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4. Syndrome of inappropriate antidiuresis

4.1. Hyponatraemia

Hyponatraemia (a plasma sodium concentration less than 130 mmols/l) is a common source of morbidity in clinical practice, occurring in 15% of hospitalized patients (28). Hyponatraemia is not invariably associated with a low serum osmolality; high concentrations of other circulating osmolytes (e.g. glucose), or a reduced plasma aqueous phase secondary to dyslipidaemia can result in hyponatraemia but normal plasma osmolality (Table 4). In many clinical situations, hyponatraemia is multifactorial.

Hyponatraemia may reflect an appropriate physiological response to volume depletion. To maintain circulating volume in hypovolaemia, baroregulated VP release may proceed despite plasma osmolalities below the osmotic threshold for VP release. This can result in hyponatraemia, which can become chronic. Though clinical assessment can identify the extracellular volume status of some patients, problems can arise in recognizing mild forms of hypovolaemia. This is important for planning intervention. Hyponatraemia due to the central salt wasting is important to differentiate from that of VP excess. They can both occur following brain injury (trauma or neurosurgery). However, central salt wasting is a hypovolaemic condition, requiring fluid resuscitation rather than restriction. Careful clinical assessment, calculation of urine sodium excretion, and adjunctive invasive monitoring may be required to differentiate the conditions.

4.2. Pathophysiology

An individual with hypoosmolar plasma, a normal circulating volume, and a plasma VP concentration high for the prevailing osmolality, has a syndrome of inappropriate antidiuresis (SIAD. Four patterns of abnormal VP secretion have been identified (29). Absolute plasma VP concentrations may not be strikingly high. The key finding is that that they are inappropriate for the prevailing plasma osmolality (Table 5).

4.3. Aetiology

Many conditions have been reported to cause SIAD, though the mechanism(s) of inappropriate VP release are not clear in many cases (Table 6). SIAD is a non-metastatic manifestation of small cell lung cancer and other malignancies. Some tumours express VP ectopically. However, excessive posterior pituitary VP secretion also occurs in association with malignancy. The normal osmoregulated VP release found in the Type D syndrome suggests an increase in renal sensitivity to VP, or the action of an additional antidiuretic factor.

Drugs induce hyponatraemia through reducing free water clearance and causing sodium/volume depletion (Table 7). Intravenous fluid therapy, a common source of iatrogenic hyponatraemia, can result in hyponatraemia when the administered water load exceeds renal and insensible water losses.

SIAD is a common mechanism of drug-induced hyponatraemia, and can reflect direct stimulation of VP release from the hypothalamus; indirect action on the hypothalamus; or aberrant resetting of the hypothalamic osmostat (30). The prevalence of hyponatraemia in patients taking high dose dopamine antagonists is greater than 25%, and is not restricted to one class of these drugs. Hyponatraemia secondary to antidepressants is well recognized, occurring with most SSRIs, and the related drug Venlafaxine. It can arise in the first few weeks of treatment. Those patients on concurrent diuretic therapy are particularly at risk; indicating hypovolaemia contributes to the hyponatraemia in many cases. Anticonvulsants are another common cause of SIAD and hyponatraemia. The frequency in patients treated with carbamazepine (CBZ) ranges from 4.8 to 40%. Increased sensitivity of central osmoreceptors and increased renal responses to VP have both been described with CBZ.

4.4. Clinical features and diagnosis

The major features in the diagnosis of SIAD are given in (Table 8). The most frequent difficulty in clinical practice is in distinguishing SIAD from chronic, mild hypovolaemia. Urine osmolality tends to be higher than plasma osmolality in both groups. Similarly, plasma VP concentrations will be detectable or elevated in both. Neither is therefore diagnostic of SIAD. Measurement of urinary sodium concentration is helpful.Renal sodium excretion is above 20mol/l in hyponaemic patients with SIAD. Recent data suggest that the measurement of urinary AQP2 excretion may be useful in the differentiation of SIAD from other causes of hyponatraemia (31).

4.5. Management of hyponatraemia

The morbidity and mortality of hyponatraemia secondary to SIAD are the result of central nervous system (CNS) dysfunction (Table 9). Values of serum sodium around 100 mmol/l are life threatening. However, patients commonly have mild symptoms or are asymptomatic, especially if hyponatraemia is less severe and develops slowly. This reflects CNS adaptation: brain oedema being limited by efflux of organic solutes. However, adaptation can complicate the management of hyponatraemia. Changes in brain volume (in response to changes in osmolar gradient across the blood-brain barrier) as serum sodium changes during the treatment can trigger CNS demyelination. This osmotic demyelination is a rare but serious complication of hyponatraemia and its treatment. It can develop within 1-4 days of rapid (>12 mmols per 24 hours) correction of plasma sodium, irrespective of the method employed to achieve it. It can even occur when sodium levels are corrected slowly. Other factors (hepatic failure, potassium depletion, malnutrition) may play a role in susceptibility. Neurological manifestations include quadriplegia, opthalmoplegia, pseudo-bulbar palsy and coma.

Chronic asymptomatic hyponatraemia, with plasma sodium concentrations greater than 125 mmol/l, may not require specific treatment. More severe degrees of hyponatraemia, particularly if symptomatic, require some form of intervention. However, there is no consensus on optimal treatment (28). Where identifiable, correction of the underlying cause(s) is appropriate. This may include withdrawal of drugs, appropriate hormone replacement, avoidance of excess fluid intake, or correction of hypovolaemia. These measures should prevent worsening hyponatraemia, but may not address the deficit in plasma sodium. Any additional intervention should adhere to two key principles.

• Correction should not risk morbidity and mortality (such as that from osmotic demyelination) in excess of that associated with the initial degree of hyponatraemia.
• Correction should be at sufficient pace to reverse life-threatening features of hyponatraemia as quickly as is feasible and safe.

It is thus key to identify the degree of symptoms attributable to hyponatraemia; the time over which hyponatraemia has developed; and the target plasma sodium to be achieved. Hyponatraemia developing over several days is associated with adaptive responses in organic osmolytes within the CNS. Rapid correction of plasma sodium in such circumstance risks changes in brain volume that can precipitate osmotic demyelination. Hyponatraemia developing over several hours is not associated with such adaptive responses. Rapid correction of sodium may be more appropriate in such circumstances, if hyponatraemia is associated with severe symptoms.

Patients with mild to moderate symptoms of hyponatraemia that cannot be attributed to rapid falls in plasma sodium should be managed conservatively. If the patient is not hypovolaemic, this can be with fluid restriction: 500-750 ml/24 hours; aiming to raise plasma sodium to 125-130 mmol/l at a rate not exceeding 8 mmols/l per 24 hours. Plasma sodium should be measured every 12 hours. If sodium levels rise rises too quickly, fluid restriction should be relaxed. Prolonged fluid restriction can be distressing, and additional measures may be required in patients with chronic hyponatraemia due to SIAD. Traditionally these have attempted to either block the release of VP, or generate renal resistance to its antidiuretic actions. Drugs to suppress neurohypophyseal VP secretion (e.g. phenytoin) have met with limited success. SIAD can be treated by inducing NDI with demeclocycline (600 to 1200 mg/day). This may take several weeks to have a maximal effect. Synthetic, non-peptide V2-R antagonists increase solute-free water excretion. This new class of aquaretics could greatly improve the management of this condition (32).

If hyponatraemia is associated with severe symptoms, and especially if it has developed rapidly, intervention with hypertonic fluids may be indicated. The target plasma sodium of such intervention should be one that reverses life-threatening complications. This may involve only a relatively small rise in sodium, not normalization. Plasma sodium concentration should rise no more than 1-2 mmol/l per hour, with a total increment of no more than 8 mmol/l per 24. One method of calculating the volume of administered fluid required over a given period is as follows (28).

• Volume required = (Change in plasma [Na+] required over target period) / (Change in plasma [Na+] produced by 1l of replacement fluid)
  The change in plasma sodium concentration brought about by 1l of fluid replacement is calculated according to the following equation.
• Change in serum [Na+] = ([Na+] concn. of replacement fluid - plasma [Na+]) / 
  (Estimated total body water (in litres) + 1)
  Total body water is calculated as a fraction of total body weight (Table 10). It is imperative that the fluid regimen is reassessed at regular intervals, guided by careful clinical assessment and laboratory monitoring. The rapid correction should be stopped if the following targets are achieved.

• Reversal of life-threatening manifestations of hyponatraemia.
• Moderation of other non-life threatening manifestations of hyponatraemia.
• Achievement of a plasma sodium concentration of 125mmols/l.

5. Adipsic and hypodipsic syndromes

Adipsic and hypodipsic disorders are characterized by inadequate spontaneous fluid intake due to defects in osmoregulated thirst. Patients deny thirst and not drink, despite dehydration and hypovolaemia. If the defect is mild, the resultant hypernatraemia is often well tolerated. Severe disorders can lead to somnolence, seizures and coma. Because of the close anatomical relationship of the osmoregulatory centers for thirst and VP release, adipsic syndromes are often associated with defects in osmoregulated VP release and HDI.

5.1. Classification and etiology

Four patterns of adipsic/hypodipsic syndrome are recognized (Table 11). Causes are outlined in Table 12. Patients with the Type A syndrome osmoregulate around a supra-normal osmolar set point and are protected from extreme hypernatraemia, as are those with the Type B syndrome. In Type C adipsia, osmoregulated thirst and VP release are absent. Patients present with adipsic HDI. Precipitants include rupture and repair of anterior communicating artery (ACA) aneurysm, as the osmoreceptors mediating both thirst and VP release receive a blood supply from perforating branches of the anterior cerebral artery and ACA. Some patients with the Type C syndrome have constitutive low level VP release, and are at risk of dilutional hyponatraemia (12).

5.2. Management 

As those with Type A and Type B adipsia are protected from extreme hypernatraemia, treatment is to recommend an obligate fluid intake of about 2l/24 hours with appropriate adjustment for climate and season. If fluid balance cannot be maintained during intercurrent illness, hospital in-patient management may be required. The adipsic HDI of the Type C syndrome can be difficult to manage. The structural and vascular problems producing the syndrome often lead to associated defects in short term memory and task organization, complicating long-term management. A pragmatic approach is to effectively dictate an acceptable urine output (1-2l/24 hours) with regular DDAVP (producing a fixed obligate antidiuresis), and to vary the daily fluid intake depending on day to day fluctuation from a target weight at which the patient is euvolaemic and normonatraemic.

• Daily fluid intake = 2L * (daily weight - target weight).

Plasma sodium should be checked weekly, to avoid the creeping development of hyper- and hyponatraemia as dry weight changes. This approach can result in stable fluid balance and successful independent living (33).