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:

• Question 30 from the first paper of 2022 (SIADH... or is it CSW?)
• Question 29 from the first paper of 2015 (SIADH and CSW)
• Question 20.1 from the first paper of 2013 (SIADH and CSW)
• Question 14.4 from the first paper of 2009 (SIADH and calculation of the sodium deficit)

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.

"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:

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