Hyponatraemia (serum sodium <135 mmol/ L) is a feature in some 15– 20% of non- selected emergency hospital admissions. It is as sociated with increased morbidity and mortality across a range of conditions and data support the association of correction of hyponatraemia with improved outcome. However, the relationship of serum sodium to clinical outcomes is not straightforward and may not be a causal one. Comorbidity and underlying disease se verity may be the more significant contributors to outcomes in patients with hyponatraemia.

VP plays a key role in many clinical situations in that include hyponatraemia. However, when VP does play a role, VP production may not be inappropriate. Hyponatraemia may reflect an appropriate physiological response to volume depletion, with baroregulated VP release persisting despite plasma osmolalities below the normal osmolar threshold for VP release. In this situation, continued physiologically appropriate VP release can lead to hyponatraemia which can be persistent. Though clinical assessment can identify the extracellular volume status of some patients, it is unreliable and has poor sensitivity and specificity.

Pathophysiology of the Syndrome of Inappropriate Antidiuresis

 An individual with hyperosmolar plasma but a normal circulating volume and in whom in whom the plasma VP concentration is high for the prevailing osmolality, has a syndrome of inappropriate antidiuresis (SIAD) due to VP excess. A variety of conditions are as sociated with SIAD. To date, four patterns of abnormal VP secretion have been identified (Table 1). Absolute plasma VP concentrations may not be strikingly high; the key finding is that that they are inappropriate for the prevailing plasma osmolality. When this obligate antidiuresis is not accompanied by decreased water intake, haemodilution is inevitable.

Table1. Classification of SIAD

Aetiology

Many conditions have been reported to cause SIAD. SIAD is a non- metastatic manifestation of small cell lung cancer and other malignancies. The mechanism(s) of inappropriate VP release in many cases of SIAD are not clear. Some tumours are an ectopic source of VP, and produce a type A syndrome. However, excessive posterior pituitary VP secretion also occurs in association with malignancy. In fact, the absence of an ectopic VP source suggests a lesion in the neurohypophysis or its regula tory afferent pathways. The similarities between SIAD type B and the changes in VP regulation in response to hypovolaemia and hypotension, suggest a single lesion in the baroregulatory afferent pathways. In contrast, the normal osmoregulated VP re lease found in the type D syndrome suggests an increase in renal sensitivity to VP, or the action of an as yet unidentified antidiuretic factor.

SIAD is a common mechanism of drug induced hyponatraemia. It can reflect direct stimulation of VP release from the hypothalamus; indirect action on the hypothalamus via effects on higher centres; or aberrant resetting of the hypothalamic osmostat.

Dopamine antagonists cause SIAD through stimulation of VP re lease. Antidepressant medication, including selective serotonin re uptake inhibitors (SSRIs), potentiate stimulatory central adrenergic input to VP- producing neurones. Opiates also stimulate inappropriate VP release through enhancing central adrenergic drive. SIAD is commonly associated with antiseizure medication. The frequency of hyponatraemia in patients treated with carbamazepine ranges from 4.8 to 40%, though the majority of such cases are asymptomatic. Carbamazepine increases both the sensitivity of central osmoceptors, and renal sensitivity to VP.

Clinical Features, Diagnosis, and Differential Diagnosis of SIAD

The major features in the diagnosis of SIAD are highlighted in Box 1. The most frequent problem in clinical practice is distinguishing SIAD from chronic, mild hypovolaemia. In both conditions, urine osmolality tends to be higher than plasma osmolality. Plasma VP will be detectable or elevated in both. Neither is therefore diagnostic of SIAD. The diagnosis hinges on confirming excretion of urine that is not maximally dilute in the context of a dilute plasma (i.e. urine concentration greater than 100 mOsml/ Kg). Renal sodium excretion should be above 30 mmol/ L to make a diagnosis of SIAD. Below this value, volume depletion should be considered the more likely cause of hyponatraemia. SIAD is often associated with urine sodium concentrations of 60 mmol/ L or more, as persisting SIAD is a volume expanded state. Consistent with this, there is evidence of mild sodium loss as other regulators of volume homeostasis attempt to minimize volume expansion.

Box1. Diagnosis of SIAD

The role of VP production or action in producing hyponatraemia can be confirmed indirectly by assessing excretion of a standard water load over a fixed time: the water load test (Table 2). Normal subjects excrete 78– 82% of the ingested water load in the 4 h observation period. This is reduced to 30– 40% in the presence of constitutive VP production or action. The test is not essential to establish a diagnosis and is not recommended as part of routine clinical practice.

Table2. Protocol for water load test

Exercise- Associated Hyponatraemia

 Extreme endurance exercise is a profound physiological stress. Non- osmoregulated VP release is a central feature of extreme endurance exercise, reflecting this physiological stress and determined principally by the duration of the event and the effort involved. Combined with reduced renal blood flow (another feature of extreme endurance exercise) this VP release can lead to a marked antidiuretic state. In this situation, fluid intake in excess of water loss can lead to hyponatraemia. Those athletes developing hyponatraemia during endurance exercise demonstrate weight gain over the course of the event, clearly implicating water intake in excess of water and electrolyte loss as the cause. There is a positive correlation between the odds ratio for developing hyponatraemia during extreme endurance exercise and the length of time taken to complete the event. ‘Occasional’ runners are therefore particularly at risk of exercise- associated hyponatraemia. They should be advised to follow their thirst and avoid rigid, time- based fluid intake. Importantly, health professionals need to be aware of the problem of exercise- associated hyponatraemia and resist resuscitation with large volumes of hypo tonic fluid in the absence of appropriate indications and without biochemical monitoring.

Nephrogenic Syndrome of Inappropriate Antidiuresis

 While loss of function mutations of the V2- R are the cause of X- linked nephrogenic diabetes insipidus, rare individuals express the reciprocal problem: constitutively activating mutations in the V2- R that lead to VP- independent, but V2- R mediated, antidiuresis resulting in persistent hyponatraemia. This nephrogenic syndrome of inappropriate antidiuresis (NSIAD) can have a variable phenotype. Although initially described in male infants with persistent hyponatraemia, the condition is not limited to males and may mani fest in adulthood. This is consistent with in the condition being X- linked but with variable expression in heterozygous females.

Central Salt Wasting

This acquired, primary natriuretic state is described as a com bination of hyponatraemia with hypovolaemia associated with neurological or (more often) neurosurgical pathologies. The definition, true prevalence, and underlying pathophysiology remain a subject of controversy. SIAD can occur in the same group of patients in whom central salt wasting (CSW) has been reported and both are associated with urine sodium concentrations greater than 40 mmol/ L. Importantly therefore, the diagnosis of CSW hinges on the natural history: the development of hyponatraemia being preceded by natriuresis and diuresis with ensuing clinical and biochemical features of hypovolaemia. In contrast to SIAD, urea and creatinine are elevated and there may be postural hypotension.

The context and opposed cause- directed management approaches to CSW and SIAD can lead to significant tension in clinical practice. CSW is a particular concern for the neurosurgical patient in whom autoregulation of cerebral blood flow is disturbed and in whom small reductions in circulating volume can reduce cerebral perfusion. The management of CSW is volume replacement with 0.9% saline; while the cause- directed approach to SIAD would often involve restriction of fluid. A cause- independent approach to the management of the neurosurgical patient with hyponatraemia needs to balance management of hyponatraemia with the need to avoid threatening cerebral perfusion and avoidable vasospasm. A prospective, single centre study including 100 cases of hyponatraemia developing after subarachnoid haemorrhage failed to identify a case of CSW. Rather, SIAD, glucocorticoid deficiency and inappropriate fluid administration were identified as the key mechanisms of hyponatraemia.

Treatment of Hyponatraemia Secondary to SIAD

Independent of the underlying cause, the morbidity SIAD reflects the impact of hyponatraemia on CNS function from cerebral oedema and primary neuronal dysfunction (Box 2.). The relationship between serum sodium and neurological function is not simple: patients with marked biochemical disturbance may have mild symptoms if hyponatraemia develops over a prolonged period. This reflects CNS adaptation to reduced osmolality through inorganic and organic ion efflux. These adaptive CNS mechanisms can complicate the management of hyponatraemia. Over rapid correction of serum sodium following the gradual development of hyponatraemia can lead to changes in brain volume as the osmolar gradient across the blood- brain barrier alters. This change in volume can trigger CNS osmotic demyelination syndrome (ODS): a rare but serious complication of hyponatraemia and its treatment. ODS develops within 1– 4 days of rapid (>10– 12 mmol/ L per 24 hours) correction of serum sodium. Other factors play a role in susceptibility: hepatic failure, potassium depletion, and malnutrition. Neurological manifestations include quadriplegia, ophthalmoplegia, pseudo- bulbar palsy, and coma.

Box2. Symptoms and signs of hyponatraemia secondary to SIAD

In SIAD, hyponatraemia with serum sodium concentrations greater than 130 mmol/ L may not require specific treatment. More significant degrees of hyponatraemia, associated with symptoms, can require intervention

Management of SIAD Associated with Severe or Moderately Severe Symptoms

 Hyponatraemia associated with severe or moderately severe symptoms requires urgent management. Treatment is cause- independent and should be given priority over establishing the aetiology of hyponatraemia. The principle of treatment is to reduce immediate risk through increasing serum sodium to a level that decreases morbidity but at a rate that does not result in harm through precipitating ODS. Critically, the immediate target should not be to normalize serum sodium.

Determining hypertonic fluid prescription by calculated serum sodium deficit is associated with a significant risk of over- rapid correction. A pragmatic approach is to use small boluses of hypertonic fluid to achieve a 5 mmol/ L rise in serum sodium in the first hour of treatment. The increase in serum sodium should be limited to 10 mmol/ L in the first 24 hours, and no more than 8 mmol/ L per 24 hours thereafter. An increase above the recommended rate should prompt review and consideration of active management with hypo tonic fluid, with or without concurrent use of DDAVP to limit or reverse the trajectory in serum sodium. Once the clinical situation is stable, investigations to establish the cause of hyponatraemia are recommended to guide cause- directed therapy.

Management of SIAD Associated with Mild to Moderate Symptoms

 Cause- directed therapy is the foundation managing SIAD in this context. In parallel, fluid restriction of 0.5– 1 L/ day is a reasonable parallel intervention. The increase in serum sodium should be limited to 8– 10 mmol/ L per 24 hours. All fluids need to be included in the restriction. As SIAD is associated with a degree of natriuresis, sodium intake should be maintained. Fluid restriction may need to be maintained for several days before sodium levels normalize and it is important that a negative fluid balance is confirmed during this period. As cause- directed therapy progresses (e.g. treatment of underlying infection or removal of drug- causing SIAD), fluid re striction can appropriately relaxed.

Drug Treatment in SIAD

If hyponatraemia persists or recurs after initial intervention, it is important that the underlying diagnosis is reviewed the intervention reconsidered. Clinical balance is key. There may be situations where withdrawal of a causal agent for SIAD (e.g. drug) is not practical or in the overall benefits of the patient. In other situations, fluid restriction may be only partly effective, be poorly tolerated, or may prove non- sustainable. Clinicians may thus have to balance the merits of incremental intervention with those of tolerating mild, persisting hyponatraemia.

V2- R antagonists (Vaptans) are a rational approach to the management of hyponatraemia due to SIAD. They are pure aquaretics, increasing renal water excretion without impacting on renal electrolyte loss. Both selective (V2- R specific) and non- selective (V2- and V1a- R antagonism) increase serum sodium in patients with normal or increased plasma volume and can increase serum sodium within 4– 6 hours. There use can be associated with over- rapid correction. In the absence of robust data on cost- utility and evidence on patient- orientated outcomes other than serum sodium, the role of V- R antagonists in the management of SIAD remains to be clarified.

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مواضيع ذات صلة

Hypothalamic Diabetes Insipidus

The Physiology of oxytocin (OT)

Regulation and Biological Actions of Growth Hormone and Prolactin

Hypothalamic Control of Growth Hormone Secretion

Corticotropin-Releasing Hormone

The Physiology of Vasopressin

Gonadotropin-Releasing Hormone

Thyrotropin-Releasing Hormone

Biosynthesis of Adrenal Cortex Mineralocorticoids, Glucocorticoids, and Some Androgens

Mechanisms of hormone action: Cell Signaling by Membrane Receptors

Biosynthesis of Peptide and Protein Hormones

Hormones and Their Communication Systems