Intravascular Volume Depletion (Hypovolemia)

Intravascular volume depletion leads to non-osmoregulated vasopressin (AVP) production and reduced free water excretion. AVP production can persist despite ensuing hyponatremia. Portal hypertension, congestive cardiac failure and hypoalbuminemia can all reduce effective circulating volume (independent of drug treatment), even in the context of excess total body sodium. Long-term diuretic use is a common cause of hyponatremia. Because it may develop slowly, patients can be relatively asymptomatic. Those on thiazide diuretics are particularly at risk as these agents produce solute loss without limiting renal concentrating ability.

Excess Hypotonic Fluid Intake

The administration or absorption of hypotonic fluids at a rate that exceeds renal free water excretion will inevitably result in hyponatremia. This can be seen with oral fluid intake (dipsogenic diabetes insipidus), intravenous fluid therapy and the absorption of hypotonic irrigating fluids following surgery to the lower renal tract or colonoscopy.

Syndrome of Inappropriate Antidiuresis (SIAD)

In SIAD there is a failure to maximally suppress AVP secretion as plasma osmolality falls below the normal osmotic threshold for AVP release. As patients continue to drink, persistent antidiuresis produces dilutional hyponatremia. Diagnosis of SIAD involves the exclusion of volume depletion and other endocrine causes of reduced free water excretion (Table 2).

The majority of patients with SIAD are euvolemic on clinical examination. Urine sodium concentration is often above 80 mmol/l.

Many drugs cause SIAD. Drug histories are therefore an important part of the clinical assessment of patients presenting with hyponatremia (Table 3).

Central Salt Wasting

This acquired primary natriuresis is a very rare cause of hyponatremia with hypovolemia. The underlying mechanism(s) remains unclear but may involve a number of processes.

• Increased release of natriuretic peptides
• Reduced sympathetic drive

Central salt wasting has been described following a variety of neurosurgical situations. Diagnosis hinges on the natural history of the process.

• The development of hyponatremia, preceded by natriuresis and diuresis
• Clinical and biochemical features of hypovolemia and renal impairment

Central salt wasting is a concern for the neurosurgical patient in whom autoregulation of cerebral blood flow is disturbed such that small reductions in circulating volume can reduce cerebral perfusion. The syndrome of inappropriate antidiuresis (SIAD) can occur in the same group of patients. As management of the two conditions is diametrically opposed, it is important to make the correct diagnosis. Recent data suggest that salt wasting is indeed a very rare cause of hyponatremia in the neurosurgical patient.

Nephrogenic SIAD

The action of AVP on renal water excretion is mediated by the G-protein-coupled type 2 AVP-receptor (V2-R). Loss-of-function mutations of the V2-R are the cause of X-linked nephrogenic diabetes insipidus. The reciprocal phenotype, mutations in the V2-R that are constitutively activating, lead to AVP-independent but V2-R-mediated antidiuresis with persistent hyponatremia. Patients may present in infancy or may remain undetected until adulthood.

Serum Osmolality

The serum osmolality (which normally ranges from 275 to 290 mOsmol/kg) is primarily determined by the concentration of serum sodium (and accompanying anions). It is reduced in most cases of hyponatremia (hypotonic hyponatremia). In some instances, hyponatremia is not associated with dilute plasma. This is termed non-hypotonic hyponatremia (Table 5).

Urine Osmolality

The normal response to hyponatremia is to suppress AVP secretion, resulting in the excretion of maximally dilute urine with an osmolality below 100 mOsmol/kg. Values above this level indicate an inability to normally excrete free water, indicating secretion and action of AVP.

Urine Sodium Concentration

The urine sodium concentration can be used to distinguish between hyponatremia caused by effective arterial volume depletion (such as in true hypovolemia, heart failure, and cirrhosis) and that caused by euvolemic/hypervolemic hyponatremia (most often due to SIAD).

The combination of urine osmolality and urine Na⁺ concentration can be used to form a utilitarian algorithm for the investigation and differential diagnosis of hyponatremia (Figure 2).

Figure 2.

Diagnostic Algorithm for Patients Presenting with Hyponatremia

General and Supportive Measures

The appropriate clinical environment for the management of hyponatremia is the one that matches the clinical needs of the patient. Management of hyponatremia in a patient with significant neurological morbidity, in whom plasma sodium is being raised over hours, requires close clinical and biochemical observation. This is best achieved in a high-dependency setting. Cerebral oedema and coma associated with hyponatremia may need supportive management with assisted ventilation.

Patients with Significant Coma or Seizures

Treatment with hypertonic sodium chloride increases plasma sodium concentration both directly and through the ensuing sodium load that increases renal sodium loss with a parallel, obligate renal water loss. 100-150ml boluses of 3% sodium chloride can be used to increase plasma sodium by some 2–4 mmol/L over the initial 2–4 hours reducing intra-cerebral pressure in the acute setting. Thereafter, the increase in plasma sodium should be limited to 10 mmol/L in the first 24 hours. Given the risk of over-correction, a pragmatic strategy is to aim for a rise of 6-8 mmol/L in first 24 hours. After the first 24 hours, the rate of rise of sodium should be limited to no more than 8 mmol/L per day.

Avoidance of over-correction is critical. If over-correction does occur, it is important to seek expert advice and consider actively controlling the rate of rise of plasma sodium with hypotonic fluid. Hypertonic fluid should be stopped when the defined clinical target (such as cessation of seizures) or a sodium concentration of 130 mmol/L is reached, whichever is first. If hypertonic sodium chloride cannot be given safely, it should not be given.

Patients with Mild or Less Severe Symptoms and Signs

The clinician has time to make a diagnosis, identify and address contributing factors if possible, and introduce a cause-dependent intervention. Importantly, the limits on rate of rise of sodium remain the same as for the patient with critical signs and symptoms. The majority of patients will have circulating volume depletion or SIAD. Where these are due to drug treatments, the removal of the causal agent may be sufficient to normalise sodium. There will be some cases where the causal agent cannot be removed or where there is an alternative diagnosis. Plasma sodium may rise faster than expected due to ‘auto correction’ of hyponatremia when an underlying cause has simply been removed e.g. correction of glucocorticoid insufficiency or withdrawal of excess desmopressin. Osmotic demyelination can still occur in these circumstances and so care must be taken to control the rise of plasma sodium such that the rate remains within target.

Fluid Challenge in Hypovolemic Hyponatremia

Mild to moderate hypovolemia can be difficult to diagnose clinically and low urine sodium excretion (<20 or 30 mmol/L) may be unreliable as a diagnostic test in the face of diuretic use or renin-angiotensin system blockade. If volume depletion is suspected, a moderate intravenous fluid challenge with 0.5–1 L N-saline over 2–4 hours may be both diagnostic and therapeutic.

Fluid Restriction in SIAD

Fluid restriction of 0.5–1 L/day is a reasonable initial intervention when excess plasma water is suspected and when the clinical condition is not critical. In patients with primary polydipsia, reduction in fluid intake remains the most reasonable approach. All fluids need to be included in the restriction. As SIAD is associated with negative sodium balance, sodium intake needs to be maintained. Several days of restriction may be required before sodium levels rise and a negative fluid balance needs to be confirmed through appropriate monitoring.

Management of Persistent Hyponatremia

Hyponatremia may persist or recur after initial intervention. It is important that the differential diagnosis is reviewed and the basis for intervention reconsidered.

• In SIAD, fluid restriction may be only partly effective or may prove non-sustainable
• Chronic liver or cardiac dysfunction may persist
• Drug therapy exacerbating hyponatremia may need to continue

Clinical decisions on further management have to balance the merits of incremental intervention with those of tolerating mild, persisting hyponatremia. Treatment aimed at simply raising plasma sodium in the absence of signs or symptoms may be of limited benefit and it is important to consider the clinical ‘trade-offs’ that may be required.

Demeclocycline

Demeclocycline has been used in SIAD. It produces a form of nephrogenic diabetes insipidus and so increases renal water loss, even in the presence of high concentrations of AVP. Treatment is 600–1,200 mg/day in divided doses. There is a lag time of some 3–4 days in onset of action. Dose adjustment needs to take this into account. Photosensitive skin reactions and renal impairment are significant adverse effects and limit clinical utility.

Vasopressin Receptor Antagonists

Vasopressin receptor antagonists (Vaptans) are a rational approach to the management of SIAD. They are classified as either selective (V2-R specific) or non-selective (V2- and V1a antagonism). Both increase renal water excretion without a significant impact on renal electrolyte loss (aquaretic action). To avoid precipitating a rapid rise in plasma Na⁺, fluid restriction should be relaxed if these drugs are introduced. They should not be used in profound hyponatremia or in patients with severe symptoms. Their role in the management of SIAD in the majority of patients remains unclear.