Regarding sodium homeostasis in critically ill patients:

a)  Outline the pathophysiological mechanisms responsible for the hyponatraemia commonly seen in hepatic and renal failure. (20% marks)

b)  List the criteria essential for diagnosis of the syndrome of inappropriate antidiuresis (SIAD). (20% marks)

c)  List 4 drugs from separate classes that may cause SIAD. (20% marks)

d)  How would you distinguish SIAD from cerebral salt wasting syndrome (CSWS)? (20% marks)

e)  List two drugs that may be useful in the management of SIAD. (20% marks)

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College Answer

a)

  • Hyponatraemia in the setting of ECF volume expansion.
  • Both however have reduced effective circulating arterial volume leading to increased AVP levels. In liver disease due to systemic vasodilatation and shunting and with CHF due to impaired cardiac output.
  • There is impaired excretion of solute free water caused in part by reduced GFR and reduced delivery of ultra filtrate to the diluting site in the nephron-renin angiotensin system is activated leading to sodium retention –overall water gain exceeds sodium gain

b)

  • Effective serum osmolality< 275mOsm/kg
  • Urine inappropriately concentrated( > 100mOsm/kg) in face of hypotonic plasma
  • Euvolaemic circulation
  • Urine sodium > 30mEq/l (accept any elevated value)
  • Absence of adrenal, thyroid or pituitary disease

c)

  • Antidepressants in particular SSRIs, TCA, MAOI
  • Anticonvulsants – carbamazepine, valproate, lamotrigine
  • Oncological agents – Vinca alkaloids, Melphalan, Methotrexate, and cyclophosphamide
  • Vasopressin analogues
  • Antidiabetics – chloropromamide
  • Other – opiates, NSAID, MDMA, interferon, amidarone, proton pump blockers

d)

  • Difficult – key difference is that patients with CSWS are volume /blood volume deplete with low CVP
  • Urine volume and sodium may be higher in CSWS than SIADH
  • Serum uric acid may be lower in SIADH than CSWS but is not consistent

e)
1. Demeclocycline
2. Tolvaptan / Conivaptan

Discussion

a) A more wordy answer as to why there is hyponatremia in hepatic and renal failure (which also works to explain CHF)

  • In hepatic and renal failure, there is loss of protein (by nephrotic syndrome or by decreased synthesis)
  • With loss of serum oncotic pressure, circulating arterial volume is decreased as fluid migrates into the interstitial compartment.
  • In addition to this, in severe liver disease the apparent decrease in circulating volume is exacerbated by portosystemic shunting
  • In response to this, there is a hypersecretion of ADH, which leads to increased water retention
  • Aldosterone is also released, increasing the reabsorption of sodium at the nephron
  • In liver disease, the concentration of both hormones is raised yet further by the impairment of their hepatic metabolism
  • The urine is usually concentrated, and the urinary sodium may be low.
  • The extracellular fluid volume expands, as does the total body sodium content; but water gain exceeds sodium gain
  • With renal failure, the capacity of the nephron to excrete water and dilute urine is further impaired by the decrease in glomerular filtration rate

b) From the chapter on Syndrome of inappropriate ADH secretion (SIADH):

Diagnostic Criteria for SIADH

  • Hypoosmolar hyponatremia
  • Urine osmolality greater than plasma osmolality
  • Urine sodium excretion greater than 20mmol/L
  • Normal renal, hepatic, cardiac, pituitary, adrenal and thyroid function
  • Absence of hypotension, hypovolemia, oedema and ADH-influencing drugs
  • Hyponatremia corrects with water restriction

c) ibid.

Drugs Associated with SIADH

  • carbamazepine
  • cyclophosphamide
  • phenothiazines
  • SSRIs
  • nicotine
  • tricyclics
  • vinca alkaloids eg. vincristine
  • interferon
  • cisplatin
  • MDMA
  • amiodarone
  • ciprofloxacin
  • sodium valproate
  • NSAIDs
  • Thiazides

d) How to tell SIADH from CSW? The trick is demonstrating that the extracellular fluid volume is reduced. With a reduced volume, the elevated vasopressin level is a sensible response to dehydration, whereas with volume expansion the vasopressin level is "inappropriate". Thus, the most important diagnostic criterion discriminating between SIADH and CSW is really the assessment of hydration.

In both conditions the ADH level is elevated, but only with euvolaemia is this "inappropriate" ADH seretion (and therefore it can then be called CSW). A heretical viewpoint (in which CSW does not exist) would call this SIADH with urinary sodium loss to compensate for daily maintenance intake, which gives the impression of salt wasting. 

e)

Drugs for management of SIADH include the following options:

  • Demeclocycline (oral)
  • Tolvaptan (oral)
  • Conivaptan (IV)
  • Lithium (oral)
  • Loop diuretics (oral or IV)
  • Urea (oral)

An excellent 2012 article by Peter Gross ("Clinical management of SIADH") discusses these options with satisfying detail.

References

References

Palmer, Biff F. "Hyponatremia in patients with central nervous system disease: SIADH versus CSW." Trends in Endocrinology & Metabolism 14.4 (2003): 182-187.

Cerdà-Esteve M, Cuadrado-Godia E, Chillaron JJ, Pont-Sunyer C, Cucurella G, Fernández M, Goday A, Cano-Pérez JF, Rodríguez-Campello A, Roquer J Cerebral salt wasting syndrome: review. .Eur J Intern Med. 2008 Jun;19(4):249-54.

Milionis, Haralampos J., George L. Liamis, and Moses S. Elisaf. "The hyponatremic patient: a systematic approach to laboratory diagnosis."Canadian Medical Association Journal 166.8 (2002): 1056-1062.

Gross, Peter. "Clinical management of SIADH." Therapeutic advances in endocrinology and metabolism (2012): 2042018812437561.

HANTMAN, DAVID, et al. "Rapid correction of hyponatremia in the syndrome of inappropriate secretion of antidiuretic hormone: an alternative treatment to hypertonic saline." Annals of Internal Medicine 78.6 (1973): 870-875.

Decaux, Guy, et al. "Treatment of the syndrome of inappropriate secretion of antidiuretic hormone with furosemide." New England Journal of Medicine 304.6 (1981): 329-330.

Decaux, Guy, et al. "Treatment of euvolemic hyponatremia in the intensive care unit by urea." Critical Care 14.5 (2010): R184.

Forrest Jr, John N., et al. "Superiority of demeclocycline over lithium in the treatment of chronic syndrome of inappropriate secretion of antidiuretic hormone." New England Journal of Medicine 298.4 (1978): 173-177.

White, Martin G., and Christopher D. Fetner. "Treatment of the syndrome of inappropriate secretion of antidiuretic hormone with lithium carbonate." New England Journal of Medicine 292.8 (1975): 390-392.

Rosner, Mitchell H. "Lixivaptan: a vasopressin receptor antagonist for the treatment of hyponatremia." Kidney international 82.11 (2012): 1154-1156.

Erickson, Kevin F., Glenn M. Chertow, and Jeremy D. Goldhaber-Fiebert. "Cost-effectiveness of tolvaptan in autosomal dominant polycystic kidney disease." Annals of internal medicine 159.6 (2013): 382-389.