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Welcome back to the tasty morsels of critical care podcast.
Way back in the way back in tasty morsel number 43 we discussed inotropes and vasopressors but there was a noticeable AHD analogue shaped hole in that post that i promised to discuss at a future stage. Well, that time has come and it’s time to run through vasopressin.
You probably first encourntered vasopressin when you heard about ADH in medical school. Anti diruetic hormone, named for what it stops Its discussion in medical school involved delving into the world of endocrinology and negative feedback loops. Something we will be studiously avoiding here. Vasopressin is an ADH analogue, very simillar in structure with very similar effects. As such vasopresin exhibits the same ADH effects but this maxes out at very low doses, much lower than what we use in sepsis. At the very high doses we use, much higher than the pituitary can secrete, it acts as a pure pressor without the inotropic effect we’re use to when using more familiar agents like noradrenaline or adrenaline.
How does it work? Well this is where the fun beings. We’re used to messing around with the adrenergic receptors but vasopressin opens up a whole new bunch of confusing letters that have a whole myriad of effects. Some of these receptors are even shared with other molecules like oxytocin. The main we’re interested in is the V1 receptor, this is found throughout vascular smooth muscle. Stimulating it causes calcium release from the sarcoplasmic reticulum leading to increased vascular tone. Note noradrenaline has the same mechanism (ca release) just through a different receptor. This vasoconstriction affects pretty much all the vasculature including things like the coronaries (not so good) but does seem to spare the pulmonary arteries meaning it may be good in those with pulmonary hypertension.
What other receptors is it worth knowing about? both for exams and the all important one-upmanship on the ward round. V2 receptors are mainly in the renal collecting ducts, this is where we get the ADH effect primarily be increasing the number and effect of something called aquaporin 2 channels. The V3 receptor causes increased ACTH, increasing cortisol secretion, and then there are the OTR and P2 receptors which my notes make no elaboration upon and i will make the dangerous assumption that they have no relevance to what we do in ICM.
Why pull out the vaso when we can get the same vasopressor effect from our beloved noradrenaline. In theory the vasopressin receptors should remain fully funcitonal in the depths of horrific metabolic acidosis that has led your patient into intensive care, the same acidosis in theory should be causing issues with the effectiveness of your catecholamines. It should cause less pulmonary arterial constriction than a catecholamine and should even have less tachyphylaxis. the above list of advantages seems to come straight from the manufacturers advert, so why doesn’t it come pre attached to every patient?
The issue gets a bit clouded due to the somewhat clouded evidence base. I’m going to run through a few of the bigger name trials that one may trot out in a viva type setting, and with all good controversial issues in ICM you could easily go the track of “on the one hand this and the other hand that” and come up with an answer with both buttocks firmly on the fence of the issue.
First up is the VASST trial, (Russel et al 2008 NEJM). Done in North America and Oz, they enrolled septic patients and randomised them to vasopressin vs a blinded infusion of 15mcg/min of norad. Once maxed out on the study drug, then open label additional norad could then be titrated to keep the MAP at target. Enrolled 800 fairly typical ICU patients, and found a 35% vs 39% mortality benefit favouring the vaso but of course this was below the somewhat arbitrary statistical significance. A somewhat underwhelming start
Second is the VANISH trial by Gordon et al, JAMA 2016. This was closer to home in the UK, with 18 ICUs. Septic patients randomised similar to the VASST trial, vaso vs blinded norad, this time at 12mcg/min. Primary outcome here was kidney based rather than mortality. 400 pts here, no clear benefit for vaso. Again, hardly compelling
Enter the meta analysis. Nagendran 2019 in CCM. This was of a decent standard being not just a mix of numbers from the trials but an individual patient meta analysis that takes individual patient data points rather than the trial aggregate. This included all the trials but unsurprisingly VASST and VANISH make up most of the numbers. No mortality benefit found but there was less need for CRRT and less arrhythmias. There was some more digital ischaemia but no clear sign of increased mesenteric ischaemia.
Hence the “on the one hand this, on the other hand that” and widely varying opinions on use of vaso. It would be perfectly reasonable to say this drug adds nothing to usual practice and i’ll stick with my catecholamines. And lots of other reasonable people look at the data and say, well this is a catecholamine sparing agent and is a balanced approach to receptor manipulation and just might spare a few filters. As you can imagine (though please don’t actually imagine this) my buttocks remain firmly on the fence getting splinters.
Reading
Russell, J. A. et al. Vasopressin versus norepinephrine infusion in patients with septic shock. New Engl J Medicine 358, 877–87 (2008).