Vasopressors II: Norepinephrine and epinephrine

Start with Part I to learn about the basic concepts of vasopressors.

Let’s discuss two of the most common inopressors in the ICU: norepinephrine and epinephrine.


Widely referred to in the US by the trade name Levophed, and in British-descent nations as “noradrenaline,” norepinephrine has become our first-line pressor for most routine use.

The history of norepinephrine has been a tumultuous one. Several decades ago, it was notorious for its poor outcomes—particularly the prevalence of distal ischemia, such as renal failure and toes falling off—that eventually earned it the moniker, “Leave ’em Dead Levophed.” Its use waned. However, it gradually made a come-back, with the understanding that the old approach of using it (in very high doses without adequate fluid resuscitation) was more to blame than the drug itself.

Norepinephrine is an inopressor. Its primary effect is vasoconstriction via alpha-1 agonism. This effect predominates clinically, to the extent that some providers believe it to be a “pure” vasoconstrictor—but not so. It has a small but important degree of beta-1 activity.

How much? This is an apples versus oranges comparison; we might call it “70/30” or “80/20” or some other balance, but those numbers would be arbitrarily invented and clinically meaningless. Think of it this way instead: norepinephrine induces vasoconstriction along with approximately enough inotropy to balance the increase in afterload.

Afterload, you should remember, is the resistance against which the heart must beat in order to push blood forward.

Starling forces of preload and afterload. Preload: the volume in the heart just prior to contraction. Afterload: the vascular resistance downstream of the heart.

Afterload is mainly determined by vascular tone, so vasoconstricting agents—like Levophed—increase afterload. This means that in order to preserve forward flow, the heart will have to work harder. It’s like downshifting the gear on a car: the load on the engine (the heart) is increased, so output will only be improved if the engine is able to meet that load. Otherwise, cardiac output can actually drop.

A young, healthy pump may be able to meet an increase in afterload without any help. However, in many older, critically ill patients, the heart is already at its limits and won’t have the reserve. It will need some extrinsic support—a positive inotrope—on top of the pressor.

This is essentially what you get from norepinephrine. You get a primary vasopressor with just enough activity on the pump to help it push through the added afterload. The net effect is therefore an elevated blood pressure with a fairly neutral effect on the heart.

For most hypotensive ICU patients, this is what we want. Thus, norepinephrine is rarely the “wrong” choice in a patient needing pressors, and is generally a reasonable place to start. However, it may not be optimal in every case.

For a patient needing a pure inotrope or inodilator, it would not be ideal. Additionally, it might not be the first choice in a patient whose cardiac activity is already hyperactive. For instance, in a patient exhibiting significant tachycardia (a 20-year-old trauma patient with sinus tach in the 140s), one could argue that the chronotropic effects of norepinephrine—relatively weak as they may be—are not needed and may even be deleterious. An even better example might be the patient who is experiencing tachyarrhythmias, such as episodes of rapid atrial fibrillation or ventricular tachycardia; in that case it may be a good idea to completely discontinue all drugs with potential proarrhythmic effects, and select a pure vasoconstrictor instead.

Or not. There isn’t much evidence supporting these arguments. This gets to a deeper problem, which is that there is relatively little data for most pressor-versus-pressor debates. Studies do exist, but generally have failed to show meaningful differences, suggesting that the subtle physiological reasons we believe one drug may be superior to another in individual patients may not be easily demonstrated in large-scale trials.

The best evidence for norepinephrine is in sepsis, particularly compared against dopamine, and the current guidelines (from the 2016 Surviving Sepsis campaign) do recommend norepinephrine as the first-line pressor in that situation.

Dose range is generally from .01 mcg/kg/min to a maximum that depends on unit policy, usually somewhere between 1.0 mcg/kg/min and 3.0 mcg/kg/min. (Weight-based dosing is a good practice, but some units still use straight doses, for which a norepinephrine dose is around 1–300 mcg/min.) It is a potent vesicant, meaning that tissue ischemia and infarction can readily occur if it extravasates from a peripheral IV site. Peripheral norepinephrine is therefore a bit sketchy; in most centers it is acceptable in low concentrations through a reliable IV as a temporary measure, but should be switched to a central line as soon as possible. Don’t be afraid to run it peripherally in a sick patient while you place a line—it’s better than leaving them hypotensive–but do place the line ASAP, then switch it over.


Epinephrine, aka “adrenaline” across the pond, is the sassy little sister to norepinephrine.

Like norepi, it is a catecholamine. And like norepi, it avidly binds at alpha-1 adrenergic receptors. Unlike norepi, it is also a potent beta-1 agonist. (It also binds beta-2, causing bronchodilation, which explains its role in anaphylaxis and asthma but is generally irrelevant when we use it as a pressor.)

Clinically speaking, it can be thought of as providing equal parts vasoconstriction and inotropy. It is still a strong vasoconstrictor, although perhaps slightly less so than norepi (for various reasons including the presence of beta-2 receptors in the peripheral vessels). However, it is far more cardioactive. This is both its greatest strength and its greatest weakness.

Epi is probably too cardioactive to use as a routine first-line pressor. At least, that is how most of us feel, although some do practice this way, and—remember that dearth of clear evidence?—it’s hard to prove them wrong. However, you will find that it tends to provoke significant tachycardia in many patients at therapeutic doses, or even subtherapeutic doses. When the heart rate is 150 and your MAP is still 50, do you keep turning up the epi?

In fairness, although sinus tachycardia is common, epinephrine does seem to cause fewer actual arrhythmias than dopamine (the other popular pressor with strong inotropic and chronotropic effects). Thus, despite the sun setting upon dopamine, epinephrine still enjoys popularity as a second- or third-line pressor for diseases like sepsis. If you have “maxed out” your Levophed, maybe this is what you add next.

(A caveat and a question to ponder: if have indeed reached the maximum dose of norepinephrine your unit believes to be safe and effective, you might legitimately wonder whether stacking on a second catecholamine—although common practice—is likely to be either safe or effective. After all, despite its different binding affinities, epinephrine is in the same class as norepinephrine, and in fact is synthesized from it in vivo. Perhaps a better choice would be an agent that works upon different receptors; see more on vasopressin later.)

At low doses, it can also be used as a fairly pure inotrope, with little pressor effect. Running epinephrine to help support the heart while using a separate norepinephrine or dopamine drip as your pressor is one approach to the patient with both distributive and cardiogenic shock, and allows separate titration of each drug to treat the separate problems. Cardiac surgeons are sometimes fond of this.

An idiosyncrasy of epinephrine is its propensity to elevate the serum lactate. Lactate is traditionally viewed as a marker of anaerobic metabolism (Type A lactic acidosis—although this idea has come under attack in recent years), and hence is often followed as an endpoint of resuscitation; it can therefore be vexing when you start an epinephrine drip and the lactate jumps from 3.0 to 5.0. But don’t fret; this is not a sign of worsening perfusion; it is a direct medication effect, or Type B lactic acidosis, related to glucose metabolism.

Epi is probably not much safer than norepinephrine when given peripherally. The exception is when given as a bolus during cardiac arrest, which is a universal practice; as an extension of this concept, it is probably acceptable to push smaller, non-code doses through a good peripheral IV when needed as well. (Norepinephrine, in contrast, is almost never pushed.) Dosing is around .01–1 mcg/kg/min, or around 2–20 mcg/min; as with norepi, the maximum dose varies widely.

In summary, epinephrine is usually used either when a greater degree of inotropy is needed than norepinephrine can provide, or it is added to norepinephrine as an additional drug.

Proceed to Part III, where we’ll discuss the pure vasoconstrictors.

4 Replies to “Vasopressors II: Norepinephrine and epinephrine”

  1. I am a young paramedic (1yr), going to get my critical care cert next year, and want to work in the ED as a PA eventually.

    Thank you for this AWESOME series on vasopressors. I love how you tie each concept back to physiology. I think it is something high level websites such as EM-Crit and the associated IBCC do a good job of, and this is right up there with that.

    Happy studying.

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