Hyponatraemia for the clinical endocrinologist

Abstract

‘The constancy of the internal milieu is the essential condition to a free life’ Claude Bernard, 1865, Introduction to the Study of Experimental Medicine Hyponatraemia is the most frequent electrolyte disorder seen in hospital practice and is by no means rare in community patients. Mild hyponatraemia (plasma sodium 130–135 mmol/l) is found in as many as 15–30% of hospitalized patients or in the institutionalized elderly,1 although the clinical significance of this finding is usually uncertain. More severe hyponatraemia (plasma Na+ < 130 mmol/l) is seen in 1–4% of inpatients and often reflects more serious underlying disease. Hyponatraemia is often asymptomatic when mild or when it develops slowly, but severe hyponatraemia (plasma sodium < 120 mmol/l), particularly if of rapid onset, is associated with substantial morbidity and can be life-threatening.2 Hospital patients with hyponatraemia have a substantial additional mortality,3 although how much this reflects the electrolyte disturbance per se, as opposed to the severity of the underlying condition(s), remains uncertain. Hyponatraemia is also an important predictor of mortality in heart failure4 and cirrhosis,5 although again this is likely to reflect the severity of the primary underlying disorder and its treatments. Unfortunately, hyponatraemia is often iatrogenic. There are several excellent detailed reviews of the physiology of sodium homeostasis, thirst and vasopressin action, as well as the pathogenic mechanisms causing hyponatraemia.6-10 Here we concentrate only upon the essential pathophysiology (below). Moderate to severe hyponatraemia bears a substantial associated morbidity and mortality.3 Thus, making a timely and accurate diagnosis and instituting appropriate therapy is crucial. Indeed, many texts teach that diagnosing the cause of hyponatraemia is key to guiding appropriate therapy. Certainly, correct management is critical as overly rapid correction of sodium may lead to severe neurological morbidity and mortality, while inadequate or inappropriate therapy has its own hazards. However, because distinguishing the cause(s) underlying an individual case of hyponatraemia is usually difficult and frequently unfeasible in clinical practice, and because there is an almost complete lack of prospective randomized controlled trial (RCT) evidence for commonly employed therapies, we concentrate on the empirically based pragmatic management of the hyponatraemic patient. We also highlight some recent advances of therapeutic promise in this complex but important area. Sodium and its accompanying anions, principally chloride and bicarbonate, are the major extracellular electrolytes and the main determinants of plasma osmolality and water homeostasis. Plasma sodium concentrations are kept within a very narrow range despite great variations in water and sodium intake. In theory, the determinants of plasma sodium are sodium intake/output and water balance. However, in practice, in the absence of relatively rare specific disorders of salt retention, the principal determinant of the plasma sodium concentration is the plasma water content. This is determined by water intake (thirst or habit) and urinary dilution. The latter is predominantly determined by arginine vasopressin (AVP, ADH), which crucially controls the regulable fraction of renal water excretion by changing water permeability in the renal collecting duct. AVP is a nonapeptide hormone, synthesized in the magnocellular neurosecretory neurones of the paraventricular and supraoptic nuclei of the hypothalamus and then stored in and released from the posterior pituitary ‘gland’. There is a close relation between plasma osmolality and plasma AVP levels, although the ‘threshold’ for AVP release may be influenced by various physiological factors such as age and pregnancy. In particular, a reduction in plasma volume shifts the relationship between plasma osmolality and AVP to the left such that AVP is released at a lower threshold of plasma osmolality. Other nonosmotic factors stimulating AVP release include decreases in arterial blood pressure and circulating blood volume, pain, nausea and vomiting, hypoglycaemia, nicotine and hypoxia. Neurohypophyseal secretion of AVP is inhibited by ethanol, caffeine and some other drugs, explaining their well-recognized mild diuretic effects. In response to AVP, concentrated urine is produced by water reabsorption across the renal collecting ducts. AVP binds to its V2 receptor in the basolateral membrane of the collecting duct principal cells, initiating cAMP-mediated phosphorylation of the aquaporin-2 water channel.11 Aquaporin-2-containing vesicles translocate from the cytosol to the apical membrane of the collecting duct, allowing passive movement of water from tubule fluid to the medullary interstitium along the osmotic gradient created by the countercurrent concentrating mechanism. The pathophysiology of AVP and aquaporin-2 has been reviewed previously.12 Several hormones also modulate sodium balance, either by increasing renal sodium reabsorption in the kidney cortical and medullary collecting tubules, e.g. aldosterone, or by affecting AVP action on the collecting ducts, e.g. glucocorticoids (as discussed below), prostaglandins, calcitonin and glucagon. Hyponatraemia almost always reflects an excess of water relative to sodium, either as a result of depletion of total body sodium in excess of concurrent body water losses, or by dilution of total body sodium by increases in total body water. In practice, both processes probably coexist in the majority of cases of moderate to severe hyponatraemia, although tests to accurately define the contributions of each mechanism are lacking in the normal clinical arena. In healthy individuals a water load is rapidly excreted. Plasma AVP levels fall on swallowing, before plasma dilution occurs, allowing prompt excretion of dilute urine.13 The maximum rate of water excretion on a regular diet is more than 10 l per day providing an enormous range of protection against the development of hyponatraemia. Therefore, the most common causes of severe hyponatraemia in adults are renal, notably therapy with thiazide diuretics, the excessive (e.g. perioperative) administration of intravenous hypotonic fluids, the myriad causes of the syndrome of inappropriate antidiuretic hormone (SIADH) and trans-urethral prostatectomy. In contrast, excess water intake (which has to be typically >> 10–15 l per day to overwhelm the body's very considerable capacity to excrete a water load in order, on its own, to cause hyponatraemia) is usually confined to massive primary polydipsia in psychiatric and hypothalamic disorders (and perhaps beer potomania which is complicated by a lack of solute intake), is a much rarer cause of hyponatraemia.9 With the increasing popularity of ‘fun running’, hyponatraemia is seen in a substantial proportion of nonelite marathon runners who gain weight during the race through excessive fluid intake, by drinking more than 3 l during the race or consumption of fluids every mile.14 The hyponatraemia may be severe and has emerged as an important cause of race-related death. Hyponatraemia is diagnosed by a low plasma sodium after exclusion of pseudohyponatraemia (Table 1). Increase in the nonaqueous phase of plasma, for example with hypertriglyceridaemia or hyperproteinaemia, gives a spuriously low sodium concentration when assayed by techniques that rely on plasma dilution. Although organic solutes such as urea (or ethanol) contribute to total osmolality their ability to move freely across almost all cell membranes renders their contribution to plasma osmolality ‘ineffective’ in influencing transmembrane shifts. Thus the total plasma osmolality is not equivalent to the ‘effective’ plasma osmolality. In contrast, osmotically effective solutes like mannitol (which cannot cross plasma membranes) can cause a true hyponatraemia by drawing water from the intracellular to the extracellular compartment. In health glucose is able to traverse cell membranes approximately freely so rendering it an ineffective osmolyte but in circumstances where the plasma glucose concentration becomes very elevated and when there is impaired cellular uptake (e.g. insulin deficiency) it becomes an effective extracellular osmolyte akin to mannitol. Strictly the extent to which the plasma glucose becomes an effective osmolyte depends on the extent to which its free intracellular movement is impaired and this is not easily measurable. This matter usually only becomes an issue when hyperglycaemia is present and practically this means hyponatraemia will be significantly corrected as glucose is lowered towards normal. Some authors have proposed methods for estimating the effective osmoles contributed by the hyperglycaemia and concluded that plasma sodium concentrations can be ‘corrected’ for hyperglycaemia by adding 1·6 mmol/l for every 5·6 mmol/l increase in glucose level.15 It has been proposed that a correction factor of 2·4 mmol/l is a better overall estimate if glucose levels are greater than 22·2 mmol/l.16 However, these calculations involve considerable assumptions and are only applicable to those of normal body composition and so will be even less valid for many hospitalised patients. We next present a brief description of the classical scenarios of moderate to severe hyponatraemia classified by the ‘volume’ status of the patient. However, although this is ‘traditional’ in such texts and sounds logical in theory, in clinical practice such distinctions may be debatable and often mixed processes appear to occur. In hypovolaemic hyponatraemia there is predominant extracellular fluid depletion, with sodium loss exceeding water loss. As volume status is low, there is a nonosmotic stimulation of AVP release in attempt to retain water and re-establish euvolaemia. The commonest cause is therapy with thiazide diuretics, especially in elderly women. However, in practice, diuretic-induced hyponatraemia often presents as clinical euvolaemia, reinforcing the gap between theory and practice in these enigmatic disorders. Hypovolaemic hyponatraemia is also seen with substantial fluid losses (typically isotonic) from the gastrointestinal tract, skin or kidney, particularly when such fluid losses are replenished with water or hypotonic fluids. In primary adrenal failure (Addison's disease), hyponatraemia is partly explained by the absence of mineralocorticoid secretion leading to urinary sodium wasting. Glucocorticoid deficiency per se also impairs the ability to excrete a water load appropriately. The mechanism behind this is not fully understood but may be the result of a combination of increased AVP secretion and renal effects, which may have a slower onset, and further limit water excretion. In adrenalectomized rats, hypothalamic AVP mRNA expression is increased and plasma AVP levels remain inappropriately elevated within the ‘normal range’ despite hypo-osmolality.17 Plasma AVP levels are also paradoxically ‘normal’ or increased despite hypo-osmolality in hyponatraemic patients with secondary adrenal failure (hypopituitarism). Such inappropriately elevated plasma AVP levels fall in response to hydrocortisone.18 Glucocorticoid deficiency also directly impairs renal water excretion by mechanisms which are still to be fully clarified but may involve both alterations in renal haemodynamics (reducing water delivery distally to the collecting ducts) and collecting duct changes promoting water reabsorption; in glucocorticoid-deficient rats aquaporin-2 water channels are up-regulated.17 Cerebral salt wasting (CSW) remains a controversial entity which has been multiply reported to occur in patients with intracranial disease, typically subarachnoid haemorrhage, and is characterized by evidence of severe renal salt wasting with resultant volume depletion and hyponatraemia.19-21 The mechanism of natriuresis is unknown, although increased concentrations of atrial and/or brain natriuretic peptide have been reported and are hypothesized to cause an increase in sodium excretion and in urine volume.22 In practice, some considerable difficulty may be encountered in differentiating CSW from SIADH. Moreover, it has been suggested that this entity is very rare and the increased prevalence of CSW described over the last three decades, is the result of reporting bias.23 In principle, the distinction is important, as logical therapy for CSW involves intravascular volume repletion, while in SIADH fluid restriction is the first-line approach. However, since the underlying mechanisms are not established and firm diagnostic criteria are lacking, distinguishing the two conditions is often difficult in practice even with central venous pressure measurements (although these are helpful to gauge volume depletion and monitor fluid replacement). Indeed, both CSW and SIADH may coexist. Hypervolaemic hyponatraemia occurs with fluid overload in conditions such as congestive cardiac failure, cirrhosis or the nephrotic syndrome, when there is paradoxical retention of sodium and water despite a total body excess of each. In such states of reduced apparent arterial blood volume, baroreceptors in the arterial circulation perceive hypoperfusion triggering an increase in AVP release and net water retention. There is evidence from animal studies and some limited human investigations to suggest that in addition to increased AVP concentrations there is also up-regulation of aquaporin-2 water channels resulting in decreased water clearance.12 Euvolaemic hyponatraemia is the most heterogeneous and common cause of hyponatraemia in hospitalized patients. It can occur in any of the above settings and additionally is seen in the following contexts. Hyponatraemia is reported in up to 10% of hypothyroid patients, although it is usually mild and rarely causes symptoms.24 In water-loading studies, patients with hypothyroidism have a diminished ability to excrete free water and fail to achieve maximum urine dilution. Although some studies have reported elevated AVP levels in patients with hypothyroidism the literature is inconsistent. In hypothyroid rats there is no up-regulation of hypothalamic AVP gene expression. The reduction in cardiac output and GFR observed in severe hypothyroidism may be nonosmotic stimuli to AVP release. Hypopituitarism is often overlooked as a cause of hyponatraemia. In a recent study, hypopituitary patients presenting with hyponatraemia had been admitted to other hospitals between one and four times before the underlying hypopituitarism was finally diagnosed.18 Previous hyponatraemic episodes were documented in 43% of these patients. Elderly patients with secondary adrenal failure are particularly prone to develop hyponatraemia. Glucocorticoid deficiency is probably the most important factor causing the hyponatraemia in hypopituitarism as the hypo-osmolality recovers as soon as cortisol deficiency is corrected and long before thyroid deficiency is biologically substituted.18 Since SIADH is a prime component of the hyponatraemia of glucocorticoid deficiency, it is usually indistinguishable from SIADH as a result of other causes (see below). SIADH is a diagnosis of exclusion and is a common complication of a wide range of clinical disorders and drugs (Table 2). The diagnostic criteria include hyponatraemia, plasma hypo-osmolality, hypertonic urine with no dehydration or oedema, and normal renal and adrenal function.25 Additional tests to confirm the diagnosis, but which are rarely used in clinical practice, include an abnormal water load test (i.e. inability to excrete at least 90% of a 20 ml/kg water load in 4 h and/or failure to dilute urine osmolality < 100 mosm/kg), and the finding of plasma AVP levels inappropriately elevated relative to plasma osmolality. In practice, the time required to obtain AVP assays mean that such data are available long after the clinical episode has ended. SIADH is characterized by hyponatraemia secondary to increased total body water resulting from impaired renal free water excretion. Patients with SIADH fail to suppress AVP secretion even when plasma osmolality falls below the normal osmotic threshold triggering AVP release (previously reviewed by Smith et al.10). Hyponatraemia in SIADH is limited by the ‘escape phenomenon’ in which urine flow rises and urine osmolality falls after a few days of free water retention to re-establish fluid balance. This effect tends to protect against water retention and severe hyponatraemia, and may be caused by reduced expression of aquaporin-2 in the collecting ducts. As many as 10–20% of patients with hyponatraemia, who have a clinical and laboratory picture consistent with SIADH, have AVP levels at or below the limits of detection by radioimmunoassay. A recent study of two unrelated infants with hyponatraemia whose clinical presentation was consistent with SIADH but who had undetectable AVP levels, identified a novel mutation in the V2 receptor leading to constitutive activation of the receptor and consequent nephrogenic syndrome of inappropriate antidiuresis’.26 Future research may identify further mutations in the V2 receptor gene and/or signalling cascade in such patients with ‘apparent’ SIADH. While thiazides and other diuretics often cause hyponatraemia, a long list of other agents cause SIADH as an uncommon effect. A comprehensive list is not within the intended scope of this article, but important examples are psychoactive drugs, which may stimulate AVP release (phenothiazines and some newer antipsychotics, tricyclics, SSRIs), renal AVP receptor agonists (dDAVP, oxytocin) and others such as chlorpromazine, carbamazepine and omeprazole. The common drug of abuse ecstasy (E, MDMA) can cause hyponatraemia. When assessing a patient with hyponatraemia, the aim is to determine the probable cause(s) of the hyponatraemia and decide the best way to treat it. Extracellular fluid volume status, symptoms and signs, the rate at which hyponatraemia developed and the severity of the hyponatraemia are assessed. An accurate history and physical examination can help determine evidence of underlying illness such as congestive cardiac failure, cirrhosis or nephrotic syndrome, Addison's disease (pigmentation), hypopituitarism and hypothyroidism. In practice, evaluation of volume status may be challenging but it should be estimated by skin turgor, pulse rate, postural blood pressure difference and jugular venous pressure, together with examination of fluid balance charts. Measurement of central venous pressure may be necessary and is probably underemployed. The symptoms of hyponatraemia are primarily neurological and are related both to the severity and, particularly, to the rapidity of the fall in the plasma sodium concentration. Patients with mild hyponatraemia (plasma sodium 130–135 mmol/l) of any duration are usually asymptomatic of hyponatraemia, although not necessarily of the underlying cause(s). Nausea and malaise are the earliest symptoms typically seen when the plasma sodium concentration falls below 125–130 mmol/l. Headache, lethargy, restlessness, and disorientation may follow as the sodium concentration falls below 115–120 mmol/l. With severe and rapidly evolving hyponatraemia seizure, coma, permanent brain damage, respiratory arrest, brain stem herniation and death may occur.27, 28 In one study of 184 patients with a plasma sodium concentration of 120 mmol/l or less, 11% presented in coma.28 In contrast, patients with chronic hyponatraemia often remain asymptomatic for prolonged periods of time (see below) and symptoms are only seen if there has been an acute exacerbation of the hyponatraemia or sometimes when the plasma sodium concentration falls below 110 mmol/l. Concomitant metabolic disturbance (acidosis, hypoxia) usually compounds the symptomatic severity. A decrease in plasma sodium concentration creates an osmotic gradient between extracellular and intracellular fluid in brain cells causing movement of water into cells, increasing intracellular volume and resulting in tissue oedema, raised intracranial pressure and neurological symptoms. The brain regulates to prevent swelling over hours to days, by transport of firstly sodium, chloride and potassium, and later organic solutes including glutamate, taurine, myo-inositol, and glutamine, from intracellular to extracellular compartments. This induces water loss and ameliorates brain swelling, and hence leads to few symptoms in patients with chronic hyponatraemia. After a thorough history and examination, measurement of plasma and urine osmolality and urine sodium concentration should be performed. Plasma glucose and lipids should be measured to detect pseudohyponatraemia. Normal renal function, thyroid function and peak cortisol levels across a short synacthen test should be recorded before a diagnosis of SIADH is made. A low uric acid level associated with hyponatraemia may be suggestive of SIADH,29 and low plasma bicarbonate levels are reported to be a guide to adrenocorticotropin deficiency.30 The plasma osmolality is reduced in most hyponatraemic patients because it is primarily determined by the plasma sodium concentration and accompanying anions. The normal response to hyponatraemia is to suppress AVP secretion, resulting in a maximally dilute urine (osmolality less than 100 mmol/kg). Higher urine osmolality values indicate an inability to excrete free water that is generally caused by continued AVP secretion. In patients with hyponatraemia and a low plasma osmolality, the urine osmolality can distinguish between impaired water excretion and primary polydipsia, in which water intake is so high that it exceeds excretory capacity. In patients with impaired water excretion caused by hypovolaemia, the urine osmolality often exceeds 450 mmol/kg. Osmolality measurements are also useful in beer/diet potomania, i.e. hyponatraemia with a low solute intake, when overt polyuria may be absent despite the production of dilute urine. More important than urine osmolality, measurement of urinary sodium allows the crucial distinction in hypovolaemic hyponatraemia between renal (high urine sodium; > 30 mmol/l) and extra-renal (low urine sodium; < 30 mmol/l) salt loss. This is key for the differential diagnosis of hyponatraemia (see Table 1) but a recent study reported that urine sodium is rarely checked, even in cases of severe hyponatraemia.31 Similarly, in euvolaemic hyponatraemia, urinary sodium levels are high in SIADH, glucocorticoid insufficiency and thiazide use, but low in prerenal (depletional) hyponatraemia with hypotonic fluid replacement. However, low urinary sodium is also an early feature of the recovery phase from diuretic use (within hours) or SIADH, highlighting the bewildering complexities of this topic for the practicing physician. Other investigations to help determine the cause of hyponatraemia include a chest X-ray to assess the fluid status of the patient and diagnose lung pathology causing SIADH. Further radiological studies, such as CT and magnetic resonance imaging (MRI) of head and thorax, are dictated by the clinical presentation. Algorithm for management of hyponatraemia. Despite the high incidence of hyponatraemia in clinical practice, there is a dearth of high quality evidence to indicate the optimal management in the clinical settings outlined above. A search of a medical database (Web of Science) revealed several thousand articles from 1981 to 2003 mentioning hyponatraemia (search parameter ‘hyponatr*’), but less than a dozen RCTs of therapy of any description (search parameters ‘hyponatr*’ and ‘controlled trial’). What recent evidence there is from controlled trials reflects the apparent commercial drive to justify the therapeutic role of vasopressin receptor antagonists in various clinical settings. Therefore, most reported management algorithms conform to ‘conventional’ clinical experience-based management strategies, although such approaches are fraught with problems, including subjective bias of more prolific authors. Suggested therapeutic strategies reflect, at best, the outcomes of anecdotal or retrospective analyses or ‘logical’ approaches. This is clearly not good enough for any strong evidence-based guidance, so what follows must be taken with this important ‘health warning’. Allowing for this, most authors agree pragmatically that the presence or absence of symptoms and the duration of the hyponatraemia should guide the treatment strategy.6 Extra caution should be taken in managing neurosurgical hyponatraemia as symptoms may be more prominent in patients with cerebral insults but may not reflect the hyponatraemia per se.32 If an underlying cause can be identified, specific therapy is indicated. For example, stopping diuretics or instituting appropriate hormone replacement therapy for glucocorticoid insufficiency and/or hypothyroidism may be the only requirement.33 Indeed, most drug-induced hyponatraemia is thought to respond to withdrawal of the offending agent and simple water restriction alone.9 Likewise it is rarely harmful to give acute hydrocortisone treatment (100 mg i.v./i.m. 6 hly for 24–48 h) and this may be life-saving in severe hyponatraemia of glucocorticoid (± mineralocorticoid) insufficiency. In acute hyponatraemia (i.e. developing in less than 48 h) prompt treatment is indicated to decrease the risk of cerebral oedema and tentorial herniation. Sodium can be rapidly corrected with apparently small risk of central pontine myelinolysis (CPM) because brain adaptive mechanisms have not occurred. The risk of CPM relates to the rate of correction34 and also the magnitude of the hyponatraemia.34, 35 There is still no consensus about the optimal rate of correction of hyponatraemia but after reviewing all the available evidence, a target rate of correction not exceeding 8 mmol/l on any day of treatment9 or an aim to raise the sodium concentration by 1–2 mmol/l per h until symptoms have resolved, while still not exceeding this target,9, 36 is recommended. Should severe symptoms not respond to correction to the specified target, this limit may be cautiously exceeded because the immediate risks of cerebral oedema are believed to outweigh the risks of demyelination.9 Therefore, acute-onset hypovolaemic hyponatraemic states can be treated with isotonic saline or, if not severe, with oral sodium supplementation. Hypervolaemic hypernatraemia indicates therapy of the underlying cause. In rapid onset euvolaemic hyponatraemia, i.e. SIADH, there are uncertainties as to whether isotonic or hypertonic solutions are the best initial approach. Given the difficulties in distinguishing mild hypovolaemia, it is our pragmatic recommendation that an initial period of treatment with isotonic saline is tried and CVP measured if there is any concern regarding cardiac function (elderly, primary heart disease, etc.). If plasma sodium fails to respond after 4–8 h, then 3% (hypertonic) saline (0·5–1 ml/kg/h) can be used to raise plasma sodium to safe levels (> 120 mmol/l), after which more conservative approaches (water restriction, demeclocycline, etc.) are employed gradually to restore water and sodium balance more fully towards normal. The evidence base for hypertonic saline is slight and safety necessitates frequent (one to two hourly) measurement of plasma sodium and electrolytes, as well as monitoring urine output and cardiovascular status. In chronic hyponatraemia (i.e. present for more than 48 h) the adaptation returning brain volume toward normal to protect against the development of cerebral oedema also creates a potential problem for therapy. An overly rapid increase in the plasma sodium concentration could lead to a rapid decrease in brain cell volume with resultant injury and demyelination.37-39 CPM is a clinical diagnosis, although there are characteristic MRI findings.40 It may not be apparent until 2–6 days after sodium correction and is often irreversible. Most patients are left with persistent neurological dysfunction including quadriplegia pseudobulbar palsy and seizures, coma and even death may occur.38 Elderly patients taking thiazide diuretics, alcoholic or malnourished patients and those with primary polydipsia appear to be at increased risk of cerebral complications after rapid correction of hyponatraemia. Premenopausal women are at particular risk of complications from postoperative hyponatraemia.2 In one study, permanent cerebral dysfunction or death was far more common in women (9%) than men (0·03%);41 75% of the women who experienced severe complications were premenopausal. Although the mechanisms are not known, in vitro, oestradiol and progesterone decrease Na+-K+-ATPase activity,42, 43 which would impair the ability to maintain brain volume by extrusion of intracellular electrolytes. In addition, in women there may be increased AVP levels as female sex hormones enhance hypothalamo-pituitary release of AVP.44 The first-line treatment in asymptomatic patients with chronic hyponatraemia (where there is no reason to suspect hypovolaemia, for which treatment is restoration of an adequate circulating volume) is gradual correction of sodium levels by fluid restriction. The aim, determined largely empirically, should be to raise plasma sodium at a maximum rate of 10 mmol/l during the first 24 h and 18 mmol/l over the first 48 h.34, 37 Restriction of fluid intake to 1 l a day should ensure a negative fluid balance. This is generally effective (and inexpensive), but severe water restriction is difficult to enforce for a prolonged period, especially in outpatient settings, as patient compliance may be variable. If fluid restriction alone does not restore sodium levels, demeclocycline, which causes nephrogenic diabetes insipidus by inhibiting AVP action in the kidney collecting duct,45 can be used. The dose is titrated to between 600 and 1200 mg/day and typically restores sodium concentrations within 5–14 days while allowing relatively unrestricted water intake. Side effects of demeclocycline include photosensitivity and nephrotoxicity and it is usually contraindicated in patients with cirrhosis or with congestive heart failure. Lithium exerts similar renal effects but is less desirable because of inconsistent results and significant additional side effects. Loop diuretics such as frusemide in combination with high dietary salt intake or salt tablets have also been used in the chronic treatment of SIADH.9 The increased salt intake replaces the diuretic-induced natriuresis while allowing water to be lost. The patient's weight and serum sodium concentration must be followed carefully as imbalance between the diuretic action and sodium ingestion can lead to serious volume depletion or overload. An alternative option proposed for the management of chronic hyponatraemia is to increase the solute intake with urea.46, 47 In rats, treatment of chronic hyponatraemia with urea was associated with a lesser incidence and severity of brain lesions.48 In addition, in a model of renal failure, uremic rats had no neurological sequelae of rapid correction of hyponatraemia, whereas all control rats developed myelinolysis or died.49 In humans, urea doses of 30 g/day cause an increased diuresis of ‘solute-free water’ allowing more liberal water intake without worsening hyponatraemia.46, 47 The major disadvantages of urea include poor palatability, gastrointestinal symptoms and development of azotemia at higher doses and it is therefore rarely used. Because the risk of development of CPM associated with rapid elevation of plasma sodium concentration, the use of hypertonic saline to correct chronic hyponatraemia is controversial and is recommended only if neurological symptoms are present and should only be instituted in a very closely monitored or intensive care setting. Isotonic saline has been used safely and effectively in chronic symptomatic hyponatraemia.50 In the elderly or in those with cardiac failure, it is probably safer to use normal (0·9%) saline to avoid fluid overload. Frequent (4–6 hourly) measurements of plasma sodium will ensure that hyponatraemia is being corrected at an appropriate rate, with more concentrated hypertonic solutions (typically 3% saline at 0·15–0·3 ml/kg/h) reserved for those who fail to improve with ‘physiogical’ (but hypertonic to the hyponatraemic patient) saline. Central venous pressure monitoring is prudent where this can be achieved in experienced units. As with all other therapies discussed above, the dearth of prospective RCT outcome data necessitate considerable caution, especially when using the more invasive approaches. The development of antagonists to the antidiuretic action of AVP has exciting therapeutic implications in the management of hyponatraemia. The first selective nonpeptide V2 receptor antagonist, OPC-31260 was introduced in 1992. Since then, other ‘aquaretics’ including VPA-985 and SR121463 with a greater receptor affinity and V2 receptor selectivity, have been synthesized. In hydrated conscious rats, V2 receptor antagonism induces a water diuresis without affecting urine electrolyte or solute excretion.51 Clinical studies have confirmed these effects in humans. OPC-31260 has been shown to increase urine volume in a dose-dependent fashion and increase plasma sodium concentration.51, 52 Maximum doses of OPC-31260 increase plasma AVP concentrations suggesting a role of the V2 receptor in either the clearance or negative-feedback regulation of AVP. Importantly there are no associated changes in haemodynamic variables or potassium concentrations providing potential benefit in the management hyponatraemia as a result of SIADH, congestive heart failure, cirrhosis, and the nephrotic syndrome. Recent clinical trials have produced the expected effects of aquaresis and correction of hyponatraemia in cirrhosis (reviewed by Ferguson et al.53), heart failure54 and SIADH.55 Hyponatraemia that is acquired in hospital is largely preventable but several antidiuretic influences such as medications, organ failure and the postoperative state can lead to its development, particularly if hypotonic fluids are administered. Iatrogenic postoperative hyponatraemia as a result of careless use of isotonic dextrose still occurs and can result in neurological damage or death.56 Mortality from severe hyponatraemia remains high, particularly in the presence of sepsis, respiratory failure, hypoxia and the presence of neurological symptoms.57 It must be remembered that fluid restriction is not the optimal therapy in all cases of hyponatraemia. In hypovolaemic hyponatraemia where ECF is depleted, the sodium deficit must be corrected. In CSW, fluid restriction will also worsen the hyponatraemia. Hypothyroidism and adrenal insufficiency should be recognized, and the clinician should always think of hypopituitarism. It is rarely fatal to give a short course of physiological doses of hydrocortisone but this can be life-saving in the dilutional hyponatraemia of unexpected hypopituitarism. The role of specific therapies including vasopressin receptor antagonists and hypertonic saline require clear corroboration in appropriately powered RCTs, but are probably valuable in selected cases of severe symptomatic hyponatraemia, if undertaken with prudence. While mild hyponatraemia is rarely of importance, moderate-severe hyponatraemia is common and can be a life-threatening problem in clinical practice. The lack of high quality data to support ‘guidelines’ advocating the various ‘conventional therapies’ is therefore a cause for considerable concern. In the era of 21st century evidence-based medicine, the absence of any controlled trial evidence for most treatments for hyponatraemia is indeed a travesty. If this article achieves nothing else, it would be fine to hope that it encourages physicians and funders to develop an evidence base to guide treatments for the commonest of electrolyte disorders. We would like to thank Dr Roger Brown for his helpful comments on the manuscript.