• •

  Hyponatremia can be classified according to natremia, tonicity, volemia, symptoms and/or speed of onset.

• •

  It is considered important to individualize the risk threshold of [Na+]p according to the patient clinical context in order to start treatment.

• •

  It is preferable to assume as chronic any presentation of hyponatremia if we do not know its speed of onset.

Due to the complexity of the critical patient with hyponatremia, its classification should be based on a series of concepts – the most widely used being natremia,30 tonicity,13 volemia,31,32 symptoms33 and/or speed of onset 22,34(Table 2).

We must discard possible pseudohyponatremia or isotonic HN,35 which constitutes a laboratory artifact found in the presence of high blood lipid or protein concentrations, where a relative increase is detected in the solid phase of plasma that can be avoided by using direct selective ion flux techniques.35 On the other hand, when plasma contains osmotically active particles (hyperglycemia, mannitol, sorbitol or contrast media) that increase plasma tonicity, water leaves the intracellular compartment, reducing [Na+]p. These are cases of hypertonic HN known as HN.36 It is important to detect these scenarios, since specific treatment is only required in the case of hypotonic or hypoosmolar HN.

One of the most important classifications is based on the presence or absence of symptoms.

The current tendency is to consider that all HN presentations have symptoms, though these may go unnoticed because they are very subtle or are masked by the background disease process, particularly in elderly patients, where an increased incidence of falls, osteoporosis, attention deficits, fractures and gait instability have been documented.37 However, in the critical patient, it is still practical to consider HN as either symptomatic or asymptomatic according to the presence or absence of neurological symptoms, which are the factors deciding the urgency of treatment.

The risk threshold for starting the treatment of hyponatremia depends on the background disease and the clinical context – the criterion being more strict in the case of neurocritical patients.3,38,39 If the speed of onset is not known, and there are no serious neurological symptoms attributable to HN, it is preferable to assume the latter as being chronic, in order to minimize the risk of ODS.24,40

• •

  Try to obtain an approximate and precise assessment of volemia in the patient with hyponatremia in order to secure a correct etiological diagnosis.

• •

  Combine different methods for the evaluation of volemia and the obtainment of a differential diagnosis of hyponatremia.

• •

  Avoid using only clinical criteria for assessing total body water and ECV in the critical patient, particularly in distinguishing between normo- versus hypovolemic patients.

Patients with HN can present hypo-, normo- or hypervolemia.31 In the critical patient, precise assessment of volemia and body water is very complex, and analytical or clinical parameters32 alone are not enough, since several causes of HN may coexist, along with specific factors that alter the exploration. In order to obtain a global view and avoid potential errors, a comprehensive evaluation is advisable – not only parametric assessment of volemia – taking into account the clinical elements, time course and volemia estimators. Traditionally, extracellular volume has been used as a reflection of ECV, and has been the parameter evaluated first in order to obtain a physiopathological interpretation.9 However, ECV is the variable that conditions the mechanisms that favor the development of HN, and is therefore the key to correct diagnosis. In this document we use the terms ECV (effective circulating volume or volemia) versus total body water in order to lessen ambiguity. The estimation of ECV is not easy41–44 and requires both the evaluation of clinical aspects and the use of instrumental methods (Table 3). The estimation is more complex when edematous conditions coexist with low and ineffective ECV (congestive heart failure, nephrotic syndrome or cirrhosis), since these scenarios are characterized by stimulation of the non-osmotic secretion of ADH and of the renin-angiotensin-aldosterone system,45 with the consequent decrease in excretion of free water and the appearance of HN.46Table 3 details the methods available for assessing effective volemia, though we are aware of the difficulties involved. Although the clinical history is crucial, in cases of doubt we can use hemodynamic monitoring to complement the diagnosis, though caution is required when using this strategy in the context of HN.

General objectives of the treatment of HN

• •

  Adjust the treatment of HN to the severity of the symptoms, the duration of the condition, and the underlying cause and physiopathology.

• •

  Prescribe individualized treatment based on the risk of over-correction versus the risk of brain edema.

• •

  Start treatment early in the case of acute or severe HN.

• •

  Avoid inadequately rapid correction of natremia, since structural neurological damage may result.

• •

  Avoid the use of HN correction formulas, due to the high risk of over-correction.

Specific objectives of treatment. Monitoring of HN

• •

  Optimize oxygenation and correct the potassium levels as part of the hyponatremia management plan.

• •

  Avoid the use of hypotonic fluids in the event of severe or symptomatic HN.

• •

  Use 3% hypertonic saline solution (HSS) when the symptoms are severe and adjust its administration to the weight of the patient (0.5–2ml/kg) according to the desired correction rate.

• •

  Follow a treatment and monitoring protocol that combines natremia elevation with ideal correction time.

• •

  Monitor the treatment of HN with data referred to Na+ in blood and urine.

In treating HN it is essential to take a series of general objectives into account, considering each case, in order to avoid delays in management or excessively rapid correction of the condition.21,34,47–49

Individualization allows us to adopt a short- to middle-term management protocol that adequately combines natremia elevation and ideal correction time (Table 4). Likewise, monitoring of the critical patient with HN must be suited to the established management plans.

We consider that hypoxemia and hypopotassemia must be taken into account in the management plan, as patients with hyponatremia and hypoxemia have a poorer prognosis,24 since hypoxemia can alter solute extrusion by blocking the Na-K-ATPase pump and thus delay the resolution of brain edema.50 Likewise, there have been reports of ODS with slow natremia correction in patients with hypopotassemia. In this regard, it has been speculated that the reduced Na-K-ATPase pump concentration in the endothelial membrane in situations of hypopotassemia may predispose to neuron damage due to the osmotic stress associated to the correction of natremia.51,52

With regard to specific treatment, we can use an infusion of 3% HSS in boluses or in perfusion.6,45,53

While a common practice, the use of formulas for calculating the correction of natremia may prove hazardous due to the high risk of over-correction or the provision of large volumes that would be prohibitive in patients with heart failure.54 These formulas regard the patient as a closed system and ignore the renal response of the subject to such infusion – thereby possibly offering inexact information.55

• •

  Use 3% HSS in hyponatremic encephalopathy, independently of the cause.

• •

  Administer 0.9% saline solution (SS) in hypovolemic HN, with close monitoring of aquaresis (water excretion without electrolyte loss) in order to avoid over-correction.

• •

  Treat the triggering cause of hypervolemic HN.

• •

  Vaptans can be used in hypervolemic HN refractory to first line treatment.

• •

  Do not use vaptans in severe or hypovolemic HN.

• •

  Diuretics can be used as adjuvant treatment in hypervolemic and normovolemic HN.

For the correction of HN we can use water restriction (WR), NaCl capsules, saline solution (normal or hypertonic),21 diuretics (furosemide), urea, vaptans and fludrocortisone.1,2,9,56 The choice of one treatment or other should be based on the underlying cause and physiopathology, the desired correction rate, and the associated comorbidities (Table 5). Loop diuretics may be useful as coadjuvants to the treatments started in euvolemic or hypervolemic HN.56

The vaptans, as V2 receptor antagonists, increase free water excretion, reducing Osmu and incrementing natremia.57 In 2006, two randomized clinical trials known as the Study of Ascending Levels of Tolvaptan in hyponatremia (SALT-1 and SALT-2) respectively compared the efficacy of tolvaptan versus placebo in 225 and 223 patients with euvolemic and hypervolemic HN – the latter being severe in at least 50% of the cases in both cohorts. These studies reported an increase in serum sodium concentration from the start until day 4 of treatment, and from the start until day 30 in all the patients treated with an initial daily dose of 15mg, which could be incremented conditioned to the observed increase in serum sodium.58 In Spain, tolvaptan has only been approved for the management of syndrome of inappropriate antidiuretic hormone secretion (SIADH)59 refractory to first line therapeutic measures, despite the scant supporting evidence, or when such measures cannot be implemented.60 It is advisable to start the treatment in the hospital setting and not to simultaneously apply WR or administer 3% HSS, due to the risk of over-correction. For this same reason, adequate fluid supply must be ensured in patients with alterations of the thirst mechanism (intubated or sedated individuals).

We consider that it might be of benefit to reduce the starting dose to 7.5mg in critical patients. In some cases the administration of a single dose has been evaluated, followed by the decision to either repeat administration or introduce continuous therapy (off-label use not contemplated in the Summary of Product Characteristics).61 If correction is too fast, the drug will have to be suspended, or the dose will have to be lowered. Reported side effects have been thirst, pollakiuria, dehydration or orthostatic hypotension.58

The hypervolemic hyponatremia usually seen in patients with heart failure, liver cirrhosis and nephrotic syndrome requires specific treatment of the background disease, which among other aspects will help to increase free water clearance and thus improve HN. However, some patients are refractory to such treatment, and although vaptans are not indicated in Spain for hyponatremia of this kind, in some cases they may be used on an off-label basis. In this regard, in patients with heart failure, the joint administration of tolvaptan and standard treatment for heart failure – including loop diuretics – was seen to result in short term improvement of the global situation and of HN, though without benefits in terms of mortality.62,63 Likewise, patients with decompensated liver cirrhosis and refractory ascites showed a good response to tolvaptan, with an increase in urine volume and natremia, and improvement of ascites.64

Hypovolemic hyponatremia is characterized by the depletion of extracellular volume, and the administration of 0.9% saline solution suffices to correct this situation.65 Vaptans would not be indicated in this type of HN or in acute symptomatic HN. The latter requires urgent management to increase natremia, and the indication in this context is 3% HSS, for although there are no data in the literature supporting the use of vaptans in this type of HN, the onset of tolvaptan action occurs after 2h, and we therefore would not obtain the immediate effect we seek.

Tolvaptan likewise has no indication in patients with hypothyroidism or adrenal gland insufficiency.66

• •

  Study the causes that may trigger secondary SIADH, and consider that primary SIADH is an exclusion based diagnosis.

• •

  In order to diagnose SIADH, the following criteria must be met: [Na+]p<135mEq/l, Osmp<275mOsm/kg, Osmu>100mOsm/kg, [Na+]u>30mmol/l with adequate Na+ supply, glomerular filtration rate (GFR)>60ml/min, normal thyroid and adrenal gland function, euvolemia, absence of diuretics and absence of physiological ADH stimulation (surgery, pain, thoracic, lung or brain involvement).

• •

  A diagnosis of SIADH without correct assessment of secondary causes may result in an incorrect diagnosis and inadequate treatment.

Syndrome of inappropriate antidiuretic hormone secretion occurs due to non-physiological ADH release (in the pituitary gland or on an ectopic basis) or as a result of increased ADH activity secondary to genetic alterations of its receptors. Antidiuretic hormone reduces the renal excretion of free water with normal excretion of Na+, giving rise to euvolemic hypoosmolar HN. The causes of SIADH include neoplasms, central nervous system (CNS) disorders, lung disease, drugs, and transient and genetic factors (mutation of the V2 receptor gene).

Although the diagnostic criteria of SIADH have been clearly defined, it is important to remember that the diagnosis is established on an exclusion basis, and that the first step is to confirm the existence of normovolemia – something that may prove very difficult in the critical patient. The second step is to check that all the validated biochemical criteria are met, and we know that this is not done in routine practice. A recent Italian study has reported that less than half of the surveyed physicians used such parameters to establish the diagnosis.67 Furthermore, in patients with subarachnoid hemorrhage, it has been seen that 70% of all situations of normovolemic HN are attributable to SIADH and 10% to cortisol defects68 – hence the importance of remembering that we must have all the criteria in order to establish a correct diagnosis, since the approach to therapy will differ accordingly.

• •

  Avoid using of WR, urea, lithium or demeclocycline for the treatment of SIADH.

• •

  Vaptans can be used for the treatment of SIADH when water restriction is not feasible and there are no serious neurological symptoms.

• •

  Natremia should be checked 6–8h after the administration of vaptans, in order to adequately adjust the next doses.

The treatment of SIADH should start by controlling the physiological stimuli that release ADH. Water restriction and the supply of solutes (NaCl capsules, proteins) are to be considered in patients with mild symptoms or a chronic syndrome onset,56 while the administration of 3% HSS can be decided in cases of severe symptoms and an acute syndrome onset .69

Water restriction remains the first line of treatment in the recently published guides on the management of HN due to SIADH, despite the recognized lack of randomized controlled trials demonstrating its efficacy or safety. The results of a hyponatremia registry showed fluid restriction to be no better than no treatment in patients with SIADH.70 Furthermore, in critical patients, WR is difficult to apply, since fluids, intravenous antibiotics or nutritional support are essential in such cases. Likewise, several days are usually needed in order for the measure to prove effective, and WR is poorly tolerated and not effective in all patients. The American guides1 have documented a series of parameters that can predict a poor response to WR: high Osmu (>500mOsm/kg), diuresis<1500ml/day [Na++K+]u>[Na+]p and a slow natremia correction rate (<2mEq/l in 24–48h).13

Although urea has repeatedly been proposed as a treatment for HN due to SIADH, the supporting evidence is far from convincing, since the existing studies are few and heterogeneous, nonrandomized, with variable doses and administration intervals, and treatment has been studied in chronic HN.71 Likewise, the correction afforded by urea is unpredictable and can be associated with dehydration or over-correction, with increased plasma urea levels. Adequate experience with the use of urea is not available, and its administration therefore cannot be recommended. The same applies to lithium or demeclocycline, since the response obtained is variable, unpredictable, and the risk of renal toxicity is high. A recent systematic review found no evidence on their safety and efficacy,72 and only 3% of the physician used them in SIADH.70 The use of these drugs therefore cannot be recommended.73

Loop diuretics in SIADH may be useful over the short term provided Osmu is high (preferably>400mOsm/kg), by increasing free water clearance through the kidneys. However, we lack randomized studies supporting their use. Such drugs could be administered in patients with transient SIADH (i.e., secondary to pneumonia or drugs that can be suspended).60

The vaptans, as V2 receptor antagonists, appear to be a logical treatment option in SIADH, since on binding to these receptors AQ2 is not inserted in the collecting tubule, thereby increasing free water clearance or aquaresis. The SALT studies58 have demonstrated the effectiveness of tolvaptan in increasing natremia in a cohort of mixed patients (SIADH, hypervolemic HN) versus placebo even one month after treatment. The vaptans usually increase natremia by 5–7mEq/l at 24h post-administration, though the effect is variable. In this regard, the European guides do not indicate vaptan use in any type of HN – one of the stated reasons being the fact that the randomized clinical trials made have been sponsored by the drug industry. Although this is a serious consideration in medicine based on evidence, in our opinion it is better to rely on well-designed studies than on case series. It would be useful to have studies comparing vaptans with the measures considered to constitute first-line therapy. According to our criterion, vaptans would not be indicated in HN with serious neurological symptoms, due to their unpredictable response and insufficiently rapid effect.

• •

  It is important to establish a differential diagnosis between SIADH and salt-wasting syndrome (SWS), since opposite treatment strategies apply to these two conditions (free water restriction versus fluid therapy).

• •

  Evaluate volemia and diuresis rate in order to distinguish between SIADH and SWS. However, both syndromes may form part of a mixed disorder, and their presentation depends on the intensity of each mechanism.

• •

  Avoid fluid loading and water restriction as a method for distinguishing between SIADH and SWS, since it may be counterproductive for the clinical course of the patient.

• •

  Determine basal cortisol for the diagnosis of adrenal insufficiency (AI). In the presence of inappropriately low values, the ACTH stimulation test is useful for distinguishing between primary and secondary presentations.

• •

  Administer 0.9% SS and intravenous glucose in the presence of hypoglycemia in patients with HN secondary to AI.

• •

  Administer replacement therapy with hydrocortisone (stress or maintenance dose) and fludrocortisone (following diagnostic confirmation), in addition to ensuring measures against hyperpotassemia in patients with HN secondary to AI.

• •

  It is important to monitor sodium in blood and urine, Osmu and the diuresis rate after starting treatment with glucocorticoids, since they can cause important aquaresis with the risk of over-correction.

• •

  The presence of HN secondary to hypothyroidism is very infrequent and can only be regarded as a cause of HN if the condition is clearly serious.

In SWS of cerebral origin, HN is of a hypovolemic hypoosmolar nature resulting from neurological dysfunction secondary to brain damage. Its definition is currently not clear,60 its diagnosis is exceptional,68 and there are doubts about the underlying physiopathogenic mechanism involved.74 Natriuresis gives rise to a decrease in ECV that stimulates ADH.75 Proximal tubule alterations favor the excretion of uric acid, Na+ and phosphorus.76 The condition is usually associated with hypouricemia, but this would not be a good marker for distinguishing between SIADH and SWS. Nevertheless, after correcting HN, the fractional excretion of uric acid may help to differentiate between the two disorders, since its value would remain elevated in the case of SWS (>12%). The treatment is based on fluid therapy to normalize ECV.76

Adrenal gland insufficiency occurs due to a deficit in adrenal hormone synthesis. In severe cases, the production of cortisol and aldosterone may be unable to meet the demands (stress), giving rise to HN. In some cases, neurological damage (traumatic brain injury or neurosurgery) gives rise to an alteration in ACTH release and secondarily to an alteration in cortisol output (secondary AI).68

• •

  We do not recommend extrarenal filtration techniques (EFTs) for the correction of HN.

• •

  Such techniques are a risk factor for the rapid correction of hyponatremia.

• •

  We suggest avoiding citrate as anticoagulant if the patient presents severe HN.

• •

  In order to avoid the rapid correction of natremia in patients with severe HN requiring EFT for any other reason, we consider the following to be useful:

• ∘

  Apply continuous extrarenal filtration techniques (CEFTs) instead of intermittent hemodialysis.

• ∘

  Add water to the commercial solutions used in CEFT to adjust to patient natremia. Use the lowest clearance dose.

• ∘

  Monitor natremia closely during CEFT.

Kidney disease is responsible for between 2 and 12% of all cases of HN. In patients requiring EFT and who suffer HN, although high uremia attenuates the effects of rapid [Na+]p elevation, over-correction caused by the technique may occur (depending on the dose used and the sodium of the fluids). An alternative for avoiding this is to add sterile water in the dialysis bags in order to keep the sodium in the solutions between 6 and 8mEq/l above the desired [Na+]p77–79 (Table 6) and apply a low and sustained dose over time.80

The generalization of the use of citrate as anticoagulant in CEFT could represent a further source of problems in the management of HN, since hypernatremia is a complication that has been associated with its use. Furthermore, although they allow easy and safe citrate use, the automated systems now employed require a specific concentration of ions in the solutions, and these must not be manipulated. Therefore, although published evidence is lacking, the physiological bases and the mode of application of citrate make it impossible to guarantee a slow or controlled increase in natremia. We therefore recommend avoiding citrate as anticoagulant in the presence of severe HN, at least until further evidence becomes available.

• •

  Reduce [Na+]p in the event of over-correction in order to avoid cerebral ODS.

• •

  Use 5% glucose solution to reduce natremia in the presence of over-correction.

• •

  Use desmopressin in cases of excessive Na+p elevation.

• •

  The rate of correction must be controlled particularly in the presence of factors favoring over-correction: hypovolemia, hypoxemia, heavy beer intake, nausea, vomiting, pain, thiazides or serotonin reuptake inhibitors, adrenal insufficiency or CEFT, among others.

The monitoring of Osmu and of urine volume may help predict the risk of over-correction.81,82 If the intended limits are exceeded, and despite the scant available evidence, the guides recommend reducing [Na+]p again using water via the enteral route, 5% glucose solution (3ml/kg/h)47 and/or desmopressin (2–4μg i.v.)83 in order to avoid ODS. Desmopressin induces the reabsorption of water by the collecting tubules, reducing natremia, and has been shown to be effective – though in the context of retrospective studies and case series.84,85