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 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.
Ectopic ADH production
"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:
|Fluid restriction||Simple, easily implemented
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
|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
|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
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. 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.