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SIADH

SIADH. Alexander Usorov, MD July 31, 2007. SIADH. Most frequent cause of hyponatremia First described by Schwartz et al in 1957 in 2 pts with bronchogenic carcinoma Arginine vasopressin was then identified. ADH. Synthesized in hypothalamus Transported down to posterior pituitary

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SIADH

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  1. SIADH Alexander Usorov, MD July 31, 2007

  2. SIADH • Most frequent cause of hyponatremia • First described by Schwartz et al in 1957 in 2 pts with bronchogenic carcinoma • Arginine vasopressin was then identified

  3. ADH • Synthesized in hypothalamus • Transported down to posterior pituitary • Released in response to hyperosmolality (major stimuli, mediated through osmoreceptors in hypothalamus) or hypovolemia (via baroreceptors in left atrium, aortic arch, etc)

  4. ADH • Binds to V2 receptors in collecting tubules • stimulates cyclic adenosine monophosphate • leads to insertion of aquaporin-2 channels into apical membranes • The goal is to facilitate the transport of solute-free water

  5. Figure Freeze-fracture appearance of vasopressin-induced intramembrane particle (IMP) aggregates in toad urinary bladder (A), toad epidermis (B), and rat kidney collecting duct (C). The morphology of the aggregates is different in all three vasopressin target cells. In the bladder, the aggregates are tightly packed linear arrays, in the skin they form orthogonally packed square arrays, and in the collecting duct principal cell they form loose clusters that are often located in shallow depressions on the cell surface. Bar = 0.25 µm.

  6. Figure Aquaporin-2 (AQP2) is internalized by clathrin-coated pits. A and B, Immunogold labeling of AQP2 in clathrin-coated pits (arrows) at the apical plasma membrane of collecting duct principal cells. An antibody against an external epitope of AQP2 was used. C and D, Label-fracture images of LLC-PK1 cells expressing AQP2. Immunogold label for AQP2 is located in intramembrane particle (IMP) clusters on the membrane (C,arrows; and is associated with membrane invaginations that resemble clathrin-coated pits (D,arrows). For more details, see Sun TX, et al. Bars = 0.25 µm.

  7. SIADH => SIAD • A slight misnomer • The name implies inappropriate secretion • 1/3rd of pts do secrete AVP independent of plasma osmolality • Others exhibit reset osmostat – AVP is fully supressed, but serum Na level is lower than nl • AVP levels may be undetectable in some pts • Some aquaporin mutations lead to concentrated urine in the absence of AVP • Therefore, the new term, Syndrome of Inappropriate Antidiuresis (SIAD) has been proposed

  8. Patterns of plasma levels of arginine vasopressin (AVP; also known as the antidiuretic hormone), as compared with plasma sodium levels in patients with SIAD, are shown. Type A is characterized by unregulated secretion of AVP, type B by elevated basal secretion of AVP despite normal regulation by osmolality, type C by a "reset osmostat," and type D by undetectable AVP. The shaded area represents normal values of plasma AVP. Adapted from Robertson

  9. Disorders associated with SIAD • Malignancies • Carcinomas, lymphomas, sarcoma • Pulmonary disorders • Infectious, asthma, CF • CNS disorders • Infectious, bleeding, masses, MS • Drugs • Chlorpropramide, SSRIs, cyclophosphomide, ecstasy

  10. Diagnosis of SIAD • Essential features • hyponatremia • plasma osm<275 • urine osm>100 • clinical euvolemia • urinary Na>40 • nl thyroid/adrenal fxn, no recent diuretic use

  11. Dx of SIAD • Supplemental features • uric acid<4 • BUN<10 • failure to correct hypoNa after NS infusion • correction of hypoNa after fluid restriction

  12. Volume status assesment • Sometimes, clinical assesment of volume status is imprecise. Dr. Berl suggests the following: • Rule out volume contraction by infusing 2L of NS over 24-48 hours. • Urine osm has to be less than 500 (to avoid severe worsening of hypoNa) • If hypoNa corrects, this suggests volume depletion NEJM 356:2064-2072

  13. Why 500 osms? • Where did Berl come up with that magic number? • Goldfarb and Rose both tell me that osmolality of administered IVF must exceed osmolality of urine • Who is right?

  14. Goldfarb-Rose Hypothesis • Prior acceptance that isotonic saline (308 osms) infusion in SIAD is useless • Electrolytes are excreted in urine • Urine osmolality in SIAD is typically >300 • water is retained => worsening hypoNa

  15. Example • Our patient • Urine osms=892 • NaCl=308 • Excess NaCl to be excreted after 1L infusion 308/892=345cc of urine • 655cc of water is retained, hence a reduction in plasma Na concentration

  16. How much lower? • Total body osmoles=TBW x Posm • Posm is equal to 2 x plasma Na • Total effective osmoles= 0.6 x 50kg x 2 x 129 = 7740 mosmol • 655 cc of water is retained, hence TBW is 30.655L • New plasma Na = total effective osmoles / (2 x TBW) 7740 / 61.2 = 127 meq/L • Our pt’s Na went down to 127

  17. Berl’s Axiom • Previous study showed an increase in plasma Na of pts with SIADH from 124 to 127 mEq/l after IV NS (Musch et al Am J Med 1995;99: 348-55) • Mean initial urinary osmolality was 429 mosm/kg • So why not give SIAD pts isotonic saline?

  18. Treating SIADH with isotonic saline • Musch et al conducted a prospective study of 17 pts with SIADH (Q J Med 1998; 91:749-753) • Goal to predict the response to isotonic saline based on either Uosm and UNa+K • 2L infusion over 24 hours • Initial plasma Na 115-130 • All pts met the criteria for SIADH • Water restriction (<750cc/day) • Stable Na intake (70-120 mEq per day)

  19. Results 11 men, 6 women mean age 64+13 • Underlying conditions of 17 pts • Lung cancer (6) • Other pulm diseases (4) • Cerebral traumatism (2) • Ovarian CA/sarcoma/cortical atrophia (1 each) • Idiopathic SIADH (2)

  20. Results cont.

  21. Weak correlation

  22. Strong correlation

  23. Discussion • 11 / 17 pts increased their plasma Na after 2L infusion • Uosms exceeded the osmolality of isotonic saline 6 / 17 pts aggravated their hypoNa mean Uosm > 538 mosm/kg

  24. Prvs assumption that rise in plasma Na by 5 mEq/L after 2L NS infusion/24h suggests hypovolemia may be incorrect • This response can be observed in SIAD pts as well • Differentiate by high urinary salt excretion • salt-depleted hypovolemic pts conserve salt

  25. Conclusion • Response to NS in SIAD can be predicted from Uosm • Study conducted in older pt’s • decreased urine concentrating ability • Younger pts are likely to have a slight decrease in serum Na • I believe in Berl

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