeed, hyponatraemia remains a very common condition, with one in every three hospitalized patients having an episode of hyponatraemia, and one in every 30 hospitalized patients having an episode of severe hyponatraemia (Table 1). Two notable differences in this study compared with previous studies should be mentioned. First, the number of patients with SIADH was relatively low, although we argue that previous studies did not always use stringent criteria for SIADH, which is a diagnosis of exclusion [14]. Secondly, the low incidence of hyponatraemia in psychiatric patients is remarkable because many psychotropic drugs, including haloperidol and serotonin reuptake inhibitors, frequently produce hyponatraemia [35,41]. A possible explanation is that in our institution psychotropic drugs are frequently withdrawn for diagnostic purposes.

Finally, a number of important limitations should be mentioned. The possible awareness of this study in our institution may have created bias toward the clinicians’ approach to hyponatraemia. However, the expectation would be that the presence of the study would only lead to a higher index of suspicion for hyponatraemia. The sample size limited the robustness with which we could analyse the data, and hence limits the power of some of the observations. We believe that a future study which compares patients with hospital-acquired hyponatraemia with a hospitalized control group without hyponatraemia would be important to identify further risk factors associated with the development of hospital-acquired hyponatraemia.

In conclusion, this study identified treatment-related factors associated with hospital-acquired severe hyponatraemia, including factors that contributed to its development (thiazide diuretics, ADH-stimulating drugs, hypotonic i.v. fluids and surgery), and factors that influenced its course (low recognition, delayed therapy and slow correction). These factors should be prevented if possible or lead to frequent monitoring of PNa and early intervention if PNa decreases to <136 mmol/l. Increased recognition and expedited therapy may be achieved by hospital warning systems, automated consultations or other surveillance systems.



   Acknowledgments
 
The authors would like to thank Dr Mitchell Halperin for helpful discussion and Mr Gert Verheij for his technical support with the retrieval of laboratory values. This work was presented in a poster session at the American Society of Nephrology Renal Week 2004, St Louis, MO.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 5. 6.05
Accepted in revised form: 25. 7.05


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