Today’s #CCRN, #CMC, #CSC education tip: VASOPRESSIN.


Today we’re going to talk about vasopressin.

Those of you who have been nursing a bit will remember when vasopressin, 40 units, IV as a bolus dose was the ACLS recommendation for the second medication to give during a cardiac arrest. The first? Epinephrine, as always. “All dead people get epi,” at least if we’re following the recommendation of the AHA. As I said before, there’s some controversy.

But we aren’t here to talk about epinephrine. Let’s look at vasopressin. The chart I posted over catecholamines is useful, but vasopressin wasn’t on it. That’s because vasopressin isn’t an alpha-1/beta-1/beta-2 drug. Nor does it metabolize into a drug that accesses those receptor sites.

Vasopressin is anti-diuretic hormone. It is necessary for life in humans and animals, and it works on the V1 and V2 receptor sites. The first is located on the membrane of a vascular smooth muscle cell and mediates vasoconstriction in much the same way as angiotensin II. The second receptor regulates water excretion by increasing water reabsorption.

Vasopressin is used to restore vascular tone in vasodilatory shock. We usually use it in sepsis, but also in vasoplegic syndromes and advanced heart failure. It’s the drug we reach for when shock is resistant to catecholamines.

There are several ways vasopressin performs its magic. We mentioned vasoconstriction and increasing water reabsorption. Other effects include modulating endrogenous nitric oxide and potentiating adrenergic agents to promote vasoconstriction.

Platelets are affected by stimulation of the V1 receptor site to provoke an increase in intracellular calcium levels. This facilitates thrombosis, but the amount of variability in aggregation response is so large it’s not possible to point to vasopressin as a cause of coagulopathy.

V1 receptor agonism doesn’t affect every part of the kidney in the same way, but selectively affects the inner (but not the outer) medulla blood flow rate, and contracts the efferent arterioles but not the afferent arterioles.

DDAVP is a selective form of vasopressin which affects only the V2 receptors, causing a release of von Willebrand factor and vasodilation in the kidney alone. Although V2 receptors are found elsewhere, for reasons most mysterious it doesn’t seems to have effects outside the renal circulation.

The vasopressin receptors are relatively resistant to downregulation. The interaction of vasopressin with arrestins, when combined with this resistance, allows vasopressin to (purportedly) bypass the downregulated myocardial adrenergic receptors.

Vasopressin is dosed in 0.01-0.04 units per minute or 0.1-0.4 units per hour. Either way, it’s particularly helpful in hypoxic/acidotic states, as well as those resistant to sympathomimetics. It’s not generally titrated–for sepsis or vasoplegic syndromes, we generally place it at 0.03 units/min and leave it. It increases MAP without affecting inotropy, as a general rule.

Although the cardiac effects of vasopressin are complex and conflicting, a few common uses have emerged over the last ten years. One is the pairing of milrinone and vasopressin. In cases of severe advanced heart failure requiring the use of inotropic agents, plus the necessity to bypass downregulated receptor sites, added to the need for diuresis in the presence of relative hypotension, vasopressin has emerged as a superior agent for maintaining vascular tone and perfusion.

It’s also an excellent choice for blood pressure support in PAH, as it avoids vasoconstriction in pulmonary circulation.

Consider adding vasopressin to levophed in refractory hypotension, particularly in septic shock. In those patients the levophed dose can get so high it blocks perfusion of the capillary beds. Starting vasopressin in these patients can allow you to reduce the rate of levophed infusions to much more reasonable levels.

Another use is in post-operative cardiac surgery patients. Maintenance on bypass circuitry for surgery has multiple effects on a patient’s physiology, which can evidence themselves in a vasoplegic scenario post-operatively. Vasopressin can prevent cardiovascular collapse in this patient population without adversely affecting inotropy.


levophed descriptionLevophed, also known as norepinephrine, is another stress hormone, and the topic for today. We’ve mentioned norepinephrine in the posts on dopamine and epinephrine, but now we’re going a little deeper.

“Levophed will leave ’em dead,” I was taught as a new nurse in the ICU, and definitely it can. Norepinephrine is a powerful alpha-1-agonist, producing intense vascular vasoconstriction. High doses of this medication will clamp the vascular system, both arterial and venous, to the extent no perfusion occurs in the capillary beds.

In other words, it increases afterload. In fact, it can increase afterload so much that it causes metabolic acidosis. Because of its venous activity it diminishes preload. At the same time, cardiac output drops as the heart rate falls. This mechanism makes it a poor choice as an inotrope.

Wait a minute…heart rate falls?

Let’s look at this. Norepinephrine has beta-1 agonist activity comparable to epinephrine, but it has NO effect on beta-2 receptor sites. But didn’t I say that beta-1 agonists increase contractility and heart rate? Yes, I did.

The increase in mean arterial pressure levophed induces will cause baroreceptor-mediated drop in heart rate, which the beta-1 stimulation of norepinephrine is often too weak to overcome. Not always, though.

We use levophed as a first-line vasoactive agent, directly behind or in conjunction with crystalloid, for hypotensive patients in the presence of infection. This state is what we refer to as “septic shock,” and I’m not going into SIRS criteria in this post. In these patients it’s unlikely to see the drop in heart rate, as the pathophysiology of sepsis results in tachycardia.

Norepinephrine doesn’t affect the alpha-2 receptor sites, which are found in the cerebral circulation. Since it lacks beta-2 activity, it also will not dilate the bronchioles, making it less than ideal in anaphylaxis or status asthmaticus. Incidentally, it’s also a poor choice in cardiogenic shock or advanced heart failure patients since it increases afterload.

The higher the dose of levophed, the more profound the effect on systemic vascular resistance. A pet peeve of mine? Receiving a patient on levophed with a MAP greater than 75. Unless of course you are a neuro nurse, in which case you are titrating for an appropriate CPP (cerebral perfusion pressure) and you should ABSOLUTELY continue, please and thank you, carry on.

PRIMARY CONSIDERATIONS: The development of tachycardia (worse in septic patients, which is our primary use of levophed), dysrhythmias (as all beta-1 agonists do), myocardial ischemia, colitis, and other effects of decreased organ perfusion.

It doesn’t really contribute to hyperglycemia like epinephrine does.

Here’s an interesting tip about norepinephrine: it must be mixed in D5W in order to provide enough acidity to prevent oxidation. Oxidation makes levophed ineffective by inactivating it.

The lungs are responsible for clearing endogenous catecholamines, and can extract about 25% of circulating norepinephrine in a single go. This clearance is diminished by halothane & nitrous oxide in animal studies, so it may be that anesthetic agents interfere with the process in our patients, too.


Epinephrine-prefillEpinephrine. #CCRN #CMC #CSC in today’s education post.

This drug, produced by the adrenal medulla in times of stress, is referred to as adrenaline. It’s a neurotransmitter that acts on the beta and alpha receptor sites much like the other inotropic medications we’ve discussed so far.

Epinephrine has ACLS-level fame, and is used for the treatment of cardiac arrest. It increases perfusion pressure to the coronary and cerebral blood vessels, as well as increasing blood flow to the skeletal muscle beds.

(Data supporting its use in resuscitation is limited–read about the controversy here.)

Epinephrine has beta-1 and beta-2 adrenergic effects, causing an increase in cardiac output and heart rate, as well as bronchodilation. This makes the medication particularly useful in the treatment of anaphylaxis.

We’ve talked about the beta-2 receptor site, and its vasodilatory properties. So how is epinephrine a treatment for shock states if it activates beta-2 receptors? It also has profound alpha-1 agonist activity, which causes vasoconstriction.

But, wait…doesn’t that mean epi works against itself?

Actually, no, because the concentration (dose) of the catecholamine at the level of the receptor site controls activation. At low doses, say, 2-10 mcg/min (0.02 mcg/kg/min-0.05 mcg/kg/min for weight-based dosing), beta stimulation predominates. At higher doses, the beta-2 stimulation is gradually overwhelmed by alpha-1 agonist activity.

What about the max on epi? Well, there is no true maximum dose of this catecholamine, but at 30 mcgs/min every receptor site accessible to epi is fully covered, so if your patient remains hypotensive adding norepinephrine or phenylephrine (targeting the same alpha-1s) is a futile endeavor. A much better alternative? Vasopressin.

PRIMARY CONSIDERATIONS: Epinephrine is proarrhythmogenic.

Renal flow is greatly reduced even if blood pressure doesn’t change…estimated 2-10 times greater effect on renal circulation when compared to norepinephrine. It also increases renin secretion.

Epinephrine has greater effects on metabolism than any of the other catecholamines we’ve mentioned. It increases blood glucose via glycogenolysis in the liver, lipolysis in adipose tissue, and inhibits insulin secretion. Lactate rises on epinephrine drips, probably due to glycogenolysis in skeletal muscles.

Effects on the gastrointestinal tract include smooth muscle relaxation. In other words, it decreases motility, which can result in nausea, particularly in post-operative patients.

Interestingly, epinephrine increases blood coagulation, possibly due to increased activity of factor V.


breathe in, breathe out

We measure all hemodynamic variables (CVP, PAs, PAWP, CO/CI) at end-expiration, because exhalation is usually the longest period of the respiratory cycle. Inhalation increases systemic venous return, but also decreases pulmonary venous return, which in turn decreases flow to the left side of the heart.

Here is that mechanism at work with bolus thermodilution:


This image demonstrates the high degree of variability from respiratory artifact. Trials 1, 3, 5 were performed at end-exhalation. Trials 2, 4, 6 were performed during inhalation.


I had some feedback from nurses on my home unit—I need to put together a critical-care basics course to teach some things we all had in human physiology or pharmacology, but have forgotten. For those new to critical care, I offer this as explanation:

There is an assumed body of knowledge within the ICU, an unspoken tradition of ways and means and facts. Some standard acute-care traditions: full moons mean a busy night, always draw a type & screen and make a patient NPO if surgery has been scheduled for the morning, give the meds scheduled for 8, 9, and 10 all at 9, always hang the fastest-infusing antibiotic first.

In the ICU we have our traditions, too. Traditions like always know who’s on call for all the specialties (determines whether you call or wait), when you get report on a post-surgical patient always ask who ran the gas (will you need to have fluids hanging to infuse or will you have time to prime), weebles wobble but they don’t fall down (#teamneuro).

Respond in the comments, either on Facebook or A Tangled Web. What’s basic knowledge to you? What do you need to remind you of the basics?


I mentioned downregulation in the previous CCRN tip of the day. Downregulation is not a concept the CCRN requires you to understand, but it is a CMC and CSC concept. It’s also something anyone who cares for advanced heart failure patients will encounter again and again. The easiest way to explain downregulation is through the […]

I mentioned downregulation in the previous #CCRN tip of the day. Downregulation is not a concept the CCRN requires you to understand, but it is a #CMC and #CSC concept. It’s also something anyone who cares for advanced heart failure patients will encounter again and again.

The easiest way to explain downregulation is through the classic example of insulin resistance. Diabetics, due to the increased amount of glucose in their bloodstream, release more insulin. Over time this causes the insulin receptors on the surface of their liver cells to degrade. The degradation causes a decrease in the number of active receptors for the hormone. This mechanism is referred to as “downregulation.”

The pathophysiology of heart failure involves chronic exposure to high levels of circulating catecholamines. Consistent high blood serum levels of norepinephrine and epinephrine interact with the beta-1, beta-2, and alpha-1 receptor sites. The mechanism proceeds essentially as described in insulin resistance.

At the bedside, this evidences itself in the fact that our standard inotropic and vasoactive drips seem to be less effective, or require higher doses to take the standard effect. It also contributes to a high level of variability, depending on which receptor sites are downgraded and to what degree.

So, getting more specific, if your patient has beta-1 receptor site downregulation, it will look like this:

56-year-old male, PMH of nonischemic cardiomyopathy, s/p right heart cath and pulmonary-artery catheter placement, admitted to your ICU with the diagnosis of cardiogenic shock with a cardiac index of 1.8. Orders for dobutamine at 5-10 mcg/kg/min, titrate to keep CI greater than 2.1.

You admit your patient and do your assessment, initiating the dobutamine drip at 2.5 mcg/kg/min initially. After the patient’s nausea has subsided, you turn it up to 5 mcg/kg/min since his heart rate and blood pressure are stable, and you wait for another forty-five minutes. When you shoot your numbers, his cardiac index has dropped to 1.6.

You titrate the drip up to 7.5 mcg/kg/min and wait forty minutes. When you check numbers again, his index has dropped to 1.5. You increase the drip to 10 mcg/kg/min and recheck in thirty minutes because your patient…your patient looks worse. Sluggish capillary refill. Ashen nailbeds. Remains nauseated. Blood pressure has dropped to the 90s systolic, and your patient is more dyspneic than before. His index is now 1.3.

What’s happening? You are seeing the consequences of downregulation at work.

So what do you do? Turn the drip off. Yes, off.

Call the doctor, and using your best SBAR communication skills, tell him what happened as you uptitrated the drip. Suggest primacor, and possibly vasopressin if necessary, to maintain an adequate blood pressure. Why those drips, and why not norepinephrine? We will cover that in another episode.


Dobutamine is another inotropic agent we use in the ICU. It’s referred to as a catecholamine—our word for an organic compound that is released by the adrenal medulla during the fight-or-flight response—but dobutamine is synthetic. It’s actually a structural analogue of isoprenaline (Isuprel), and is administered as a racemic mixture (*important fact*).

This medication is administered primarily for patients in cardiogenic shock, but is also utilized heavily in the advanced heart failure population. It can be a home infusion for those patients. It’s also used for stress testing, interestingly enough. Make sure you hold the beta-blocker that morning.

Dobutamine acts on three different receptor sites on the surface of the myocardial cell. It directly stimulates the beta-1 receptors, the beta-2 receptors, and the alpha receptors. The fact it’s a racemic mixture ensures that the alpha activity of dobutamine is balanced. Because dobutamine (unlike dopamine) does not act on dopamine receptors, it doesn’t promote the release of norepinephrine. This means it won’t increase afterload despite its action on the sympathetic nervous system.

  • Beta-1 activity: agonist, increases contractility and heart rate
  • Beta-2 activity: agonist, resulting in vasodilation of blood vessels in skeletal muscle tissue, as well as dilating bronchioles
  • Alpha-1 activity: balanced agonist and antagonist activity via the (+) and (-) isomers

The effects of dobutamine are dose-dependent. The primary hemodynamic factor followed for titration of the drip is cardiac index. Standard dose range is 2.5-20 mcg/kg/min, and may be titrated by 2.5 mcgs every 15 minutes or so. Increase in heart rate is more marked starting around 12 mcg/kg/min.

Dobutamine increases myocardial metabolism and oxygen consumption. This mechanism results in worsened myocardial ischemia and angina may occur. Hence its use during stress testing…

Effects on other systems

Nausea and vomiting can be quite pronounced, as activation of the beta-2 receptor sites slows gastric motility. This effect can be worse in patients who are diabetic, as well as those who have received anesthetic medications.

Dobutamine stimulates glycogenolysis in skeletal muscle and gluconeogenesis in the liver, which raises blood sugar, as well as insulin secretion in the pancreas, to drive said serum glucose into the cell. If your patient is a diabetic, however…

It increases renin secretion from the kidney. This results in activation of the RAAS, which is a mechanism for hypertension.

It inhibits histamine release.

PRIMARY CONSIDERATIONS: Administration of dobutamine can contribute to down-regulation of the beta-receptors. It’s also proarrythmogenic, and can precipitate ventricular and supraventricular arrhythmias, as well as cause chest pain from angina.