8/20/2019 Syndrome of Inappropriate Antidiuretic Hormone Secretion_ Practice Essentials, Background, Pathophysiology
http://slidepdf.com/reader/full/syndrome-of-inappropriate-antidiuretic-hormone-secretion-practice-essentials 1/5
3/4/2016 Syndrome of Inappropriate Antidiuretic Hormone Secretion: Practice Essentials, Background, Pathophysiology
http://emedicine.medscape.com/article/246650-overview
Syndrome of Inappropriate Antidiuretic HormoneSecretion
Author: Christie P Thomas, MBBS, FRCP, FASN, FAHA; Chief Editor: Vecihi Batuman, MD, FACP, FASNmore...
Updated: Oct 28, 2015
Practice Essentials
The syndrome of inappropriate antidiuretic hormone (ADH) secretion (SIADH) isdefined by the hyponatremia and hypo-osmolality resulting from inappropriate,continued secretion or action of the hormone despite normal or increased plasmavolume, which results in impaired water excretion. The key to understanding thepathophysiology, signs, symptoms, and treatment of SIADH is the awareness thathe hyponatremia results from an excess of water rather than a deficiency of
sodium.
Signs and symptoms
Depending on the magnitude and rate of development, hyponatremia may or maynot cause symptoms. The history should take into account the followingconsiderations:
In general, slowly progressive hyponatremia is associated with fewer symptoms than is a rapid drop of serum sodium to the same valueSigns and symptoms of acute hyponatremia do not precisely correlate withthe severity or the acuity of the hyponatremiaPatients may have symptoms that suggest increased secretion of ADH, suchas chronic pain, symptoms from central nervous system or pulmonary tumorsor head injury, or drug useSources of excessive fluid intake should be evaluatedThe chronicity of the condition should be considered
After the identification of hyponatremia, the approach to the patient depends on theclinically assessed volume status. Prominent physical findings may be seen only insevere or rapid-onset hyponatremia and can include the following:
Confusion, disorientation, deliriumGeneralized muscle weakness, myoclonus, tremor, asterixis, hyporeflexia,ataxia, dysarthria, Cheyne-Stokes respiration, pathologic reflexesGeneralized seizures, coma
See Presentation for more detail.
Diagnosis
In the absence of a single laboratory test to confirm the diagnosis, SIADH is bestdefined by the classic Bartter-Schwartz criteria, which can be summarized as
follows[1] :
Hyponatremia with corresponding hypo-osmolalityContinued renal excretion of sodiumUrine less than maximally dilute
Absence of clinical evidence of volume depletion Absence of other causes of hyponatremiaCorrection of hyponatremia by fluid restriction
The following laboratory tests may be helpful in the diagnosis of SIADH:
Serum sodium, potassium, chloride, and bicarbonate
Plasma osmolalitySerum creatinineBlood urea nitrogenBlood glucoseUrine osmolalitySerum uric acidSerum cortisolThyroid-stimulating hormone
The patient’s volume should be assessed clinically to help rule out the presence of hypovolemia.
Imaging studies that may be considered include the following:
Chest radiography (for detection of an underlying pulmonary cause of SIADH)Computed tomography or magnetic resonance imaging of the head (for detection of cerebral edema occurring as a complication of SIADH, for
8/20/2019 Syndrome of Inappropriate Antidiuretic Hormone Secretion_ Practice Essentials, Background, Pathophysiology
http://slidepdf.com/reader/full/syndrome-of-inappropriate-antidiuretic-hormone-secretion-practice-essentials 2/5
3/4/2016 Syndrome of Inappropriate Antidiuretic Hormone Secretion: Practice Essentials, Background, Pathophysiology
http://emedicine.medscape.com/article/246650-overview
identification of a CNS disorder responsible for SIADH, or for helping to rule
out other potential causes of a change in neurologic status)
See Workup for more detail.
Management
Treatment of SIADH and the rapidity of correction of hyponatremia depend on thefollowing:
Degree of hyponatremiaWhether the patient is symptomaticWhether the syndrome is acute (< 48 hours) or chronicUrine osmolality and creatinine clearance
If the duration of hyponatremia is unknown and the patient is asymptomatic, it isreasonable to presume chronic SIADH. Diagnosis and treatment of the underlyingcause of SIADH are also important.
In an emergency setting, aggressive treatment of hyponatremia should always beweighed against the risk of inducing central pontine myelinolysis (CMP). Suchreatment is warranted as follows:
Indicated in patients who have severe symptoms (eg, seizures, stupor, coma,and respiratory arrest), regardless of the degree of hyponatremiaStrongly considered for those who have moderate-to-severe hyponatremiawith a documented duration of less than 48 hours
The goal is to correct hyponatremia at a rate that does not cause neurologiccomplications, as follows:
Raise serum sodium by 0.5-1 mEq/hr, and not more than 10-12 mEq in thefirst 24 hours
Aim at maximum serum sodium of 125-130 mEq/L
In an acute setting (< 48 hours since onset) where moderate symptoms are noted,reatment options for hyponatremia include the following:
3% hypertonic saline (513 mEq/L)Loop diuretics with salineVasopressin-2 receptor antagonists (aquaretics, such as conivaptan)Water restriction
In a chronic asymptomatic setting, the principal options are as follows:
Fluid restrictionVassopressin-2 receptor antagonistsIf vasopressin-2 receptor antagonists are unavailable or if local experiencewith them is limited, other agents to be considered include loop diuretics withincreased salt intake, urea, mannitol, and demeclocycline
See Treatment and Medication for more detail.
Contributor Information and Disclosures
Author Christie P Thomas, MBBS, FRCP, FASN, FAHA Professor, Department of Internal Medicine, Division of Nephrology, Departments of Pediatrics and Obstetrics and Gynecology, Medical Director, Kidney andKidney/Pancreas Transplant Program, University of Iowa Hospitals and Clinics
Christie P Thomas, MBBS, FRCP, FASN, FAHA is a member of the following medical societies: AmericanCollege of Physicians, American Heart Association, American Society of Nephrology, Royal College of Physicians
Disclosure: Nothing to disclose.
Coauthor(s)Mony Fraer, MD, FACP, FASN Associate Professor, Division of Nephrology, Department of Medicine, Universityof Iowa Hospitals and Clinics; Staff Physician, Iowa City Veterans Affairs Medical Center
Disclosure: Nothing to disclose.
Specialty Editor BoardEleanor Lederer, MD Professor of Medicine, Chief, Nephrology Division, Director, Nephrology Training Program,Director, Metabolic Stone Clinic, Kidney Disease Program, University of Louisville School of Medicine; ConsultingStaff, Louisville Veterans Affairs Hospital
Eleanor Lederer, MD is a member of the following medical societies: American Association for the Advancementof Science, International Society of Nephrology, American S ociety for Biochemistry and Molecular Biology,
American Federation for Medical Research, American S ociety for Bone and M ineral Research, American S ocietyof Nephrology, American Society of Transplantation, Kentucky Medical Association, National Kidney Foundation,Phi Beta Kappa
Disclosure: Received grant/research funds from Dept of Veterans Affairs for research; Received salary from American Society of Nephrology f or asn council position; Received salary from University of Louisville for employment; Received salary from University of Louisville Physicians for employment; Received contractpayment from American Physician Institute for Advanced Professional Studies, LLC for independent contractor;Received contract payment from Healthcare Quality Strategies, Inc for independent cont.
8/20/2019 Syndrome of Inappropriate Antidiuretic Hormone Secretion_ Practice Essentials, Background, Pathophysiology
http://slidepdf.com/reader/full/syndrome-of-inappropriate-antidiuretic-hormone-secretion-practice-essentials 3/5
3/4/2016 Syndrome of Inappropriate Antidiuretic Hormone Secretion: Practice Essentials, Background, Pathophysiology
http://emedicine.medscape.com/article/246650-overview
Chief Editor Vecihi Batuman, MD, FACP, FASN Huberwald Professor of Medicine, Section of Nephrology-Hypertension,Tulane University School of Medicine; Chief, Renal Section, Southeast Louisiana Veterans Health Care System
Vecihi Batuman, MD, FACP, FASN is a member of the following medical societies: American College of Physicians, American S ociety of Hypertension, American S ociety of Nephrology, International Society of Nephrology
Disclosure: Nothing to disclose.
AcknowledgementsHoward A Bessen, MD Professor of Medicine, Department of Emergency Medicine, UCLA School of Medicine;Program Director, Harbor-UCLA Medical Center
Howard A Bessen, MD is a member of the following medical societies: American College of EmergencyPhysicians
Disclosure: Nothing to disclose.
Keenan Bora, MD Fellow, Medical Toxicology, Detroit Medical Center; Attending Physician, Medical Center Emergency Services, Detroit
Keenan Bora, MD is a member of the following medical societies: American A cademy of Clinical Toxicology, American Academy of Emergency Medicine, American College of Emergency Physicians, American College of Medical Toxicology, and American Medical Association
Disclosure: Nothing to disclose.
Meher Chaudhry, MD Chief Resident, Department of Emergency Medicine, Detroit Receiving Hospital,University Health Center
Disclosure: Nothing to disclose.
Sonali Deshmukh, MBBS Consulting Staff, Omaha Nephrology, Nebraska
Sonali Deshmukh, MBBS is a member of the following medical societies: American Society of Nephrology
Disclosure: Nothing to disclose.
R obert J Ferry Jr, MD Chief, Division of Pediatric Endocrinology and Metabolism, Le Bonheur Children'sHospital; Professor, Department of Pediatrics, University of Tennessee Health Science Center at Memphis; St.Jude Children's Research Hospital, Memphis, TN; Brigade Surgeon, 36th Sustainment Brigade, U.S. Army;
Adjunct Professor, Pediatric Surgery Department, King Saud University, Riyadh, Saudi Arabia
Robert J Ferry Jr, MD is a member of the following medical societies: American Academy of Pediatrics, American Diabetes Association, American Medical Association, Endocrine Society, Lawson-Wilkins PediatricEndocrine Society, Society for Pediatric Research, and Texas Pediatric Society
Disclosure: Nutropin Speakers Bureau Honoraria Speaking and teaching; Genotropin Speakers Bureau HonorariaSpeaking and teaching; Eli Lilly & Co. Grant/research funds Investigator; MacroGenics, Inc. Grant/research fundsInvestigator; Ipsen, S.A. (formerly Tercica, Inc.) Grant/research funds Investigator; NovoNordisk SAGrant/research funds Investigator; Diamyd Investigator
Stephen Kemp, MD, PhD Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas College of Medicine and Arkansas Children's Hospital
Stephen Kemp, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical E ndocrinologists, American P ediatric Society, Endocrine Society, Phi BetaKappa, Southern Medical Association, and Southern Society for Pediatric Research
Disclosure: Nothing to disclose.
Eleanor Lederer, MD Professor of Medicine, Chief, Nephrology Division, Director, Nephrology Training Program,Director, Metabolic Stone Clinic, Kidney Disease Program, University of Louisville School of Medicine; ConsultingStaff, Louisville Veterans Affairs Hospital
Eleanor Lederer, MD is a member of the following medical societies: American Association for the Advancementof Science, American Federation for Medical Research, American Society for Biochemistry and Molecular Biology, American S ociety for Bone and Mineral Research, American S ociety of Nephrology, American S ocietyof Transplantation, International Society of Nephrology, Kentucky Medical Association, National KidneyFoundation, and Phi Beta Kappa
Disclosure: Dept of Veterans Affairs Grant/research funds Research
Lynne Lipton Levitsky, MD Chief, Pediatric Endocrine Unit, Massachusetts General Hospital; AssociateProfessor of Pediatrics, Harvard Medical School
Lynne Lipton Levitsky, MD is a member of the following medical societies: Alpha Omega A lpha, American Academy of Pediatrics, American Diabetes Association, American P ediatric Society, Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, and Society for Pediatric Research
Disclosure: Pfizer Grant/research funds P.I.; Tercica Grant/research funds Other; Eli Lily Grant/research fundsPI; NovoNordisk Grant/research funds PI
Chike Magnus Nzerue, MD Associate Dean for Clinical Affairs, Vice-Chairman of Internal Medicine, MeharryMedical College
Chike Magnus Nzerue, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American S ociety of Nephrology, and National Kidney Foundation
8/20/2019 Syndrome of Inappropriate Antidiuretic Hormone Secretion_ Practice Essentials, Background, Pathophysiology
http://slidepdf.com/reader/full/syndrome-of-inappropriate-antidiuretic-hormone-secretion-practice-essentials 4/5
3/4/2016 Syndrome of Inappropriate Antidiuretic Hormone Secretion: Practice Essentials, Background, Pathophysiology
http://emedicine.medscape.com/article/246650-overview
Disclosure: Nothing to disclose.
Jose F Pascual-y-Baralt, MD Chief, Division of Pediatric Nephrology, San Antonio Military Pediatric Center;Clinical Professor, Department of Pediatrics, University of Texas Health Science Campus
Jose F Pascual-y-Baralt, MD is a member of the following medical societies: American A cademy of Pediatrics, American Society of Nephrology, American Society of Pediatric Nephrology, Association of Military Surgeons of the US, and International Society of Nephrology
Disclosure: Nothing to disclose.
Alexandr Rafailov, MD Staff Physician, Department of Emergency Medicine, State University of New YorkDownstate/Ki ngs County Hospital
Disclosure: Nothing to disclose.
Arlan L Rosenbloom, MD Adjunct Distinguished Service Professor Emeritus of Pediatrics, University of Florida;Fellow of the American Academy of Pediatrics; Fellow of the American College of Epidemiology
Arlan L Rosenbloom, MD is a member of the following m edical societies: American A cademy of Pediatrics, American College of Epidemiology, American P ediatric Society, Endocrine Society, Florida Pediatric Society,Lawson-Wilkins Pediatric Endocrine Society, and Society for Pediatric Research
Disclosure: Nothing to disclose.
Erik D Schraga, MD Consulting Staff, Department of Emergency Medicine, Mills-Peninsula Emergency Medical Associates; Consulting Staff, Permanente M edical Group, Kaiser P ermanente, S anta Clara Medical Center
Disclosure: Nothing to disclose.
Richard H Sinert, DO Associate Professor of Emergency Medicine, Clinical Assistant Professor of Medicine,Research Director, State University of New York College of Medicine; Consulting Staff, Department of Emergency Medicine, Kings County Hospital Center
Richard H Sinert, DO is a member of the following medical societies: American College of Physicians andSociety for Academic Emergency Medicine
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center Collegeof Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Pharmacy Editor, Medscape
Disclosure: Nothing to disclose.
References
1. Bartter FC, Schwartz WB. The syndrome of inappropriate secretion of antidiuretic hormone. Am J M ed .
1967 May. 42(5):790-806. [Medline].
2. Sterns RH. Disorders of plasma sodium--causes, consequences, and correction. N Engl J Med . 2015 Jan 1.372 (1):55-65. [Medline].
3. Verbalis JG, Berl T. Disorders of water balance. Brenner BM. Brenner & Rector's The Kidney . 8th ed.Saunders; 2007. Vol 1: 459-491.
4. Elhassan EA, Schrier RW. Hyponatremia: diagnosis, complications, and management including V2receptor antagonists. Curr Opin Nephrol Hypertens. 2011 Mar. 20(2):161-8. [Medline].
5. Kohen I, Voelker S, Manu P. Antipsychotic-induced hyponatremia: case report and literature review. Am J
Ther . 2008 Sep-Oct. 15(5):492-4. [Medline].
6. Vitting KE, Gardenswartz MH, Zabetakis PM, et al. Frequency of hyponatremia and nonosmolar vasopressin release in the acquired immunodeficiency syndrome. JAMA. 1990 Feb 16. 263(7):973-8.[Medline].
7. Hoorn EJ, Lindemans J, Zietse R. Development of severe hyponatraemia in hospitalized patients:
treatment-related risk factors and inadequate management. Nephrol Dial Transplant . 2006 Jan. 21(1):70-6.[Medline].
8. Schrier RW. Body water homeostasis: clinical disorders of urinary dilution and concentration. J Am Soc
Nephrol . 2006 Jul. 17(7):1820-32. [Medline].
9. Stelfox HT, Ahmed SB, Khandwala F, Zygun D, Shahpori R, Laupland K. The epidemiology of intensivecare unit-acquired hyponatraemia and hypernatraemia in medical-surgical intensive care units. Crit Care.2008. 12(6):R162. [Medline]. [Full Text].
10. Upadhyay A, Jaber BL, Madias NE. Incidence and prevalence of hyponatremia. Am J M ed . 2006 Jul. 119(7Suppl 1):S30-5. [Medline].
11. Ayus JC, Varon J, Arieff AI. Hyponatremia, cerebral edema, and noncardiogenic pulmonary edema inmarathon runners. Ann Intern Med . 2000 May 2. 132(9):711-4. [Medline].
12. Kumar S, Fowler M, Gonzalez-Toledo E, Jaffe SL. Central pontine myelinolysis, an update. Neurol Res.2006 Apr. 28(3):360-6. [Medline].
8/20/2019 Syndrome of Inappropriate Antidiuretic Hormone Secretion_ Practice Essentials, Background, Pathophysiology
http://slidepdf.com/reader/full/syndrome-of-inappropriate-antidiuretic-hormone-secretion-practice-essentials 5/5
3/4/2016 Syndrome of Inappropriate Antidiuretic Hormone Secretion: Practice Essentials, Background, Pathophysiology
http://emedicine.medscape.com/article/246650-overview
Medscape Reference © 2011 WebMD, LLC
13. Ellison DH, Berl T. Clinical practice. The syndrome of inappropriate antidiuresis. N Engl J Med . 2007 May17. 356(20):2064-72. [Medline].
14. Renneboog B, Musch W, Vandemergel X, Manto MU, Decaux G. Mild chronic hyponatremia is associatedwith falls, unsteadiness, and attention deficits. Am J M ed . 2006 Jan. 119(1):71.e1-8. [Medline].
15. Usala RL, Fernandez SJ, Mete M, Cowen L, Shara NM, Barsony J, et al. Hyponatremia Is Associated WithIncreased Osteoporosis and Bone Fractures in a Large US Health System Population. J Clin Endocrinol Metab. 2015 Aug. 100 (8):3021-31. [Medline].
16. Clayton JA, Le Jeune IR, Hall IP. Severe hyponatraemia in medical in-patients: aetiology, assessment andoutcome. QJM . 2006 Aug. 99(8):505-11. [Medline].
17. Decaux G. Is asymptomatic hyponatremia really asymptomatic?. Am J M ed . 2006 Jul. 119(7 Suppl 1):S79-82. [Medline].
18. Hew-Butler T, Noakes TD, Siegel AJ. Practical management of exercise-associated hyponatremicencephalopathy: the sodium paradox of non-osmotic vasopressin secretion. Clin J Sport Med . 2008 Jul.18(4):350-4. [Medline].
19. Sterns RH, Silver SM. Cerebral salt wasting versus SIADH: what difference?. J Am Soc Nephrol . 2008Feb. 19(2):194-6. [Medline].
20. Yee AH, Burns JD, Wijdicks EF. Cerebral salt wasting: pathophysiology, diagnosis, and treatment.Neurosurg Clin N Am. 2010 Apr. 21(2):339-52. [Medline].
21. Tian W, Fu Y, Garcia-Elias A, et al. A loss-of-function nonsynonymous polymorphism in theosmoregulatory TRPV4 gene is associated with human hyponatremia. Proc Natl Acad Sci U S A. 2009
Aug 18. 106(33):14034-9. [Medline]. [Full Text].
22. Feldman BJ, Rosenthal SM, Vargas GA, et al. Nephrogenic syndrome of inappropriate antidiuresis. N Engl J Med . 2005 May 5. 352(18):1884-90. [Medline].
23. Maesaka JK, Miyawaki N, Palaia T, Fishbane S, Durham JH. Renal salt wasting without cerebral disease:
diagnostic value of urate determinations in hyponatremia. Kidney Int . 2007 Apr. 71 (8):822-6. [Medline].
24. [Guideline] Spasovski G, Vanholder R, Allolio B, Annane D, Ball S, Bichet D, et al. Clinical practiceguideline on diagnosis and treatment of hyponatraemia. Nephrol Dial Transplant . 2014 Apr. 29 Suppl 2:i1-i39. [Medline].
25. Sterns RH, Hix JK, Silver S. Treating profound hyponatremia: a strategy for controlled correction. Am J
Kidney Dis. 2010 Oct. 56 (4):774-9. [Medline].
26. Zeltser D, Rosansky S, van Rensburg H, Verbalis JG, Smith N. Assessment of the efficacy and safety of intravenous conivaptan in euvolemic and hypervolemic hyponatremia. Am J Nephrol . 2007. 27(5):447-57.[Medline].
27. Decker BC. Disorders of Water Excess: Hyponatremia. Dale DC, Federman DD, eds. ACP Medicine. BCDecker; 2007. Vol 1:
28. Nemerovski C, Hutchinson DJ. Treatment of hypervolemic or euvolemic hyponatremia associated with heartfailure, cirrhosis, or the syndrome of inappropriate antidiuretic hormone with tolvaptan: a clinical review.Clin Ther . 2010 Jun. 32(6):1015-32. [Medline].
29. Schrier RW, Gross P, Gheorghiade M, Berl T, Verbalis JG, Czerwiec FS, et al. Tolvaptan, a selective oralvasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med . 2006 Nov 16. 355(20):2099-112.[Medline].
30. Berl T, Quittnat-Pelletier F, Verbalis JG, et al. Oral tolvaptan is safe and effective in chronic hyponatremia.J Am Soc Nephrol . 2010 Apr. 21(4):705-12. [Medline]. [Full Text].
31. Gross P. Treatment of hyponatremia. Intern Med . 2008. 47(10):885-91. [Medline].
32. Marik PE, Rivera R. Therapeutic effect of conivaptan bolus dosing in hyponatremic neurosurgical patients.Pharmacotherapy . 2013 Jan. 33(1):51-5. [Medline].
