Management of hyponatraemia in older people: old threats and new opportunities

Abstract

Hyponatraemia is the commonest electrolyte abnormality seen in clinical practice, and is especially prevalent in frail, older people. However, the serious implications of hyponatraemia in this age group are seldom recognized by clinicians. Hyponatraemia is associated with osteoporosis, impaired balance, falls, hip fractures and cognitive dysfunction. Even mild, apparently asymptomatic hyponatraemia is associated with prolonged stays in hospital, institutionalization and increased risk of death. Emerging evidence of the potential benefits of improved treatment of hyponatraemia is slowly generating renewed clinical interest in this area. The development of specific vasopressin-2 receptor antagonists (vaptans) has the potential to revolutionize the management of hyponatraemia, in particular for the syndrome of inappropriate antidiuretic hormone. However, challenges remain for the attending physician. Diagnosing the cause or causes of hyponatraemia in older people is difficult, and incorrect diagnosis can lead to treatment that worsens the electrolyte imbalance. Established treatments are often poorly tolerated and patient outcomes remain poor, and the role of vaptans in the treatment of older people is unclear. This review summarizes the existing evidence base and highlights areas of controversy. It includes practical guidance for overcoming some common pitfalls in the management of the elderly patient with hyponatraemia.

Keywords

arginine vasopressin elderly hyponatraemia syndrome of inappropriate antidiuretic hormone tolvaptan vasopressin receptor antagonist

Introduction

Hyponatraemia is the commonest electrolyte abnormality seen in clinical practice. It is recognized that severe hyponatraemia can be symptomatic and life threatening. However, there is comparatively little awareness of the growing evidence that even a mild degree of chronic hyponatraemia can have serious clinical consequences. Similarly, the importance of the speed of onset of hyponatraemia as a prognostic marker is not always appreciated. This review highlights historic difficulties and important new insights and developments in the management of hyponatraemia in older people.

Presentation

Hyponatraemia is often discovered incidentally on routine blood testing. It is classically divided into mild (130–134 mmol/l), moderate (125–129 mmol/l) and severe (<125 mmol/l). Symptoms attributable to hyponatraemia are caused chiefly by excessive entry of water into brain cells and include malaise, headache, nausea and confusion. Since brain cells can adapt to changes in plasma tonicity over time, more severe symptoms such as seizures, coma or even death occur mainly in rapid-onset hyponatraemia. However, in older people, hyponatraemia may be an important contributor to the major geriatric syndromes such as immobility and falls [Renneboog et al. 2006], bone demineralization [Verbalis et al. 2009], hip fractures [Gankam Kegne et al. 2008] and cognitive impairment [Miller, 2006].

Prevalence

Hyponatraemia complicates a wide range of clinical entities but is especially prevalent in older people. The overall prevalence in the hospital population is about 15% [Upadhyay et al. 2006] but is much higher in certain vulnerable populations, such as admissions to acute geriatric medicine, where hyponatraemia is observed in almost half of all cases [Hoyle et al. 2006]. Chronic hyponatraemia is present in 18% of nursing home residents [Miller et al. 1995]. The reasons for the higher prevalence in old age relate to increased prevalence of comorbidity, high rates of prescribing of drugs known to cause hyponatraemia and ageing-related changes to homeostatic mechanisms (see Table 1) [Soiza et al. 2008].

Table 1.

Reasons for increased prevalence of hyponatraemia in old age.

High prevalence of conditions known to cause hyponatraemia

• Chronic congestive cardiac failure

• Chronic kidney disease

• Dehydration

• Bronchopneumonia

• Neurological disease, including stroke

• Malignancy

Frequently prescribed drugs causing hyponatraemia

• Thiazide diuretics

• Selective serotonin reuptake inhibitors

• Neuroleptic medications

• Carbamazepine.

Age-related changes in homeostatic mechanisms that contribute to hyponatraemia

• Decreased glomerular filtration rate

• Decreased urinary concentrating ability

• Decreased aldosterone levels

• Increased levels of arginine vasopressin

• Increased levels of atrial natriuretic peptide

• Lower sensitivity of thirst mechanisms

• Difficulty imbibing fluids (e.g. because of physical or cognitive impairment)

Prognosis

Mortality depends on the severity of hyponatraemia and can approach 50% when severe [Clayton et al. 2006]. However, there is often a mismatch between the severity of the symptoms and the degree of hyponatraemia [Arieff et al. 1976]. This is partly because the speed of onset of hyponatraemia is of greater prognostic significance than the degree of hyponatraemia itself. Two groups have independently shown that the drop in hyponatraemia had a greater effect than severity of hyponatraemia on key clinical outcomes, such as length of stay in hospital, mortality and institutionalization [Chua et al. 2007; Gill et al. 2006]. Nevertheless, a large prospective study of around 98,000 admissions to hospital showed even mild hyponatraemia is associated with increased mortality [Walkar et al. 2009]. There is still some debate over how much of the increased risk of death is directly attributable to hyponatraemia, and how much is due to underlying disease. Consequently, it remains unclear if better management of hyponatraemia itself leads to improvements in mortality, though there is growing evidence that it might [Walkar et al. 2009; Clayton et al. 2006; Hoorn et al. 2006]. Moreover, the finding that the drop in serum sodium during hospital admission is strongly associated with adverse outcome in older people [Chua et al. 2007] also suggests that active strategies to prevent or minimize hyponatraemia in hospital will improve outcomes. However, evidence of improvement in clinically meaningful outcomes with better management of hyponatraemia remains very limited and equivocal.

Underlying causes

Although hyponatraemia has many potential causes, the commonest cause is believed to be the syndrome of inappropriate antidiuretic hormone (SIADH) [Hannon and Thompson, 2010; Huda et al. 2006]. Given the high prevalence of hyponatraemia in older people, SIADH should also be highly prevalent in this population. However, the causes of hyponatraemia in older people have rarely been specifically studied, and older people are notoriously underrepresented in the medical literature. A very recent Israeli study made the important finding that hyponatraemia in older people is often multifactorial rather than attributable to a single entity [Shapiro et al. 2010]. The authors diagnosed SIADH in 39 out of 86 (45%) elderly individuals, making it the commonest cause. However, the reliability of these data has been challenged [Soiza and Hoyle, 2010] because the diagnosis of SIADH depends crucially on patients being in a euvolaemic state, and there is no reliable biomarker of volaemic status in older people [Hoyle et al. 2010]. Further research is required to better delineate the common causes of hyponatraemia in older people and a reliable biomarker of volaemic status needs to be developed.

Management

Management of hyponatraemia is notoriously challenging and evidence suggests it is often poorly managed [Thompson, 2010; Huda et al. 2006; Baron and Hutchinson, 2005]. The key to successful treatment is accurate diagnosis of the underlying causes. Diagnostic algorithms have been developed to help with this, with determination of volaemic status a key step in guiding further management [Verbalis et al. 2007]. However, because of the multiple pathologies underlying hyponatraemia in older people [Shapiro et al. 2010], coupled with discrepancies in clinical assessment [Hoyle et al. 2010], the result is often an unclear diagnosis and incorrect treatment. Owing to poorer compensation mechanisms, the frail older person with concomitant disease has little room for treatment error, so safe and effective initial therapeutic management is essential for optimal outcomes. However, established treatments such as saline infusions, fluid restriction, demeclocycline, loop diuretics, urea and lithium are often unpredictable, with variable efficacy and toxicity [Cawley, 2007].

Correction of hyponatraemia itself probably improves outcomes [Verbalis et al. 2007; Clayton et al. 2006]. When hyponatraemia is of rapid onset (<48 h) and associated with severe neurological symptoms, a rapid but modest correction (2–4 mmol/l over 1 h) is recommended with a bolus infusion of 100 ml of 3% saline [Verbalis et al. 2007]. In this situation, even a small decrease in cerebral oedema can have a major effect on raised intracranial pressure [Battison et al. 2005]. Failure to correct hyponatraemia by more than 4 mmol/l in 24 h is associated with poor outcome [Nzerue et al. 2003]. However, if correction of serum sodium is too rapid (>12 mmol/l in 24 h) this can result in potentially fatal osmotic demyelination syndrome. The challenge for clinicians is to provide therapy that keeps the patient safe from serious complications of hyponatraemia while avoiding correction rates that risk iatrogenic injury [Sterns et al. 2009]. An important expert consensus guideline developed in 2007 noted the ‘substantial morbidity and mortality’ of severe hyponatraemia observing that ‘optimal treatment strategies (in severe hyponatraemia) are not established’ [Verbalis et al. 2007]. Much ambiguity remains with conventional treatment for osmotic demyelination syndrome since it is difficult to determine hyponatraemic aetiology and duration, while consensus on the rate of correction remains elusive [Snell and Bartley, 2008]. Nevertheless, most experts agree that correction should never exceed 10 mmol/l in 24 h or 18 mmol/l in 48 h [Verbalis et al. 2007].

Treatment of chronic hyponatraemia has often been neglected by clinicians, probably because it is incorrectly perceived to be benign or because it is challenging to diagnose and treat. Nevertheless, correction of chronic hyponatraemia has the potential to deliver significant individual and public health benefits. A number of therapeutic strategies are available, and the development of oral vasopressin receptor antagonists has the potential to revolutionize this area of practice.

Established therapies

Isotonic saline (0.9%) infusion

Intravenous isotonic saline is used to treat acute hypovolaemic hyponatraemia. Especially in the elderly population, immobility, reduced cognitive function, comorbidities and malnutrition are the main compounding factors that may lead to dehydration. Treatment is dependent on accurate assessment of a patient’s volaemic state, which includes assessing skin turgor, jugular venous pressure, postural changes in blood pressure and pulse, buccal mucous membranes, degree of thirst and presence of oedema. Clinical assessment is often incorrect, resulting in older people with fluid depletion being wrongly treated with fluid restriction, ultimately worsening the hyponatraemia. Furthermore, no clinical sign or collective set of signs has proven reliability in older people with hyponatraemia [Hoyle et al. 2010], for example, about a fifth of healthy, community-dwelling people aged 65 or over have postural hypotension, an otherwise good marker of hypovolaemia in younger people [Rutan et al. 1992]. Measurement of urinary sodium and osmolality is helpful in diagnosing the cause of hyponatraemia [Soiza et al. 2008], but does not normally help distinguish hypovolaemia from SIADH. To deal with this uncertainty, we recommend seeking expert advice and considering a trial of 1 l intravenous isotonic saline infusion over 2 h in symptomatic patients with severe hyponatraemia when there is doubt if they are hypovolaemic or euvolaemic. Serum sodium and evidence of hypervolaemia should be checked thoroughly as there is a theoretical possibility of pulmonary oedema and overly rapid correction of hyponatraemia, particularly in older people, so expert clinical supervision is recommended. A good response in serum sodium immediately after the infusion would be most consistent with hypovolaemia, while hyponatraemia in SIADH does not respond to 0.9% saline [Verbalis et al. 2007]. Consideration could be given to a further and final 500 ml trial over 2 h if the results and clinical progression are equivocal and there is no suspicion of hypervolaemia. It is important to note that this method has not been evaluated in any scientific study so its sensitivity and specificity is unknown, but may be much better tolerated and give faster results than a trial of enforced fluid restriction. Ultimately, clinicians should always be prepared to revise their diagnosis and therapeutic strategy if there is no improvement in hyponatraemia.

Discontinuation of drugs

Eliminating possible causes of hyponatraemia is an essential part of treatment. A medication review of the patient should be carried out and careful consideration should be given to substituting, reducing the dose or stopping medications associated with low sodium. The potential conflict between the need to treat hyponatraemia and the underlying indication for the responsible medication must be acknowledged and may need discussion and expert advice (e.g. from a geriatrician, endocrinologist or psychiatrist, depending on the situation). Polypharmacy is commonly encountered in older people. In particular, diuretics and selective serotonin reuptake inhibitors are frequently prescribed, both of which can lead to low serum sodium. Prescribed medications are a contributing factor in the development of severe hyponatraemia in almost half of all cases seen in older people in hospital [Shapiro et al. 2010]. Hyponatraemia as a result of drug–drug interactions is also an important consideration. Thiazide diuretics and nonsteroidal anti-inflammatory drugs increase the risk of developing hyponatraemia in older people [Aaseth et al. 2001]. Discontinuation of drugs can be combined with an isotonic saline infusion with careful monitoring of the clinical and biochemical response.

Fluid restriction

Fluid restriction, to around 800 ml/day is used when a patient presents with euvolaemic hyponatraemia such as in SIADH [Kumar and Berl, 1998]. This form of treatment for hyponatraemia is often slow and can be difficult for patients to maintain in the long term because of hidden liquids in foods and discomfort with thirst [Zieste et al. 2009; Adrogue and Madias, 2000]. Unfortunately, thirst remains a prominent feature in SIADH because of downward resetting of the thirst ‘osmostat’ [Smith et al. 2004], that is, thirst is induced at a lower plasma osmolality than is normal.

Demeclocycline

Demeclocycline is a longer-term treatment option used in euvolaemic patients with SIADH, in particular secondary to a malignancy. It is often reserved for cases in which fluid restriction has failed. At the level of the kidneys, demeclocycline works by achieving a nephrogenic diabetes insipidus effect through an unknown mechanism in around 60–70% of cases [Zieste et al. 2007], but is ineffective in the remainder. One issue is the unpredictability of its effect, occurring any time from two to several days after initiation, and caution must be taken to avoid overly rapid correction and even development of hypernatraemia. Demeclocycline is sometimes tolerated poorly by patients because it can cause nausea and skin photosensitivity, as well as being associated with nephrotoxicity [Curtis et al. 2002].

Hypertonic saline (3% or 5%)

Hypertonic saline is very rarely indicated, and few experts recommend its use, but it can be given as an infusion or in a bolus of either 3% or 5% solution. The 5% solution is not recommended to avoid confusion with 5% dextrose solution. Hypertonic saline is only used in the treatment of acute symptomatic hyponatraemia characterized by severe symptoms, such as loss of consciousness and seizures [Gross et al. 1998]. Treatment difficulty lies in getting an optimum balance, as too slow a correction or overcorrection of hyponatraemia can lead to further complications [Sterns et al. 1994]. Overcorrection leading to hypernatraemia as a result of treatment may require supplementation with hypotonic fluids [Soupart and Decaux, 1996]. These problems can be minimized with checks every 2 h of serum sodium so that the treatment is tailored to the individual patient [Moritz and Ayus, 2010]. Provision of such intensive monitoring and the risks of complications restrict usage of hypertonic saline to patients in intensive care or high-dependency units under specialist supervision.

Salt tablets

The concept of treating low serum sodium with sodium supplements has intuitive appeal. However, sodium chloride tablets are seldom helpful in treatment because hyponatraemia usually reflects an imbalance in total body water, rather than sodium depletion. Even in conditions associated with high sodium losses, daily dietary sodium intake is almost always adequate to maintain normal sodium concentration [Hew-Butler et al. 2006]. Cases with poor oral intake are normally best treated with intravenous supplementation. Salt tablets should be avoided in most patients with euvolaemic and hypervolaemic hyponatraemia because the resulting thirst and increased water intake and retention can worsen hyponatraemia.

Diuretics

Loop diuretics such as furosemide are indicated in all forms of hypervolaemic hyponatraemia [Verbalis et al. 2007]. Loop diuretics can help to correct hyponatraemia in SIADH [Hantman et al. 1973], but they can also worsen hyponatraemia by increasing urinary sodium excretion [Gross, 2008]. Therefore, they are not recommended for use in euvolaemic hyponatraemia. There are no studies of diuretic therapy in the context of SIADH in older people specifically. Thiazide diuretics have no therapeutic role and are frequently implicated in the aetiology of hyponatraemia in older people [Shapiro et al. 2010].

Other potentially therapeutic agents that are not recommended

Lithium reduces the maximum concentrating ability of the kidney, helping to minimize sodium loss and water retention [Waller et al. 1988]. Lithium induces a nephrogenic diabetes insipidus effect in a third of cases [Baylis and Heath, 1978] by downregulating vasopressin-stimulated aquaporin-2 expression [Nielsen et al. 2008]. However, expert consensus is that lithium is less desirable than alternatives due to its inconsistent results and significant adverse effects and toxicities [Sherlock and Thompson, 2010; Verbalis et al. 2007]. Urea, given orally or as an infusion, has been suggested as an option for euvolaemic hyponatraemia, particularly SIADH. Urea can produce a rapid correction of hyponatraemic brain oedema while being associated with a reduced risk of myelinolysis [Sterns et al. 1994]. The benefits of oral urea in SIADH are that it allows a less rigorous fluid restriction, although difficulties include lack of availability in some countries, bad taste and development of azotemia [Verbalis et al. 2007]. Consequently, lithium and urea are seldom used in the treatment of hyponatraemia in older people.

Vasopressin receptor antagonists

Owing to the high prevalence of SIADH, the development of specific antidiuretic hormone (arginine vasopressin) receptor blockers was long awaited. These agents are theoretically superior to the alternatives above in the treatment of SIADH as they target the underlying pathological mechanism specifically. Their potent diuretic effect means they may also have a role in hypervolaemic hyponatraemia [Shoaf et al. 2007]. Their effect in this regard is often termed ‘aquaretic’ because they promote excretion of solute-free water, as opposed to the natriuresis seen with conventional diuretic drugs. The relevant receptor is the V₂ receptor found on the basolateral membrane of the cells in the distal convoluted tubules and the collecting ducts of the kidney, as well as the vascular endothelium. There are two other vasopressin receptors (V_1a and V_1b) whose activation causes several effects, including vasoconstriction, platelet aggregation, inotropic stimulation (V_1a) and pituitary adrenocorticotropic hormone secretion (V_1b) [Thibonnier et al. 1998].

The first vasopressin receptor antagonist (vaptan) to be developed was conivaptan, which acts on both V_1a and V₂ receptors [Decaux, 2001]. Conivaptan has been licensed in the USA for the treatment of euvolaemic or hypervolaemic hyponatraemia for about 5 years. Fears about the potential for drug interactions resulted in US Food and Drug Administration approval for use in hospital for a maximum of 4 days and in intravenous form only, despite being potentially suitable for oral administration [Ghali et al. 2006]. Interest in this group of drugs has been reinvigorated with the more widespread availability of the first oral vaptan approved for long-term use, tolvaptan. In the USA, tolvaptan has a license for the treatment of both hypervolaemic hyponatraemia and SIADH, but in the UK it is currently restricted to the SIADH only. All vaptans are inhibitors of the cytochrome P450 3A4 system, with conivaptan displaying particular potency in this regard, hence the limitations on its license. Tolvaptan also differs from conivaptan in being a selective V₂ receptor antagonist. Other selective V₂ receptor antagonists include mozavaptan [Saito et al. 1997], lixivaptan [Wong et al. 2003] and satavaptan [Soupart et al. 2006], but these are not available to prescribing clinicians at the time of writing.

Safety and adverse effects

In two randomized controlled trials that included patients with hyponatraemic SIADH (n = 91), heart failure (n = 71) or cirrhosis (n = 63) aged up to 100 years (SALT-1 and SALT-2), the prevalence of serious adverse effects after treatment with tolvaptan was similar to that seen with placebo [Schrier et al. 2006]. Common adverse effects in the first month of therapy included thirst (14%), dry mouth (13%), weakness (9%), constipation (9%) and nausea (8%). Tolvaptan also demonstrated a good safety profile after a median 9.9 months of treatment in a large trial of patients with heart failure [Konstam et al. 2007], but only 10% of patients had hyponatraemia. The long-term safety profile of tolvaptan in the setting of hyponatraemia was assessed in an open-label extension of the SALT trials called SALTWATER [Berl et al. 2010]. According to the authors, six of 111 patients in the study had to discontinue treatment because of probable adverse drug reactions (each for a different reason: ventricular tachycardia, irritability, hypernatraemia, anorexia, renal failure, pruritus). Pollakiuria, polydipsia and polyuria were also seen, but in only 10% or less of patients. This reassuring adverse-effect profile is perhaps surprising given the extreme diuresis observed in early studies, typically averaging over 5 l of urine excretion per day [Shoaf et al. 2007].

It is uncertain whether tolvaptan would be as well tolerated in frail, older people. Despite the inclusion of some extremely elderly people in trials of tolvaptan, the mean age of participants was just 60 years in SALT-1, 62 years in SALT-2 and 65 years in SALTWATER. The tolerability in the age group with arguably the most to gain from this treatment is therefore still unclear and it seems reasonable to postulate that some frailer patients would require urinary catheterization and even intravenous saline infusion to protect against incontinence and excessive sodium and water loss.

Efficacy and effectiveness

Results from SALT-1 and SALT-2 showed convincingly that tolvaptan was superior to placebo at increasing serum sodium concentration within 24 h and up to 30 days after dose administration [Schrier et al. 2006]. The improvement in sodium was accompanied by a significant improvement in symptom score using the Mental Component of the Medical Outcomes Study 12-item Short-Form General Health Survey [Ware et al. 1995]. Tolvaptan was also more effective than fluid restriction at normalizing serum sodium in one small, randomized trial [Gheorghiade et al. 2006]. However, serum sodium concentration was found to fall again within a week of discontinuing the drug [Schrier et al. 2006]. Indeed, 85% of patients who went on to participate in the open-label SALTWATER trial were hyponatraemic again at entry [Berl et al. 2010], suggesting that chronic treatment with tolvaptan would be required to maintain normonatraemia. Given the high cost of the drug (currently priced in the UK at approximately £75 (€86/US$119) per day of treatment [British National Formulary]) it remains unclear what its role in clinical practice will be.

Tolvaptan was not significantly better than placebo at improving mortality in the EVEREST study of patients with chronic heart failure [Konstram et al. 2007], although a subgroup analysis of patients with hyponatraemia has not yet been published. While there remains a lack of convincing evidence on ‘hard’ endpoints, such as improved quality of life, decreased mortality, reduction in length of stay in hospital or evidence of cost effectiveness, it is unlikely to become a commonly used therapy in clinical practice. It may nevertheless find niche roles for short-term use in relatively acute, severe euvolaemic hyponatraemia (e.g. after chemotherapy in patients with cancer), or in symptomatic, chronic hyponatraemia secondary to SIADH when fluid restriction has failed and commissioners or insurers are generous enough to cover the cost of the drug.

Although these findings may initially suggest an extremely limited role for the potential use of vaptans in very elderly people, this may prove to be their most lucrative market for the following reasons: hyponatraemia is more common in this increasingly prevalent age group; the clinical implications of any improvements in balance and cognition will be much greater than in a younger population; the economic burden of falls [Heinrich et al. 2010] and cognitive impairment [Luengo-Fernandez et al. 2010] is huge; and the shortened life expectancy of older people with hyponatraemia may make the prospect of potentially lifelong treatment more palatable to healthcare funders.

Conclusions

Hyponatraemia in older people remains a common yet neglected area of clinical practice. Recent advances in the understanding of the pathological associations of even apparently asymptomatic chronic hyponatraemia, and the development of new therapeutic options have created renewed interest in this condition. Improved treatment of hyponatraemia could deliver significant health and economic benefits in the form of fewer falls and hip fractures, improved cognition, and reductions in hospital stay and institutionalization. However, evidence of these benefits with improved management remains scant and clinicians still face the challenge of appropriate diagnosis and cost-effective selection of therapeutic options. Future work should focus on improving current diagnostic tools or algorithms. In particular, a valid biomarker of volaemic status in older people with hyponatraemia is especially desirable. New and emerging therapies should focus on gathering evidence of their safety and benefits in terms of ‘hard’ clinical outcomes and cost effectiveness.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

Dr Soiza is a member of an Otsuka Pharmaceuticals (UK) advisory board.

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