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1.1 Definition, incidence, risk factors, pathophysiology and causes

Hyponatraemia is defined as a serum sodium level < 130 mEq/L. It occurs in 4% of cancer patients and is most often seen in patients with lung, central nervous system, nasopharynx, duodenum, stomach, pancreas, ureter, prostate or uterus cancer. Clinically significant hyponatraemia in cancer patients is relatively uncommon.

Serum sodium is regulated by thirst, anti-diuretic hormone (ADH), the renin-angiotensin-aldosterone system and the kidney.
·    Increases in serum osmolarity above the normal range (280-300 mOsm/kg) stimulate hypothalamic osmoreceptors, which cause an increase in thirst and in circulating levels of ADH. ADH increases free water re-absorption from the urine.
·    Aldosterone is synthesized by the adrenal cortex and is regulated primarily by serum potassium. Aldosterone causes absorption of sodium at the distal renal tubule.
·    The healthy kidney regulates sodium balance independently of ADH or aldosterone by varying the degree of sodium absorption at the distal tubule.

Hyponatraemia can be classified as
·    Hypovolaemic hyponatraemia, in which total body water (TBW), total body sodium and extracellular fluid (ECF) volume are decreased;
·    Euvolaemic hyponatraemia in which TBW is increased while total sodium is normal. The ECF volume is increased minimally to moderately, but there is no oedema; and
·    Hypervolaemic hyponatraemia, in which total body sodium and TBW is increased while ECF is markedly increased resulting in oedema.

In cancer patients the most common reason of hyponatraemia is the Syndrome of Inappropriate Anti-diuretic Hormone Secretion (SIADH). This is caused by the secretion of ectopic vasopressin (AVP) or vasopressin-like peptide. This causes an excess of renal water reabsorption resulting in a dilutional hyponatraemia. Due to the volume expansion, aldosterone secretion is reduced with progressive salt loss in the urine.
SIADH is present in patients with small cell lung carcinoma, pancreatic cancer, lymphomas, mesothelioma, and primary and metastatic brain tumours. It is also a treatment complication of vinca alkaloids, vinorelbine, alkylating agents (high-dose cyclophosphamide and less commonly low-dose cyclophosphamide, melphalan and chlorambucil) and combination chemotherapy including cisplatin-based regimens. Also chemotherapy-induced nausea, simulating  AVP release and excessive pre-hydration for cisplatin administration cause SIADH.

Salt-wasting nephropathy may be secondary to cisplatin chemotherapy, adrenal insufficiency (reduced aldosterone secretion) and cerebral salt-wasting (associated with intracranial surgery and subarachnoid bleeding). Patients are clinically hypovolemic (orthostatic hypotension, tachycardia and rapid weight loss), non-oliguric and the urine contains high levels of sodium.

Other causes of hyponatraemia are pneumonia; active tuberculosis; pulmonary abscess; asthma; central nervous system infections, hypothyroidism; adrenal insufficiency or trauma. It is also associated with medication (acetazolamide, amiloride, amphotericin, atovaquone, thiazide diuretics, amiodarone, basiliximab, angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors, carbamazepine, carvedilol, celecoxib, clofibrate, desmopressin, donepezil, eplerenone, gabapentin, haloperidol, heparin, indomethacin, ketorolac, loop diuretics, nimodipine, oxcarbazepine, opiates, oxytocin, pimozide, propafenone, proton pump inhibitors, sirolimus, ticlopidine, selective serotonin reuptake inhibitors, sulfonylureas, trazodone, tolbutamide, zalcitabine, and zonisamide); poor dietary intake; large amounts of beer and after use of recreational drugs (e.g. ecstasy).


2.1 Clinical presentation

Hyponatremia is physiologically significant when it causes extracellular hypo-osmolarity and a shift of free water from the vascular to the intracellular space. Although cellular oedema is well tolerated by most tissues, cerebral oedema might be life-threatening.

•    Patients with acute hyponatraemia (developing over 48 hours or less) may develop cerebral oedema and morbidity and mortality are due to brainstem herniation and mechanical compression of vital midbrain structures.

•    Patients with chronic hyponatraemia experience milder degrees of cerebral oedema and might die due to status epilepticus (sodium < 110 mEq/L) or cerebral pontine myelinolysis (demyelination syndrome when chronic hyponatraemia is corrected too quickly).

•    Symptoms due to hyponatraemia relate to the severity and the rapidity of onset.

o    When serum sodium gradually decreases, levels as low as 110 mEq/L may be reached with minimal symptoms; while a sudden fall in 24-48 hours may lead to severe cerebral oedema, coma, or brainstem herniation.

o    Symptoms may be mild anorexia, nausea and vomiting, muscle cramps, concentration difficulties, confusion, lethargy, agitation, headache, seizures, coma, or status epilepticus.

•    Physical findings are highly variable and dependent on the degree and the duration of hyponatraemia. Most prominent physical signs are neurological disturbances: changes in conscience (agitation to coma), cognitive impairment (e.g. difficulty with short-term recall; loss of orientation to person, place, or time; confusion or depression) and focal or generalized seizures. Signs of brainstem herniation include coma; fixed, unilateral, dilated pupil; decorticate or decerebrate posturing and respiratory arrest

•    Patients may exhibit signs of hypovolaemia or hypervolaemia

o    Dry mucous membranes, tachycardia, diminished skin turgor and orthostasis are observed in hypovolaemic hyponatraemia due to excessive loss of body fluids and replacement with inappropriately diluted fluids

o    Pulmonary rales, S3 gallop, peripheral oedema, or ascites in hypervolaemic hyponatraemia due to excess retention of sodium and free water (e.g. cirrhosis, nephrotic syndrome, congestive heart failure).

2.2 Diagnosis

The diagnosis of hyponatraemia is made by serum analysis.

Pseudohyponatraemia should be excluded and may be caused by incorrect sampling (e.g. venous puncture proximal to an infusion of hypotonic saline or dextrose in water); hyperglycaemia; mannitol administration; hyperlipidaemia; or hyperproteinaemia.

Urine sodium levels distinguish renal causes of hyponatraemia from non-renal causes.

SIAHD is diagnosed by a decreased osmolality ( 100 mOsm/kg of water during hypotonicity; clinical euvolemia with no signs of volume depletion of extracellular fluid (no orthostasis, tachycardia, decreased skin turgor of dry mucous membranes) and no clinical signs of excessive volume of extracellular fluid (no oedema or ascites); urinary sodium > 40 mmol/L with normal dietary salt intake; normal thyroid and adrenal function and no recent use of diuretic agents. Additional arguments are plasma uric acid < 4 mg/dL; blood urea nitrogen < 10 mg/dL; elevated plasma vasopressin levels despite the presence of hypotonicity and clinical euvolemia.

Serum thyroid-stimulating hormone and free thyroxine should be checked if hypothyroidism is suspected. Adrenal function should be assessed, via random serum cortisol levels or an adrenocorticotropic hormone (ACTH) stimulation test, in patients who recently have taken oral corticosteroids or in any patient suspected of having cortisol deficiency.


The prognosis of hyponatraemia depends on its severity and rapidity of onset. If adequately handled prognosis is determined by the underlying condition.


4.1 Prevention

Prophylactic measures aiming at decreasing the risk of hyponatraemia include the management of excessive diarrhoea, vomiting or hydration used before chemotherapy.

4.2 Treatment

Appropriate treatment of hyponatraemia depends upon the type, the severity of symptoms, and the severity of hyponatraemia.
Rapid identification and correction of serum sodium is necessary in patients with severe acute hyponatraemia to avert brainstem herniation and death.

* Causes of hyponatraemia (e.g. tumour, non-tumoural causes) should be identified and corrected when possible. If possible, medication causing hyponatraemia should be discontinued. The source of free water must be identified and eliminated.
* Neurological symptoms due to hyponatraemia are an acute life-threatening condition and immediate supportive care should include anticonvulsant therapy to patients with seizures, a standard option, on a type C basis, intubation and initiation of hyperventilation to reduce intracranial pressure in case of signs of brainstem herniation is suitable for individual clinical use ,on a type C basis. Hypotonic IV fluids should be avoided because they may exacerbate cerebral oedema.
* Hyponatreamia should be corrected immediately in symptomatic patients.
* In patients with brainstem herniation and sodium levels below 120 mEq/L, a rapid serum sodium increase by 4-6 mEq/L should be realized during the first 1-2 hours with hypertonic (3%) saline, asa standard option, on a type C basis. The dose volume required in adults is calculated by: (desired change in serum sodium)(TBW)/(Sodium in IV fluid – current serum sodium), in which TBW = body weight x 0.6. Further correction should proceed at an overall rate that is no greater than 0.5 mEq/L/hour or 12 mEq/L/day.
* In patients with chronic hyponatraemia, hyponatraemia is corrected at a rate of less than 0.5 mEq/L/hour or 12 mEq/L/day to prevent cerebral pontine myelinolysis, as an individualized option,on a type C basis.
* Patients with hypovolaemic hyponatraemia may be treated with isotonic saline; serum sodium levels should be monitored frequently to ensure that serum sodium increases no faster than 0.5 mEq/L/hour or 12 mEq/L/day, as an individualized option, on a type C basis
* Patients with hypervolaemic hyponatraemia should be treated with sodium and water restriction, which is an individualized option, on a type C basis. Fluid restriction to 500 ml/day may correct hyponatraemia
* Patients with euvolaemic hyponatraemia should be treated with free water restriction, which is anindividualized option, on a type C basis.
* A number of treatments can be used to correct hyponatremia in asymptomatic SIADH patients
* Water restriction on the basis of urinary and plasma electrolytes is the mainstay of therapy. The associated negative water balance raises the serum sodium concentration toward normal. The maximum tolerated fluid intake is proportional to the oral osmotic load, so adequate intake of dietary protein and salt should be encouraged.
* Urea, 30g/day is a method to enhance water excretion and can be used chronically in ambulatory patients, but is poorly tolerated; therefore, it is considered  as an individualized option, on a type C basis.
* Demeclocycline (300-600 mg twice daily) reduces urinary osmolality and increases serum sodium levels by action on the collecting tubule cell to diminish its responsiveness to ADH, thereby increased water excretion This drug should be considered as suitable for individual clinical use, on a type C basis, only in the rare patient with persistent marked hyponatremia who is unresponsive to or cannot tolerate water restriction, a high salt intake, and a loop diuretic. Renal function should be monitored, since nephrotoxicity can occur.
* Vasopressin receptor antagonists act on the ADH receptors (V1a, V1b, and V2): V2 receptors primarily mediate the antidiuretic response, V1a and V1b receptors principally cause vasoconstriction and mediate adrenocorticotropin release, respectively. The vasopressin receptor antagonists produce a selective water diuresis without affecting sodium and potassium excretion.
* Conivaptan (20 mg loading dose followed by a continuous IV infusion of either 40 or 80 mg/day for four days) is a non-specific vasopressin receptor antagonist for treatment of euvolemic and hypervolemic hyponatremia in patients with moderate-to-severe hyponatremia and symptoms but not seizures, delirium, or coma, which would warrant the use of hypertonic saline. It can increase sodium levels by 6 mmol/L. This is an individualized option, on a type 2 level of evidence. Infusion-site reactions are common occurring in as many as 50% of patients and its metabolism by the 3A4 isoform of cytochrome P450 (CYP3A4) can result in drug interactions.

Oral selective V2 vasopressin-receptor antagonists (tolvaptan, satavaptan, and lixivaptan) are being developed and should be considered as investigational, on a type 2 level of evidence.


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Ellison DH, Berl T. Clinical practice. The syndrome of inappropriate antidiuresis. N Engl J Med 2007; 356: 2064-72 [Medline]

Ghali JK, Koren MJ, Taylor JR, Brooks-Asplund E, Fan K, Long WA, Smith N. Efficacy and safety of oral conivaptan: a V1A/V2 vasopressin receptor antagonist, assessed in a randomized, placebo-controlled trial in patients with euvolemic or hypervolemic hyponatremia. J Clin Endocrinol Metab 2006; 91: 2145-52 [Medline]

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Zeltser D, Rosansky S, van Rensburg H, Verbalis JG, Smith N; Conivaptan Study Group. Assessment of the efficacy and safety of intravenous conivaptan in euvolemic and hypervolemic hyponatremia. Am J Nephrol 2007; 27: 447-57 [Medline]

Dr. Dirk Schrijvers (Reviewer)
University Hospital Antwerp – Antwerp, Belgium

Dr. Silvia Spinazzé (Associate Editor)
START Programme