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 AVP’s 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]

or [3] have an uncertain mechanism). [2] potentiate effects of AVP action. At this rate of correction.Following correction of hyponatremia. the adaptive process does not match the extrusion kinetics. neoplasia. 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. resulting in a significant overshoot above normal brain contents within the first 48 hours after correction. Electrolyte brain content returns to normal levels by the fifth day after correction. The brain cells are thus subject to osmotic injury. and advanced liver disease predispose patients to this devastating complication. and drug induced (which include those that [1] stimulate AVP release. bacterial.5 mEq/L/h for patients with severe hyponatremia. Electrolytes rapidly reaccumulate in the brain ECF within 24 hours. tuberculous. Certain factors such as hypokalemia. severe malnutrition. and fungal) Midfacial hypoplasia Multiple sclerosis Perinatal hypoxia Rocky Mountain spotted fever Schizophrenia Shy-Drager syndrome Subarachnoid hemorrhage Subdural hematoma . Organic osmolytes return to normal brain content very slowly over 5-7 days. 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-Barré syndrome Head trauma Herpes zoster (chest wall) Hydrocephalus Hypoxic ischemic encephalopathy Meningitis (viral. when organic osmolytes return to normal. Irreversible neurologic damage and death may occur when the rate of correction of Na+exceeds 0.[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. pulmonary diseases. a condition termed osmotic demyelination.

carcinoid tumors. fungal) Pneumothorax Positive pressure ventilation Pulmonary abscess Pulmonary fibrosis Sarcoidosis Tuberculosis Viral pneumonia Drugs that stimulate AVP release are as follows: Acetylcholine Antineoplastic agents .g. vincristine. and ovarian tumors  Other . and colon Genitourinary .Adenine arabinoside. carbamazepine.Carcinomas of the duodenum. pancreas. and prostate.Brain tumors.Lung carcinoma and mesothelioma Gastrointestinal .     Ventriculoatrial shunt obstruction Wernicke encephalopathy Neoplasia disorders are as follows: Pulmonary . ureter/bladder. 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. ifosfamide. Morphine . carcinomas of cervix. neuroblastoma (olfactory). nasopharyngeal carcinoma. lymphoma. bacterial [mycoplasmal]. Ewing sarcoma. cyclophosphamide. oxcarbazepine Halothane Haloperidol Histamine Isoproterenol Lorcainide Opiates e. vinblastine Barbiturates Bromocriptine Carbachol Chlorpropamide Clofibrate Cyclopropane Dibenzazepines (eg. leukemia.Adrenocortical carcinoma.

paroxetine) Thiothixene The list of drugs that can induce SIADH is long. Miscellaneous causes are as follows:    Exercise-induced hyponatremia Giant cell arteritis HIV infection . phenformin. melphalan. methotrexate. SIADH has been reported as an adverse effect of multiple psychotropic medications.      Nicotine (inhaled tobacco) Nitrous oxide Phenothiazines (eg. the remaining hyponatremic patients fulfill most of the criteria for SIADH. When defined as plasma Na+ concentration of less than 135 mEq/L.  Idiopathic Epidemiology Occurrence in the United States Hyponatremia is the most common electrolyte derangement occurring in hospitalized patients. thioridazine) Thiopental MAOIs (eg.[3] Many chemotherapeutic drugs cause nausea. desipramine) Drugs that potentiate the effects of AVP action (primarily facilitates peripheral action of ADH) are as follows:      Clofibrate Griseofulvin Hypoglycemic agents – Metformin.Hyponatremia has been reported in as many as 40% of adult patients with HIV infection. imatinib Ciprofloxacin Clomipramine Ecstasy Phenoxybenzamine Na+ valproate SSRIs (eg. nonsteroidal anti-inflammatory drugs  Theophylline  Triiodothyronine  Vasopressin analogs (eg. sertraline. tolbutamide Oxytocin (large doses) Prostaglandin synthetase inhibitors (inhibit renal PGE2 synthesis) – Indomethacin. tranylcypromine) Tricyclic antidepressants (eg. DDAVP) Drugs with an uncertain mechanism are as follows:         Antineoplastic agents – Cisplatin. fluoxetine. AVP. which is a powerful stimulus of vasopressin secretion. amitriptyline. Patients with acquired immunodeficiency syndrome (AIDS) can have many potential causes for increased ADH secretion. aspirin.[4] Although one third of the hyponatremic patients with AIDS are clinically hypovolemic. including volume depletion and infection of the lungs and the CNS. the prevalence of hyponatremia in hospitalized patients has been reported in different studies as being between . SIADH is also a leading cause of hyponatremia in children following chemotherapy or stem cell transplantation.

evidence suggests that even mild hyponatremia can cause significant impairment.and age-related demographics Increasing age (>30 y) is a risk factor for hyponatremia in hospitalized patients. Patients whose serum Na+ is rapidly corrected. acute onset. patients who present with neurologic symptoms or have severe hyponatremia even without symptoms may develop permanent neurologic impairment. but not severe. This effect may be greater in elderly persons.[1] Prognosis The prognosis of SIADH correlates with the underlying cause and to the effects of severe hyponatremia and its overzealous correction. although this may be an association with low body weight rather than sex.5% and 30%. especially gynecologic or related procedures.[10] The risk is increased in persons with hepatic failure. However. the hyponatremia was hospital acquired or aggravated by the hospitalization and may be secondary to the administration of hypotonic intravenous (IV) fluids. 7. including spastic quadriparesis and pseudobulbar palsy.[8] Low body weight is also a risk factor for hyponatremia.[8] Men appear to be more likely to develop mild or moderate.2. such as unsteady gait. and medications used. Predictors for higher morbidity and mortality rates include being hospitalized. large burns. who are more sensitive to changes in serum Na+. Typical features are disorders of upper motor neurons. such as in patients with chronic kidney disease.[7] When . 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.[12] The mortality of patients with hyponatremia (Na+ < 130 mEq/L) is increased 60-fold compared with that of patients without documented hyponatremia. can also develop permanent neurologic impairment from central pontine myelinolysis (CPM). as well as mental disorders ranging from confusion to coma. there is no proven treatment.[11] Premenopausal patients undergoing surgery. However. 6. [9]  Noncardiogenic pulmonary edema may develop. Sex. and lead to frequent falls. overly rapid correction of hyponatremia. mild hyponatremia was considered relatively asymptomatic. potassium depletion. and those with serum Na of less than 105 may also have an increased risk. Successful treatment of pulmonary or CNS infection also can lead to correction of SIADH. hyponatremia.[5.  CPM is the feared complication of excessive. although this may be partly related to their comorbid conditions rather than to the hyponatremia itself. This can lead to cerebral herniation. pain. and severity of hyponatremia. Once CPM occurs as a complication. Morbidity and mortality Previously.[5] SIADH can also arise postoperatively from stress. Rapid and complete recovery tends to be the rule with drug-induced SIADH when the offending agent is withdrawn. especially those who are asymptomatic. Women appear to be more prone to drug-induced hyponatremia and to exercise-induced hyponatremia (marathon runners). especially in marathon runners. and malnutrition. However. Complications The following complications are noted in SIADH:  Cerebral edema may be observed when plasma osmolality decreases faster than 10 mOsm/kg/h. 8] In the majority of cases.

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

This was more of an issue in the past in the United States. cirrhosis with portal hypertension. volume contraction. when the conventional method of measuring Na+ (ie. leading to an overall increase in plasma volume without an actual decrease or dilution of Na+ in the aqueous phase. This results from the osmotic effect of glucose drawing water into the intravascular space. nausea. Plasma osmolality is high in this situation.002 = mEq/L decrease in Na+ Plasma protein level .Cortisol deficiency. the proteins and lipids cause an increase in the nonaqueous phase of plasma. The correction factors are as follows:   Plasma triglycerides (g/L) x 0. Pseudohyponatremia may continue to be a problem in parts of the world where flame photometry is still used to measure Na+. Exercise-induced hyponatremia Exercise-induced hyponatremia has been reported during prolonged exercise such as in marathon runners and triathletes. thus avoiding the error of pseudohyponatremia.025 = mEq/L decrease in Na+ The newer method (using ion-specific Na+ electrodes) measures the Na+ in the aqueous phase only. usually in warmer climates. Pseudohyponatremia should be suspected when the measured plasma osmolality is normal in the presence of hyponatremia. flame-emission spectrophotometry) measured the aqueous and nonaqueous phases of plasma. This is a form of transient hyponatremia that corrects itself as hyperglycemia is reversed.[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. Hyperglycemia Elevated glucose levels decrease the measured serum Na+ levels by 1. Some athletes with cerebral edema also develop noncardiogenic pulmonary edema. 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.       disorders (congestive heart failure. exogenous ADH (eg. hypothyroidism.8 (g/L) x 0. such as mannitol or dextran. and NSAIDs). vasopressin.Acute kidney injury (AKI) or chronic kidney disease (CKD) Other states of ADH excess .6 mEq/L for every 100 mg/dL increase in glucose. Na+ is contained in the aqueous phase of plasma.[11] A similar form of hyponatremia can occur with any osmotically active substance in plasma. which can lead to severe hyponatremia associated with neurological symptoms. severe nephrotic syndrome) Renal failure .[9] Cerebral salt wasting . deamino-D-arginine-vasopressin.

The evidence in favor of CSW rests on the following points: (1) the presence of a negative salt balance. The absence of cortisol thus removes this inhibitory effect. they have a lower. however. Measurement of AVP or atrial natriuretic peptide levels is not helpful because they have been known to vary even in persons with SIADH.Reduced in CSW and normal or increased in SIADH Salt wasting . fluid intake no greater than insensible losses leads to a predictable fall in serum Na. CSW is defined as the renal loss of Na+ with intracranial disease.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+.Gross in CSW and self-limited in SIADH Urine output . (2) the development of volume contraction (by definition. including the roles of natriuretic peptides and neural regulatory mechanisms. but their threshold for ADH release is reduced. which. The mineralocorticoid fludrocortisone has been used as part of the treatment of CSW.Occasionally in CSW and frequent in SIADH Over the years. CSW is treated with Na+ replacement. 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. 17] Vasopressin-resistant polyuria with hyponatremia. Na+ administration in persons with CSW corrects the hyponatremia and the fluid loss. much debate has been focused on the existence of this entity. Various mechanisms have been postulated. with resultant salt wasting and polyuria. should prompt consideration of CSW in the differential diagnosis. particularly in the setting of cerebral injury or cerebral disease or when accompanied by dehydration. the effect is temporary. CSW must be distinguished from SIADH because management of these 2 conditions differs significantly. Some individuals probably carry a nonsynonymous polymorphism (P19S) in the transient . which leads to hyponatremia and a decrease in extracellular fluid volume. Renal disease With declining renal function.Polyuria in CSW and variable in SIADH Hypouricemia . and (3) the fact that patients with CSW respond to salt and volume replacement rather than to fluid restriction. but stable. The differences and similarities in findings for CSW and SIADH are itemized as follows:       Hyponatremia . in patients with SIADH. increasing the release of ADH.Present in both CSW and SIADH Urine Na .[17] Adrenal insufficiency Cortisol has a negative feedback effect on ADH and corticotropin-releasing hormone.Increased in both CSW and SIADH Volume . Therefore. plasma Na+ concentration. Reset osmostat Persons with this entity have a normal response to changes in osmolality. In patients on long-term dialysis with no urine output.[16. which is diametrically opposite to that for SIADH. however. is not sustained because of regular maintenance dialysis. patients with SIADH are euvolemic).

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

serum osmolality is generally lower than urine osmolality.Normal skin turgor. These conditions include congestive heart failure. The disease is likely to present in early infancy. which remain valid today. thus moving the plasma osmolality toward normal. Inappropriate water retention causes the dilutional hyponatremia. cirrhosis. blood pressure within the reference range  Absence of other causes of hyponatremia . and nephrotic syndrome. in SIADH.” 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. However. they are predicted to be low. drugs that impair renal water excretion  Correction of hyponatremia by fluid restriction Hyponatremia (ie. resulting in a spontaneously active receptor and unregulated water reabsorption. These should be evident on clinical examination because of the presence of peripheral edema with elevated jugular venous pressure. the urine Na+ concentration . ascites. Therefore.This is a rare X-linked recessive genetic disease secondary to gain of function mutations in the V2 receptor. Approach Considerations In the absence of a single laboratory test to confirm the diagnosis. hypothyroidism. However. serum Na+ < 135 mmol/L) with concomitant hypo-osmolality (serum osmolality < 280 mOsm/kg) and high urine osmolality is the hallmark of SIADH. glucocorticoid deficiency). plasma hypo-osmolality. 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 .Adrenal insufficiency (mineralocorticoid deficiency. pulmonary rales. and increased urinary osmolality. it does not indicate if the ADH secretion is “inappropriate. In the setting of serum hypo-osmolality. hepatic disease. ADH secretion is usually suppressed to allow the excess water to be excreted. which is generally more than 40 mEq/d (usually 50-100 mEq/d). with euvolemic hyponatremia.[19] If AVP levels are measured. Na+ handling is not abnormal and the urine Na+concentration reflects Na+ intake. renal disease with salt wastage. although so far only 2 patients have been described with this disorder. Urine Na+ concentration in persons with SIADH is usually more than 40 mEq/L because. The laboratory features are identical to those of SIADH. these findings only indicate that ADH is present and acting on the distal nephron. urine osmolality of more than 100 mOsm in the context of plasma hypo-osmolality is sufficient to confirm ADH excess. If ADH secretion is shut down completely. or stigmata of advanced liver disease. SIADH is best defined by the classic criteria introduced by Bartter and Schwartz in 1967. 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. pituitary insufficiency.” In SIADH. cardiac failure. urine should have an osmolality of less than 100 mOsm.

and urate. with unaffected bicarbonate (HCO3-). In these patients. If both hypokalemia and metabolic alkalosis are present. The anion gap is further decreased because the volume expansion probably reduces the tubular reabsorption of unmeasured anions. urinary Na+ excretion is a reflection of Na+ intake and. consider diuretic therapy or vomiting as the cause of hyponatremia. 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. such as sulfate. as in healthy patients. If hyperkalemia and metabolic acidosis coexist with hyponatremia. therefore. Serum bicarbonate Serum bicarbonate remains within the reference range despite hypotonic expansion of body fluids in SIADH. However. patients with SIADH may have a urine Na+ level of less than 40 mEq/L. both of which avert a dilutional fall in the serum bicarbonate concentration. in the setting of Na+ restriction in patients with SIADH or in . Movement of potassium from the intracellular space to the extracellular space prevents dilutional hypokalemia. Serum Na Hyponatremia (ie. Anion gap The anion gap is reduced in SIADH secondary to equal dilution of serum Na+and chloride. phosphate. Thus. consider adrenal insufficiency and volume depletion leading to AKI. chloride. potassium. on a low-Na+ diet. serum Na+ < 135 mmol/L) is a defining feature of SIADH. the hyponatremia is associated with measured serum hypo-osmolality. As hydrogen ions move intracellularly. Serum potassium Serum potassium concentration generally remains unchanged.in persons with SIADH can be modulated by dietary Na+ intake. Laboratory Tests Order the following tests to help in the diagnosis of SIADH:          Serum Na+. 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. Urinary Na excretion In SIADH. usually is greater than 20 mmol/L. urinary loss of Na+ continues despite significant hyponatremia. they are exchanged for potassium in order to maintain electroneutrality.

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

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

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. 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. However. Despite the correct use of these formulas. Therefore. Electrolyte free water intake can be restricted. 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. Emergent treatment should also be strongly considered for those with moderate-to-severe hyponatremia with a documented duration of less than 48 hours. Attention should also be paid to the prevention of severe hypokalemia in conjunction with treatment of hyponatremia.5 mEq/L per hour. The goal is to correct hyponatremia at a rate that does not cause neurologic complications. total correction in the first 24 hours must not exceed 10-12 mEq.5-1 mEq/h. the amount of time needed to correct a given degree of hyponatremia is as follows: Time Needed for Correction = (Desired Na+ . Previous    . Administration of 3% hypertonic saline should be restricted to these emergent circumstances. some authors recommend an immediate bolus of 100 mL of 3% hypertonic saline repeated every 10 minutes until symptoms resolve.and has an osmolality of 1026 mOsm/L. The diuresis induced by furosemide has a urine solute concentration roughly equivalent to half-normal saline.[13] The approximate Na+ deficit can be estimated by using the following formula (0. and both neurological symptoms and serum Na+ should be monitored frequently to achieve the desired target and to prevent overcorrection.[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. Patients still require frequent retesting of their serum Na+ concentration.[11] However. to bring the Na+ value to a maximum level of 125 -130 mEq/L. they have not been prospectively studied.of the degree of hyponatremia.5 L/kg for females):  Na+ Deficit (mEq) = (Desired Na+ . thus. excretion of free water occurs.Measured Na+) x 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. In the special situation of exercise-induced hyponatremia with neurological symptoms. these formulas should serve only as guidelines. The objective is to raise serum Na+ levels by 0. This has led some authors to recommend a lower target of 8 mEq in 24 hours.Measured Na+)/0. and not more than 10-12 mEq in the first 24 hours. 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). hyponatremia is often corrected too rapidly.6 L/kg x Weight (kg) Three-percent hypertonic saline has 513 mEq/L each of Na+ and Cl.

Water restriction The degree of water restriction depends on the prior water intake. the approach to correction varies. The drug is given as a 20-mg loading dose followed by a continuous infusion or as intermittent boluses.Acute Setting In the acute setting (ie. irritability. agents that competitively block ADH action and increase water excretion are called aquaretics. In persons with SIADH. treatment options for the hyponatremia include 3% hypertonic saline (513 mEq/L). a certain volume of water must be excreted. This patient then excretes the solute load in 1. Conivaptan is a parenteral nonpeptide dual AVP V1a. Water restriction to about 500-1500 mL/d (or even lower in some cases) is usually prescribed. One of the functions of the kidneys is to excrete solutes in varying amounts of water. If water intake is lowered below total obligatory fluid losses (insensible losses plus volume of urine required to excrete the osmolar load). and. Depending on the rate of development of hyponatremia. if the urine osmolarity is fixed at 300 mOsm/kg. inability to concentrate. Although easier to maintain in the hospital setting. and they are useful in the treatment of the hyponatremia in SIADH. loop diuretics with saline. altered mood) or absent. urine osmolality is fixed at a certain value. then vasopressin-2 receptor antagonists (aquaretics) or water restriction are both options.5 L of urine. nausea. 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. his or her urine osmolality is fixed at 600 mOsm/kg. this becomes difficult for patients to follow in an outpatient setting. which is approved for use in hospitalized patients with euvolemic (dilutional) and hypervolemic hyponatremia. 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. then serum osmolality rises because a net loss of water occurs. and vomiting. When water intake is restricted. and the degree of hyponatremia. For example. conivaptan together . On the other hand. the use of hypertonic saline may be warranted (discussed under Emergent Care).[1] There are 2 aquaretics that are currently approved by the US Food and Drug Administration (FDA).and V2-receptor antagonist. the expected ongoing fluid losses. for the kidneys to eliminate an "X" amount of solutes. because of SIADH. If symptoms are less severe (headache. consider a patient who has a net solute load of 900 mOsm/kg/day that must be excreted. If an acute onset and moderate neurologic symptoms have occurred. Collectively. The insensible losses of relatively hypotonic fluids also contribute to net water loss. vasopressin-2 receptor antagonists (aquaretics). The patient's serum Na+ level and clinical status must be monitored often to determine the need for continued aggressive therapy. then 3 L of urine is required to excrete the same osmolar load. The pivotal studies in euvolemic hyponatremia showed that compared with fluid restriction alone. but it should not be used for more than 4 days. delirium. disorientation. < 48 h since onset) with moderate symptoms such as confusion. The term "vaptan" has been coined to officially name all the members of this new class of drugs. and water restriction.

TBW equals body weight in kg multiplied by 0. The excreted Na+ is replaced with 3% hypertonic saline or with normal saline (NaCl 154 mEq/L). If the underlying cause of SIADH has resolved. excretion of free water occurs. if urine output (plus insensible losses) exceeds water intake. the principal options are fluid restriction and V2 receptor antagonists (see Acute Setting). Serum Na+ and osmolality and urine osmolality should be checked frequently to monitor the change in serum Na+ and the rate of correction. 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.with a 2 L fluid restriction over 4 days increased serum Na by 6 mEq/L.6.[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. Thus. the patient can be discharged in 24-48 hours if neurological symptoms have resolved or the patient was asymptomatic at presentation. If the measured sum of urinary potassium and Na+ with furosemide is greater than the plasma Na. and it is best to avoid fluid restriction during the dosefinding phase. Excess water that must be removed to correct the hyponatremia can be calculated using total body water (TBW). 23] The drug is started at 15 mg once daily and titrated up to 60 mg daily as required. Chronic Setting In the chronic asymptomatic setting. assuming that the total body solute or water has not changed. then hypertonic saline rather than normal saline should be used to replace excreted Na. thus avoiding a net Na+ loss while effecting a loss of free water. The diuresis induced by furosemide has a urine solute concentration roughly equivalent to half-normal saline.[21] Tolvaptan is a selective oral V2 receptor antagonist also approved for use in hospitalized patients for hypervolemia and euvolemic hyponatremia. In the pivotal studies. The primary risk of using these drugs is an excessively rapid rate of correction of serum Na. 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. Furosemide Furosemide and other loop diuretics can be used to increase the excretion of free water. Tolvaptan can also be considered for long-term therapy of chronic hyponatremia. although with withdrawal of the drug. the drug can be withdrawn after 2-4 weeks. cirrhosis. and SIADH. serum Na+ falls back to that seen in the placebo group. the patient may need to be admitted again before reinitiating tolvaptan. If V2 receptor antagonists are not available or if local experience . These drugs should be avoided in hypovolemic hyponatremia. which included patients with CHF.[25] free water already present to excrete this load. If the serum Na+ falls again and if is less than 125 for more than 48 hours. while carefully monitoring serum Na+ daily for the next 5 days. thus. producing water excretion without electrolyte excretion and eliminating the need for fluid restriction.[22. with a median increase of 4 mEq/L by 23 hours. They offer the benefit of prompt correction of serum Na+. Other sources of free water intake should be restricted as well. Once the drug is initiated. tolvaptan compared with fluid restriction alone increased serum Na by 8 mEq/L over 30 days.

3% sodium chloride solution) can be dramatically successful in some patients. does not cause edema or increase body weight. furosemide) and the replacement of urine output with a solution that contains a higher Na+concentration (ie. BUN 80 mg/dL or more.with these agents is very limited. Urea should be used with great care in patients with serum creatinine of 2 mg/dL or more. and demeclocycline. To avoid gastric upset.5 g/kg body weight) without major adverse effects. or bilirubin of 2 mg/dL or more. other therapeutic modalities include chronic loop diuretics with increased salt intake. 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. Hypernatremia and dehydration may occur if the patient does not have free access to water. to avoid progressive azotemia. Increased urinary loss of water decreases free water retention. which can result in central pontine myelinolysis (CMP). and hepatic encephalopathy. Medication Summary Vasopressin receptor antagonists inhibit the V2 receptor. Because urine osmolality is fixed in persons with SIADH. These medications should be initiated in a closely monitored setting to prevent rapid correction of serum Na+. Urea is available as a powder. 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. rapid onset of action. the obligatory urine volume can be increased by increasing the osmotic or solute load. Urea is a relatively nontoxic compound and. urea. 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. Urea Urea is a solute that must be excreted by the kidneys. which is dissolved in water and taken orally during or after meals. it can be taken with an antacid. mannitol. Urea can be administered on a long-term basis (0.[26] View full drug information Conivaptan (Vaprisol) . The use of a combination of a loop diuretic (eg. as opposed to sodium chloride treatment. reducing the number of aquaporin-2 water channels in the renal collecting duct and decreasing the water permeability of the collecting duct. 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. hyperammonemia.

The overall effect is an increase in free water excretion by the kidneys. Diuretics. View full drug information Furosemide (Lasix) Furosemide increases excretion of water by interfering with the Na+-K+-Cl. results in inhibition of Na+ and Cl. View full drug information . In patients with syndrome of inappropriate antidiuretic hormone secretion (SIADH) with euvolemic hyponatremia. It is indicated for hospitalized patients with more severe euvolemic or hypervolemic hyponatremia. Diuretics. Na+ and Cl. It is indicated for hypervolemic and euvolemic hyponatremia (ie.excretion also increase. in turn. serum Na level < 125 mEq/L) or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction. but to a lesser extent than water excretion.Conivaptan is a parenteral nonselective vasopressin receptor antagonist used for the treatment of euvolemic hyponatremia in hospitalized patients. Initiate or reinitiate the drug in a hospital environment only since there may be overly rapid correction of the hyponatremia. Loop Class Summary These agents are often used in the treatment of hypervolemic hyponatremia. it increases thirst (potentially limiting its effects) and is expensive. and syndrome of inappropriate antidiuretic hormone secretion (SIADH). Osmotic Agents Class Summary These agents induce diuresis by elevating the osmolarity of the glomerular filtrate. Concomitantly.(Na-K-2Cl) transporter. diuretics are usually used in conjunction with normal saline to replenish the Na+excreted with the diuresis. liver cirrhosis. thereby hindering the tubular reabsorption of water. with little electrolyte loss. Conivaptan increases urine output of mostly free water. View full drug information Tolvaptan (Samsca) Tolvaptan is an oral selective vasopressin V2-receptor antagonist. Na+ is reabsorbed more distally and the excreted urine is hypo-osmolar in relation to serum. It is used for hyponatremia associated with CHF.reabsorption in the ascending loop of Henle. However. that.

thus. It is no longer available in most countries and may be nephrotoxic in patients with liver failure. It decreases brain edema. thereby hindering the tubular reabsorption of water. Concomitantly. and induces Na+ retention. it is not indicated for the emergency management of symptomatic hyponatremia. which can correct the excess of water seen in SIADH. Urea is known to promote diuresis. restores medullary tonicity. 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. The drug's onset of action may be delayed by over a week. as a 15-20% solution. It is typically used intravenously. View full drug information Demeclocycline Demeclocycline is a tetracycline derivative that induces diabetes insipidus by impairing the generation and action of cAMP. Na+ and Clexcretion also increase but to a lesser extent than water excretion.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. One of its adverse effects is nephrogenic diabetes insipidus and polyuria. . thus interfering with the action of AVP on the collecting duct. Tetracyclines Class Summary Demeclocycline is an older tetracycline.