Let’s move now to the most “selective” vasoconstrictors available to us: phenylephrine and vasopressin.
We have discussed the pharmacological balance between stimulatory cardiac effects, which make an “inotrope,” and vasoconstrictive effects, which make a “pressor.” Different drugs lean different ways on this spectrum, but it’s natural to ask is whether some drugs are pure vasoconstrictors, with no activity on the heart at all.
There are—sort of. Let’s start with…
Often called by the trade name “Neosynephrine” (or just “Neo”), this can be a polarizing drug.
It is a catecholamine-mediated pressor with virtually pure alpha-1 activity—that is, pure vasoconstriction. With little to no beta effects, it should be cardiac neutral. Is that good?
If you’ve been paying attention, you may be able to guess why that could be both useful and troublesome.
The upside: rather than trying to balance two competing interests, you can isolate one. If you have a pure vasodilatory problem (a low SVR), you can respond with a pure vasoconstrictor. What might be a pure vasodilatory problem? “Pure” is a tough standard, but many of the problems we see are primarily vasodilatory, including sepsis, sedation-related hypotension, and even the non-specific SIRS response we see in many of the critically ill.
In such folks, you might think phenylephrine is a clever idea. Perhaps you would be right. But perhaps not.
As we discussed in Part II, even if the underlying problem is vasodilation, that doesn’t mean pure squeeze is all you need. Vasoconstriction increases afterload on the heart, which then needs increased inotropy to maintain cardiac output against the added workload. If the heart cannot meet that demand on its own, it will need some extrinsic support. And if the drug you’re using is a pure vasoconstrictor, the heart will be out of luck.
Thus, although phenylephrine may be a “pure vasoconstrictor” on paper, in practice it can actually have a negative inotropic effect, by adding to afterload without any additional cardiac squeeze. This is not good (although some would counter by arguing that raising the diastolic blood pressure can improve coronary perfusion and indirectly support cardiac output that way).
The truth is, even primarily vasodilatory problems (sepsis, sedation, etc) are, in reality, usually multifactorial. Usually, there is some blunting of cardiac function as well, sometimes a lot—all the more reason to give the heart a little help.
For these reasons, phenylephrine sits no higher than second on the pressor hierarchy for most of us, and for many it’s even further down the list—or absent altogether. (Some have a practically ancestral hatred of the stuff and would ban it from the ICU completely, given their druthers.) But most will reach for it eventually, once they’ve maxed out one, two, or more pressors. Dosing is around .1–6 mcg/kg/min (or about 20–200 mcg/min).
As mentioned in Part II, the best time to use it might be when the heart already seems to be hyperactive, and you think your patient—with a heart rate of 130, who keeps having runs of ventricular tachycardia—could do without any additional cardiac stimulation.
There is also a notion that phenylephrine is safer to administer via peripheral IVs than other agents, and is occasionally used for this purpose until a central line can be placed. This is probably nonsense.
Finally, phenylephrine can be administered in small boluses, similar to epinephrine. This practice of using “push-dose pressors” is primarily an anesthesia trick, used to support blood pressure when it transiently dips due to sedation, but can be quite handy in the ICU as well, either to address short-term hypotension (a drop in BP after a too-vigorous push of hydromorphone, which you expect to resolve soon), or as a bridge to a more permanent solution (i.e. while awaiting a pressor drip). Premixed, prefilled 10ml phenylephrine syringes, aka “Neo sticks” are available in many ICUs, and are almost a prerequisite to this practice; you can mix it yourself on the fly, but drug math during a high-stress situation is fraught with risk and tough to recommend. (It may be wiser to grab a prefilled epinephrine set from the code cart and just push tiny aliquots of that.) In any case, the typical push dose of a 10mcg/1ml phenylephrine mix is about 50–200mcg (.5–2ml), and the effect lasts around 10–20 minutes.
What if you want a pure vasoconstrictor, but you’re tired of all these catecholamines? In that case, you want…
Vasopressin (aka arginine vasopressin) is the first pressor we’ve discussed that truly breaks the mold.
It is not a catecholamine. It does not bind adrenergic receptors—alpha, beta, or otherwise. Instead, it is a synthetic form of the antidiuretic hormone (ADH) produced in the posterior pituitary.
ADH is mainly known for its renal effects of reabsorbing free water, which is mediated by binding V2 receptors in the distal tubules. However, in the (much higher) dose ranges we use in the ICU, binding of V1 receptors in the vascular smooth muscle overwhelms this, and the dominant effect becomes one of vasoconstriction. Indeed, the renal effects are not usually appreciable when we use pressor-dose IV vasopressin.
On the face of it, vasopressin is therefore a pure vasoconstrictor which uses a separate pathway from our other pressors, and that is theoretically appealing. Why flog the adrenergic receptors with two, three, or four drugs that work on the same sites when we could achieve a combined, synergistic effect by stacking different mechanisms?
But there’s more to it than that. Vasopressin is an odd duck. In common understanding, it is more of an “on” or “off” hormone than the catecholamines, which the body titrates fluidly. When vasopressin is present in physiologic amounts, vascular tone is maintained; when it is absent, there is pathological vasodilation. And in many of our patients, it may be absent.
The concept is this: a patient with a normal hypothalamic-pituitary axis, capable of secreting normal amounts of ADH on a normal day, may nevertheless find themselves unable to produce sufficient ADH to meet the increased demands of critical illness. This causes a “relative vasopressin deficiency,” which may sound suspiciously like handwaving, but which laboratory data has demonstrated in a significant proportion of ICU patients. (This idea of an inability to meet the hormonal demands of critical illness will reappear when we discuss “relative adrenal insufficiency.”)
A vasopressin depleted patient needs vasopressin repletion and replacement, much like a hypokalemic patient needs potassium. So suppose we have a patient in shock. They are started on a first-line pressor, usually norepinephrine. The dose is titrated until it is high. Then we say, “maybe they’ll respond to vasopressin,” and we add a fixed dose vasopressin drip, in the hope that it will allow us to reduce the dose of the catecholamine infusion. This “pressor sparing” effect seems beneficial, although it may make you wonder why it’s better to have someone on less catechols + vasopressin versus more catechols alone. (After all, vasopressin is a pressor too.) But it seems healthier.
There are some other consequences of this idiosyncratic drug personality:
- You probably cannot “overdose” someone on vasopressin. Normal, non-vasopressin-deficient patients have been shown to have no response to it. In other words, if I gave it to you now, you wouldn’t become hypertensive.
- Many would argue that if the patient has no response to vasopressin (i.e. no reduction in pressor requirement), they are probably not deficient and continuing it has no value.
- Those same people may argue that if a patient does respond to vasopressin, we need not continue it forever, since after a prolonged infusion (perhaps a couple days) they should be “vasopressin replete.”
- It is not usually titrated. The most common practice is to run a straight dose, usually .03 or .04 units/minute, either on or off. Some people like to quasi-titrate it by halfing the dose (e.g. to .02 u/min) before turning it off. And a few people will fully titrate, although usually just to gradually wean from .04 to 0.
How many of these notions are completely true? Who knows. But it’s an interesting drug, and some recent data suggests it may even eventually become a first-line pressor in some situations.
Since it has no cardiac effects, it may have the same role as phenylephrine in tachycardic patients, without the distaste that some providers have for phenylephrine. Also, it probably produces more splanchnic vasoconstriction than other pressors, which may be good (for a GI bleeder) or bad (for mesenteric ischemia, new bowel anastamoses, etc).
It is not often bolused, except in cardiac arrest, where it can be pushed in place of one of the epinephrine doses (40 units), although this was removed from the ACLS recommendations in 2010 for lack of evidence.
Finally, since catecholamine receptors are pH-dependent (their quaternary structures being maintained by hydrogen bonds), catecholamine infusions are believed to become ineffective in severe acidemia. (How severe? Who knows, but probably below a pH of about 7.10 your pressors aren’t working very well.) Vasopressin may have a role in these cases, as it is felt to be less dependent on normal pH.
Phew! Wasn’t that fun? Come back for Part IV where we discuss the tumultuous history of dopamine.