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syndrome of inappropriate antidiuretic hormone; SIADH; nephrogenic syndrome of inappropriate antidiuresis; NSIAD

Not diagnosed in patients on diuretics. Volume depletion caused by diuretic induces ADH secretion. [4] Etiology: 1) central nervous system disorders [5] a) meningitis, encephalitis b) brain abscess c) CNS infections d) subarachnoid hemorrhage, subdural hematoma e) ischemic stroke f) neoplasm* g) Guillain-Barre syndrome h) lupus erythematosus i) multiple sclerosis j) Shy-Drager syndrome k) delirium tremens l) acute intermittent porphyria m) trauma, skull fracture* n) hydrocephalus o) cavernous sinus thrombosis 2) psychiatric disorders 3) infections a) Rocky Mountain spotted fever b) HIV1 infection, AIDS c) Legionnaire's disease 4) pharmacologic agents* a) anticonvulsants - carbamazepine - valproate b) cyclophosphamide c) chlorpropamide d) vasopressin, desmopressin, oxytocin (also see drugs that increase vasopressin) e) thiazide diuretics (especially the elderly) f) vincristine, vinblastine g) antidepressants - tricyclic antidepressants - amitriptyline - selective serotonin reuptake inhibitors (SSRI) & - serotonin norepinephrine reuptake inhibitors (SNRI) - mirtazapine h) neuroleptics, antipsychotics - phenothiazines - thioridazine - thiothixene - haloperidol - aripiprazole, risperidone, ziprasidone, olanzapine, clozapine i) bromocryptine j) narcotics (opiates), tramadol k) NSAIDs & COX2 inhibitors l) methylenedioxymethamphetamine (Ecstasy) m) clofibrate n) ifosfamide o) nicotine 5) pulmonary disease [5] a) pneumonia b) tuberculosis c) aspergillosis d) pulmonary abscess, empyema e) asthma f) cystic fibrosis g) positive pressure ventilation 6) neoplasms causing ectopic production of ADH [5] a) small cell carcinoma of the lung b) pancreatic cancer, gastric cancer, duodenal cancer c) non-Hodgkin's lymphoma d) Hodgkin's disease e) thymoma f) mesothelioma g) carcinoma of the genitourinary tract - prostate cancer, bladder cancer endometrial cancer, ureteral cancer h) Ewing's sarcoma i) oropharyngeal cancer (squamous cell carcinoma) - head & neck cancer 7) postoperative state a) nausea b) pain c) anesthesia d) orthopedic surgery, esp. premenopausal women [4] e) hypophysectomy 8) endocrine disorders - hypothyroidism - glucocorticoid insufficiency, adrenal insufficiency 9) stress 10) endurance exercise (marathon) [5] 11) familial disorders - gain of function mutations in vasopressin V2 receptor 12) increase intrathoracic pressure & decreased venous return to the heart increase risk for SIADH 13) idiopathic * most common causes in adults [4] Pathology: - cerebral edema in symptomatic patients [2] Genetics: - gain of function mutations in vasopressin V2 receptor Clinical manifestations: 1) clinical euvolemia 2) initial presentation with non-specific symptoms a) headache b) nausea/vomiting is common c) dysgeusia is common 3) delirium may occur 4) severe hyponatremia a) obtundation b) seizures c) coma d) hypoxia e) respiratory arrest [2] 5) also see hyponatremia Laboratory: 1) serum chemistries a) hypotonic hyponatremia a] serum Na+ low b] serum osmolality low - of secondary importance to hyponatremia [4] b) normal renal function, adrenal function & thyroid function 1] serum creatinine normal 2] serum glucose normal 3] serum K+ normal 4] serum TSH normal c) serum chloride low, corresponding to low serum Na+ d) decreased serum urea nitrogen may be present (< 10 mg/dL) - case where BUN is 6.0 mg/dL, serum creatinine 0.9 mg/dL [2] e) decreased serum uric acid may be present (< 4 mg/dL) f) osmolal gap: measured & calculated serum osmols NOT different 2) urine chemistries a) less than maximally dilute urine 1] urine osmolality generally > 100 mosm/kg H20 - elderly may not be able to dilute urine < 150 mOsm/kg H2O [4] 2] urine osmolality > plasma osmolality confirmatory b) elevated urine Na+, generally > 20 meq/L - urine Na+ > 40 meq/L rules out hypovolemia [2] c) fractional excretion of sodium > 1% d) fractional excretion of urea > 50% e) 24 hour urine volume is low Special laboratory: - water load test (rarely used) Differential diagnosis: - polydipsia - 24 hour urine volume is high - urine osmolality may be maximally dilute Management: 1) acute treatment a) indications - symptomatic patients, neurologic symptoms - severe hyponatremia b) 3% saline infusion - increase serum sodium < 0.5 meq/L/hour & - < 10 meq/L/24 hours, < 18 meq/L/48 hrs [2] - target: formerly 4-6 meq/24 hours [2] - 6-10 meq/L/24 hours aligns with guidelines (2023) [10] - central pontine myelinolysis is danger of too rapidly correcting serum sodium - D5W +/- desmopressin for overcorrection of hyponatremia [2] - ref [2] recommends D5W + desmopressin - infusion of normal saline can result in worsening of hyponatremia [2] c) boluses of hypertonic saline may result in more-rapid neurological improvement without serious adverse events [6] d) IV loop diuretic (Bumetanide, Bumex; furosemide, Lasix) may be given for volume overload e) serum Na+ is usually corrected to 120 meq/L f) conivaptan IV or tolvaptan PO for life-threatening euvolemic & hypervolemic hyponatremia in hospitalized patients g) urea 7.5-90 grams daily (via nasogastric tube or orally) [12] 2) chronic treatment (asymptomatic patients) a) may not be necessary after recovery from precipitating illness b) water restriction 500 mL to 1 L/day (restriction of all fluids) [8] - fluid restriction to 500 mL/day may lead to dehydration & orthostasis in the elderly - no restriction on dietary sodium [2] - increase solute intake (urea 15 g BID mixed with fruit juice) for low plasma osmolality & high urine osmolality not responding to fluid restriction [8,9] c) increased salt & protein intake d) loop diuretic (Lasix, Bumex) e) salt tablets, furosemide, or both no better than fluid restriction alone [7] f) demeclocycline 300-600 mg/day - doses as high as 600-1200 mg/day may be used - do NOT use in patients with cirrhosis 3) unless hyponatremia is indicated as acute, treat a chronic hyponatremia [2]

Related

hyponatremia vasopressin (antidiuretic hormone, ADH)

General

syndrome neuroendocrine disease

Database Correlations

OMIM 300539

References

  1. Manual of Medical Therapeutics, 28th ed, Ewald & McKenzie (eds), Little, Brown & Co, Boston, 1995, pg 47-48
  2. Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2006, 2009, 2012, 2015. 2018, 2021. - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022 - Medical Knowledge Self Assessment Program (MKSAP) 20 American College of Physicians, Philadelphia 2025
  3. Harrison's Principles of Internal Medicine, 14th ed. Fauci et al (eds), McGraw-Hill Inc. NY, 1998, pg 2009
  4. Geriatrics Review Syllabus, American Geriatrics Society, 5th edition, 2002-2004; 7th edition 2010 - Geriatric Review Syllabus, 10th edition (GRS10) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2019
  5. Ellison DH and Berl T Clinical Practice: The syndrome of inappropriate antidiuresis N Engl J Med 2007, 356:2064 PMID: 17507705
  6. Garrahy A, Dineen R, Hannon AM et al. Continuous versus bolus infusion of hypertonic saline in the treatment of symptomatic hyponatremia caused by SIAD. J Clin Endocrinol Metab 2019 Sep 1; 104:3595. PMID: 30882872 https://academic.oup.com/jcem/article-abstract/104/9/3595/5381922?redirectedFrom=fulltext
  7. Vongsanim S, Pin-On P, Ruengorn C, Noppakun K. Efficacy of furosemide, oral sodium chloride, and fluid restriction for treatment of syndrome of inappropriate antidiuresis (SIAD): An open-label randomized controlled study (the EFFUSE-FLUID trial). Am J Kidney Dis 2020 Aug; 76:203 PMID: 32199708 https://www.ajkd.org/article/S0272-6386(19)31172-2/fulltext
  8. NEJM Knowledge+ Endocrinology
  9. Rondon-Berrios H, Tandukar S, Mor MK et al Urea for the Treatment of Hyponatremia. Clin J Am Soc Nephrol. 2018 Nov 7;13(11):1627-1632. PMID: 30181129 PMCID: PMC6237061 Free PMC article.
  10. Seethapathy H, Zhao S, Ouyang T et al. Severe hyponatremia correction, mortality, and central pontine myelinolysis. NEJM Evid 2023 Sep 26; 2:EVIDoa2300107. PMID: 38320180 https://evidence.nejm.org/doi/10.1056/EVIDoa2300107
  11. Adrogue HJ, Madias NE. The Syndrome of Inappropriate Antidiuresis. N Engl J Med. 2023 Oct 19;389(16):1499-1509. PMID: 37851876 Review. https://www.nejm.org/doi/pdf/10.1056/NEJMcp2210411
  12. Chander S, Kumari R, Lohana AC et al. Urea to treat hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion: A systematic review and meta-analysis. Am J Kidney Dis. 2024 Oct 1:S0272-6386(24)00984-3 PMID: 39362395 https://www.ajkd.org/article/S0272-6386(24)00984-3/fulltext
  13. Warren AM, Grossmann M, Christ-Crain M, et al. Syndrome of inappropriate antidiuresis: from pathophysiology to management. Endocr Rev. 2023;44:819-861. PMID: 36974717
  14. Ali SN, Bazzano LA. Hyponatremia in Association With Second-Generation Antipsychotics: A Systematic Review of Case Reports. Ochsner J. 2018 Fall;18(3):230-235. PMID: 30275787 PMCID: PMC6162139 Free PMC article. Review.