Syndrome of Inappropriate Antidiuretic Hormone Secretion

Author: Christie P Thomas, MBBS, FRCP, FASN, FAHA; Chief Editor: Vecihi Batuman, MD, FACP, FASN Background The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most common cause of euvolemic hyponatremia in hospitalized patients. The syndrome is defined by the hyponatremia and hypo-osmolality that results from inappropriate, continued secretion and/or action of antidiuretic hormone (ADH) despite normal or increased plasma volume, which results in impaired water excretion. The antidiuretic hormone (ADH) promotes the reabsorption of water from the tubular fluid in the collecting duct, the hydro-osmotic effect, and it does not exert a significant effect on the rate of Na+ reabsorption. A second action of ADH is to cause arteriolar vasoconstriction and a rise in arterial blood pressure, the pressor effect. Physiology of ADH Arginine vasopressin (AVP), the naturally occurring ADH in humans, is an octapeptide similar in structure to oxytocin. AVP is synthesized in the cell bodies of neurons in the supraoptic and paraventricular nuclei of the anterior hypothalamus and travels along the supraopticohypophyseal tract into the posterior pituitary. Here, it is stored in secretory granules in association with a carrier protein, neurophysin, in the terminal dilatations of secretory neurons that rest against blood vessels. The major stimuli for AVP secretion are hyperosmolality and effective circulating volume depletion, which are sensed by osmoreceptors and baroreceptors, respectively. Osmoreceptors are specialized cells in the hypothalamus that perceive changes in the extracellular fluid (ECF) osmolality. Baroreceptors are located in the carotid sinus, aortic arch, and left atrium; these receptors participate in the nonosmolar control of AVP release by responding to a change in effective circulating volume. Three known receptors bind AVP at the cell membrane of target tissues: V1a, V1b (also known as V3), and V2; these mediate AVPs various effects. V1a receptor is the vascular smooth muscle cell receptor but is also found on a number of other cells, such as hepatocytes, cardiac myocytes, platelets, brain, and testis. The V1a receptors signal by activation of phospholipase C and elevation in intracellular calcium, which, in turn, stimulates vasoconstriction. V1b (V3) receptors are found predominantly in the anterior pituitary, where they stimulate ACTH secretion. V2 receptors are coupled to adenylate cyclase, causing a rise in intracellular cyclic adenosine monophosphate (cAMP), which serves as the second messenger. V2 receptors are found predominantly on the basolateral membrane of the principal cells of the connecting tubule and collecting duct of the distal nephron.[1] Activation of the V2 receptor results in insertion of the water channel aquaporin-2 in the luminal membrane of the collecting duct, thus making it more permeable to water. Activation of the V2 receptors also increases urea and Na+chloride reabsorption by the ascending limb of loop of Henle, thus increasing medullary tonicity and providing the osmotic gradient for maximal water absorption.[1] V2 receptors are also found in vascular endothelial cells and stimulate the release of von Willebrand factor.[1]

Normally, AVP secretion ceases when plasma osmolality falls below 275 mOsm/kg. This decrease causes increased water excretion, which leads to a dilute urine with an osmolality of 40100 mOsm/kg. When plasma osmolality rises, AVP is secreted, which results in an increase in water reabsorption and an increase in urine osmolality to as much as 1400 mOsm/kg. An 8-10% reduction in circulating volume also significantly increases AVP release. In most physiologic states, the volume receptors and osmoreceptors act in concert to increase or decrease AVP release. However, a reduction in actual or effective circulating volume is an overriding stimulus for secretion of AVP and takes precedence over extracellular osmolality when osmolality is normal or reduced. Finally, AVP is also released in response to stressful stimuli, such as pain or anxiety, and by various drugs. The released AVP is rapidly metabolized in the liver and kidneys and has a half-life of 15-20 minutes. Pathophysiology The key to understanding the pathophysiology, signs, symptoms, and treatment of SIADH is the awareness that the hyponatremia in this syndrome is a result of an excess of water and not a deficiency of Na+. SIADH consists of hyponatremia, inappropriately elevated urine osmolality (>100 mOsm/kg), and decreased serum osmolality in a euvolemic patient. SIADH should be diagnosed when these findings occur in the setting of otherwise normal cardiac, renal, adrenal, hepatic, and thyroid function; in the absence of diuretic therapy; and in absence of other factors known to stimulate ADH secretion, such as hypotension, severe pain, nausea, and stress. In general, the plasma Na+ concentration is the primary osmotic determinant of AVP release. In persons with SIADH, the nonphysiological secretion of AVP results in enhanced water reabsorption, leading to dilutional hyponatremia. While a large fraction of this water is intracellular, the extracellular fraction causes volume expansion. Volume receptors are activated and natriuretic peptides are secreted, which causes natriuresis and some degree of accompanying potassium excretion (kaliuresis). Eventually, a steady state is reached and the amount of Na+ excreted in the urine matches Na intake. Ingestion of water is an essential prerequisite to the development of the syndrome; regardless of cause, hyponatremia does not occur if water intake is severely restricted. In addition to the inappropriate AVP secretion, persons with this syndrome may also have an inappropriate thirst sensation, which leads to an intake of water that is in excess of free water excreted. This increase in water ingested may contribute to the maintenance of hyponatremia. Neurologic manifestations Neurologic complications in SIADH occur as a result of the brain's response to changes in osmolality. Hyponatremia and hypo-osmolality lead to acute edema of the brain cells. The rigid calvaria prevent expansion of brain volume beyond a certain point, after which the brain cells must adapt to persistent hypo-osmolality. However, a rapid increase in brain water content of more than 5-10% leads to severe cerebral edema and herniation and is fatal. In response to a decrease in osmolality, brain ECF fluid moves into the CSF. The brain cells then lose potassium and intracellular organic osmolytes (amino acids, such as glutamate, glutamine, taurine, polyhydric alcohol, myoinositol, methylamine, and creatinine). This occurs concurrently to prevent excessive brain swelling.[2]

Following correction of hyponatremia, the adaptive process does not match the extrusion kinetics. Electrolytes rapidly reaccumulate in the brain ECF within 24 hours, resulting in a significant overshoot above normal brain contents within the first 48 hours after correction. Organic osmolytes return to normal brain content very slowly over 5-7 days. Electrolyte brain content returns to normal levels by the fifth day after correction, when organic osmolytes return to normal. Irreversible neurologic damage and death may occur when the rate of correction of Na+exceeds 0.5 mEq/L/h for patients with severe hyponatremia. At this rate of correction, osmolytes that have been lost in defense against brain edema during the development of hyponatremia cannot be restored as rapidly when hyponatremia is rapidly corrected. The brain cells are thus subject to osmotic injury, a condition termed osmotic demyelination. Certain factors such as hypokalemia, severe malnutrition, and advanced liver disease predispose patients to this devastating complication.[2] Etiology SIADH is most often caused by either inappropriate hypersecretion of ADH from its normal hypothalamic source or by ectopic production. The causes of SIADH can be divided into 4 broad categories: nervous system disorders, neoplasia, pulmonary diseases, and drug induced (which include those that [1] stimulate AVP release, [2] potentiate effects of AVP action, or [3] have an uncertain mechanism). Nervous system disorders are as follows:

Acute psychosis Acute intermittent porphyria Brain abscess Cavernous sinus thrombosis Cerebellar and cerebral atrophy Cerebrovascular accident CNS lupus Delirium tremens Encephalitis (viral or bacterial) Epilepsy Guillain-Barr syndrome Head trauma Herpes zoster (chest wall) Hydrocephalus Hypoxic ischemic encephalopathy Meningitis (viral, bacterial, tuberculous, and fungal) Midfacial hypoplasia Multiple sclerosis Perinatal hypoxia Rocky Mountain spotted fever Schizophrenia Shy-Drager syndrome Subarachnoid hemorrhage Subdural hematoma

Ventriculoatrial shunt obstruction Wernicke encephalopathy Neoplasia disorders are as follows:

Pulmonary - Lung carcinoma and mesothelioma Gastrointestinal - Carcinomas of the duodenum, pancreas, and colon Genitourinary - Adrenocortical carcinoma; carcinomas of cervix, ureter/bladder, and prostate; and ovarian tumors Other - Brain tumors, carcinoid tumors, Ewing sarcoma, leukemia, lymphoma, nasopharyngeal carcinoma, neuroblastoma (olfactory), and thymoma Pulmonary disorders are as follows:

Acute bronchitis/bronchiolitis Acute respiratory failure Aspergillosis (cavitary lesions) Asthma Atelectasis Bacterial pneumonia Chronic obstructive lung disease Cystic fibrosis Emphysema Empyema Pneumonia (viral, bacterial [mycoplasmal], fungal) Pneumothorax Positive pressure ventilation Pulmonary abscess Pulmonary fibrosis Sarcoidosis Tuberculosis Viral pneumonia Drugs that stimulate AVP release are as follows: Acetylcholine Antineoplastic agents - Adenine arabinoside, cyclophosphamide, ifosfamide, vincristine, vinblastine Barbiturates Bromocriptine Carbachol Chlorpropamide Clofibrate Cyclopropane Dibenzazepines (eg, carbamazepine, oxcarbazepine Halothane Haloperidol Histamine Isoproterenol Lorcainide Opiates e.g. Morphine

Nicotine (inhaled tobacco) Nitrous oxide Phenothiazines (eg, thioridazine) Thiopental MAOIs (eg, tranylcypromine) Tricyclic antidepressants (eg, amitriptyline, desipramine) Drugs that potentiate the effects of AVP action (primarily facilitates peripheral action of ADH) are as follows:

Clofibrate Griseofulvin Hypoglycemic agents Metformin, phenformin, tolbutamide Oxytocin (large doses) Prostaglandin synthetase inhibitors (inhibit renal PGE2 synthesis) Indomethacin, aspirin, nonsteroidal anti-inflammatory drugs Theophylline Triiodothyronine Vasopressin analogs (eg, AVP, DDAVP) Drugs with an uncertain mechanism are as follows:

Antineoplastic agents Cisplatin, melphalan, methotrexate, imatinib Ciprofloxacin Clomipramine Ecstasy Phenoxybenzamine Na+ valproate SSRIs (eg, sertraline, fluoxetine, paroxetine) Thiothixene The list of drugs that can induce SIADH is long. SIADH has been reported as an adverse effect of multiple psychotropic medications.[3] Many chemotherapeutic drugs cause nausea, which is a powerful stimulus of vasopressin secretion. SIADH is also a leading cause of hyponatremia in children following chemotherapy or stem cell transplantation. Miscellaneous causes are as follows:

Exercise-induced hyponatremia Giant cell arteritis HIV infection - Hyponatremia has been reported in as many as 40% of adult patients with HIV infection. Patients with acquired immunodeficiency syndrome (AIDS) can have many potential causes for increased ADH secretion, including volume depletion and infection of the lungs and the CNS.[4] Although one third of the hyponatremic patients with AIDS are clinically hypovolemic, the remaining hyponatremic patients fulfill most of the criteria for SIADH. Idiopathic Epidemiology Occurrence in the United States Hyponatremia is the most common electrolyte derangement occurring in hospitalized patients. When defined as plasma Na+ concentration of less than 135 mEq/L, the prevalence of hyponatremia in hospitalized patients has been reported in different studies as being between

2.5% and 30%.[5, 6, 7, 8] In the majority of cases, the hyponatremia was hospital acquired or aggravated by the hospitalization and may be secondary to the administration of hypotonic intravenous (IV) fluids.[5] SIADH can also arise postoperatively from stress, pain, and medications used. However, not all hospital-acquired hyponatremia is SIADH and SIADH should be differentiated from the hyponatremia that occurs in patients with limited capacity to excrete free water, such as in patients with chronic kidney disease. Sex- and age-related demographics Increasing age (>30 y) is a risk factor for hyponatremia in hospitalized patients.[8] Men appear to be more likely to develop mild or moderate, but not severe, hyponatremia.[8] Low body weight is also a risk factor for hyponatremia. Women appear to be more prone to drug-induced hyponatremia and to exercise-induced hyponatremia (marathon runners), although this may be an association with low body weight rather than sex.[1] Prognosis The prognosis of SIADH correlates with the underlying cause and to the effects of severe hyponatremia and its overzealous correction. Rapid and complete recovery tends to be the rule with drug-induced SIADH when the offending agent is withdrawn. Successful treatment of pulmonary or CNS infection also can lead to correction of SIADH. However, patients who present with neurologic symptoms or have severe hyponatremia even without symptoms may develop permanent neurologic impairment. Patients whose serum Na+ is rapidly corrected, especially those who are asymptomatic, can also develop permanent neurologic impairment from central pontine myelinolysis (CPM). Complications The following complications are noted in SIADH:

Cerebral edema may be observed when plasma osmolality decreases faster than 10 mOsm/kg/h. This can lead to cerebral herniation. [9] Noncardiogenic pulmonary edema may develop, especially in marathon runners. CPM is the feared complication of excessive, overly rapid correction of hyponatremia. Typical features are disorders of upper motor neurons, including spastic quadriparesis and pseudobulbar palsy, as well as mental disorders ranging from confusion to coma.[10] The risk is increased in persons with hepatic failure, potassium depletion, large burns, and malnutrition.[11] Premenopausal patients undergoing surgery, especially gynecologic or related procedures, and those with serum Na of less than 105 may also have an increased risk. Once CPM occurs as a complication, there is no proven treatment. Morbidity and mortality Previously, mild hyponatremia was considered relatively asymptomatic. However, evidence suggests that even mild hyponatremia can cause significant impairment, such as unsteady gait, and lead to frequent falls. This effect may be greater in elderly persons, who are more sensitive to changes in serum Na+.[12] The mortality of patients with hyponatremia (Na+ < 130 mEq/L) is increased 60-fold compared with that of patients without documented hyponatremia, although this may be partly related to their comorbid conditions rather than to the hyponatremia itself. Predictors for higher morbidity and mortality rates include being hospitalized, acute onset, and severity of hyponatremia.[7] When

the Na+ concentration drops below 105 mEq/L, life-threatening complications are much more likely to occur.[11] In a retrospective case note review by Clayton and colleagues, patients with a multifactorial cause for hyponatremia in an inpatient setting had significantly higher mortality rates.[13] The etiology of hyponatremia was a more important prognostic indicator than the level of absolute serum Na+ in the patients. The outcome was least favorable in patients who were normonatremic at admission and became hyponatremic during the course of their hospitalization. History Hyponatremia is usually detected by laboratory testing. Depending on the magnitude and rate of development, hyponatremia may or may not cause symptoms. In general, slowly progressive hyponatremia is associated with fewer symptoms than is a rapid drop of serum Na+ to the same value. Patients with moderate, chronic hyponatremia may have decreased reaction times, cognitive slowing, and ataxia resulting in frequent falls.[12, 14] Signs and symptoms of acute hyponatremia do not precisely correlate with the severity or the acuity of the hyponatremia. Some patients with profound hyponatremia may be relatively asymptomatic. Anorexia, nausea, and malaise are early symptoms and may be seen when the serum Na+ level is less than 125 mEq/L. A further decrease in the serum Na+ level can lead to headache, muscle cramps, irritability, drowsiness, confusion, weakness, seizures, and coma. These occur as osmotic fluid shifts result in cerebral edema and increased intracranial pressure. Important considerations related to the history are symptoms that reflect the cause of SIADH. Patients may have symptoms that suggest increased secretion of ADH, such as chronic pain, symptoms from CNS or pulmonary tumors (eg, hemoptysis, chronic headaches), or head injury, and drug use. It is important to determine if the patient has had excessive fluid intake because of inappropriate thirst or psychogenic polydipsia or because hypotonic fluids were administered in a healthcare setting. The history may also give important information about the chronicity of the condition, which may, in turn, influence the rate of correction of hyponatremia. Physical Examination After the identification of hyponatremia, the approach to the patient depends on the clinically assessed volume status. In SIADH, the patient is typically euvolemic and normotensive. Peripheral and pulmonary edema, dry mucous membranes, reduced skin turgor, and orthostatic hypotension are usually absent. Edema in a hyponatremic patient warrants consideration of another hyponatremic state, such as congestive heart failure (CHF) or cirrhosis, or chronic kidney disease. Prominent physical examination findings may be seen only in severe or rapid-onset hyponatremia and can include confusion, disorientation, delirium, generalized muscle weakness, myoclonus, tremor, asterixis, hyporeflexia, ataxia, dysarthria, Cheyne-Stokes respiration, pathologic reflexes, generalized seizures, and coma. Conditions in which renal water handling is impaired include the following:

Effective circulating volume depletion - GI losses (eg, diarrhea, vomiting), renal losses (eg, diuretic therapy, adrenal insufficiency, primary renal salt wasting), skin losses, edematous

disorders (congestive heart failure, cirrhosis with portal hypertension, severe nephrotic syndrome) Renal failure - Acute kidney injury (AKI) or chronic kidney disease (CKD) Other states of ADH excess - Cortisol deficiency, hypothyroidism, exogenous ADH (eg, deamino-D-arginine-vasopressin, vasopressin, oxytocin) Decreased solute intake Nephrogenic syndrome of inappropriate anti-diuresis (NSIAD) Disorders with normal water excretion include the following: Primary polydipsia Reset osmostat Cerebral salt wasting Pseudohyponatremia Extreme elevations in plasma lipids or proteins can increase the plasma volume and can reduce the measured plasma Na+concentration. Na+ is contained in the aqueous phase of plasma; the proteins and lipids cause an increase in the nonaqueous phase of plasma, leading to an overall increase in plasma volume without an actual decrease or dilution of Na+ in the aqueous phase. This was more of an issue in the past in the United States, when the conventional method of measuring Na+ (ie, flame-emission spectrophotometry) measured the aqueous and nonaqueous phases of plasma. The correction factors are as follows:

Plasma triglycerides (g/L) x 0.002 = mEq/L decrease in Na+ Plasma protein level - 8 (g/L) x 0.025 = mEq/L decrease in Na+ The newer method (using ion-specific Na+ electrodes) measures the Na+ in the aqueous phase only, thus avoiding the error of pseudohyponatremia. Pseudohyponatremia should be suspected when the measured plasma osmolality is normal in the presence of hyponatremia. Pseudohyponatremia may continue to be a problem in parts of the world where flame photometry is still used to measure Na+. Hyperglycemia Elevated glucose levels decrease the measured serum Na+ levels by 1.6 mEq/L for every 100 mg/dL increase in glucose. This results from the osmotic effect of glucose drawing water into the intravascular space. Plasma osmolality is high in this situation. This is a form of transient hyponatremia that corrects itself as hyperglycemia is reversed.[11] A similar form of hyponatremia can occur with any osmotically active substance in plasma, such as mannitol or dextran. Exercise-induced hyponatremia Exercise-induced hyponatremia has been reported during prolonged exercise such as in marathon runners and triathletes, usually in warmer climates, which can lead to severe hyponatremia associated with neurological symptoms.[15] The syndrome appears to arise because of excessive water consumption during the physical exercise coupled with loss of sodium chloride in sweat and nonosmotic stimulation of AVP secretion (from stress, volume contraction, nausea, and NSAIDs). Some athletes with cerebral edema also develop noncardiogenic pulmonary edema.[9] Cerebral salt wasting

The term cerebral salt wasting (CSW) was introduced in the 1950s to describe an entity seen with certain cerebral disorders that can impair the ability of the kidneys to conserve Na+, with resultant salt wasting and polyuria. CSW is defined as the renal loss of Na+ with intracranial disease, which leads to hyponatremia and a decrease in extracellular fluid volume.[16, 17] Vasopressin-resistant polyuria with hyponatremia, particularly in the setting of cerebral injury or cerebral disease or when accompanied by dehydration, should prompt consideration of CSW in the differential diagnosis. CSW must be distinguished from SIADH because management of these 2 conditions differs significantly. The differences and similarities in findings for CSW and SIADH are itemized as follows:

Hyponatremia - Present in both CSW and SIADH Urine Na - Increased in both CSW and SIADH Volume - Reduced in CSW and normal or increased in SIADH Salt wasting - Gross in CSW and self-limited in SIADH Urine output - Polyuria in CSW and variable in SIADH Hypouricemia - Occasionally in CSW and frequent in SIADH Over the years, much debate has been focused on the existence of this entity. The evidence in favor of CSW rests on the following points: (1) the presence of a negative salt balance, (2) the development of volume contraction (by definition, patients with SIADH are euvolemic), and (3) the fact that patients with CSW respond to salt and volume replacement rather than to fluid restriction. Various mechanisms have been postulated, including the roles of natriuretic peptides and neural regulatory mechanisms. Measurement of AVP or atrial natriuretic peptide levels is not helpful because they have been known to vary even in persons with SIADH. CSW is treated with Na+ replacement, which is diametrically opposite to that for SIADH. Na+ administration in persons with CSW corrects the hyponatremia and the fluid loss; however, in patients with SIADH, the effect is temporary. The mineralocorticoid fludrocortisone has been used as part of the treatment of CSW.[17] Adrenal insufficiency Cortisol has a negative feedback effect on ADH and corticotropin-releasing hormone. The absence of cortisol thus removes this inhibitory effect, increasing the release of ADH. Renal disease With declining renal function, patients have a decreasing ability to excrete free water and the more advanced the reduction in GFR, the easier it is for patients to become hyponatremic with unrestricted fluid intake. In patients on long-term dialysis with no urine output, fluid intake no greater than insensible losses leads to a predictable fall in serum Na, which, however, is not sustained because of regular maintenance dialysis. Reset osmostat Persons with this entity have a normal response to changes in osmolality, but their threshold for ADH release is reduced. Therefore, they have a lower, but stable, plasma Na+ concentration. Some individuals probably carry a nonsynonymous polymorphism (P19S) in the transient

receptor potential vanilloid 4 (TRPV4) channel, part of the osmoreceptor system, since this mutation has been shown to be associated with hyponatremia.[18] The reset osmostat has been observed in pregnant women. Increased human chorionic gonadotropin levels have been implicated to play a role in this condition. The serum Na+ concentration falls by approximately 5 mEq/L in the first 2 months of pregnancy and remains stable until after delivery, when it returns to normal levels. Recognizing this entity is important because it does not require treatment. Psychogenic polydipsia This condition is characterized by an increase in water intake attributed to a defect in the thirst mechanism. In some patients, the osmotic threshold for thirst is reset below the reset for release of ADH. This disorder is mostly observed in patients with psychosis. Water excretion is normal in these patients, and water restriction corrects the hyponatremia. In a patient on a normal diet and an average solute (protein and salts) intake, a substantial amount of water must be imbibed for hyponatremia to develop. Consider an individual who has 700 mOsm (primarily consisting of urea, Na+, potassium, and chloride) to excrete per day. Ordinarily, this person can vary his or her urine osmolality between 50 and 1400 mOsm/L and thus can excrete the osmotic load in a minimum of 500 mL and a maximum of 14 L. As long as his or her fluid intake is between these extremes, he or she adjusts urine osmolality to excrete the load. To become hyponatremic, such an individual must drink more than 14 L/d. Decreased solute intake This disorder is observed in persons who drink hyponatremic fluids without adequate food intake. The condition is described in individuals who drink beer (beer potomania) and thrive on little else and thus have substantially reduced protein and salt intake. The daily solute intake directly influences the osmotic load to be excreted. With poor nutritional intake, the osmotic load may be as little as 200 mOsm; in this situation, it can be excreted in a maximum of 4 L. Ingestion of a larger quantity of solute-free fluids without other avenues for water loss can result in the development of hyponatremia. Diuretics and hyponatremia Diuretics can cause mild-to-severe hyponatremia. Thiazide diuretics cause hyponatremia more often than loop diuretics. This is related to the different sites of action of these agents. Loop diuretics act in the medullary thick ascending limb and prevent Na+ absorption in the medullary thick ascending limb. This interferes with the concentrating ability by diminishing medullary osmolality. The Na+ can be reabsorbed once it reaches the distal tubule and the collecting duct. The thiazide diuretics prevent Na+ absorption in the distal tubule and do not interfere with the medullary concentrating ability or the effect of ADH. However, the distal tubule is the diluting segment of the nephron, and diminished Na+ absorption here increases urine osmolality and prevents the excretion of hypotonic urine. In patients who are susceptible to this effect, hyponatremia is usually observed within 2 weeks. After that, a new steady state is reached and further changes in serum Na+ only occur with an added stimulus such as vomiting and diarrhea. Nephrogenic syndrome of inappropriate antidiuresis (NSIAD)

This is a rare X-linked recessive genetic disease secondary to gain of function mutations in the V2 receptor, resulting in a spontaneously active receptor and unregulated water reabsorption. The laboratory features are identical to those of SIADH, with euvolemic hyponatremia, plasma hypo-osmolality, and increased urinary osmolality. The disease is likely to present in early infancy, although so far only 2 patients have been described with this disorder.[19] If AVP levels are measured, they are predicted to be low. Hypervolemic hyponatremia Other conditions to consider in the differential diagnosis of hyponatremia are those that are associated with hypervolemia in which the baroreceptors perceive reduced effective circulating volume and stimulate AVP secretion. These conditions include congestive heart failure, cirrhosis, and nephrotic syndrome. These should be evident on clinical examination because of the presence of peripheral edema with elevated jugular venous pressure, pulmonary rales, ascites, or stigmata of advanced liver disease. Approach Considerations In the absence of a single laboratory test to confirm the diagnosis, SIADH is best defined by the classic criteria introduced by Bartter and Schwartz in 1967, which remain valid today. They can be summarized as follows[20] :

Hyponatremia with corresponding hypoosmolality Continued renal excretion of Na+ Urine less than maximally dilute Absence of clinical evidence of volume depletion - Normal skin turgor, blood pressure within the reference range Absence of other causes of hyponatremia - Adrenal insufficiency (mineralocorticoid deficiency, glucocorticoid deficiency), hypothyroidism, cardiac failure, pituitary insufficiency, renal disease with salt wastage, hepatic disease, drugs that impair renal water excretion Correction of hyponatremia by fluid restriction Hyponatremia (ie, serum Na+ < 135 mmol/L) with concomitant hypo-osmolality (serum osmolality < 280 mOsm/kg) and high urine osmolality is the hallmark of SIADH. However, these findings only indicate that ADH is present and acting on the distal nephron; it does not indicate if the ADH secretion is inappropriate. A good clinical examination is required to confirm that the hyponatremia is not the result of decreased effective intravascular volume from volume depletion or from states of volume excess such as congestive heart failure and cirrhosis for which the secretion of ADH is appropriate. In SIADH, serum osmolality is generally lower than urine osmolality. In the setting of serum hypo-osmolality, ADH secretion is usually suppressed to allow the excess water to be excreted, thus moving the plasma osmolality toward normal. If ADH secretion is shut down completely, urine should have an osmolality of less than 100 mOsm. Therefore, urine osmolality of more than 100 mOsm in the context of plasma hypo-osmolality is sufficient to confirm ADH excess. Inappropriate water retention causes the dilutional hyponatremia. Urine Na+ concentration in persons with SIADH is usually more than 40 mEq/L because, in SIADH, Na+ handling is not abnormal and the urine Na+concentration reflects Na+ intake, which is generally more than 40 mEq/d (usually 50-100 mEq/d). However, the urine Na+ concentration

in persons with SIADH can be modulated by dietary Na+ intake. Thus, on a low-Na+ diet, patients with SIADH may have a urine Na+ level of less than 40 mEq/L. Laboratory Tests Order the following tests to help in the diagnosis of SIADH:

Serum Na+, potassium, chloride, and bicarbonate Plasma osmolality Serum creatinine Blood urea nitrogen Blood glucose Urine osmolality Serum uric acid Serum cortisol Thyroid-stimulating hormone Serum osmolality In persons with SIADH, the hyponatremia is associated with measured serum hypo-osmolality. Serum Na Hyponatremia (ie, serum Na+ < 135 mmol/L) is a defining feature of SIADH. Serum bicarbonate Serum bicarbonate remains within the reference range despite hypotonic expansion of body fluids in SIADH. This is postulated to be due to the movement of hydrogen ions into the cells and to increased hydrogen ion excretion by the renal tubules, both of which avert a dilutional fall in the serum bicarbonate concentration. Serum potassium Serum potassium concentration generally remains unchanged. Movement of potassium from the intracellular space to the extracellular space prevents dilutional hypokalemia. As hydrogen ions move intracellularly, they are exchanged for potassium in order to maintain electroneutrality. If both hypokalemia and metabolic alkalosis are present, consider diuretic therapy or vomiting as the cause of hyponatremia. If hyperkalemia and metabolic acidosis coexist with hyponatremia, consider adrenal insufficiency and volume depletion leading to AKI. Anion gap The anion gap is reduced in SIADH secondary to equal dilution of serum Na+and chloride, with unaffected bicarbonate (HCO3-). The anion gap is further decreased because the volume expansion probably reduces the tubular reabsorption of unmeasured anions, such as sulfate, phosphate, and urate. Urinary Na excretion In SIADH, urinary loss of Na+ continues despite significant hyponatremia. In these patients, as in healthy patients, urinary Na+ excretion is a reflection of Na+ intake and, therefore, usually is greater than 20 mmol/L. However, in the setting of Na+ restriction in patients with SIADH or in

patients with volume depletion due to extrarenal losses, the urinary Na+ concentration may be very low. Urinary osmolality Patients with hyponatremia should turn off ADH and have a urine that is maximally dilute (ie, 50-100 mOsm/kg); however, in patients with SIADH, the urinary osmolality is usually submaximally dilute (ie, >100 mOsm/kg). One of the more common errors in recognizing SIADH is the failure to realize that the urines osmolality must be only inappropriately elevated and not necessarily greater than the corresponding serum osmolality. BUN levels Blood urea nitrogen (BUN) levels are unusually low, usually below 10 mg/dL. A low BUN level in SIADH occurs secondary to volume expansion because urea is distributed in total body water. Hypouricemia Hypouricemia (uric acid < 4 mg/dL) is frequently observed in patients with SIADH during the period of hyponatremia. An increase in fractional uric acid excretion (usually >9%) occurs as a result of volume expansion and a decrease in distal tubular reabsorption. In contrast, the serum uric acid is usually increased in hypovolemia. A decrease in serum uric acid concentration has been suggested as a screening procedure in patients with hyponatremia secondary to SIADH. However, hypouricemia lacks sensitivity and specificity for making the diagnosis of SIADH. Glomerular filtration rate The glomerular filtration rate (GFR) is increased as a result of extracellular water expansion induced by water retention. ADH The use of radioimmunoassay for ADH may provide supportive evidence for the diagnosis of SIADH. However, the values are not usually available quickly enough to assist in clinical decision making. Moreover, although the plasma ADH is typically elevated, this determination is not as important for the diagnosis of SIADH. Volume Assessment Hypovolemia The patient should be assessed clinically to help rule out the presence of hypovolemia. Clues from the physical examination include hypotension with or without orthostasis, dry mucosae, cold peripheries, reduced skin turgor, and low central venous pressures (if central venous pressure or pulmonary capillary wedge pressure measurements are available). In persons with hypovolemic hyponatremia, the urinary Na+ concentration is usually less than 20 mEq/L and the fractional excretion of Na+ is low. Thus, if the urinary Na+ concentration is less than 25 mEq/L, volume depletion from extrarenal volume loss should be excluded. Volume depletion causes an appropriate (nonosmotic) secretion of ADH and leads to hyponatremia if hypotonic fluid is used to replace isotonic fluid losses. Typically, a volumedepleted person responds to thirst induced by volume depletion by drinking free water.

Replacing isotonic losses (lost from the extracellular compartment) with water or hypotonic fluids makes a patient hyponatremic. Hypovolemia can also be associated with a urine Na+ concentration more than 25 mEq/L if the source of volume loss is the kidney. Thus, diuretic use, mineralocorticoid deficiency, and saltlosing nephropathies can lead to hyponatremia with a high urine Na+ concentration. Hypervolemia The presence of peripheral edema with elevated jugular venous pressure, pulmonary rales, or ascites indicates increased volume, such as in heart failure or cirrhosis (with other signs of liver failure). Euvolemia In euvolemic states, before attributing the hyponatremia to SIADH, renal disease and endocrine disorders such thyroid, pituitary, and adrenal insufficiency should be excluded. Imaging Studies Chest radiographs Chest radiographs may reveal an underlying pulmonary cause of SIADH. CT or MRI scans Computed tomography (CT) scanning or magnetic resonance imaging (MRI) of the head may be appropriate in selected cases. The study may show evidence of cerebral edema (eg, narrowing of the ventricles), a complication of SIADH, or may identify a CNS disorder responsible for SIADH (eg, brain tumor). CT scanning or MRI can also help rule out other potential causes of a change in neurologic status. Approach Considerations The treatment of SIADH and the rapidity of correction of hyponatremia depend on the degree of hyponatremia, on whether the patient is symptomatic, and on whether it is acute (< 48 h) or chronic. The urine osmolality and creatinine clearance also must be considered when choosing the type of therapy. If no history is available to determine the duration of hyponatremia and if the patient is asymptomatic, it is reasonable to presume the condition is chronic. Diagnosis and treatment of the underlying cause of SIADH is also important. Extreme hyponatremia and an inappropriate approach to its treatment can both have disastrous consequences; consultation with a nephrologist should be sought early in difficult cases. Correcting hyponatremia too rapidly may result in central pontine myelinolysis (CPM) with permanent neurologic deficits. It is important to remember that even severe hyponatremia can correct rapidly with just fluid restriction if that hyponatremia is associated with absent ADH secretion (eg, psychogenic polydipsia). Emergent Care Aggressive treatment of hyponatremia should always be weighed against the risk of inducing CMP. CMP is a rare but serious complication and can develop one to several days after aggressive treatment of hyponatremia. Aggressive management of hyponatremia is indicated in patients with severe symptoms such as seizures, stupor, coma, and respiratory arrest, regardless

of the degree of hyponatremia. Emergent treatment should also be strongly considered for those with moderate-to-severe hyponatremia with a documented duration of less than 48 hours. The goal is to correct hyponatremia at a rate that does not cause neurologic complications. The objective is to raise serum Na+ levels by 0.5-1 mEq/h, and not more than 10-12 mEq in the first 24 hours, to bring the Na+ value to a maximum level of 125 -130 mEq/L. Administration of 3% hypertonic saline should be restricted to these emergent circumstances, and both neurological symptoms and serum Na+ should be monitored frequently to achieve the desired target and to prevent overcorrection. Other authors have recommended a rate of initial correction of 1-2 mEq/L/h in severely symptomatic patients until symptoms resolve (or for the first 3-4 h). However, total correction in the first 24 hours must not exceed 10-12 mEq. CMP has been reported in cases in which the initial correction exceeded 12 mEq and even in cases in which the correction was 9-10 mEq/24 h. This has led some authors to recommend a lower target of 8 mEq in 24 hours. In the special situation of exercise-induced hyponatremia with neurological symptoms, some authors recommend an immediate bolus of 100 mL of 3% hypertonic saline repeated every 10 minutes until symptoms resolve.[15] Formulas for the dose and rate of hypertonic saline have been proposed based on a Na+ deficit to calculate the rate of administration of hypertonic fluids.[11] However, they have not been prospectively studied. Despite the correct use of these formulas, hyponatremia is often corrected too rapidly. Therefore, these formulas should serve only as guidelines. Patients still require frequent retesting of their serum Na+ concentration.[13] The approximate Na+ deficit can be estimated by using the following formula (0.5 L/kg for females):

Na+ Deficit (mEq) = (Desired Na+ - Measured Na+) x 0.6 L/kg x Weight (kg) Three-percent hypertonic saline has 513 mEq/L each of Na+ and Cl- and has an osmolality of 1026 mOsm/L. The volume of hypertonic saline needed to correct that deficit can be calculated as follows: Volume of 3% Saline = (Na+ Deficit)/513 mEq/L Na+ Assuming a rate of correction of chronic hyponatremia of 0.5 mEq/L per hour, the amount of time needed to correct a given degree of hyponatremia is as follows: Time Needed for Correction = (Desired Na+ - Measured Na+)/0.5 mEq/L per hour The rate of infusion of hypertonic saline is as follows: Rate = (Volume of 3% Saline)/(Time Needed for Correction) Furosemide increases excretion of free water and has been used along with hypertonic saline in severe cases to limit treatment-induced volume expansion. The diuresis induced by furosemide has a urine solute concentration roughly equivalent to half-normal saline; thus, excretion of free water occurs. Electrolyte free water intake can be restricted. Combining furosemide with hypertonic saline and water restriction may lead to a faster rate of correction of serum Na and requires that serum Na+ osmolality and urine osmolality be checked frequently to monitor the change in serum Na+values and to prevent overcorrection. Attention should also be paid to the prevention of severe hypokalemia in conjunction with treatment of hyponatremia. Previous

Acute Setting In the acute setting (ie, < 48 h since onset) with moderate symptoms such as confusion, delirium, disorientation, nausea, and vomiting, treatment options for the hyponatremia include 3% hypertonic saline (513 mEq/L), loop diuretics with saline, vasopressin-2 receptor antagonists (aquaretics), and water restriction. Depending on the rate of development of hyponatremia, the approach to correction varies. If an acute onset and moderate neurologic symptoms have occurred, the use of hypertonic saline may be warranted (discussed under Emergent Care). If symptoms are less severe (headache, irritability, inability to concentrate, altered mood) or absent, then vasopressin-2 receptor antagonists (aquaretics) or water restriction are both options. The patient's serum Na+ level and clinical status must be monitored often to determine the need for continued aggressive therapy. Water restriction The degree of water restriction depends on the prior water intake, the expected ongoing fluid losses, and the degree of hyponatremia. Water restriction to about 500-1500 mL/d (or even lower in some cases) is usually prescribed. Although easier to maintain in the hospital setting, this becomes difficult for patients to follow in an outpatient setting. One of the functions of the kidneys is to excrete solutes in varying amounts of water. In persons with SIADH, urine osmolality is fixed at a certain value; for the kidneys to eliminate an "X" amount of solutes, a certain volume of water must be excreted. If water intake is lowered below total obligatory fluid losses (insensible losses plus volume of urine required to excrete the osmolar load), then serum osmolality rises because a net loss of water occurs. The insensible losses of relatively hypotonic fluids also contribute to net water loss. The key is sufficient restriction of water intake so that the excretion of free water from all sources is in excess of that taken in. For example, consider a patient who has a net solute load of 900 mOsm/kg/day that must be excreted, and, because of SIADH, his or her urine osmolality is fixed at 600 mOsm/kg. This patient then excretes the solute load in 1.5 L of urine. On the other hand, if the urine osmolarity is fixed at 300 mOsm/kg, then 3 L of urine is required to excrete the same osmolar load. When water intake is restricted, the body mobilizes theVasopressin receptor antagonists Inhibition of the AVP V2 receptor reduces the number of aquaporin-2 water channels in the renal collecting duct and decreases the water permeability of the collecting duct. Collectively, agents that competitively block ADH action and increase water excretion are called aquaretics, and they are useful in the treatment of the hyponatremia in SIADH. The term "vaptan" has been coined to officially name all the members of this new class of drugs.[1] There are 2 aquaretics that are currently approved by the US Food and Drug Administration (FDA). Conivaptan is a parenteral nonpeptide dual AVP V1a- and V2-receptor antagonist, which is approved for use in hospitalized patients with euvolemic (dilutional) and hypervolemic hyponatremia. The drug is given as a 20-mg loading dose followed by a continuous infusion or as intermittent boluses, but it should not be used for more than 4 days. The pivotal studies in euvolemic hyponatremia showed that compared with fluid restriction alone, conivaptan together

with a 2 L fluid restriction over 4 days increased serum Na by 6 mEq/L, with a median increase of 4 mEq/L by 23 hours.[21] Tolvaptan is a selective oral V2 receptor antagonist also approved for use in hospitalized patients for hypervolemia and euvolemic hyponatremia.[22, 23] The drug is started at 15 mg once daily and titrated up to 60 mg daily as required, and it is best to avoid fluid restriction during the dosefinding phase. In the pivotal studies, which included patients with CHF, cirrhosis, and SIADH, tolvaptan compared with fluid restriction alone increased serum Na by 8 mEq/L over 30 days, although with withdrawal of the drug, serum Na+ falls back to that seen in the placebo group.[24] This is a useful drug to consider in a patient in whom serum Na+ does not rise by 2 mEq in the first 24 hrs after a 1000-mL fluid restriction. Once the drug is initiated, the patient can be discharged in 24-48 hours if neurological symptoms have resolved or the patient was asymptomatic at presentation. If the underlying cause of SIADH has resolved, the drug can be withdrawn after 2-4 weeks, while carefully monitoring serum Na+ daily for the next 5 days. If the serum Na+ falls again and if is less than 125 for more than 48 hours, the patient may need to be admitted again before reinitiating tolvaptan. Tolvaptan can also be considered for long-term therapy of chronic hyponatremia.[25] free water already present to excrete this load. Thus, if urine output (plus insensible losses) exceeds water intake, a net water loss occurs and the serum Na+ level returns towards normal. The vaptans can have a profound effect on serum Na and they should be used by physicians experienced in the management of hyponatremia. These drugs should be avoided in hypovolemic hyponatremia. The vaptans are more likely to be effective compared with fluid restriction alone in patients in whom the sum of urinary potassium and Na+ concentration is greater than the plasma concentration. They offer the benefit of prompt correction of serum Na+, producing water excretion without electrolyte excretion and eliminating the need for fluid restriction. The primary risk of using these drugs is an excessively rapid rate of correction of serum Na. Furosemide Furosemide and other loop diuretics can be used to increase the excretion of free water. Excess water that must be removed to correct the hyponatremia can be calculated using total body water (TBW). TBW equals body weight in kg multiplied by 0.6, assuming that the total body solute or water has not changed. The diuresis induced by furosemide has a urine solute concentration roughly equivalent to half-normal saline; thus, excretion of free water occurs. The excreted Na+ is replaced with 3% hypertonic saline or with normal saline (NaCl 154 mEq/L), thus avoiding a net Na+ loss while effecting a loss of free water. Other sources of free water intake should be restricted as well. If the measured sum of urinary potassium and Na+ with furosemide is greater than the plasma Na, then hypertonic saline rather than normal saline should be used to replace excreted Na. Serum Na+ and osmolality and urine osmolality should be checked frequently to monitor the change in serum Na+ and the rate of correction. Chronic Setting In the chronic asymptomatic setting, the principal options are fluid restriction and V2 receptor antagonists (see Acute Setting). If V2 receptor antagonists are not available or if local experience

with these agents is very limited, other therapeutic modalities include chronic loop diuretics with increased salt intake, urea, mannitol, and demeclocycline. Urea Urea is a solute that must be excreted by the kidneys. Because urine osmolality is fixed in persons with SIADH, the obligatory urine volume can be increased by increasing the osmotic or solute load. Increased urinary loss of water decreases free water retention. This therapy can be used in chronic and acute settings if the urine osmolality is low and can increase the serum Na+by up to 5 mEq/L/day. Urea is a relatively nontoxic compound and, as opposed to sodium chloride treatment, does not cause edema or increase body weight. Urea can be administered on a long-term basis (0.5 g/kg body weight) without major adverse effects. Urea is available as a powder, which is dissolved in water and taken orally during or after meals. To avoid gastric upset, it can be taken with an antacid. Urea can also be used continuously in patients with cerebral hemorrhage via a gastric tube or intravenously to prevent a rapid fall in intracranial pressure. Urea should be used with great care in patients with serum creatinine of 2 mg/dL or more, BUN 80 mg/dL or more, or bilirubin of 2 mg/dL or more, to avoid progressive azotemia, hyperammonemia, and hepatic encephalopathy. Hypernatremia and dehydration may occur if the patient does not have free access to water. Medication Summary Vasopressin receptor antagonists inhibit the V2 receptor, reducing the number of aquaporin-2 water channels in the renal collecting duct and decreasing the water permeability of the collecting duct. The use of a combination of a loop diuretic (eg, furosemide) and the replacement of urine output with a solution that contains a higher Na+concentration (ie, 3% sodium chloride solution) can be dramatically successful in some patients. Concomitant use of furosemide increases free water excretion relative to Na+ excretion by the kidneys, thus correcting fluid expansion induced by hypertonic sodium chloride solution. Vasopressin-Related Class Summary The potential benefits of these drugs include the predictability of their effect, rapid onset of action, and limited urinary electrolyte excretion. Conivaptan and tolvaptan are currently the only vasopressin receptor antagonists that are commercially available in the United States and FDAapproved for the treatment of euvolemic hyponatremia in hospitalized patients. These medications should be initiated in a closely monitored setting to prevent rapid correction of serum Na+, which can result in central pontine myelinolysis (CMP).[26] View full drug information Conivaptan (Vaprisol)

Conivaptan is a parenteral nonselective vasopressin receptor antagonist used for the treatment of euvolemic hyponatremia in hospitalized patients. Conivaptan increases urine output of mostly free water, with little electrolyte loss. It is indicated for hospitalized patients with more severe euvolemic or hypervolemic hyponatremia. View full drug information Tolvaptan (Samsca)

Tolvaptan is an oral selective vasopressin V2-receptor antagonist. It is indicated for hypervolemic and euvolemic hyponatremia (ie, serum Na level < 125 mEq/L) or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction. It is used for hyponatremia associated with CHF, liver cirrhosis, and syndrome of inappropriate antidiuretic hormone secretion (SIADH). Initiate or reinitiate the drug in a hospital environment only since there may be overly rapid correction of the hyponatremia. However, it increases thirst (potentially limiting its effects) and is expensive. Diuretics, Loop Class Summary These agents are often used in the treatment of hypervolemic hyponatremia. In patients with syndrome of inappropriate antidiuretic hormone secretion (SIADH) with euvolemic hyponatremia, diuretics are usually used in conjunction with normal saline to replenish the Na+excreted with the diuresis. View full drug information Furosemide (Lasix)

Furosemide increases excretion of water by interfering with the Na+-K+-Cl- (Na-K-2Cl) transporter; that, in turn, results in inhibition of Na+ and Cl- reabsorption in the ascending loop of Henle. Na+ is reabsorbed more distally and the excreted urine is hypo-osmolar in relation to serum. Diuretics, Osmotic Agents Class Summary These agents induce diuresis by elevating the osmolarity of the glomerular filtrate, thereby hindering the tubular reabsorption of water. The overall effect is an increase in free water excretion by the kidneys. Concomitantly, Na+ and Cl- excretion also increase, but to a lesser extent than water excretion. View full drug information

Urea

Urea is used for the treatment of SIADH refractory to or in patients noncompliant with other therapies or when other therapies are not available. Urea is known to promote diuresis. It decreases brain edema, restores medullary tonicity, and induces Na+ retention. Isosmotic concentration of dextrose or invert sugar is coadministered with urea to prevent hemolysis produced by pure solutions of urea. View full drug information Mannitol (Osmitrol)

Mannitol promotes a rapid free-water diuresis by elevating the osmolarity of the glomerular filtrate, thereby hindering the tubular reabsorption of water. Concomitantly, Na+ and Clexcretion also increase but to a lesser extent than water excretion. It is typically used intravenously, as a 15-20% solution. Tetracyclines Class Summary Demeclocycline is an older tetracycline. One of its adverse effects is nephrogenic diabetes insipidus and polyuria, which can correct the excess of water seen in SIADH. It is no longer available in most countries and may be nephrotoxic in patients with liver failure. View full drug information Demeclocycline

Demeclocycline is a tetracycline derivative that induces diabetes insipidus by impairing the generation and action of cAMP, thus interfering with the action of AVP on the collecting duct. The drug's onset of action may be delayed by over a week; thus, it is not indicated for the emergency management of symptomatic hyponatremia.