Sodium and water perturbations in patients who had an acute stroke: clinical relevance and management strategies for the neurologist

Hyponatraemia

In acute stroke, AVP release from the posterior pituitary secretory granules is stimulated by various factors, including increased serum hyperosmolality, hypovolaemia due to decreased fluid intake, nausea, stress, pain and drugs (eg, oxcarbazepine, carbamazepine, selective serotonin reuptake inhibitors). Water retention or (less often) loss of effective solutes (sodium and potassium) in excess of water can also lead to hyponatraemia.22 Hyponatraemia caused by water retention occurs only under conditions that impair renal water excretion and does not tend to occur in patients with primary polydipsia in which excessive water intake can overwhelm the normal renal excretory capacity.22 The higher the plasma AVP, the more concentrated the urine. In most patients with SIADH, increasing water consumption does not adequately suppress AVP, and the urine remains concentrated. This leads to water retention, which increases total body water that subsequently lowers serum sodium levels by a dilutional effect.23 Additionally, the increase in total body water transiently expands the extracellular fluid volume causing increased urinary sodium excretion, which returns the extracellular fluid volume towards normal and further lowers serum sodium levels. Besides renal failure, primary polydipsia and low dietary solute intake, the majority of causes of hyponatraemia are associated with an absolute or relative excess of AVP (despite the presence of hypotonicity) often caused by SIADH or depletion of effective circulating intravascular volume.22

Hypernatraemia

When hypernatraemia arises in acute stroke, it is usually the result of patients not having free access to water or due to the development of diabetes insipidus (DI). Much rarer are cases of poststroke hypernatraemia caused by hypodipsia secondary damage to the thirst centre.24 If patients have free access to water, hypernatraemia is exceptional since the thirst centre is often intact after an acute stroke and is effective in preventing hypernatraemia from developing. When serum sodium levels rise, stimulation of the thirst centre and secretion of AVP occurs resulting in increased water intake and reduction in urinary water loss leading to normalisation of serum osmolality (figure 1). This maintains serum osmolality in a narrow range despite daily variations of water and sodium intake, and insensible water losses.25 If the thirst centre is damaged from the stroke, often caused by intraventricular haemorrhage, despite the secretion of AVP and the preservation of urinary concentration, hypernatraemia will develop with reductions in urine volume excretion and elevations in urine specific gravity because the patient is unable to compensate to increase free water consumption.

General management principles

The critical aspect towards the successful management of sodium and water perturbations requires a comprehensive understanding of the pathophysiological mechanism, accurate clinical assessment of the volume status of the patient (ie, hypovolaemia, euvolaemia or hypervolaemia), and identification of whether the hyponatraemia and hypernatraemia is acute (<48 hours) or chronic (≥48 hours) as management strategies differ. In order to establish the diagnosis and aetiology of hyponatraemia, a careful history and physical examination is required and biochemical investigations such as serum sodium, urine sodium, serum osmolality, urine osmolality, thyroid function tests and 8:00 hour serum cortisol may be needed. Management should then target towards treating the underlying aetiology and correcting the hyperosmolality or hypoosmolality.

Management of hyponatraemia

Restoration of volume depletion is imperative in the treatment of hypovolemic hyponatraemia, whereas treatment of hypervolaemic and euvolaemic hyponatraemia is more complex. In addition to correcting the underlying cause (eg, withdrawal of an offending drug), fluid restriction, administration of hypertonic solution, loop diuretics, urea and vasopressin-receptor antagonists (eg, vaptans) are amongst other therapeutic options that could be considered. Although there are clinical practice guidelines for the treatment of non-stroke hyponatraemia, currently, there is no specific reference to the treatment of hyponatraemia in patients who had an acute stroke.30 41 Fluid restriction may not be appropriate in patients who had an acute stroke due to increased risk of decreased cerebral perfusion, and is contraindicated when the patient is hypovolaemic, such as hyponatraemia caused by CSWS. Additionally, isotonic saline administration should be avoided in patients who had an acute stroke with euvolaemic hyponatraemia caused by SIADH since the hyponatraemia may worsen if the urine osmolality is higher than serum osmolality. In such patients, careful administration of hypertonic 3% saline is more appropriate, especially as the overlap between SIADH and CSWS often makes it difficult to differentiate between these two conditions. The differences between these two conditions are highlighted in table 1. Conversely, in a patient who had an acute stroke who is actively seizing, a bolus of hypertonic 3% saline at a dose of 2 mL/kg (maximum 100 mL) should be administered over 10–60 min and can be repeated if seizures are still evident.30 At any time during the hypertonic 3% saline infusion, the patient and the serum sodium levels must be monitored closely for any signs of deteriorating neurological status or symptoms of fluid overload.

Urea has been proposed as a potential therapeutic option as it exerts beneficial effects on cerebral oedema regardless of changes in sodium levels.42 However, clinical experience with urea administration in patients who had an acute stroke remains limited and we recommend avoiding it in hypovolaemic hyponatraemia since it induces increased renal water excretion leading to exacerbation of volume depletion and decreased cerebral perfusion.

Tolvaptan (an oral V2 receptor antagonist) is approved in the USA for the treatment of euvolaemic and hypervolaemic hyponatraemia and in Europe only for the treatment of hyponatraemia secondary to SIADH.43 On the other hand, intravenous conivaptan (a dual V1a/V2 receptor antagonist) is approved in the USA for short-term use (≤4 days) in hospitalised patients with non-hypovolaemic hyponatraemia.44 Vaptans are contraindicated in severe symptomatic hyponatraemia (serum sodium <120 mmol/L), in hypovolaemic hyponatraemia, and in patients with impaired thirst mechanisms because reductions in renal perfusion may increase the likelihood of over-rapid correction of serum sodium levels. Furthermore, studies conducted to evaluate the efficacy of vaptans in hyponatraemic patients who had an acute stroke are still lacking. Hence, use of vaptans in acute stroke should be limited only to patients with non-hypovolaemic hyponatraemia refractory to other treatment modalities, including hypertonic 3% saline.

For acute symptomatic hyponatraemia, increasing serum sodium levels by 4–6 mmol/L can decrease the risk of herniation and stop seizure activity. Larger increases should be avoided and can be harmful to patients with chronic hyponatraemia. European guidelines in non-stroke patients recommend rapid hypertonic 3% saline infusion depending on severity of symptoms, with two 150 mL boluses over 20 min with a sodium level assessment between boluses,30 whereas US expert panels recommend 100 mL hypertonic 3% saline bolus over 10 min and repeated as needed for symptom management in severe clinical cases.41 We recommend that the rate of correction for acute, symptomatic hyponatraemia to be 8–10 mmol/L in the first 24 hours. Serum sodium levels need to be monitored closely to minimise the risk of overcorrection (ie, no faster than 10–12 mmol/L/day for the first 24 hours), and avoid the administration of isotonic fluids and large volumes of hypertonic fluids to patients with underlying congestive heart failure or chronic renal failure (two common comorbidities in patients who had an acute stroke), as this may lead to cardiac decompensation and pulmonary oedema. In hypovolaemic hyponatraemic patients who had an acute stroke, it is imperative to avoid an overly rapid rise in serum sodium levels when volume depletion is restored as an abrupt decrease in AVP secretion and a rapid diuresis may occur. Large volumes of urine excretion at this juncture indicates an inappropriate overcorrection of hypovolaemia.

Because most hyponatraemia cases are chronic, when there is doubt of the duration of hyponatraemia, the presumption should be that the patient has chronic hyponatraemia. In this setting, large increases in serum sodium levels (10 mmol/L in 24 hours or 18 mmol/L in 48 hours) should be avoided, unless the patient is actively seizing. In patients at high risk of osmotic demyelination syndrome (eg, hypokalaemia, alcoholism, liver disease and malnutrition), correction should not exceed 4–6 mmol/L/day, whereas in patients with low risk, target maximum rise of 4–8 mmol/L/day with a target maximum limit not to exceed 10–12 mmol/L in any 24 hours or 18 mmol/L in any 48 hours is recommended.31

In severe hyponatraemia cases, cerebral oedema may develop as water shifts from extracellular stores to balance out the relative hyponatraemia in the vascular space. To compensate this shift from causing too many homoeostatic changes, the brain loses osmotic solutes to try to protect itself from cerebral oedema.43 If hyponatraemia is corrected too rapidly, brain cells shrink as serum sodium is corrected.45 It has been previously established that correction of the sodium should not occur more rapidly than approximately 0.5–1 mmol/L/hour or a total of 10 to 12 mmol/L per 24 hours, while some have even proposed not to exceed 6 mmol/L.46 Once treatment has commenced to correct the hyponatraemia, frequent serum sodium checks should be performed to allow close monitoring and adjustment of fluid infusion rates. If the serum sodium level begins to rise too rapidly and adjustment of intravenous fluids is insufficient to slow down the over rapid correction, infusion of hypotonic fluids to decrease the serum sodium level may be required to prevent the development of osmotic demyelination syndrome. This complication can be caused by exceeding generally agreed safe limits of serum sodium correction, with corrections greater than 12 mmol/L over 24 hours, 25 mmol/L over 48 hours, or inadvertent hypernatraemia during correction of hyponatraemia,47 resulting in rapid swelling of the nervous system parenchyma that cannot adapt quickly enough to the changing osmolality. Despite the severity and devastating consequences of this syndrome, neurologists should not shy away from aggressively treating symptomatic patients who had an acute stroke with hyponatraemia because without prompt treatment, seizures, coma or death may ensue.

Management of hypernatraemia

Effective management of hypernatraemia in patients who had an acute strokes requires addressing the underlying aetiology in preventing further loss of water or hypertonic sodium gain. Once eunatraemia is achieved, treatment could involve, for example, withholding loop diuretics, administering insulin in the case of hyperglycaemic, treating vomiting or diarrhoea, withholding/adjusting hypertonic tube feeds or administering desmopressin (DDAVP) for those who have developed DI. Careful history and clinical examination to determine the volume status and measurement of urine sodium and osmolality will help to ascertain the aetiology. Patients with hypovolaemia on presentation should be resuscitated with hypotonic fluids regardless of the presenting serum sodium level until vital signs are normalised. The choice of fluid replacement for hypernatraemia should be dilute relative to serum in order to replace the water deficit. This requires the estimation of the amount of water that has been lost and can be calculated by using the formula proposed by Adrogué et al.27

Water deficit (L) = [(measured sodium/normal sodium) – 1]

The choice of replacement solution to be given and infusion rate are important factors to avoid overcorrection of the hypernatraemia. Serum sodium levels should be corrected by no more than 8 to 15 mmol/L/day, which may take longer than 48 hours in patients with severe hypernatraemia (>160 mmol/L).27 An exception is patients with acute hypernatraemia (<48 hours) who can be safely be corrected rapidly at a rate of 1 mmol/L/hour. As in management of hyponatraemia, frequent measurement of serum sodium levels is critical for monitoring the response to therapy and adjusting the rate or choice of intravenous fluid. Except for hypovolaemic patients requiring resuscitation with isotonic 0.9% saline, all other patients should receive either half 0.45% saline or 5% dextrose water infusions to replace the water deficit and ongoing fluid losses.

Patients with hypervolaemic hypernatraemia present a different therapeutic challenge as the volume expansion in these patients inhibits the release of AVP, thereby promoting water excretion in the urine. Cessation of the inciting factors and administration of water is usually the initial step. Treatment with loop diuretics would enhance more aquaresis than natriuresis, thereby exacerbating the hypertonicity. Infusing dextrose 5% water would address the hypertonicity, but might worsen the volume overload state. Simultaneous use of intravenous dextrose 5% water and loop diuretics can be used to lower the serum sodium in addition to achieving a net negative total body water balance. Rarely, haemodialysis has been used, especially in cases where hydration with or without diuresis have failed to bring the sodium level down to the desired target or in patients with worsening renal function in whom there are indications for renal replacement therapy.46

For patients with DI, DDAVP treatment can be administered orally, intranasally, subcutaneously or intravenously. Thiazide diuretics rarely can be considered as it decreases urine volume and increase urine osmolality. The mechanism of the paradoxical antidiuretic effect of thiazides in DI is thought to be related to volume contraction, leading to an increase in proximal tubular reabsorption of water and sodium thereby decreasing distal delivery of water and subsequent excretion.

Despite the paucity of data, hyperosmolar agents (eg, mannitol and hypertonic 3% saline) are still used by some clinicians in patients who had an acute stroke to induce hypernatraemia in order to decrease raised intracranial pressure and to prevent cerebral oedema.48 49 As there are currently no accepted consensus guidelines regarding optimal serum sodium levels in patients who had an acute stroke, we recommend that hyperosmolar agents be used cautiously in bolus form only to selected patients (those without risk factors, eg, alcoholism, liver disease, renal disease and previous strokes that would suggest a poorer prognosis) and closely monitor serum sodium levels targeting levels to not exceed 145 mmol/L. Box 3 summarises our recommendations for management of hyponatraemia and hypernatraemia in patients who had an acute stroke.