A step-by-step guide for the diagnosis and management of hyponatraemia in patients with stroke

Abstract

Hyponatraemia is common in patients with stroke and associated with adverse outcomes and increased mortality risk. The present review presents the underlying causes and provides a thorough algorithm for the diagnosis and management of hyponatraemia in stroke patients. Concomitant diseases and therapies, such as diabetes, chronic kidney disease and heart failure, along with diuretics, antidepressants and proton pump inhibitors are the most common causes of hyponatraemia in community. In the setting of acute stroke, the emergence of hyponatraemia might be attributed to the administration of hypotonic solutions and drugs (ie. mannitol and antiepileptics), poor solute intake, infections, as well as stroke-related conditions or complications, such as the syndrome of inappropriate secretion of antidiuretic hormone, cerebral salt wasting syndrome and secondary adrenal insufficiency. Diagnostically, the initial step is to differentiate hypotonic from non-hypotonic hyponatraemia, usually caused by hyperglycaemia or recent mannitol administration in patients with stroke. Determining urine osmolality, urine sodium level and volume status are the following steps in the differentiation of hypotonic hyponatraemia. Of note, specific parameters, such as fractional uric acid and urea excretion, along with plasma copeptin concentration, may further improve the diagnostic yield. Therapeutic options are based on the duration and symptoms of hyponatremia. In the case of acute or symptomatic hyponatraemia, hypertonic saline administration is recommended. Hypovolaemic chronic hyponatremia is treated with isotonic solution administration. Although fluid restriction remains the first-line treatment for the rest forms of chronic hyponatraemia, therapies increasing renal free water excretion may be necessary. Loop diuretics and urea serve this purpose in patients with stroke, whereas sodium-glucose transport protein-2 inhibitors appear to be a promising therapy. Nevertheless, it is yet unclear whether the appropriate restoration of sodium level improves outcomes in such patients. Randomized trials designed to compare therapeutic strategies in managing hyponatraemia in patients with stroke are required.

Introduction

Hyponatraemia is a frequently encountered electrolyte disorder both in hospitalized and community patients with a reported incidence up to 30% and 8%, respectively.^1–4 Low sodium (Na⁺) levels are commonly noticed in neurologic diseases, including stroke, and are present in 38–54% of such patients.^5–9 In this setting, hyponatraemia and water balance exhibit detrimental effects on the injured brain and might increase the corresponding mortality by 60%.^6,8,9

Clinical symptoms owing to hyponatraemia are related with the severity, the onset and rate of change of serum Na⁺ levels. The presence of a serum Na⁺ concentration lower than 135 mEq/l is defined as hyponatraemia. In case it develops over a period of < 48 h, hyponatraemia is considered acute, whereas chronic hyponatraemia may be present for > 48 h or over an unclear duration. Its severity is classified according to the serum Na⁺ concentration: (1) severe hyponatraemia: Na⁺ < 120 mEq/l, (2) moderate hyponatraemia: Na⁺ 120–129 mEq/l and (3) mild hyponatraemia: Na⁺ 130–134 mEq/l.^10,11 Clinical symptoms of acute hyponatraemia range from mild headache, confusion, nausea and vomiting to seizures, respiratory arrest, coma or even death. ¹² On the contrary, a patient with chronic hyponatraemia might present with nausea and vomiting, fatigue, gait instability, falls and attention deficits. ¹² Overall, the management of hyponatremia remains problematic in everyday clinical practice due to its prevalence under widely different conditions and prompts towards the endorsement of an institution-based approach with regard to diagnosis and treatment algorithms. ¹¹

As hyponatraemia might play a significant role in the clinical course of patients with stroke, early recognition and appropriate management are critical to preventing from potential complications.

Incidence of hyponatraemia in patients with stroke

Hyponatraemia incidence ranges between 4% and 60% in patients with stroke.^6,8,9 The rate of hyponatraemia was as high as 40% in the setting of acute stroke according to a small study, including patients with ischaemic (n = 55) and hemorrhagic (n = 55) stroke. ¹³ Likewise, the incidence of hyponatraemia was 43% in a series of 100 patients with ischaemic stroke (n = 47) or intracerebral haemorrhage (n = 53) during their hospitalization. Of note, hyponatraemia was more frequent in patients with intracerebral haemorrhage (51.9% versus 36.4%). ¹⁴

A meta-analysis of 12 cohorts with 21,973 stroke patients evaluating the effect of hyponatraemia on their mortality risk demonstrated that the prevalence rate of hyponatraemia was 12.2% upon their admission (11.9% for ischaemic and 13.3% for haemorrhagic stroke). ⁸

Pathophysiology of hyponatraemia and its effect on the brain

The balance of Na⁺ levels is based on kidneys’ capability of excreting free water.^15,16 Specific osmoreceptors in the hypothalamus expressing transient receptor potential cation channels regulate Na⁺ levels and are responsible for the link between brain volume and Na⁺ concentration. Normal homeostatic response to low serum Na⁺ levels is mediated by the subfornical organ in the brain and results in decreased thirst and secretion of antidiuretic hormone (ADH), also known as arginine vasopressin. ADH binds to V2 receptors in the principal cells of the renal collecting duct resulting in water insertion through aquaporin into the highly concentrated medullary interstitium and finally in reduced water excretion. ¹⁵

In most patients, hyponatraemia develops because ADH is secreted non-osmotically leading to increased re-absorption of renal water. Non-osmotic ADH release by the posterior pituitary induced by specific stimuli from the paraventricular or supraoptic nuclei is the most common cause of hyponatraemia in hospitalized patients, including those with stroke. Causes of non-osmotic ADH release include a low effective circulating volume; several concomitant diseases and drugs; and nonspecific stimuli such as anxiety, stress, pain and nausea. Other less frequent hyponatraemia-inducing mechanisms include the ectopic production of ADH (i.e. lung cancer, pneumonia, subarachnoid haemorrhage), drugs that may enhance the renal effects of ADH (i.e. cyclophosphamide) and rarely a vasopressin-like effect caused by an activating mutation of the vasopressin-2 receptor gene. ¹⁵

The pathophysiology of hyponatraemia’s effect on the brain is complex due to both acute and chronic means of cerebral adaptation. Hyponatraemic hypotonicity generates an osmotic gradient resulting in the movement of water into glial and neuronal cells. In the setting of acute hyponatraemia, homeostatic mechanisms against hypotonicity prevent from substantial cellular swelling. Specifically, osmotically active molecules, such as glutamate, and ions, including sodium, potassium and chloride, excreted by the neurons decrease the osmotic gradient and result in their water loss. On the contrary, surrounding astrocytes protect neurons from active swelling by transferring osmotically active amino acids allowing neurons to maintain their normal volume, while the former subsequently swell. This dynamic process initiates within minutes and can last for hours. Astrocyte volume is restored over a more extended time as astrocytes extrude additional osmotically active osmolytes, but this makes them vulnerable to injury from rapid normalization of the serum Na⁺ concentration. The entire process can last for up to 48 h, while concurrent downregulation of aquaporin channels may take up to a week or longer before reaching homeostasis.^7,17 Considering these pathophysiological changes related to hyponatraemia, the already injured brain cells in a patient with stroke would be more susceptible to further damage.

Clinical significance of hyponatraemia in patients with stroke

Physicians should be vigilant in stroke patients with low serum Na⁺ levels, because rapid correction of chronic hyponatraemia can lead to cerebral dehydration and add to the neurologic injury which manifests as a biphasic illness called ‘osmotic demyelination syndrome’ (ODS).^18,19 Serum Na⁺ concentrations lower than 106 mEq/l, hypokalaemia, alcoholism, malnutrition and advanced liver disease are its well-established predisposing factors. An initial improvement in symptoms is followed by a gradual onset of new neurologic findings that might mimic a stroke. ODS usually appears 2–6 days after rapid serum Na⁺ correction. Symptoms vary from mild to striking psychomotor changes, such as psychiatric changes, catatonia, limb tremor, myoclonus, parkinsonism and paresis/plegia of any or all limbs, including bulbar musculature. The most severely affected patients become ‘locked in’, unable to move, speak or swallow due to central pons demyelination.^7,17 Therefore, physicians should be alert for such symptoms in order to exclude ODS apart from other stroke-related complications. Although ODS may result in permanent disability or death, many patients, even those who have previously required ventilator support, can fully recover.^7,17 Despite these early neurologic symptoms, brain imaging may remain normal for as long as 4 weeks after the onset of ODS. Thus, a normal brain scan does not exclude ODS diagnosis. The finding of classic magnetic resonance imaging is diffusion restriction within the central pons with characteristic trident pattern that predates T2 signal changes. ²⁰

The association of hyponatraemia with increased mortality risk has been well-established in patients with common clinical conditions, such as acute myocardial infarction, heart failure, cirrhosis and chronic kidney disease, while its treatment seems to improve their survival.^21–26 Similar results have been found in the setting of acute stroke.^6,8,9 According to a systematic-review and meta-analysis including 21,973 patients with stroke, hyponatraemia was associated with a higher short-term [hazard ratio (HR): 1.78; 95% confidence interval (CI): 1.19–2.75] and long-term mortality risk (HR: 2.23, 95% CI: 1.30–3.82). ⁸ Likewise, another meta-analysis investigated the effect of hyponatraemia on mortality risk and hospitalization length in 10,745 stroke patients. Patients with hyponatraemia exhibited a higher 90-day mortality risk [odds ratio (OR): 1.73; 95% CI: 1.24–2.42] and were hospitalized longer (mean difference, 10.68 days; 95% CI: 7.14–14.22) than those with normal Na⁺ levels. A higher tendency of in-hospital mortality was noticed in patients with hyponatraemia compared with those with normal serum Na⁺ levels (OR: 1.61; 95% CI: 0.97–2.69). ⁹

Hyponatraemia might also be related with other adverse outcomes in stroke patients. A retrospective study (n = 2474) demonstrated that hyponatraemia in the setting of acute stroke doubled the risk of early post-stroke seizure. ²⁷ Another retrospective cohort involving a total of 4900 hyponatraemic patients and 19,545 matched comparisons showed that hyponatraemia increased dementia risk (adjusted HR: 4.29, 95% CI: 3.47–5.31). Noticeably, patients with coexistent hyponatraemia and stroke exhibited significantly higher rates of dementia as compared with those with stroke and normal Na⁺ levels. ²⁸ In another study involving 3585 patients with acute ischaemic stroke, hyponatraemia upon admission was associated with stroke severity and worse disposition at hospital discharge (i.e. requirement for new extended placement in health care facilities or hospice). ²⁹ Finally, considering the association between chronic hyponatraemia and increased incidence of falls, ³⁰ the former could adversely affect the rehabilitation of a patient with stroke.

Despite the evidence above, it has not been elucidated whether causality between hyponatraemia and these complications really exists, or low Na⁺ levels are just an indicator of concomitant disease burden leading to adverse outcomes. In this context, it will be of paramount importance to know whether the appropriate restoration of Na⁺ level improves the outcomes in patients with acute stroke. To the best of our knowledge, only one observational study including 464 consecutive patients with spontaneous intracerebral haemorrhage has shown that restoration of serum Na⁺ levels did not improve mortality rates. ³¹

Causes and diagnostic algorithm for hyponatraemia in stroke

Non-hypotonic hyponatraemia

As shown in Figure 1, the initial step in the diagnostic algorithm for hyponatraemia is to measure serum osmolality to determine whether hyponatraemia represents a true hypo-osmolar state. Although high urea concentrations could be present in stroke patients with chronic kidney disease and might also increase measured osmolality, it is an ineffective osmole and does not actually contribute to effective serum osmolality (tonicity). Hence, urea does not ‘attract’ water to the extracellular fluid compartment and does not result in hyponatraemia. Thus, in a patient with hyponatraemia, normal or elevated effective serum osmolality indicates the presence of either additional active osmoles or pseudohyponatraemia.^10,11,32

Figure 1.

Diagnostic algorithm for hyponatraemia in patients with stroke.

ECF, extracellular fluid; SIADH, syndrome of inappropriate antidiuretic hormone secretion.

Non-hypotonic hyponatraemia is usually caused by hyperglycaemia,^33,34 but might also be triggered by the administration of mannitol or a hypertonic radiocontrast.^10,11,32 Indeed, type 2 diabetes is a well-established risk factor for stroke, and hyperglycaemia is frequently observed in patients with ischaemic stroke upon their admission (8–83%). ³⁵ Estimates of serum Na⁺ concentration corrected for the presence of hyperglycaemia can be obtained from the following equations: corrected Na⁺ levels (Na⁺_c) = measured Na⁺ + 2.4 × [(glucose, mg/dl – 100)/100] or measured Na⁺ + 2.4 × [(glucose, mmol/l – 5.5)/5.5]. This means that 2.4 mmol/l should be added to the measured serum Na⁺ concentration for every 5.5 mmol/l (or 100 mg/dl) incremental rise in serum glucose concentration above a standard serum glucose concentration of 5.5 mmol/l (or 100 mg/dl). ¹¹ Furthermore, patients with severe stroke and increased intracranial pressure might be treated with mannitol. ³⁶ In this setting, mannitol could also account for hyponatraemia during its administration as it creates a transcellular osmotic gradient by increasing plasma osmolality, leading to water movement out of the cells and serum Na⁺ concentration reduction by means of dilution.^10,11,32 Finally, computed tomographic (CT) angiography with CT perfusion is recommended by current guidelines for selecting acute stroke candidates for mechanical thrombectomy between 6 and 24 h after last known well. ³⁷ Considering the fact that the ionic contrast media used in angiography is hypertonic, ¹⁰ patients recently having underwent a CT angiography might present with hypertonic hyponatraemia.

Non-hypotonic hyponatraemia can also be caused by pseudohyponatraemia, a laboratory artefact that may occur with high concentrations of triglycerides, cholesterol and proteins in hyperproteinaemic diseases, such as plasma cell myeloma.^10,11,32,34 Considering their association with increased atherothrombotic risk,^38–40 factors resulting in pseudohyponatraemia might not be rare in patients with stroke. Pseudohyponatraemia was seen more frequently with flame photometric measurement of serum Na⁺ concentration than with the currently used ion-selective electrodes. Nonetheless, pseudohyponatraemia might still occur, due to the dilution of venous blood samples and the assumption of a constant distribution between water and the solid Na⁺ phase when its concentration is calculated.^10,11,32 In case of pseudohyponatraemia, the result will be within the normal range when serum osmolality is measured in an undiluted sample. If serum osmolality cannot be measured, direct potentiometry using a blood gas analyser will yield the true Na⁺ levels, as this measures Na⁺ concentration in an undiluted sample too.^10,11

Hypotonic hyponatraemia

Before proceeding to the identification of urine osmolality (UOsm) and urine Na⁺ concentration (UNa⁺), early identification of acute or symptomatic hyponatraemia is recommended to identify patients who must be promptly treated (Figure 1).^10,11

UOsm

UOsm ⩽ 100 mOsm/kg

The first recommended step in differentiating causes of hypotonic hyponatraemia is the interpretation of a spot urine UOsm (Figure 1). In case of UOsm ⩽ 100 mOsm/kg (or specific gravity ⩽ 1.003), relative excess water intake or administration by the caregiver along with limited intake of solid food would be acceptable causes of hypotonic hyponatraemia in a patient with stroke. This is attributed to the fact that the daily water removal by the kidneys depends on solute excretion and thus solute intake. Depending on the kidney’s urine diluting ability, 50–100 mmol of solutes, such as urea and salts, are required to remove ~1 litre of fluids. In case of low solute intake, the number of available osmoles can be insufficient to remove the amount of the ingested water.^10,11,32 Hyponatraemia might also occur if a patient receives large amounts of water (in isolated instances more than 10–15 l/d) or in case of a concurrent impairment in water excretion as this happens in the setting of central nervous system dysfunction, chronic kidney disease, treatment with antipsychotic agents, and in nausea or stress-induced ADH secretion. ¹⁵ Other causes, such as primary polydipsia or beer potomania syndrome, might also account for hypotonic hyponatraemia with low UOsm, but are less frequently noticed in patients with stroke.^10,11,32

Decreased UOsm is also observed in some patients with reset osmostat syndrome when water intake reduces serum osmolality below the new threshold for ADH release. In reset osmostat syndrome, there is a change in the set point as well as in the slope of the osmoregulation curve, but the response to changes in osmolality remains intact. Of note, reset osmostat syndrome is a variant of the syndrome of inappropriate ADH secretion (SIADH) and is present in about ~30% of patients with SIADH.^10,11

UOsm > 100 mOsm/kg

If UOsm > 100 mOsm/kg (or specific gravity > 1.003), current guidelines recommend interpreting UNa⁺ on a spot urine sample taken simultaneously with a blood sample to assess the volume status.^10,11

Urine sodium concentration

UNa⁺ ⩽ 30 mmol/l

If UNa⁺ points out to be ⩽ 30 mmol/l, low effective arterial volume is considered as the cause of hypotonic hyponatraemia (Figure 1). Diuretics, the most prescribed antihypertensive drugs, are a frequent cause of hypotonic hypovolemic hyponatraemia in the community, but also in patients with stroke. Diarrhoea and vomiting might also contract extravascular volume leading to hyponatraemia.^10,11 Patients with stroke might present with such symptoms due to complications, such as increased intracranial pressure or infections during their hospitalization, such as clostridium difficile infection, antibiotic-associated diarrhoea or sepsis.^41–43 Third spacing, such as bowel obstruction, pancreatitis, sepsis or muscle trauma may markedly reduce effective circulating blood volume through fluid leakage,^10,11 but these are rarely noticed in patients with stroke.

UNa⁺ can also be low in hypervolaemic patients with heart failure, liver cirrhosis or nephrotic syndrome, due to the reduced effective circulating arterial volume.^10,11 Elderly patients with heart failure might be frequently diagnosed with stroke, ¹⁸ whereas liver cirrhosis or nephrotic syndrome might be also associated with stroke due to their increased thrombotic risk.^44–46

UNa⁺ > 30 mmol/l

If UNa⁺ is > 30 mmol/l, occult diuretics and extracellular fluid status should be checked to proceed with the differentiation of likely causes of hyponatraemia (Figure 1). As diuretic increase renal Na⁺ excretion, UNa⁺ might be increased when it is measured within the time range that it remains active. Diuretics and mainly thiazides are a common cause of hyponatraemia in clinical practice and in patients with stroke. Thiazides were initially believed to cause hyponatraemia by inducing renal Na⁺ loss leading to volume depletion, but they might directly induce ADH release or increase the response of the collecting renal duct. Potassium-sparing diuretics such as mineralocorticoid receptor blockers (spironolactone and eplerenone) and amiloride are also associated with hyponatraemia. Despite the potential for causing more UNa⁺ loss, loop diuretics rarely result in hyponatraemia as they reduce osmolality in the renal medulla limiting thus kidney’s urine concentration ability. To conclude, clinicians must interpret UNa⁺ concentrations ⩾ 30 mmol/l with caution in case of treatment with diuretics and keep in mind that patients may not be aware of being treated with diuretics or that their use may not have been recorded. Of note, a fractional urine excretion of uric acid (FE_UA) ⩾ 12% may be superior to UNa⁺ concentration to differentiate reduced effective circulating volume from SIADH as the underlying cause of hyponatraemia in case of diuretic therapy.^10,11 Likewise, copeptin, which is coproduced by the enzymatic cleavage of the vasopressin prohormone, can be used as a surrogate marker for vasopressin. In that case, plasma copeptin levels have been found higher in patients with hypo- or hypervolemic hyponatremia than in patients with SIADH. Considering the fact that hypovolemia is characterized by high plasma copeptin and low UNa⁺, the plasma copeptin to UNa⁺ ratio might be useful in differentiating hypovolemic hyponatraemia from SIADH. Nevertheless, its specificity has not been proved high yet. On the contrary, low plasma copeptin levels are diagnostic for hyponatremia due to polydipsia. ¹⁰

In the absence of diuretics, a clinical assessment of the volume status may aid further the differential diagnosis. Symptoms such as tachycardia, postural hypotension, dry skin mucosa and a low central venous pressure indicate depletion of circulating volume. In that case, apart from occult diuretics as previously mentioned, vomiting, primary hypoaldosteronism and renal or cerebral salt wasting syndrome (CSW) would be the most usual causes of hyponatraemia (Figure 1).^10,11 Severe vomiting could be a sign of increased endocranial pressure, a complication of stroke. ⁴¹ Interestingly, metabolic alkalosis associated with vomiting represents one of the conditions in which volume depletion may not be associated with decreased UNa⁺, despite the activation of the renin–angiotensin system. In this clinical setting, urinary chloride excretion is low (<10–20 mmol/l) due to increased renal re-absorption of chloride. ³² Second, patient previously treated with corticosteroids can be complicated with primary hypoaldosteronism in the setting of acute stroke if corticosteroid therapy is interrupted abruptly. Primary hypoaldosteronism causes renal Na⁺ loss, contracted extracellular fluid volume and hyponatraemia. Although primary adrenal insufficiency usually presents with other clinical symptoms and biochemical abnormalities, physicians should keep in mind that hyponatraemia can be its first and only sign. Of note, only one study has investigated its prevalence in the setting of acute ischemic stroke and shown that 18 of 58 patients (31%) had relative adrenal insufficiency. ⁴⁷ Third, renal salt wasting can also occur in patients with salt-losing nephropathies, such as tubulopathy after chemotherapy or in analgesic nephropathy, medullary cystic kidney disease and certain pharmacological compounds inhibiting the kidney’s ability to re-absorb appropriate Na⁺ amounts.^10,11 Finally, renal Na⁺ loss has been documented in patients with intracranial disorders and mostly in those with subarachnoid bleeding. ⁴⁸ This renal salt wasting syndrome has been rather confusingly named ‘cerebral’ salt wasting (CSW), and brain natriuretic peptide has been implicated in its pathogenesis. Because diagnosis may be difficult, and both SIADH and secondary adrenal insufficiency are more common in this clinical setting, CSW might be overdiagnosed. ⁴⁸ In clinical practice, there are cases of hyponatremia potentially attributed to SIADH or CSW that cannot be strictly separated or both can be present. Nevertheless, CSW recognition is of major importance because its treatment requires volume resuscitation rather than water restriction, as SIADH.^10,11,48

SIADH is a diagnosis of exclusion and should be considered as a cause of hyponatraemia in patients with stroke having UOsm > 100 mOsm/kg, UNa⁺ > 30 mmol/l and normal extracellular fluid volume. However, its formal diagnosis requires the exclusion of other possible causes of low Na⁺ levels (Figure 1). One such possible cause is adrenal insufficiency.^10,11 Patients with stroke could be complicated with secondary adrenal insufficiency due to pituitary ischaemia or haemorrhage. ⁴⁹ As in SIADH, hypocortisolism stimulates ADH, and hyponatraemia develops through non-suppressed vasopressin activity. Hyponatraemia owing to hypothyroidism is very rare other than in myxoedema coma, which is also associated with a decrease in cardiac output and glomerular filtration rate.^10,11

In SIADH, ADH release occurs independently from effective serum osmolality or circulating volume and might be caused by increased release by the pituitary gland or from ectopic production. Nausea, pain, stress, general anaesthesia and a variety of drugs are non-specific, but remain a potent stimuli for ADH secretion and a frequent cause of SIADH in hospitalized patients with stroke.^10,11 Commonly used drugs in the community, such as diuretics, proton pump inhibitors, tricyclic antidepressants, selective serotonin reuptake inhibitors or other drugs potentially used in the setting of acute stroke, such as antiepileptics (carbamazepine, oxcarbazepine, sodium valproate) or antipsychotics (i.e. aloperidol) might result in SIADH in patients with stroke. ⁵⁰ These drugs may result in either increased ADH release or increased susceptibility of the collecting renal duct to the ADH.^10,11 Infections, such as inspiration pneumonia, are frequent complications of patients with stroke also leading to increased ADH ectopic production and hyponatraemia. ⁴³ Other frequent causes of increased inappropriate ADH secretion include cancers (i.e. small cell lung carcinoma) or central nervous system diseases.^10,11 Although subarachnoid haemorrhage is the most common central nervous disease associated with SIADH, stroke can also result in increased ADH release. ⁴⁸ Finally, genetic disorders causing SIADH have been recently identified (i.e. polymorphisms resulting in a loss-of-function of TRPV4, a gain-of-function mutation in the vasopressin 2 receptor).^10,11

Physicians should bear in mind that the causes of hyponatraemia in patients with stroke remain largely unknown. ⁵ Observational studies investigating the impact of hyponatremia on mortality risk in hospitalized patients with stroke have demonstrated that those with hyponatremia are more likely to have diabetes (68% versus 35%), ⁵¹ chronic kidney disease (19% versus 9%), ⁵¹ liver disease (9% versus 2%), ³¹ chronic heart failure (16% versus 12%) ²⁹ or to be treated with thiazide diuretics (29% versus 20%) compared with those having normal sodium levels. ³¹ These findings are in agreement with the results of a large retrospective study which showed that heart failure, diabetes and renal failure were among the 10 most frequently encountered diagnoses among 10,899 hospitalized patients with hyponatremia. ⁵²

Furthermore, evidence on the aetiology of hyponatremia in patients with stroke is limited and controversial. A few studies (n = 28–353 subjects) have indicated SIADH as the predominant cause of stroke-associated hyponatremia (67–90%), while a recent one has shown that CSW was the main cause of hyponatremia (44%) among 100 patients with stroke. ¹⁴ Considering their different management, physicians should cast their attention to any clinical findings of volume contraction in the case of CSW. On the contrary, an increased fractional urine excretion of urea (FE_Urea > 55%) has good sensitivity and specificity for differentiating SIADH from CSW. FE_UA is frequently analysed in patients with hyponatraemia, but it is high in both SIADH and CSW (FE_UA > 12%). However, it must be noticed that FE_UA normalizes only in SIADH during treatment.^10,11

Caveats in interpreting UNa⁺ levels

When interpreting UNa⁺ values, the following caveats should be emphasized. First, low UNa⁺ levels are also noticed in patients consuming a low Na⁺ diet, which does not happen frequently in Western populations. In that case, it should be emphasized that UNa⁺ < 30 mmol/l does not necessarily exclude SIADH. Second, occult use of diuretics will increase renal Na⁺ excretion. Finally, chronic kidney disease might complicate differential diagnosis of hyponatraemia. Patients with chronic kidney disease may be less able to re-absorb sodium. In addition, advanced chronic kidney disease usually impairs water excretion, complicating the evaluation of the role of vasopressin in water balance.^10,11

Treatment of hyponatraemia in stroke

It should be emphasized that during any intervention restoring patients’ Na⁺ levels, physicians should rigorously search for solutions, drugs or factors contributing to or provoking hyponatraemia. In addition, the correction rate should be frequently checked until Na⁺ levels stabilization and not exceed 10 mmol/l per day. In case this happens, infusion of an electrolyte-free water solution (10 ml/kg) with or without 2 μg desmopressin can be administered.^10,11

Acute or symptomatic hyponatraemia

As shown in Figure 2, hypertonic saline (typically 3% NaCl) is recommended for the treatment of acute or symptomatic hyponatraemia.^10,11 Hypertonic saline is an effective and potentially life-saving treatment for cerebral oedema caused by hyponatraemia, as the high extracellular Na⁺ concentration immediately removes water from the intracellular space.^10,11 In case of patients with hypervolemic hyponatraemia, hypertonic saline can be combined with loop diuretics.^10,11

Figure 2.

Algorithm for the management of hyponatraemia in patients with stroke.

In every step of hyponatraemia treatment, physicians should rigorously search for and stop non-essential fluids, medications and other factors that can contribute to or provoke hyponatraemia. In addition, cause-specific treatment is strongly recommended.

In case of severe symptoms, regardless of hyponatraemia being acute or chronic, intravenous administration of 150 ml 3% hypertonic saline over 20 min two to three times as needed is recommended until symptoms are resolved or until a target of 5 mmol/l Na⁺ increase is achieved during the first hour (Figure 2). If these do not happen, infusion of 3% hypertonic saline should be continued aiming for an additional 1 mmol/l/h Na⁺ increase until serum Na⁺ concentration increases 10 mmol/l in total or it reaches 130 mmol/l, whichever occurs first. Of note, physicians should not expect patients with severe symptoms to fully recover immediately, as brain needs some time to fully recover. They should also be aware that sometimes it may not be possible to assess an improvement in symptoms, such as in the case of a stroke patient, who can also be intubated and sedated. Finally, the contribution of any potassium (K⁺) correction to an increase in Na⁺ concentrations should be considered and can be estimated with the formula of Adrogue–Madias: expected change in serum Na⁺ = [(infusate Na⁺ + infusate K⁺) – serum Na⁺) / (total body water + 1]. Of note, the estimated total body water (litre) is calculated as ~50% of body weight approximately (0.6 in non-elderly men and 0.5 in non-elderly women; 0.5 and 0.45 in elderly men and women, respectively).^10,11

In case of moderate symptoms or acute asymptomatic hyponatraemia exceeding 10 mmol/l, a single intravenous infusion of 150 ml 3% hypertonic saline over 20 min is recommended (Figure 2).^10,11

Chronic asymptomatic hyponatraemia

Apart from hypovolemic hyponatraemia, which can be treated with isotonic saline or balanced crystalloid solution, the treatment of chronic hyponatraemia relies on reducing free water intake and increasing renal free water excretion (Figure 2). Fluid restriction (<1 l/d) remains the cornerstone therapy for chronic hyponatraemia. The urine to serum electrolyte ratio [(UNa⁺ + UK⁺) / serum Na⁺] indicates if the patient is in an antidiuretic or aquaretic phase and can also help estimate the degree of fluid restriction required to increase serum Na⁺ concentration. In case of a ratio > 1, a stricter fluid restriction is recommended (<500 ml/d), which is difficult to adhere to, and pharmacologic therapy is often required to increase renal free water excretion. Current guidelines unanimously recommend increasing solute intake with 0.25–0.50 g/kg per day of urea or a combination of low-dose loop diuretics and oral sodium chloride in moderate or profound chronic hyponatraemia owing to SIADH (Figure 2).^10,11 Although there is controversial evidence regarding the efficacy in improving clinical outcomes and safety of vaptans, lithium and demeclocycline,^10,11 sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been recently proposed as a potential treatment option for hospitalized patients with SIADH-induced hyponatraemia.^53,54

Vaptans are competitive antagonists of vasopressin receptors without detectable agonist activity. ⁵⁵ Until now, two of them (intravenous conivaptan and oral tolvaptan) have been approved for the treatment of clinically significant euvolemic and hypervolemic hyponatremia in hospitalized patients. ⁵⁵ Nevertheless, it should be emphasized that they have been related to overcorrection of hyponatraemia,^56,57 and they are contra-indicated in severe symptomatic hyponatraemia (serum sodium < 120 mmol/l), in hypovolemic hyponatraemia or in patients with impaired thirst mechanisms, which is common in patients with stroke.^10,11 Moreover, considering the fact that statin therapy is commonly used in the setting of acute ischemic stroke, physicians should keep in mind that vaptans inhibit cytochrome P450 3A4 (CYP3A4) and such a co-administration is contra-indicated. ⁵⁵

SGLT2i were initially developed as antidiabetic drugs due to the induction of pronounced glucosuria, but they have been recently involved in the treatment of heart failure and chronic kidney disease regardless of the presence of diabetes. ⁵⁸ The theory that the induction of osmotic diuresis with SGLT2i could be an effective therapeutic option for SIADH through the consequent increased excretion of free water was initially confirmed by a small study in 14 healthy volunteers with desmopressin-induced SIADH, where empagliflozin led to a significant increase in urinary free water excretion. ⁵⁴ Likewise, a double-blind, randomized trial including 88 hospitalized patients with SIADH-induced hyponatremia < 130 mmol/l showed that a short-treatment (4 days) with empagliflozin in addition to standard fluid restriction led to a stronger increase in plasma sodium concentration compared with placebo. ⁵³ Hypoglycemia, hypotension, euglycemic diabetic ketoacidosis and acute kidney failure are rare complications of the treatment with SGLT2i. ⁵⁹ In this context, SGLT2i should be avoided in critically ill hospitalized patients with acute stroke.

Caveats in treatment of hyponatraemia in patients with stroke

Current guidelines for the management of hyponatraemia do not refer specifically to patients with stroke. Thus, physicians should pay attention to some crucial points. First, any fluid resuscitation used for the restoration of low sodium levels should consider the type of stroke. Cerebral perfusion is important in the setting of acute ischemic stroke, but control and reduction of blood pressure is crucial in patients with hemorrhagic stroke. ⁶⁰ Nevertheless, a close monitoring of patients’ volume status and a vigilant fluid balance management are strongly recommended in both conditions. ⁶⁰ Second, any intervention aiming fluid restriction may be inappropriate in stroke patients due to increased risk for deteriorating an already impaired cerebral circulation. In addition, fluid restriction is also contra-indicated in hypovolemic states such as CSW, which can be misdiagnosed as SIADH.^10,11,48 On the contrary, isotonic saline administration, commonly used in stroke patients, should be avoided in patients with SIADH-related hyponatraemia as it can aggravate hyponatraemia.^10,11 Considering its neuroprotective effects and lower ODS risk compared with other therapies,^10,11 urea may be an attractive option in treating stroke patients with hyponatraemia due to SIADH. It should be emphasized, however, that the clinical experience with urea administration is limited, especially in patients with stroke. Despite the evidence showing that conivaptan diminishes the cerebral edema and blood–brain barrier disruption in an experimental stroke model,^61,62 studies evaluating the role of vaptans in hyponatraemic patients with stroke are lacking. On the contrary, the neuroprotective effects along with the well-established cardiorenal benefits of glucose cotransporter-2 inhibitors cast them a promising therapy of non-hypovolemic chronic hyponatraemia. ⁶³ Finally, the presented algorithms for the restoration of sodium levels herein could also be used in patients with brain injuries, considering the increased prevalence of hyponatremia and its common aetiologies, such as SIADH and CSW, in the latter. ⁶⁴ Nevertheless, intracerebral haemorrhage is a separate disease with different causes and pathophysiology than stroke and thus any intervention should be personalized.

Conclusion

Hyponatraemia is a common electrolyte disorder in patients with stroke and is associated with adverse clinical outcomes and increased mortality risk. The complexity of its underlying causes warrants a careful differential diagnosis considering patients’ comorbidities, concomitant drug therapy, physical findings and laboratory evaluation, which will guide the corresponding management decisions. Despite the lack on relevant data, the treatment of hyponatraemia is expected to improve outcomes in patients with acute stroke. Randomized clinical trials are needed to investigate the efficacy and safety of the available therapies in stroke patients diagnosed with hyponatraemia.