eMedicine Specialties > Nephrology > Acid-Base, Fluid, and Electrolyte Disorders
Syndrome of Inappropriate Secretion of Antidiuretic Hormone: Treatment & Medication
Updated: May 28, 2009
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
Treatment
Medical Care
The treatment of SIADH and the rapidity of correction of hyponatremia depend on whether the patient is symptomatic or asymptomatic from hyponatremia and whether it is an acute or chronic condition. The mainstay of treatment of acute and chronic SIADH is water restriction. 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, presuming that the condition is chronic is reasonable. Diagnosis and treatment of the underlying cause of SIADH (if known) is also important.
Extreme hyponatremia and an inappropriate approach to treatment can have disastrous consequences, and consultation with a nephrologist should be sought early in difficult cases.
- Acute setting (ie, <48 h since onset and usually with symptoms)
- Administer sodium chloride, hypertonic saline, and loop diuretics, and initiate water restriction (see Chronic setting below).
- The goal is to correct hyponatremia at a rate that does not cause neurologic complications. The objective is to raise serum sodium levels by 0.5-1 mEq/h, or not more than 10-12 mEq in the first 24 hours, to bring the sodium value to a maximum level of 125 mEq/L.
- Depending on the rate of development of hyponatremia, the approach to correction varies. If an acute onset and neurologic symptoms have occurred, the use of hypertonic saline may be warranted. Three percent normal saline has 513 mEq/L each of sodium and chloride and has an osmolality of 1026 mOsm/L.
- Hypertonic saline is usually combined with furosemide to limit treatment-induced volume expansion. The diuresis induced by furosemide has a solute concentration roughly equivalent to half-normal saline, thus excretion of free water occurs. Electrolyte free water intake is restricted. Check serum sodium and osmolality and urine osmolality frequently to follow the change in serum sodium values and to prevent overcorrection.
- The recommended rate of correction initially equals 1-2 mEq/L/h in severely symptomatic patients, until symptoms resolve (or for the first 3-4 h). Total correction in the first 24 hours must not exceed 10 mEq. Osmotic demyelination 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. Some authors have recommended a lower target of 8 mEq in 24 hours.
- The change in serum sodium per liter of infused saline can be calculated as follows:
- [infusate sodium (mEq/L) - initial serum sodium (mEq/L)] / [total body water + 1 (L)]*
- *Where total body water is 0.6 multiplied by body weight for men and 0.5 multiplied by body weight for women. This formula calculates the change in the serum sodium concentration after infusion of 1 L of sodium chloride solution. The infusate sodium is the sodium in the replacement fluid of choice. The initial serum sodium level is the patient's sodium value at presentation.
- Normal saline (3%): Infusate sodium is 513 mEq/L.
- Normal saline (0.9%): Infusate sodium is 154 mEq/L.
- Normal saline (0.45%): Infusate sodium is 77 mEq/L.
- For example, if the patient's serum sodium level is 115 mEq/L and total body water level is 35, then substituting in the above equation produces (513-115)/(35+1) = 11. This means that 1 L of 3% normal saline increases the serum sodium by 11 mEq. If the rate at which the correction must be made is known (not >10 mEq/24 h), the rate of infusion can be calculated.
- The patient's serum sodium level and clinical status must be monitored often to determine the need for continued aggressive therapy.
- Chronic setting
- Newer modalities include water restriction; a high-sodium, high-protein diet; loop diuretics; urea; and V2 receptor antagonists. Demeclocycline is rarely used, and lithium is not used anymore.
- Water restriction
- Water restriction to about 500 mL/d (or even lower in some cases) is prescribed. Although easy 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.
- For example, consider a patient who has a net solute load of 900 mOsm/kg/d 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 the free water already present to excrete this load. Thus, if urine output exceeds water intake, a net water loss occurs and the serum sodium level returns to normal. 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.
- 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. 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 without major adverse effects. (A case report of a 5-year treatment has been noted.) 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.
- The dose is calculated based on body weight (0.5 g/kg body weight). This amounts to approximately 30 g of urea in a 60-kg adult. The osmolar load of 30 g of urea is 500 mOsm. The usual dose is approximately 30 g/d but can range from 30-90 g/d. This therapy can be used in both chronic and acute settings if the urine osmolality is low. This treatment can increase the serum sodium level by as much as 5 mEq/L/d.
- After the oral administration of urea, a slight and transient (3-4 h) increase in diuresis and osmolar free water excretion occurs. This helps move excess free water and helps relieve brain edema.
- Exercise caution because urea should be used with great care in patients with levels of serum creatinine of more than 2 mg/dL, BUN of more than 80 mg/dL, or bilirubin of more than 2 mg/dL to avoid progressive azotemia, hyperammonemia, and/or hepatic encephalopathy. Hypernatremia and dehydration may occur if the patient does not have free access to water.
- Adverse effects may include (1) hypersensitivity, (2) azotemia, (3) active intracranial bleeding, (4) marked dehydration, (5) frank liver failure, and (6) phlebitis and thrombosis (if infused into veins of the lower extremities, especially in elderly patients).
- Vasopressin receptor antagonists
- Vasopressin receptor antagonists were first designed in the 1970s by Manning and Sawyer. These were peptide antagonists that were limited by their poor bioavailability and short biological half-life. In 1992, Yamamura et al characterized the first nonpeptide V2 receptor antagonist, OPC-31260. Since then, several new nonpeptide antagonists have been synthesized. Some examples are SR-121463A, WAY-VPA-985, OPC-41061, VPA-343, and YM-087. Some of these V2 receptor antagonists are now in clinical development.
- Inhibition of the 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 increase water excretion are called aquaretics, and they should prove useful in the treatment of SIADH by competitively blocking ADH action. The term "vaptan" has been coined to officially name all the members of this new class of drugs.
- Studies in humans are ongoing. Phase I studies with OPC-31260 demonstrated safety in humans. Phase II trials have also documented human safety and efficacy in such conditions as SIADH, cirrhosis, and congestive heart failure. Together, these studies demonstrate that nonpeptide vasopressin antagonists can be given orally or parenterally, and they have a purely dose-dependent aquaretic (water diuresis) effect, as opposed to a natriuretic/saluretic effect.
- Conivaptan is a nonpeptide dual AVP V1a- and V2-receptor antagonist. The FDA approved this drug for parenteral use in hospitalized patients with euvolemic (dilutional) and hypervolemic hyponatremia.
- Tolvaptan (OPC-41061) was approved by the US Food and Drug Administration (FDA) in May 2009 in hospitalized patients.4 Trials with other orally active, selective V2-receptor antagonists, such as lixivaptan (VPA-985) and satavaptan (SR-121463), are ongoing. Concerns exist with the employment of these agents in a clinical setting, and they should be used only by physicians who are experienced in the management of hyponatremia.
Medication
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Arginine vasopressin antagonists
Treats hyponatremia through V2 antagonism of AVP in the renal collecting ducts. This effect results in aquaresis (excretion of free water).
Conivaptan (Vaprisol)
Arginine vasopressin antagonist (V1A, V2) indicated for euvolemic (dilutional) and hypervolemic hyponatremia. Increases urine output of mostly free water, with little electrolyte loss.
Adult
20 mg IV loading dose (infuse over 30 min), followed by 20 mg via continuous IV infusion over 24 h; continue treatment for additional 1-3 d as a 20-mg/d continuous IV infusion; may titrate up to 40 mg/d if necessary
Pediatric
Not established
Sensitive CYP3A4 substrate and potent CYP3A4 inhibitor; coadministration with potent CYP3A4 inhibitors significantly increases Cmax and AUC; coadministration with CYP3A4 substrates (eg, midazolam, simvastatin, amlodipine) may increase substrate's toxicity; significantly decreases digoxin clearance
Documented hypersensitivity; hypovolemic hyponatremia; coadministration with potent CYP3A4 inhibitors (eg ketoconazole, itraconazole, clarithromycin, ritonavir, indinavir)
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Rapid correction of serum sodium level may result in serious sequelae (eg, osmotic demyelination); may cause infusion site reactions, hypokalemia, headache, thirst, and vomiting; caution with hepatic impairment; limited data available in CHF and hepatic or renal impairment
Tolvaptan (Samsca)
Selective vasopressin V2-receptor antagonist. Indicated for hypervolemic and euvolemic hyponatremia (ie, serum sodium level <125 mEq/L) or less-marked hyponatremia that is symptomatic and has resisted correction with fluid restriction. Used for hyponatremia associated with congestive heart failure, liver cirrhosis, and syndrome of inappropriate secretion of antidiuretic hormone. Initiate or reinitiate in hospital environment only.
Adult
15 mg PO qd initially; may increase at 24-h intervals to 30 mg/d; not to exceed 60 mg/d
Pediatric
Not established
CYP3A substrate, P-gp inhibitor, and weak CYP3A inhibitor; CYP3A inhibitors (see Contraindications) may lead to marked increase in serum concentrations; avoid coadministration with moderate CYP3A inhibitors (eg, erythromycin, fluconazole, aprepitant, diltiazem, verapamil); also avoid coadministration with CYP3A inducers (eg, rifampin, rifabutin, rifapentine, barbiturates, phenytoin, carbamazepine, St. John's wort), as these may decrease tolvaptan serum levels by up to 85% and thereby decrease effectiveness; coadministration with grapefruit juice results in a 1.8-fold increase of serum levels; dose reduction may be required when coadministered with P-gp inhibitors (eg, cyclosporine)
May increase risk for hyperkalemia when administered with drugs known to increase serum potassium levels (eg, ACE inhibitors, potassium-sparing diuretics); may increase serum levels of P-gp substrates (eg, digoxin)
Documented hypersensitivity; urgent correction of hypovolemia; individuals unable to sense or respond to thirst; hypovolemic hyponatremia; strong CYP 3A inhibitors (eg, ketoconazole, clarithromycin, itraconazole, ritonavir, indinavir, nelfinavir, saquinavir, nefazodone, telithromycin); anuria
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Initiate only in hospital setting, since serum sodium levels and volume status require close monitoring; rapid rise in sodium levels may cause osmotic demyelination syndrome, resulting in serious neurologic sequelae, including dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma, and death; use caution with cirrhosis, since may increase risk for GI bleeding; may cause hyperkalemia and other electrolyte concentration abnormalities; common adverse effects include thirst, xerostomia, asthenia, constipation, pollakiuria or polyuria, and hyperglycemia
Antibiotics
Agents that inhibit the action of ADH may be used.
Demeclocycline (Declomycin)
Indicated for SIADH. Interferes with action of vasopressin (ADH) at renal collecting duct by impairing generation and action of cAMP. This results in a state similar to nephrogenic diabetes insipidus. Onset of action may be delayed by >1 week; therefore, not indicated for emergent management of symptomatic hyponatremia.
Adult
150 mg PO qid or 300 mg bid
Pediatric
<8 years: Not recommended
>8 years: 3-6 mg/lb (6-12 mg/kg) PO divided bid/qid, depending on severity of disease
Bioavailability may decrease with coadministration of antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; may increase hypoprothrombinemic effects of anticoagulants (monitor prothrombin activity); coadministration with oral contraceptives may decrease effects of oral contraceptives, causing breakthrough bleeding and increased risk of pregnancy
Documented hypersensitivity
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines
More on Syndrome of Inappropriate Secretion of Antidiuretic Hormone |
| Overview: Syndrome of Inappropriate Secretion of Antidiuretic Hormone |
| Differential Diagnoses & Workup: Syndrome of Inappropriate Secretion of Antidiuretic Hormone |
 Treatment & Medication: Syndrome of Inappropriate Secretion of Antidiuretic Hormone |
| Follow-up: Syndrome of Inappropriate Secretion of Antidiuretic Hormone |
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References
Schwartz WB, Bennett W, Curelop S, et al. A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone. 1957. J Am Soc Nephrol. Dec 2001;12(12):2860-70. [Medline].
Clayton JA, Le Jeune IR, Hall IP. Severe hyponatraemia in medical in-patients: aetiology, assessment and outcome. QJM. Aug 2006;99(8):505-11. [Medline].
Decaux G. Is asymptomatic hyponatremia really asymptomatic?. Am J Med. Jul 2006;119(7 Suppl 1):S79-82. [Medline].
Wong F, Blei AT, Blendis LM, et al. A vasopressin receptor antagonist (VPA-985) improves serum sodium concentration in patients with hyponatremia: a multicenter, randomized, placebo-controlled trial. Hepatology. Jan 2003;37(1):182-91. [Medline].
Adrogué HJ, Madias NE. Hyponatremia. N Engl J Med. May 25 2000;342(21):1581-9. [Medline].
Arieff AI, Llach F, Massry SG. Neurological manifestations and morbidity of hyponatremia: correlation with brain water and electrolytes. Medicine (Baltimore). Mar 1976;55(2):121-9. [Medline].
Bichet DG, Razi M, Lonergan M, et al. Hemodynamic and coagulation responses to 1-desamino[8-D-arginine] vasopressin in patients with congenital nephrogenic diabetes insipidus. N Engl J Med. Apr 7 1988;318(14):881-7. [Medline].
Decaux G. Long-term treatment of patients with inappropriate secretion of antidiuretic hormone by the vasopressin receptor antagonist conivaptan, urea, or furosemide. Am J Med. May 2001;110(7):582-4. [Medline].
Decaux G, Brimioulle S, Genette F, et al. Treatment of the syndrome of inappropriate secretion of antidiuretic hormone by urea. Am J Med. Jul 1980;69(1):99-106. [Medline].
Decaux G, Genette F. Urea for long-term treatment of syndrome of inappropriate secretion of antidiuretic hormone. Br Med J (Clin Res Ed). Oct 24 1981;283(6299):1081-3. [Medline].
Decaux G, Prospert F, Penninckx R, et al. 5-year treatment of the chronic syndrome of inappropriate secretion of ADH with oral urea. Nephron. 1993;63(4):468-70. [Medline].
Gerbes AL, Gulberg V, Gines P, et al. Therapy of hyponatremia in cirrhosis with a vasopressin receptor antagonist: a randomized double-blind multicenter trial. Gastroenterology. Apr 2003;124(4):933-9. [Medline].
Gross P. Treatment of severe hyponatremia. Kidney Int. Dec 2001;60(6):2417-27. [Medline].
Gross P, Verbalis J, Berl T. Hyponatremia management with a once-daily, oral vasopressin V2 receptor antagonist for up to one year: first report of the tolvaptan SALT2 study [oral presentation]. Presented at the ASN Congress. November 11, 2005.
Harrigan MR. Cerebral salt wasting syndrome. Crit Care Clin. Jan 2001;17(1):125-38. [Medline].
Maesaka JK. An expanded view of SIADH, hyponatremia and hypouricemia. Clin Nephrol. Aug 1996;46(2):79-83. [Medline].
Miller M. Syndromes of excess antidiuretic hormone release. Crit Care Clin. Jan 2001;17(1):11-23, v. [Medline].
Palm C, Pistrosch F, Herbrig K, et al. Vasopressin antagonists as aquaretic agents for the treatment of hyponatremia. Am J Med. Jul 2006;119(7 Suppl 1):S87-92. [Medline].
Palm C, Reimann D, Gross P. The role of V2 vasopressin antagonists in hyponatremia. Cardiovasc Res. Aug 15 2001;51(3):403-8. [Medline].
Robertson GL. Antidiuretic hormone. Normal and disordered function. Endocrinol Metab Clin North Am. Sep 2001;30(3):671-94, vii. [Medline].
Rose BD, Post TW, eds. Clinical Physiology of Acid-Base and Electrolyte Disorders. 5th ed. New York: McGraw-Hill; 2000.
[Best Evidence] Schrier RW, Gross P, Gheorghiade M, Berl T, Verbalis JG, Czerwiec FS, et al. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med. Nov 16 2006;355(20):2099-112. [Medline]. [Full Text].
Seldin DW, Giebisch GH, eds. The Kidney: Physiology and Pathophysiology. Vol 1. Philadelphia: Lippincott-Raven; 1991:1133-74.
Serradeil-Le Gal C, Wagnon J, Valette G, et al. Nonpeptide vasopressin receptor antagonists: development of selective and orally active V1a, V2 and V1b receptor ligands. Prog Brain Res. 2002;139:197-210. [Medline].
Soupart A, Decaux G. Therapeutic recommendations for management of severe hyponatremia: current concepts on pathogenesis and prevention of neurologic complications. Clin Nephrol. Sep 1996;46(3):149-69. [Medline].
Sterns RH. Severe symptomatic hyponatremia: treatment and outcome. A study of 64 cases. Ann Intern Med. Nov 1987;107(5):656-64. [Medline].
Sterns RH. The treatment of hyponatremia: first, do no harm. Am J Med. Jun 1990;88(6):557-60. [Medline].
Verbalis JG. AVP receptor antagonists as aquaretics: review and assessment of clinical data. Cleve Clin J Med. Sep 2006;73 Suppl 3:S24-33. [Medline].
Verbalis JG. Vasopressin V2 receptor antagonists. J Mol Endocrinol. Aug 2002;29(1):1-9. [Medline].
Further Reading
Keywords
syndrome of inappropriate secretion of antidiuretic hormone, syndrome of inappropriate secretion of ADH, SIADH, ADH, antidiuretic hormone, antidiuretic hormone disorder, arginine vasopressin, AVP, hyponatremia, low serum osmolality, expanded extracellular volume, water balance, impaired water excretion, dilutional hyponatremia
