Vasopressin aka arginine vasopressin  (AVP), aka antidiuretic hormone is the topic for today's podcast. We briefly review what we have already covered and then start walking the bleeding edge with some new applications and ways to use vasopressin.

Background

Made in the hypothalamus and the supraoptic nuclei and stored in the posterior pituitary. Turns out, this year, it was discovered that it is also produced in the kidney in response to hypertonicity.

Big drops in BP are needed to trigger vasopressin release in which case plasma levels increase exponentially in contrast to changes in osmolality when levels increase only linearly. [doi:10.1053/j.jvca.2009.09.006]

3 Receptor Types

Plasma half life of 5-15 minutes (other sources state 10-35 minutes), metabolized by renal and liver vasopressinases

Little effect in healthy subjects, but marked effect in septic shock [10.1097/00003246-199708000-00012]

Very expensive!

Analogues

Terlipressin

After 22 years, terlipressin (longer acting and V1 specificity) has finally been approved after 18 years for use in the USA with the on-label indication for hepatorenal syndrome. Terlipressin has V1/V2 ratio around 2.2 compared to Vasopressins 1:1 ratio.

dDAVP

V2 specificity. Used for DI. Also for its effects on vWF and Factor VIII release pushed its use for  VWF disease, uremia related platelet dysfunction, and in aspirin reversal to promote platelet aggregation and coagulation.

Indications

Sepsis

Early sepsis sees high levels of plasma vasopressin but then depletion as the sepsis progresses (likely both to endogenous response, but also endotoxin causing unnecessary release of vasopressin).

If you are giving vasopressin, you should probably give steroids as well [Reanalysis of VASST Trial 10.1097/CCM.0b013e3181961ace] as they are synergistic and showed reduced mortality, without steroids it was associated with increased mortality.

Trauma

Arginine vasopressin was mixed in saline with a final concentration of 0.4 U/mL. A 4-U bolus of AVP or an equivalent volume of saline placebo was given before starting the study infusion (either AVP or placebo) at 0.04 U/min. We've discussed the preliminary trial, AVERT Shock [10.1001/jamasurg.2019.2884] before on the show and we will have Carrie Sims on soon.

Right Heart Failure

Vasopressin has the least constriction of the pulmonary vasculature of any of the vasopressors, hence it is ideal for right heart failure, pulmonary hypertension, and massive PE when the patient needs their MAP augmented.

Anything Bad Chronic Liver

• Hepatorenal syndrome
• Variceal Bleeds

Pts on ACE inhibitors and ARBs

[28235174]

Adverse Effects

Decreased Splanchnic Perfusion

Skin and Limb/Digit Ischemia

these are the big ones!

There is an abstract that some papers have claimed showing mesenteric ischemia with whopping doses, but I can't see that in the actual write-up [Bracco et al. Intensive Care Med 2001;27:S138]

Cardiac Ischemia

Doesn't seem to be present at the doses we are using

Hyponatremia?

This was a question posed by an EMCrit listener.

[https://doi.org/10.1177/0885066613507410]

In VASST, only one patient wound up with a Na < 130 meq/L

Push-Dose Vasopressin

EM Case report used 1 unit dilute to 1 unit/ml in post-arrest hypotension [10.1016/j.jemermed.2019.12.026]

their write-up recommends 0.5-1 u every 2-5 minutes, onset ~2 minutes, duration 5-20 minutes

Liver transplant case report used 3 pushes of 0.4 units [10.1213/01.ANE.0000215232.42488.6D]

Given vasopressin's excellence in patients with right heart failure and pulmonary hypertension, it is a good choice in those scenarios.

Mixing Instructions from J Emerg Med Case Report (1 U/mL))

• Obtain a 20 mL syringe filled with 19 mL of 0.9% saline
• Inject one mL of vasopressin (20 unit per mL) into the syringe.
• Shake syringe well. This will now give you one unit per mL. Administer 0.5-1 mL (0.5-1 unit) every two to five minutes titrating to desired blood pressure.

Mixing Instructions from Perioperative Push-Dose Pressor Paper (0.4 U/mL)

[10.1177/08971900221096967]

• Use 2 vials of 20 unit/mL vasopressin to draw 2 mL total into a 3 mL syringe
• Inject into 100 mL NS bag
• Draw up 10 mL from mixture in 10 mL syringe for administration
• Final concentration 0.4 units/ml
• They use an initial dose of 1-2 units

preferred for patients on RASS inhibitors?

In the Sims et al. Trauma study, most of the doses were given peripherally

I wrote to one of my Trauma Anesthesia buddies (and previous guest) and here is what he sent back:

Re: Push-Dose Vasopressin

I have been using push-dose vasopressin for many years. Among anesthesiologists, its adoption varies widely—some, like myself, use it frequently, while others, particularly from the older generation, may not use it at all.

Historical Perspective: The use of vasopressin in the OR began primarily in cardiac surgery, where many patients were found to be vasoplegic after cardiac bypass, likely due to depleted levels of endogenous vasopressin. Over time, its use expanded beyond the cardiac operating room, particularly as the literature on sepsis began to embrace vasopressin, leading to its adoption as a push-dose medication in other settings. Vasopressin also emerged as a rescue treatment for vasoplegia refractory to catecholamines, especially in patients taking ACE inhibitors or ARBs. In these patients, vasopressin often proves to be the only effective therapy when other interventions fail to raise blood pressure. Furthermore, emerging evidence from trauma literature points to vasopressin deficiency during hemorrhagic shock, as the endogenous reserve from the posterior pituitary can be depleted after 30-40 minutes, and transfused blood lacks vasopressin. This understanding has led to the AVERT Shock trial, which showed its benefits and good safety profile in hemorrhagic shock.

How I Use It: I typically dilute a 20-unit vial in a 20 ml syringe, resulting in a concentration of 1 unit/ml. Depending on the degree of shock and the specific circumstances, I administer an initial bolus of 2-4 units—leaning towards the higher end (up to 4 units) in hemorrhagic shock and using lower doses in septic shock or as a rescue pressor. The 4-unit dose is considered the maximum physiologic replacement dose, essentially restoring vasopressin levels from zero to normal; beyond this dose, vasopressin acts purely as a vasopressor.

In some institutions, and in my practice, vasopressin is now used as the main rescue pressor instead of phenylephrine. Its advantages include a longer half-life of 20-30 minutes after a bolus, which is significantly longer than the few minutes of effect seen with phenylephrine. It does not effect heart rate which is helpful when somebody is super tachy.  I have not encountered any issues administering it via a peripheral IV, given the benign dose and dilution; some clinicians even use a lower dilution of 0.5 units/ml.

Caveats: It’s crucial not to overlook hypovolemia, understanding that vasopressin may temporarily mask it. Care must be taken to avoid gut ischemia, which can occur rapidly, particularly with higher doses or infusion errors. I am aware of a few cases where this has happened, typically with high-dose or misdosed drips, due to vasopressin’s potent splanchnic vasoconstrictor effects.

I have also attached a presentation I give on pressors at various meetings, mainly focused on vasopressin. You can quote me – my practice is open as I'm director of quality for the department : )

—Roman Dudaryk, MD

Vasopressin Load Test

Vasopressin Loading for Refractory septic shock (VALOR) study

based on the prior work from the same group on Vaso loading with 1 unit push [34017842]

takes a while to take effect when given at the low standard doses, especially if not put in the bloodstream properly

These authors previously discussed a 1 u load prior to infusion initiation

Vasopressin was introduced to patients with septic shock who were administered noradrenaline≥0.2 μg/kg/min. In the study protocol, vasopressin was intravenously administered as a bolus of 1 U for loading, followed by its continuous intravenous administration at 0.017 units/minute (1 unit/hr) b/c of the authors opinion that the slight stature of many Japanese patients made this low dose a better choice.

they posited responders and non-responders could be differentiated with a cut-off of MAP increase >22 mmHg within 3-5 minutes after push (prior trial showed 18 was the cut-off, so maybe we can use the easy number of 20?)

1 in each group had mesenteric ischemia, 2 pts in non-responder group had digital ischemia, 1 patient in responder group had cardiac ischemia

Vasopressin Timing

Great Review Paper – Vasopressin timing and use

Exogenous administration of vasopressin in patients with septic shock may be considered hormone replacement therapy because of the findings that vasopressin concentrations appropriately rise in the early phase of septic shock then quickly decline to subtherapeutic concentrations within the first 24 h after shock onset.[9,15-17]

Three Key Papers

• VASST
• VANISH
• Third just in abstract: Oliveira, S., et al. “Early vasopressin application in shock study.” Critical care 18.Suppl 1 (2014): P158.

If they need it is earlier better???

Reduction of norepi dose with MAP>=65 at 6 hours after initiation is associated with better outcome

Questions Raised

• Can patients who will respond to vasopressin’s initiation be identified preemptively?
• When is the most ideal time during the course of shock to initiate vasopressin in a patient?
• What clinical marker should be used as an indicator for vasopressin’s initiation?
• What is the maximum safe vasopressin dose?
• Should the vasopressin dosage be titrated?
• What therapeutic intervention should be undertaken in individuals who do not respond to vasopressin initiation?
• How should vasopressin be discontinued in patients in the convalescent phase?

Where am I in 2024 for Septic Shock?

When you hit 0.15-0.2 mcg/kg/min of NORepi, add vaso and steroids to the mix

Additional New Information

A listener on twitter points out the possibility of DI after discontinuation of a vasopressin infusion, citing this paper: [10.5005/jp-journals-10071-24244]

More on EMCrit

• EMCrit 138 – Vasopressor Basics
• EMCrit 375 – Vasopressors for Early Hemorrhage?
• EMCrit 201 – Deeper on Vasopressors and Athos 3 with Mink Chawla
• Pulmcrit Wee- Vasopressin vs. norepinephrine for vasoplegic shock after cardiac surgery(Opens in a new browser tab)
• EMCrit 205 – Push-Dose Pressors Update(Opens in a new browser tab)

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Scott Weingart, MD FCCM

Editor-in-Chief, at EMCrit.org

An ED Intensivist from NY.
Professor
Nassau University Medical Center
No conflicts of interest (coi).

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