Continuing Education Activity

Syndrome of inappropriate antidiuretic hormone ADH release (SIADH) is a condition defined by the unsuppressed release of antidiuretic hormone (ADH) from the pituitary gland or nonpituitary sources or its continued action on vasopressin receptors. The condition was first detected in two patients with lung cancer by William Schwartz and Frederic Bartter in 1967. They developed the classic Schwartz and Bartter criteria for diagnosing SIADH, which has not changed. SIADH is characterized by impaired water excretion leading to hyponatremia with hypervolemia or euvolemia. This activity reviews the causes, presentation, and diagnosis of SIADH and highlights the interprofessional team's role in its management.

Objectives:

• Outline the benign and malignant causes of the syndrome of inappropriate antidiuretic hormone.
• Describe the blood and urine features of the syndrome of inappropriate antidiuretic hormone.
• Summarize the treatment options for the syndrome of inappropriate antidiuretic hormone.
• Review the importance of improving care coordination among interprofessional team members to improve outcomes for patients affected by inappropriate antidiuretic hormone syndrome.

Introduction

Syndrome of inappropriate antidiuretic hormone ADH release (SIADH) is a condition defined by the unsuppressed release of antidiuretic hormone (ADH) from the pituitary gland or nonpituitary sources or its continued action on vasopressin receptors. The condition was first detected in two patients with lung cancer by William Schwartz and Frederic Bartter in 1967. They developed the classic Schwartz and Bartter criteria for the diagnosis of SIADH, which has not changed. SIADH is characterized by impaired water excretion leading to hyponatremia with hypervolemia or euvolemia.[1][2][3]

Etiology

Most commonly, SIADH occurs secondary to another disease process elsewhere in the body. Hereditary SIADH, also known as nephrogenic SIADH, has been ascribed to the gain of function mutation in vasopressin 2 (V2) receptors in the kidneys. 

Conditions Frequently Leading to SIADH

Central nervous system disturbances: Any central nervous system (CNS) abnormality can enhance ADH-release from the pituitary gland, leading to SIADH. These disorders include stroke, hemorrhage, infection, trauma, mental illness, and psychosis.

Malignancies: Small cell lung cancer (SCLC) is the most common tumor leading to ectopic ADH production. Less commonly, extrapulmonary small cell carcinomas, head and neck cancers, and olfactory neuroblastomas also cause ectopic ADH release.

Drugs: A number of drugs associated with SIADH act by enhancing the release or effect of ADH. The most common drugs include carbamazepine, oxcarbazepine, chlorpropamide, cyclophosphamide, and selective serotonin reuptake inhibitors (SSRI). Carbamazepine and oxcarbazepine act in part by increasing the sensitivity to ADH. Chlorpropamide increases the number of V2 receptors in collecting tubules. As high-dose intravenous cyclophosphamide is given with a fluid load to prevent hemorrhagic cystitis, SIADH in such patients is a particular problem, leading to potentially fatal hyponatremia. SSRIs cause SIADH by an unknown mechanism, but people above 65 years of age are more at risk. "Ecstasy" (methylenedioxymethamphetamine), a drug of abuse, is particularly associated with the direct release of ADH. (It also stimulates thirst, which further worsens hyponatremia.) Less commonly, non-steroidal anti-inflammatory drugs (NSAIDs), opiates, interferons, methotrexate, vincristine, vinblastine, ciprofloxacin, haloperidol, and high dose imatinib have been linked with SIADH. 

Surgery: Surgical procedures are often associated with hypersecretion of ADH, a response that is probably mediated by pain afferents.[4]

Pulmonary disease: Pulmonary diseases, particularly pneumonia (viral, bacterial, tuberculous), can lead to SIADH by unknown mechanisms. A similar response has infrequently been seen in patients with asthma, atelectasis, acute respiratory failure, and pneumothorax.

Hormone deficiency: Both hypopituitarism and hypothyroidism may be accompanied by hyponatremia and a SIADH picture that can be corrected by hormone replacement. 

Hormone administration: SIADH can be induced by exogenous hormone administration, as with vasopressin (to control gastrointestinal bleeding), desmopressin (dDAVP, to treat von Willebrand disease, hemophilia, or platelet dysfunction), and oxytocin (to induce labor). All three act by increasing the activity of the vasopressin-2 (V2; antidiuretic) receptors.

Human Immunodeficiency Virus (HIV) infection: A common laboratory manifestation seen in HIV infection, either with the acquired immune deficiency syndrome (AIDS) or early symptomatic HIV infection, is hyponatremia. It can be due to SIADH, or it can be due to volume depletion, secondary to adrenal insufficiency or gastrointestinal losses. Pneumonia, due to Pneumocystis carinii or other organisms and CNS infections by opportunistic pathogens, is also responsible for SIADH. [5]

Hereditary SIADH: A gain of function mutation in the gene for the renal V2 receptors (located on the X chromosome) is responsible for hereditary SIADH. Such mutation locks the renal V2 receptors in a continuous active state, leading to excessive water absorption and hyponatremia, which in turn is resistant to vasopressin receptor antagonists. 

Epidemiology

The incidence of SIADH increases with age but, recently, a higher incidence of SIADH has been reported in children. Children and older adults are more hyponatremic, particularly when hospitalized for respiratory and CNS infections like pneumonia or meningitis. SIADH is also more prevalent in hospitalized, post-operative patients due to the administration of hypotonic fluids, drugs, and the body's response to stress. 

Pathophysiology

ADH, also known as arginine vasopressin, is formed in the hypothalamus and stored in the posterior pituitary via a pituitary stalk. The main function of ADH is osmoregulation. However, a severe reduction in effective blood volume shifts the function of ADH to volume regulation, even at the expense of effective plasma osmolality or tonicity. "Plasma osmolality" should be differentiated from "effective plasma osmolality" or "plasma tonicity," as the latter is determined by effective osmoles in the extracellular fluid  (ECF) such as sodium (which is not freely permeable across cell membranes), the main component of the ECF. Glucose and urea also increase the plasma osmolality, but these are ineffective osmoles as they are freely permeable across the cell membranes and do not take part in maintaining plasma tonicity.  

Osmoregulation

The most important and primary function of ADH is to maintain the plasma tonicity, primarily by an alteration in water balance. Osmoreceptors detect the change in effective plasma osmolality in the hypothalamus. A decrease in tonicity prevents ADH release and prevents water retention. An increase in tonicity causes ADH release, which acts on V2 receptors on the luminal surface of cortical and medullary collecting tubular cells. Under the influence of ADH, unique aquaporin-2 water channels are formed by the fusion of pre-formed cytoplasmic vesicles in the tubular cells, and water is absorbed down the concentration gradient. Once the water is absorbed, these channels are removed by endocytosis and returned to the cytoplasm. The osmoreceptors are extremely sensitive, responding to alterations in the plasma tonicity of as little as 1%.[6] The osmotic threshold for ADH release in humans is about 280 to 290 mOsmol/kg. There is little circulating ADH below this level, and the urine should be maximally diluted with an osmolality below 100 mOsmol/kg. Above the osmotic threshold, there is a relatively linear rise in ADH secretion. This system is so efficient that the plasma osmolality does not typically vary by more than 1% to 2%, despite wide water intake fluctuations.[7]

In patients with SIADH, levels of ADH are high even in the presence of decreased plasma osmolality and/or hyponatremia. Excess water absorption keeps the blood volume high or normal. 

Volume Regulation

An acute drop in blood pressure as sensed by " volume receptors" rather than "osmoreceptors" causes ADH release (along with other hormones like rennin and epinephrine), which generates free water absorption from the kidneys. This can potentially lead to hyponatremia and a decrease in effective ECF osmolality. So, the main focus in rapid and/or substantial decrease in blood volume is "volume regulation," even at the cost of osmolality. This effect is more prominent in patients with liver disease or cardiac disease, and hyponatremia in such patients is the direct predictor of a worse prognosis.[8]

History and Physical

Clinical manifestations of SIADH can be due to hyponatremia and decreased ECF osmolality, which causes the water to move into the cells causing cerebral edema. Signs and symptoms depend upon the rate and severity of hyponatremia and the degree of cerebral edema. The earliest clinical manifestations of acute hyponatremia include nausea and malaise, which may be seen when the serum sodium concentration falls below 125 to 130 mEq/L (normal 135 to 145mEq/L). Vomiting is an ominous sign for patients with acute hyponatremia. With a more severe and acute fall in sodium concentration, headache, lethargy, obtundation, and eventually, seizures can occur. Coma and respiratory arrest can occur if the serum sodium level falls below 115 to 120 mEq/L. Acute hyponatremia encephalopathy may be reversible, but permanent neurologic damage or death can occur, particularly in premenopausal women.

Chronic hyponatremia allows cerebral adaptation, and the patients remain asymptomatic despite a serum sodium concentration below 120mmol/L. Nonspecific symptoms like nausea, vomiting, gait disturbances, memory, cognitive problems, fatigue, dizziness, confusion, and muscle cramps can occur with chronic hyponatremia. Sign and symptoms or mild and chronic hyponatremia are often subtle and missed during the history and physical examination. Nausea and vomiting affect approximately one-third of patients with chronic hyponatremia who have a serum sodium concentration of less than 120 mmol/L. Idiopathic SIADH is more common in patients over 65 years of age, and mild to moderate hyponatremia in such patients may contribute to fractures in addition to a higher risk of falls and gait problems. 

History must include inquiry about head injury, chronic pain, smoking, weight loss, pulmonary symptoms, drug intake, or substance abuse (particularly heroin and ecstasy), in addition to all the above-mentioned symptoms. The clinicians should evaluate the source of excess fluid, and the chronicity of the condition merits consideration. 

Physical examination should include assessment of volume status, as these patients are typically euvolemic. Skin turgor and blood pressure are within the normal range. Moist mucus membranes with no evidence of jugular venous pulsation or edema typically indicate euvolemia. Detailed neurological and chest examinations are necessary.

Evaluation

There is no single best test to diagnose SIADH. Patients usually present with hyponatremia with normal volume status. Schwartz and Bartter made a clinical criterion in 1967, which is still valid up to the date.[9][10][11]

The Schwartz and Bartter Clinical Criterion

• Serum sodium less than 135mEq/L
• Serum osmolality less than 275 mOsm/kg
• Urine sodium greater than 40 mEq/L (due to ADH-mediated free water absorption from renal collecting tubules)
• Urine osmolality greater than 100 mOsm/kg
• The absence of clinical evidence of volume depletion - normal skin turgor, blood pressure within the reference range
• The absence of other causes of hyponatremia - adrenal insufficiency, hypothyroidism, cardiac failure, pituitary insufficiency, renal disease with salt wastage, hepatic disease, drugs that impair renal water excretion.
• Correction of hyponatremia by fluid restriction

Renal function tests and random blood sugar tests are necessary to check hyperglycemia and uremia as these are the potential causes of pseudohyponatremia. 

Tests for SIADH

• Serum osmolality and serum sodium
• Urine sodium concentration and osmolality
• Renal function tests: BUN and creatinine
• BSR (Blood sugar random)
• Thyroid profile
• Serum cortisol
• Serum K+, bicarbonate, chloride
• Fasting lipid profile
• Liver function tests

Clinicians must rule out hypothyroidism and adrenal insufficiency before labeling the patient with SIADH. Further tests are required to find out underlying causes according to history. Patients with long-standing smoking history, weight loss, or pulmonary symptoms must have a chest X-ray and CT scan to look for SCLC. 

Treatment / Management

The patients with SIADH have a combination of ADH-induced water retention and secondary solute loss. The overall solute loss is more prominent than water retention in patients with chronic SIADH. SIADH treatment involves correction and maintenance of corrected sodium levels and correction of underlying abnormalities such as hypothyroidism or pulmonary or CNS infection. The goal of sodium correction is more than 130 mEq/L.

The choice of treatment depends essentially upon the severity of symptoms at presentation. A mild but rapid fall in sodium levels can cause severe symptoms like delirium, confusion, and seizures, while chronic but significant hyponatremia (less than 125 mEq/L) may produce mild or no symptoms. So, in patients with mild to moderate symptoms, the mainstay of the treatment is the restriction of oral water intake with the goal of less than 800 mL/day. If hyponatremia is persistent, sodium chloride in the form of oral salt tablets or intravenous saline can be given. Loop diuretics such as furosemide (20 mg twice daily) can also be added to salt tablets as it helps decrease the urine concentration and thereby increase water excretion, particularly among the patients whose urine osmolality is much higher than serum osmolality (greater than 500 mOsm/kg).[12]

 To correct sodium levels, it should be known that urine osmolality in such patients is usually twice the amount of serum osmolality, i.e., greater than 500 mOsm/kg. So, the fluid needed to correct the sodium levels must have an osmolality that is more than urine osmolality. Isotonic saline may not correct hyponatremia in such patients, or it may even worsen hyponatremia and symptoms. Therefore, a solution with an electrolyte concentration greater than the urine electrolyte concentration must be used. Three percent hypertonic saline (osmolality 513 mOsm/kg) is used for this purpose in patients with severe symptomatic or resistant hyponatremia. Also, the rate of correction is an important factor. It should not exceed more than 8 mEq/L per 24 hours or 0.5 to 1 mEq/L per hour. More rapid correction can result in osmotic demyelination of the CNS, leading to severe lethal complications such as osmotic demyelination syndrome ("locked-in" syndrome), causing quadriplegia.[13]

Patients presenting with severe symptoms such as seizures, confusion, or delirium need urgent initial correction with hypertonic saline infusion for the first few hours rather than just water restriction. A 100 mL bolus of 3% hypertonic saline is given in the first 3 to 4 hours, and sodium levels are measured within 2 to 3 hours so that further doses can be adjusted to avoid correcting too rapidly. A rise of 3 to 4 mEq/L within the first few hours in such distressing conditions can be justified. If the patient's mental status does not improve, more boluses of 100 mL hypertonic saline can be given in the same way as above until symptoms get better. 

Vasopressin receptor antagonists such as conivaptan (IV) or tolvaptan (oral) are also available and approved for severe persistent SIADH. These drugs prevent ADH-mediated free water retention by antagonizing V2 receptors and correct hyponatremia. Tolvaptan is hepatotoxic and should not be given to patients with liver disease. Intravenous conivaptan is very effective in correcting hyponatremia and baseline mental status in hospitalized patients. Other therapies, like lithium or demeclocycline, are also effective in SIADH, but both drugs are nephrotoxic and have other potential side effects; therefore, they should only be used when other therapies fail.[14]

Differential Diagnosis

The differential diagnoses of SIADH include all the causes of hyponatremia.

If the serum osmolality is reduced and urine osmolality is >100mOsm/kg, the volume status of the patient needs to be estimated and the likely cause identified as follows:[15]

• Euvolemia - SIADH
• Hypervolemia - Cardiac failure, cirrhosis
• Hypovolemia - Vomiting, diarrhea

Prognosis

The prognosis for patients with SIADH depends on the underlying cause and the effects of severe hyponatremia and potential overcorrection. Prompt and complete recovery is generally the case with drug-induced SIADH once the offending agent is withdrawn.

Complications

SIADH complications will hinge on how low blood sodium levels become. Potential complications include:

• Headaches
• Memory problems
• Depression
• Tremors
• Muscle cramps

More severe potential complications include:

• Respiratory failure
• Seizures
• Hallucinations
• Coma
• Death

Deterrence and Patient Education

The patient needs to follow strict guidelines for fluid intake to prevent further buildup. As a result, they also need to understand the signs and symptoms of hypo and hypernatremia and seek clinician assistance immediately if they develop any of these. Compliance with treatment for the underlying cause is necessary.

Enhancing Healthcare Team Outcomes

The management of patients with SIADH requires an interprofessional healthcare team approach because of the diverse etiologies and the challenge in treating the patient successfully without causing further complications. The aim is to control the primary condition causing SIADH and monitor the fluid status and electrolytes. The nursing staff and clinicians involved must work as an interprofessional team to minimize complications and provide the best care. Several newer agents are available that can lower or block actions of ADH, but expertise is necessary when using these medications; therefore, the team also requires pharmacist input. The prognosis for patients with SIADH depends on the cause. For benign causes, the prognosis is excellent, but those cases caused by malignancies tend to have a poor outcome.[16][17] [Level 5]