Understanding the symptoms and clinical significance of reduced plasma/serum sodium (hyponatremia)

Reduced plasma/serum sodium (hyponatremia), widely defined as plasma/serum sodium <135 mmol/L, is the most common electrolyte disturbance encountered in clinical practice; around 15-20 % of patients requiring hospitalization are either hyponatremic at admission or become hyponatremic during admission. The symptomatic effect of hyponatremia depends largely on its severity and rapidity of onset.

Mild hyponatremia, i.e. plasma/serum sodium in the approximate range of 130 to 136 mmol/L, is usually not associated with symptoms, but most patients whose plasma/serum is <125 mmol/L will experience non-specific symptoms (nausea, vomiting, headache) that are more severe if the decrease is rapid (within 24-48 hours). Severe hyponatremia (serum/plasma sodium <115 mmol/L), particularly of rapid onset, is associated with marked confusion, seizures and coma; without emergent treatment, severe hyponatremia can be fatal. 

Explanation of these effects of hyponatremia is contained in this recently published review article that makes clear that all symptoms are neurological in origin, and result from the exquisite sensitivity of brain cells to reduction in extracellular fluid (ECF) osmolality – an inevitable consequence of hyponatremia.  

By way of introduction, the authors explain that serum/plasma sodium concentration is the principal determinant of plasma (ECF) osmolality; as serum/plasma sodium falls, so too does ECF osmolality. They make the fundamental point that since cells have a semi-permeable membrane, an inevitable consequence of reduced ECF osmolality (and therefore hyponatremia) is movement of water into cells until intracellular and extracellular osmolality are equal.

Influx of water causes cells to swell in size. The neurological effect of hyponatremia is primarily due to brain swelling (cerebral edema) because the cells of which the brain is composed are swollen with water. 

Following this introduction, the authors proceed to detailed discussion of the brain cell mechanisms that normally protect against fluctuations in ECF osmolality and tend to prevent brain cell swelling during mild hyponatremia. Symptomatic hyponatremia implies that these adaptive responses are either overwhelmed or not yet fully operational.

The authors discuss these adaptive responses under two headings: early mechanisms (that start within minutes of reduction in osmolality and are fully effective within a few hours) and late mechanisms (that are only fully effective around 4 days later). Recognition that full adaptation of the brain to hyponatremia is time-dependent helps to explain why symptoms of hyponatremia are more likely to be present if the reduction occurs acutely rather than slowly, over a prolonged period (days or weeks). 

Under the heading ”hyponatremic encephalopathy (HNE)” the authors explore in more detail the symptomatic (neurological) effect of severe hyponatremia whilst continuing to make the important distinction between acute and chronic onset. They observe that ”the most striking and severe symptoms of HNE are related to compression of the brain parenchyma against the rigid skull”.

This compression, due to cerebral edema, can cause seizures, coma and, if not relieved, brain herniation and death. These dramatic effects of hyponatremia are most likely if the onset of hyponatremia is acute and severe but can occur following an acute reduction of plasma sodium in a patient with pre-existing chronic hyponatremia.

The authors highlight research that challenges the long-held view that mild/moderate chronic hyponatremia is essentially benign; it is now clear that this condition can result in subtle neurological effects, manifest particularly in the elderly as attention deficit, gait imbalance and falls.

A significant part of this review article is devoted to the treatment of patients with symptomatic hyponatremia, i.e. those with HNE. Correction of plasma sodium concentration by administration of iv fluid (either hypertonic or normal saline) or salt tablets is the mainstay; with correction of plasma sodium comes normalization of ECF osmolality, reduction in cerebral edema/intracranial pressure and relief of symptoms.

In a long and informative section, the authors caution against too rapid increase in plasma sodium concentration during treatment of chronic hyponatremia, as this can cause nerve demyelination and consequent permanent brain damage. The pathophysiology of this condition, called osmotic demyelination syndrome (ODS), is described in some detail, and the authors offer an algorithm for treatment of severe hyponatremia that minimizes risk of ODS. 

In conclusion of their review, which lends on 108 references, the authors highlight areas of current uncertainty about hyponatremia and its treatment that warrant further research.