Syndrome of inappropriate ADH secretion (SIADH)

Syndrome of inappropriate ADH secretion is a situation where the ADH hypersecretion is... inapropriate... in contrast to all the other situations where it might be elevated "appropriately". Now, one must acknowledge that a raised ADH level is a perfectly reasonable response to hypovolemia, but it is difficult to use the word "appropriate" to describe ADH elevation in states of apparent volume depletion such as cirrhosis, congestive cardiac failure or myxoedema. The name "syndrome of inconvenient ADH secretion" might have been better, and we can still keep the acronym.

As one might imagine, elevated vasopressin levels tend to result in water retention, and a dilutional hyponatremia develops. These patients have no way of increasing their water excretion in response to an increased water intake.The urinary mechanisms of solute excretion remain intact, hence the high urinary sodium.

The college loves SIADH. Among causes of hyponatremia, it is over-represented in the SAQs:

Unfortunately, Oh's Manual only devotes one paragraph to this condition. Its wedged in between an expansive treatise on TURP syndrome and an even shorter paragraph on cerebral salt wasting.

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

Non-Drug-Related Causes of SIADH

Ectopic ADH production

  • Small cell lung cancer
  • Leukaemia
  • Lymphoma
  • Thymoma
  • Neuroendocrine tumours
  • Pancreatic adenocarcinoma


CNS disorders

  • Cerebral trauma
  • Brain tumour (primary or secondary)
  • Meningitis or encephalitis
  • Brain abscess
  • Subarachnoid haemorrhage
  • Acute intermittent porphyria
  • Guillain–Barré syndrome
  • SLE

Pulmonary diseases

  • Pneumonia
  • Tuberculosis
  • Lung abscess

Drugs Associated with SIADH

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


"How is this not cerebral salt wasting?"

The key feature if hypovolemia. These patients are dry and they produce a high urine output; in contrast SIADH patients are normovolemic, and have low urine output. The trick to discriminating between these two conditions lies in the ability to demonstrate that the body fluid volume is decreased. In both conditions the ADH level is elevated, but in cerebral salt wasting the ADH is elevated appropriately because the patient is hypovolemic, and so it cannot possibly be SIADH by definition.

Now, this statement is not to be taken as an endorsement of CSW as a genuine disease state; many smarter people with serious endocrinology cred argue that it may not exist.  The controversy is discussed in greater detail in the Required Reading chapter on cerebral salt wasting from the Neurology and Neurosurgery section.

Management of SIADH

Mitchell H Rosner (2012), in his homage to a novel vaptan agent, has an excellent table of the different therapeutic options, which I have shamelessly plagiarised below:

Therapy Benefits Drawbacks
Fluid restriction Simple, easily implemented

Minimal cost

Can be useful in patients with urine osmolality <400–600 mosmol/kg
Minimally effective and requires several days to achieve correction

Hard for patients to remain compliant
Demeclocycline Effective in raising serum sodium Slow response

Potentially nephrotoxic

Loop diuretics with or without salt supplementation May allow relaxation of fluid restriction and decreases urine-concentrating ability Requires careful titration and monitoring

Risk for other electrolyte abnormalities
Urea Effective and inexpensive Palatability

Limited availability
Hypertonic (3%) saline Effective for severe acute and symptomatic chronic hyponatremia Risk of overly rapid correction

Requires careful, intensive monitoring
Vasopressin receptor antagonists Targets excessive arginine vasopressin

Safe and effective

Predictable rise in sodium values

No risk for concomitant electrolyte disorders

Induces polyuria

Requires close monitoring of serum sodium at initiation with inpatient admission

Usually, fluid restriction is enough - but it is distasteful: people are thirsty, and want to drink; it seems cruel to forbid nanna her extra cup of tea. Moreover, sometimes you just can't fluid restrict somebody (see the SAH section below). Ergo, one resorts to pharmacological measures. Question 29 from the first paper of 2015 asked for specific drug options. These may include:

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

Gross (2012) discusses these options in more detail in his article.

  • Lithium is very 1970s. It is known to interfere with the effect of ADH on the collecting duct, thereby causing nephrogenic DI. White et al (1975) were probably the last people to write about it as a serious option for SIADH. Certainly, the affect change and weight gain side effects were probably a major turn-off, and only tolerable if the alternative were hyponatremic seziures and coma.
  • Demeclocycline is a tetracycline antibiotic, and is given orally ( an antibiotic (600–1200 mg/day).  It also causes nephrogenic DI, and this side effect can be used to our advantage. Forrest et al (1978) found it was effective in patients whose SIADH was resistant to lithium, and concluded that it was a superior agent. Certainly, one does not see much literature about this use of lithium from the late 1970s onwards, which probably means that everybody was in agreement. Unfortunately, it is also not without problems. Beyond causing the usual panel of tetracycline problems for the foetus, it also sabotages birth control pills, is horribly nephrotoxic and causes skin photosensitivity.
  • Loop diuretics are a very old-school means of restoring water balance; Decaux et al (1981) and Hantman et al (1973) reported good results with relatively massive-sounding doses (10-40mg/hour infusion). Losses of all the other electrolytes are a major concern- that is probably the main limiting factor.
  • Urea (given orally, at 0.5-1.0g/kg per day) is also an old-school treatment, which is cheap and apparently effective (Decaux et al, 2010). Cheapness is a great advantage: for $1AU, one may become the proud owner of a 30g baggie. It works by increasing the excretion of free water, essentially working as an osmotic diuretic. It seem the major barrier it its widespread use is its foul taste: apparently, it is bitter as hell, though thankfully it does not smell of anything toilet-related. One better be comfortable with that flavour, if one were going to be consuming 35-70g of it every day (potentially for the rest of one's life). The virtues of urea enjoy a thorough treatment at the Renal Fellow Network (a post from July of 2012).
  • The vaptan drugs (tolvaptan the oral, conivaptan the IV preparation, and now the new lixivaptan) are V2 receptor antagonists with a reasonably clean side effect profile.  They lead to a predictable increase in serum sodium. Unlike the other listed therapies, they are not a work-around, but rather the direct solution to a problem of ADH hypersecretion. Pity about the cost. One month of tolvaptan therapy costs $5670.00 in 2013 dollars. One could buy just over 170kg of urea with that kind of money.

SIADH in the context of subarachnoid haemorrhage

Question 30 from the first paper of 2022 asked the candidates what they were planning to do with a patient whose sodium was trivially depressed (126 mmol/L) and who had a high grade subarachnoid haemorrhage. The problem is, whereas normally you would fluid-restrict these patients, in this scenario you wouldn't want to do that, because hypovolemia promotes vasospasm. Also, you can't just leave it and monitor them, as for these people hyponatremia is associated with a poor outcome. Thus, you're forced to replace the sodium intravenously, while maintaining a high or normal fluid balance.

    Treatment options
    • Hypertonic saline infusion to increase sodium to the desired concentration (the endpoint is to get above 135 mmol/L)
    • Slow increase of sodium concentration into the normal range over the course of at least 24 hours (that would be a rise of 9 mmol/L)
    • Options to maintain normal sodium levels include:
      • fludrocortisone to increase sodium retention
      • vaptan drugs such as tolvaptan or conivaptan to block renal ADH receptors
      • Urea, to induce osmotic water elimination and sodium resorption
  • Monitoring
    • Check serum sodium every 4-6 hours
    • Monitor bedside fluid balance to ensure it remains neutral or increased
  • Support
    • Maintain normovolemia with isotonic crystalloid rich in sodium: normal saline or Plasmalyte would be appropriate
    • Avoid large volumes of hypotonic fluids


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.