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Hyponatremia is the most common electrolyte disorder encountered in clinical practice, with a prevalence that ranges from 1% to 30% depending upon the care setting.1-4 Recent studies have estimated it to be present in three million to six million individuals in the United States, with a corresponding cost of $1.6 billion to 3.6 billion annually.5,6
Although many cases are mild and relatively asymptomatic, hyponatremia and its treatment can either directly or indirectly contribute to substantial morbidity and mortality.7 Although the risks that arise from severe hyponatremia and its overly rapid correction are well recognized, even mild and asymptomatic hyponatremia has been found to be associated with gait instability, falls, an increased risk for fractures, and impairment of attention.8-12
In almost every clinical situation where hyponatremia is encountered, it is associated with a significantly increased risk of morbidity and mortality. For instance, in a study of patients aged 65 years or older admitted to a community hospital, those with a serum sodium less than 130 mmol/L had a 1.95 times increased relative risk (RR) of death during their hospital stay.13
Similarly, in ICU patients with a serum sodium level below 125 mmol/L, the RR of death was 2.10 times greater than ICU patients with higher serum sodium levels.14 There is also a clear gradation of mortality risk according to the severity of hyponatremia, with a mortality as high as 50% in patients with a plasma sodium less than 115 mmol/L.15
In many cases, the high mortality rate can, at least partially, be attributed to the illness that precipitated the hyponatremia (such as heart failure or cirrhosis). However, a more direct relationship between hyponatremia and mortality risk was suggested by a study by Hoorn et al that reported higher mortality rates (37% vs. 13%) in those patients who did not receive specific or appropriate therapy targeted to the electrolyte abnormality.16
Broadly speaking, hyponatremia can be caused by either dilution of the serum sodium by excess retained free water or by excessive sodium and/or potassium losses in excess of water. However, the vast majority of clinically encountered cases of hyponatremia are due to excess free water retention by the kidney driven by arginine vasopressin (AVP), which also is called anti-diuretic hormone (ADH). In these cases, the secretion of AVP from the posterior pituitary can be secondary to a specific underlying condition such as cirrhosis or congestive heart failure (CHF) or secondary to a primary problem in osmoregulation (syndrome of inappropriate anti-diuretic hormone secretion [SIADH]).
Clinically, these disorders of serum sodium can be distinguished by clinical examination of volume status, as those patients with CHF or cirrhosis will display clear manifestations of volume overload while those patients with SIADH are euvolemic. In fact, the vast majority of patients with euvolemic hyponatremia have SIADH.
In patients with euvolemic hyponatremia due to SIADH, AVP secretion is not suppressed despite the fact that the plasma osmolality is normal or decreased.17-19 AVP then acts through binding of the vasopressin type-2 receptor to increase the water permeability of the collecting duct of the kidney, thereby returning free water to the extracellular fluid and lowering the serum sodium. SIADH can develop as result of numerous disease processes and medications (See Table 1).20