Clinical manifestations

Presentation and course

Clinical symptoms of SIADH are reflected in the severity of hyponatremia and its acuity. Severe hyponatremia is defined as serum sodium less than 125 mmol/L and may manifest with hallucinations, seizures, altered mental status including coma, and death when acute (less than 48 hours). If hyponatremia has been chronic then these symptoms may be milder (15). Moderate hyponatremia between 125 to 129 mmol/L may include milder symptoms such as cognitive change, headache, and general fatigue. It is especially important to clarify the chronicity of hyponatremia, not only for recognition of symptoms and risk, but also for guiding therapeutic correction of the sodium level. Rapid overcorrection can lead to permanent neurologic deficits known as osmotic myelinolysis, which is further described under outcomes (11).

Prognosis and complications

The morbidity and mortality associated with SIADH may be due either to the underlying etiology causing SIADH or to the consequences of hyponatremia. As discussed in the section above, acute hyponatremia can lead to severe neurologic deficits and even death if not detected and corrected acutely. Chronic hyponatremia has also been associated with increased morbidity and mortality. In patients hospitalized for cirrhosis, myocardial infarction, pneumonia, and heart failure, hyponatremia has been associated with an increased risk of mortality when compared with normonatremic patients admitted with the same diagnosis (06). It has also been demonstrated that even mild hyponatremia (less than 135 mmol/L) increases the risk of falls (OR 1.61) and bone fractures (OR 2.14) in elderly persons (08).

Biological basis

Etiology and pathogenesis

The human body tightly regulates the serum osmolality within 280 to 295 mOsm/kg. Arginine vasopressin or antidiuretic hormone (ADH), as referred to in this article, is the primary neurohormonal signal for the kidneys to prevent aquaresis and stimulates thirst. Within the collecting ducts of the nephron, ADH binds V2 receptors, leading to an increase in aquaporin-2 channels at the membrane and allowing for increased water permeability along an osmotic gradient. This leads to resorption of water at the collecting tubules and subsequent concentration of urine. In absence of ADH, aquaporin channels are endolytically retrieved, and normal aquaresis occurs. ADH is secreted by the posterior pituitary gland in response to signals from the anterior hypothalamus. The predominant variables that affect this stimulus are osmoreceptive and baroreceptive. When peripheral baroreceptors (ie, carotid sinus, aortic arch) detect a drop in pressure, ADH release is stimulated. Conversely, if a change of osmolality is detected, for example due to polydipsia, then ADH secretion is suppressed to nearly undetectable levels, and dilute urine is produced until return to the normal osmolality threshold (32). The TRVP family of receptors has been identified as osmoreceptors (31). Hyponatremia secondary to SIADH is the result of water retention due to 1 of 2 mechanisms: dysregulated release of ADH or gain-of-function mutations in the V2 receptors of the renal collecting tubules (09).

Epidemiology

SIADH is one of the leading causes of hyponatremia in hospitalized patients. In a multinational registry analysis of patients with euvolemic hyponatremia, the most common underlying etiology of SIADH was tumor related (23.4%). Drug induced causes comprised of 17.8%, whereas other pulmonary disease was 10.7% and CNS disease 8.5%. In 34.8% of patients, the source was unidentified or other associated causes (33).

Differential diagnosis

When considering the diagnosis of SIADH, it is important to rule out other etiologies of hyponatremia.

Hypovolemic hyponatremia is the most important differential to recognize as it is readily reversible, and absence of recognition can lead to life threatening complications including multi-system organ failure. Hyponatremia of this type occurs when the overall intravascular solute is depleted, such as with vomiting or diarrhea, and the concentration mechanism of the urine is maximized as stimulated by the baroreceptive responses.

Pseudohyponatremia (also known as hyperosmotic hyponatremia) is a laboratory artifact that occurs when high levels of lipids or proteins are present in serum, such as patients with triglyceridemia or paraproteinemia. A confirmation test for true hyponatremia would be to check the serum osmolality in this scenario. Another form of artificial hyponatremia is that of hyperosmotic hyponatremia including hyperglycemic states and iatrogenic hyperosmolar states such as with the use of mannitol. This occurs when the increased osmolarity of the serum drives free water into the extracellular space, thereby reducing the concentration of sodium. This is often incorrectly referred to as pseudohyponatremia.

Hypervolemic hyponatremia is typically seen in disease states in which the effective hemodynamic volume and pressure is low, thus activating the anterior hypothalamus to release ADH, such as in heart failure and cirrhosis. Due to low cardiac output and decreased perfusion pressures, the patient may be clinically volume overloaded, but the physiologic mechanisms to contract and retain water are activated.

This is distinguished from excess free water states such as primary polydipsia or beer potomania in which not enough solute and excess water is consumed. Other iatrogenic forms of hyponatremia include diuretic use (thiazides and loop diuretics).

Another less common, though important disease to consider as an etiology for hyponatremia, is adrenal insufficiency. In this setting, deficiency in cortisol or aldosterone can lead to ADH secretion. Hypothyroidism is also noted as a potential cause for hyponatremia; however, the evidence for causality is weak and hyponatremia is typically only noted in severe cases of hypothyroidism, such as seen in myxedema coma (18).

For patients with neurologic disease, an important differential to consider is cerebral salt wasting. This is often difficult to distinguish from SIADH as patients with neurologic injury can have either or both. Most commonly associated with subarachnoid hemorrhage, cerebral salt wasting is the loss of sodium via renal loss. It can clinically be distinguished by hypovolemic state, as free water will be excreted with sodium. The urine concentration in this setting is often normal. Unlike the management of SIADH, which often entails fluid restriction, cerebral salt wasting requires restoration of intravascular volume (23; 20).

Diagnostic workup

The diagnostic criteria are largely unchanged from that initially described by Schwartz and Bartterer. It requires decreased effective osmolality less than 275 mOsm/kg of H20, urine osmolality greater than 100 mOsm/kg of H20, clinical euvolemia, urinary sodium greater than 40 mmol/L, normal thyroid and adrenal function, and no recent diuretic use (03). Despite these criteria, the diagnosis can be difficult to establish and clinical determinations of euvolemia uncertain. Low blood urea nitrogen, low serum uric acid, and high urine sodium may be suggestive of SIADH (10). Fractional excretion of uric acid may be useful in distinguishing SIADH from that of diuretic use, with FEua greater than 12% having the highest sensitivity and specificity (12). Copeptin, which is a cleaved byproduct of ADH, has generated interest as a means to distinguishing forms of hyponatremia, but data have been mixed and may be most useful in distinguishing primary polydipsia and hypovolemic hyponatremia (05; 19).

It is important to remember that SIADH requires exclusion of the differential diagnoses for hyponatremia as listed in the previous section. When the diagnosis of SIADH is established, it is also likely a symptom of an underlying disorder and workup should involve evaluations for the etiology.

An initial thorough review of medications is indicated. The most common implicated medications include antidepressants (SSRI, MAOI, and TCA), phenothiazine antipsychotics, and antiepileptics (most commonly, lamotrigine, oxcarbazepine, carbamazepine, and valproic acid). Other medications that have been implicated include chemotherapeutic drugs (vinca alkaloids, platinum compounds, methotrexate, ifosfamide, and cyclophosphamide) and illicit drugs such as MDMA and levamisole (11).

Even targeted therapies, such as anti-VEGFR drugs and immune checkpoint inhibitors (which have become very popular treatments of certain oncologic malignancies) have been associated with hyponatremia and SIADH. The exact mechanism of hyponatremia in the antiangiogenic drugs is unknown. However, in the immune checkpoint inhibitors, hyponatremia is related to hypophysitis associated with immune-related side effects of the drugs (15).

Central nervous systems pathologies that might result in SIADH are vast and may include tumors, stroke, hemorrhage, traumatic injury, or infection. Rarely would hyponatremia lead to the diagnosis of CNS disease without any other presenting neurologic symptoms. Another related neurologic etiology of SIADH is the transient hyponatremia that occurs following pituitary resection as part of the well-described “triple-phase response.” This may occur following sellar mass resections, which is where there is initial suppression of ADH presenting as diabetes insipidus, followed by release of ADH with clinical hyponatremia before a longer standing impairment of ADH production ensues (14).

Perhaps more importantly, a work-up for malignancy is indicated, particularly if hyponatremia is present with other concerning symptoms such as weight loss. Small cell lung cancer is the most common association and is known to be an ectopic source of ADH secretion (17). There have been reports of lymphoma, GI malignancy, and oropharyngeal malignancy also leading to SIADH. Though lung malignancy is the most commonly recognized pulmonary pathology, it can also be seen in cystic fibrosis and in infectious pulmonary disease with bacterial pneumonia, tuberculosis, fungal infections, etc.

Hereditary forms of inappropriate diuresis have been identified. Although not all of these directly cause an excess of ADH, they do cause alterations in normal functioning of the system as described previously. Mutations leading to a loss of the TRVP4 receptor leads to insensitivity of the osmole receptors, thereby blunting suppression of ADH in the setting of low serum osmolality (29). Mutations in the V2 receptor can result in gain of function leading inappropriate resorption of water, similar to the effect of ADH (13).

Management

Traditionally, fluid restriction was the therapy of choice for management of SIADH if symptoms were clinically mild or absent. Based on an analysis of a hyponatremia registry, fluid restriction alone only generates modest increases in sodium (median 1 ml/dL per day), and only half of patients treated with fluid restriction alone will successfully correct greater than 5 mmol/L (33).

For moderate to severe symptoms of hyponatremia (ie, with neurologic symptoms), correction with hypertonic saline is recommended by both European and United States guidelines. Though they vary in dosage, both recommend a small bolus 100 to 150 ml of 3% hypertonic saline to increase the serum sodium between 4 to 6 mmol/L to prevent life threatening cerebral edema (32; 28).

An alternative osmotic agent in raising serum sodium is enteral urea. European guidelines recommend this as an alternative therapy at 0.25 to 0.5 g/kg daily. There are also data to suggest safety for use in patients with critical neurologic injury with SIADH (22; 02). A commercial formulation of enteral urea has become available in the United States and may be considered for sodium correction in the inpatient setting (24). Caution is advised in patients with cirrhosis.

Vasopressin antagonists, tolvaptan and conivaptan, have been FDA approved in the United States for the treatment of hyponatremia secondary to SIADH. They work by disrupting the binding of ADH to vasopressin receptors, thereby preventing the insertion of water channels into the membrane of the collecting duct (04). Randomized controlled trials demonstrate conivaptan intravenous at 40 mg per day, increased plasma sodium by 6.3 mmol/L (35), and tolvaptan (oral) by 3.6 mmol/L over 4 days (25). Post marketing analysis has suggested that in clinical use, the rate of correction may be more rapid with 1 study reporting up to 25% of patients with SIADH correcting greater than 12 mEq/L per day, with the highest risk being in patients with low serum sodium (less than or equal to 121 mEq/L) and low serum urea nitrogen (less than or equal to 10mg/dL) with tolvaptan (16). It is important to note that in the above-mentioned randomized trials, patients with serum sodium less than 120 mEq/dL were excluded, as were patients with symptomatic neurologic deficits. This is especially important when considering its use in neurologic patients, as normal thirst response may help protect patients from overcorrection, which may be lacking in the neurologic population. Therefore, it is recommended to discontinue fluid restriction and hypertonic therapies when treating with vasopressin receptor antagonists (32; 04). Medications that have fallen out of favor in the treatment of hyponatremia include lithium and demeclocycline. These medications are not recommended due to their variable efficacy and adverse side effect profiles (28).

The rate of appropriate correction in chronically hyponatremic patients is debated and grows more conservative with emerging evidence. Although previous correction of no greater than 12 mmol/L within the first 24 hours was considered safe, more recent case reports of post-therapy neurologic complications at these rates have led to changes in recommendations. Currently, the European guidelines recommend no greater than 10mmol/L within the first day, and no greater than 8 mmol/L during the second day. The United States guidelines take an even more conservative approach recommending 4 to 8 mmol/L per day, and if the patient is at high risk for osmotic demyelination (cirrhosis, hypokalemia, alcoholism), then 4 to 6 mmol/lL per day is recommended.

Outcomes

Scientific evidence that correction of serum sodium reduces morbidity and mortality has been variable despite the support of evidence that hyponatremia leads to worse outcomes in hospitalized patients and leads to chronic comorbidities such as falls and bone fractures. The most feared complication of sodium correction is osmotic demyelination in a patient who is chronically hyponatremic and corrected too rapidly. In patients who are chronically hyponatremic (greater than 24 hours), there is a reduction in organic osmolytes intracellularly. With correction of sodium, there is efflux of free water extracellularly and cell shrinkage. Progressive neurologic symptoms occur over days. Neurologic symptoms such as quadriparesis can be permanent. It has been long recognized that this can occur in extrapontine sites. Patients at increased risk include patients with liver disease, liver transplant, alcoholism, and malnutrition (27).

Special considerations

Pregnancy

Mild hyponatremia is expected in normal pregnancy. Typically, there is a reduction in osmolality of approximately 10 mOsm/kg and in sodium by 5 mmol/L. Pregnancy is an example of reset osmostat, in which vasopressin is secreted still at a lower osmolality. SIADH can occur during pregnancy and if correction is required, fluid restriction should not be overly aggressive due to the risk of developing oligohydramnios. Fluid restriction of 1.5 L is recommended. If more aggressive correction is required, hypertonic saline may be used (21).

Anesthesia

As in any metabolic derangement, the initiation of general anesthesia should await the normalization, or at least stabilization, of serum sodium concentration.