I remember a time when I thought the treatment of chronic SIADH was going to be revolutionized by the vaptans. These small molecular ADH antagonists would interrupt the disease the precise mechanism of disease. I expected a Banting and Best like revolution. (If you have not seen the story of the discovery of insulin take a moment to watch the movie, Glory Enough for All, especially if you thought the greatest thing to come out of Canada was Tim Horton’s)
The initial data was promising with convincing studies on conivaptan and tolvaptan, but something happened on the way to SIADH nirvana.
First the EVEREST trial went sideways. In heart failure:
- Angiotensin 2 is elevated and blocking it prolongs life
- The sympathetic nervous system is up-regulated and blocking it prolongs life
- Aldosterone is elevated and blocking it prolongs life
- ADH is elevated and blocking it doesn’t do a damn thing
With no hope for a heart failure indication the drug was marketed solely as a treatment for hyponatremia where it was shown to be effective. The pitch was that doctors should not discharge people with hyponatremia and tolvaptan was faster and more effective than the previous standard of care. The drug was priced for short-term inpatient use at $300 a pill tolvaptan was a non-starter for chronic outpatient SIADH.
The side effects reported for demeclocycline and lithium were such that we recommend not using them for any degree of hyponatraemia.
Fluid restriction, the cornerstone of therapy, is difficult to maintain and in severe cases is insufficient to correct hyponatremia (I’m thinking of patients with negative free water clearance). Urea has a good track record but I have not heard of it being used in the United States. Salt tablets can help, but often are inadequate to correct the hyponatremia.
On the list of possible treatments are loop diuretics. I have tried loops in hyponatremia on a number of occasions and though the math works, in my hands I have not found them to be effective. In the past, I have used loops in hospitalized patients with hyponatremia. The results have been underwhelming. But I know have a loop diuretic success story in a patient with significant but stable outpatient hyponatremia.
+1 “@medicalaxioms: Nothing aggravates a nephrologist like a kidney that refuses to obey the math.”
— Joel Topf (@kidney_boy) March 31, 2014
I met the patient when he was admitted to the ICU with mental status changes due to a sodium south of 120. This was not his first episode of hyponatremia. We corrected the sodium and restored normal mentation. We did a thorough work-up, looking for the etiology of the SIADH and despite some promising leads that turned into blind alleys, I am quite confident, now, that this is idiopathic SIADH.
During subsequent outpatient follow-up he had persistent hyponatremia with sodiums running in the high 120’s. During this time, treatment consisted of salt tablets and fluid restriction. A couple of visits ago I added torsemide, and boom the two sodiums since have been 138 and 134.
Here is the sodium and urine osmolality over time. It plummets after the torsemide is started. This increases the free water clearance.