1. Syndrome of inappropriate anti-diuretic hormone secretion (SIADH)
Hari Krishnan Nair
Clinical Observer – Critical Care Medicine Boston Children’s Hospital

2. Introduction
•A disorder of impaired water excretion caused by the inability to suppress the secretion of antidiuretic hormone (ADH)
–Inappropriate, continued secretion or action of ADH despite normal or increased plasma volume
–Results in impaired water excretion, and subsequently hyponatremia and hypo-osmolality
Bartter FC, Schwartz WB. The syndrome of inappropriate secretion of antidiuretic hormone. Am J Med. May 1967;42(5):790-806.

3. Physiology of ADH

4. ADH
•Arginine vasopressin (AVP)
–Naturally occuring ADH in humans
–Synthesized in the anterior hypothalamus, and transported to the posterior pituitary
•Stimuli for AVP secretion
–Hyperosmolarity – sensed by osmoreceptors in the hypothalamus
–Circulating volume depletion – sensed by baroreceptors in carotid sinus, aortic arch and left atrium

5. ADH receptors
•V1a
–Stimulates vasoconstriction
•V1b
–Stimulates ACTH secretion
•V2
–Insertion of the water channel aquaporin-2 in the luminal membrane of the collecting duct, thus making it more permeable to water
Verbalis JG, Berl T. Disorders of water balance. In: Brenner BM. Brenner & Rector's The Kidney. Vol 1. 8th ed. Saunders; 2007:459-491.

6. ADH physiology
•Normally, when plasma osmolality falls below 275 mOsm/kg, AVP secretion stops.
–increases water excretion, which leads to a dilute urine with an osmolality of 40-100 mOsm/kg.
•When plasma osmolality rises (or 8-10% reduction in circulating volume), AVP secretion increases.
–increase in water reabsorption and an increase in urine osmolality to as much as 1400 mOsm/kg.
Clinical laboratory evaluation of the syndrome of inappropriate secretion of antidiuretic hormone. Decaux G, Musch W. CJASN July 2008 vol. 3 no. 4 1175-1184

7. Pathogenesis of SIADH

8. Pathogenesis
•The release of ADH is not inhibited by a reduction in plasma osmolality.
•The nonphysiological secretion of AVP results in enhanced water reabsorption, leading to dilutional hyponatremia.
•Transient expansion of extracellular fluid volume.
•Volume receptors are activated and natriuretic peptides are secreted, which causes natriuresis and some degree of accompanying kaliuresis.

9. SIADH
•Hyponatremia
•Inappropriately elevated urine osmolality (>100 mOsm/kg)
•decreased serum osmolality
in a euvolemic patient,
in the setting of:
–normal cardiac, renal, adrenal, hepatic, and thyroid function;
–in the absence of diuretic therapy;
–in absence of other factors known to stimulate ADH secretion, such as hypotension, severe pain, nausea, and stress.

10. Neurological pathophysiology
•Hyponatremia and hypo-osmolality cause acute cerebral edema.
•Brain ECF moves into CSF
–Brain cells lose potassium, amino acids like glutamate, glutamine, taurine, myoinositol and creatinine
•Following correction of hyponatremia
–Overshoot of electrolytes in 24 hours
–Return to normal slowly over 5-7 days
•Rapid correction of hyponatremia (>0.5 mEq/L/h)
–Lost electrolytes cannot be restored as rapidly
–Osmotic demyelination
Elhassan EA, Schrier RW. Hyponatremia: diagnosis, complications, and management including V2 receptor antagonists. Curr Opin Nephrol Hypertens. Mar 2011;20(2):161-8.

11. Patterns of ADH secretion
•Type A
–Erratic, unregulated release of ADH
–No relation to plasma osmolality
•Type B
–Modest and constant leak of ADH
•Type C
–Downward resetting of the osmostat
–Plasma Na concentration is normally regulated and is stable at a lower level (125-135 mEq/L)
•Type D
–Normal ADH secretion
–Urine is still concentrated
–Germ cell mutation in which V2 receptor is activated
–Production of an antidiuretic compound other than AVP

12. Etiology

13. Causes
•CNS disturbances
–Stroke, hemorrhage, infection, trauma, psychosis
•Malignancies
–Small cell carcinoma of lung
–Head and neck malignancies
–Olfactory neuroblastoma
–Extrapulmonary small cell carcinoma

14. Causes
•Drugs
–Chlorpropamide
–Carbamazepine
–Cyclophosphamide, vincristine, cisplatin, methotrexate
–SSRIs – fluoxetine, sertraline
–MAO inhibitors
–NSAIDs, opiates
–Sodium valproate
–INF alpha, INF gamma
Kohen I, Voelker S, Manu P. Antipsychotic-induced hyponatremia: case report and literature review. Am J Ther. Sep-Oct 2008;15(5):492-4.

15. Causes
•Surgery
–Trans-sphenoidal pituitary surgery
•Inappropriate ADH release from the injured posterior pituitary
•Fall in plasma Na is most severe on 6th-7th post-op day
•Pulmonary disease
–Pneumonia, asthma, pneumothorax
•Hormone deficiency
–Hypopituitarism, hypothyroidism
•Iatrogenic
–Desmopressin – for von Willebrand disease or hemophilia
–Oxytocin
–Vasopressin – for control of GI bleeding

16. Presentation

17. Presentation
•Depending on the magnitude and rate of development, hyponatremia may or may not cause symptoms.
•Signs and symptoms of acute hyponatremia do not precisely correlate with the severity or the acuity of the hyponatremia. Some patients with profound hyponatremia may be relatively asymptomatic.
Decaux G. Is asymptomatic hyponatremia really asymptomatic?. Am J Med. Jul 2006;119(7 Suppl 1):S79-82.

18. Presentation
•When serum sodium <125 mEq/L
–Anorexia, nausea, malaise
•Further decrease
–headache, muscle cramps, irritability, drowsiness, confusion, weakness, seizures, and coma
•Symptoms from CNS or pulmonary tumors
–hemoptysis, chronic headaches

19. Physical examination
•Euvolemic and normotensive
•No edema or dry mucous membranes or reduced skin turgor
•Severe or rapid-onset hyponatremia
–delirium, muscle weakness, myoclonus, hyporeflexia, dysarthria, Cheyne-Stokes respiration, generalized seizures, and coma.

20. Workup

21. Laboratory tests
•Serum sodium: <135 mmol/L
•Serum potassium: unchanged
•Urinary Na excretion: >20 mmol/L
•Urinary osmolality: >100 mOsm/kg
•BUN: <10 mg/dL
•Serum uric acid: <4 mg/dL
•GFR: increased

22. Imaging
•Chest X-ray
–To find out an underlying pulmonary cause
•CT and MRI

23. Management

24. Therapies to raise serum sodium
•Treatment of the underlying disease, if possible
•Initial therapy to raise the serum sodium
•Prolonged therapy in patients with persistent SIADH

25. Treatment of underlying cause
•Hormone replacement in adrenal insufficiency or hypothyroidism
•Treatment of infections such as pneumonia, meningitis or tuberculosis
•Cessation of offending drugs

26. Emergent Care

27. Emergent Care
•Correction of hyponatremia
–Aggressive treatment vs risk of inducing central pontine myelinolysis
•Aggressive management
–In case of seizures, stupor, coma, respiratory arrest regardless of the degree of hyponatremia

28. Emergent Care
•Correction of hyponatremia at a rate that does not cause neurologic complications
–Raise serum Na levels by 0.5-1 mEq/h, and not more than 10-12 mEq in the first 24 hours
–To bring Na value to a maximum of 125-130 mEq/L
•3% hypertonic saline
•Furosemide
–Increases free water excretion
–Limits treatment-induced volume expansion
Hew-Butler T, Noakes TD, Siegel AJ. Practical management of exercise-associated hyponatremic encephalopathy: the sodium paradox of non-osmotic vasopressin secretion. Clin J Sport Med. Jul 2008;18(4):350-4.

29. Emergent Care
•Combining
–Furosemide
–hypertonic saline
–water restriction
may lead to a faster rate of correction of serum Na
•Requires frequent checking of serum Na+ osmolality and urine osmolality

30. Acute Setting

31. Acute Setting
•< 48 hours since onset
•Moderate symptoms like confusion, disorientation, nausea, vomiting
•Treatment options
–3% hypertonic saline
–Loop diuretics with saline
–Vasopressin-2 receptor antagonists
–Water restriction

32. Acute Setting
•Acute onset and moderate neurological symptoms
–3% hypertonic saline
•Less severe symptoms (headache, irritability, altered mood) or no symptoms
–Vasopressin-2 receptor antagonists
–Water restriction

33. Water restriction
•Mainstay of therapy
•Water restriction depends on
–prior water intake
–expected ongoing fluid losses
–degree of hyponatremia
•500 – 1500 mL/day
•In case of subarachnoid hemorrhage
–Fluid restriction reduces BP and promotes cerebral vasospasm and infarction
–Treated with hypertonic (3%) saline

34. Vasopressin receptor antagonists
•Inhibition of V2 receptor (Aquaretics)
–Reduces the number of aquaporin-2 water channels in the collecting duct, reducing its water permeability
•Vaptans
–Conivaptan
–Tolvaptan

35. Vaptans
•Conivaptan
–Parenteral dual V1a- and V2-receptor antagonist
–20mg loading dose, followed by continuous infusion or as intermittent boluses
•Should not be used for more than 4 days
–Conivaptan + 2 L fluid restriction over 4 days
•Increased serum Na by 6 mEq/L
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.

36. Vaptans
•Tolvaptan
–Oral V2 receptor antagonist
–Started at 15mg daily and titrated up to 60 mg daily as required
–Tolvaptan + fluid restriction
•Increased serum Na by 8 mEq/L over 30 days
–Patient can be discharged in 24-48 hours if neurological symptoms have resolved
–Drug can be withdrawn after 2-4 weeks, while carefully monitoring serum Na daily for the next 5 days
Nemerovski C, Hutchinson DJ. Treatment of hypervolemic or euvolemic hyponatremia associated with heart failure, cirrhosis, or the syndrome of inappropriate antidiuretic hormone with tolvaptan: a clinical review. Clin Ther. Jun 2010;32(6):1015-32.

37. Vaptans – benefits and risks
•Benefits
–prompt correction of serum Na+
–producing water excretion without electrolyte excretion
–eliminating the need for fluid restriction.
•Risk
–excessively rapid rate of correction of serum Na.

38. Chronic Setting

39. Chronic Setting
•Fluid restriction
•V2 receptor antagonists
•Loop diuretics
•Urea
•Mannitol
•Demeclocycline

40. Urea
•Increases urinary loss of water along with urea, and decreases free water retention
•Can be administered on a long-term basis (0.5 g/kg body weight) as a powder dissolved in water along with meals
•Can also be given via G tube or IV in patients with cerebral hemorrhage to prevent a rapid fall in intracranial pressure

41. Mannitol
•Promotes free-water diuresis by elevating the osmolarity of the glomerular filtrate.
•Used intravenously, as a 15-20% solution.

42. Tetracyclines
•Demeclocycline
–Induces diabetes insipidus
–Impairs generation and action of cAMP, interfering with the action of AVP on the collecting duct
–Onset of action may take over a week
•Not indicated for emergency management
Cherrill DA, Stote RM, Birge JR, Singer I. Demeclocycline treatment in the syndrome of inappropriate antidiuretic hormone secretion. Ann Intern Med. 1975 Nov;83(5):654–656.

43. Thank You