Until recently I believed that prolonged vasopressor administration requires a central line, to avoid extravasation.  I lumped together all vasopressors, treating them all as equal.  I used the occurrence of an extravasation reaction from one vasopressor as evidence that all vasopressors could cause extravasation reactions (the fallacy of inappropriate generalization).  Upon closer examination, these beliefs aren't supported by evidence (1).

Current evidence & practice

Cardenas-Garcia 2015 demonstrated the safety of infusing peripheral vasopressors for days (including norepinephrine, phenylephrine, and dopamine).  They achieved this by using a strict protocol mandating several conditions, including:

• only a vein > 4 mm large (measured via ultrasonography) could be used
• IV must be in the arm contralateral to the blood pressure cuff
• IV could not be located in the hand, wrist, or antecubital fossa
• position of IV must be documented in vein with ultrasonography prior to use
• 18G or 20G IV only
• verification of blood return from IV line every 2 hours

This protocol allowed the avoidance of central lines in most cases, thereby reducing complications while cutting costs.  Unfortunately, very few units can perform this demanding protocol.  At most shops, peripheral vasopressors remain a temporizing measure only, limited to use for a few hours.

It would be useful to have a strategy for prolonged peripheral vasopressor infusions, without such a complicated protocol.  One way to achieve this would be to use vasopressors which are less likely to cause skin necrosis if they extravasate.  This could increase the margin of safety, allowing for a simpler infusion protocol.

Concentrated epinephrine and phenylephrine are safe for subcutaneous use

At Genius General Hospital, our epinephrine infusion is mixed in the pharmacy by combining 4 ml of 1:1000 epinephrine with 250 ml of D5W.  The 1:1000 epinephrine used is actually intended for subcutaneous use (picture above).  The package insert recommends administering a dose of up to 1000 micrograms of epinephrine subcutaneously.

Phenylephrine is similarly obtained by reconstituting 2 ml of 10 mg/ml solution in 250 ml of NS.  For decades, the concentrated form of phenylephrine was also recommended for subcutaneous use, at doses up to 10000 mcg.  This was allowable as an unapproved medication due to its longstanding use.  In 2012 phenylephrine gained FDA approval for IV administration, but didn't receive approval for subcutaneous administration.  This may relate to five episodes of skin necrosis in the FDA database (2).  Nonetheless, concentrated phenylephrine has been given subcutaneously for decades without reports of skin necrosis in the published medical literature.  Micromedex and Epocrates still recommend subcutaneous phenylephrine to prevent hypotension during anesthesia:

Why might peripheral epinephrine and phenylephrine be safe?

If concentrated epinephrine and phenylephrine are safe for subcutaneous injection, then extravasation of diluted infusions should be tolerated.  Why might these drugs be safer than other vasopressors?

Epinephrine functions as its own antidote

Epinephrine has a unique dual effect on skin arteries which may explain its unusual safety profile:

• Epinephrine stimulates alpha-receptors, causing dermal artery vasoconstriction that promotes ischemia and skin necrosis.
• Epinephrine also stimulates beta-2 receptors, causing dermal artery vasodilation.  This protects against skin necrosis.  For example, subcutaneous terbutaline (a beta-2 receptor agonist) may be intentionally injected subcutaneously to treat vasopressor extravasation (Stier 1999).

The beta-2 activity of epinephrine may function as a “built-in” antidote, preventing skin necrosis in cases of extravasation.  Dopamine and norepinephrine only stimulate beta-1 receptors, so they lack this safety feature.

Phenylephrine: More gentle overall?

The safety profile of phenylephrine might reflect two factors:

1. Phenylephrine seems less acidic compared to norepinephrine or dopamine.  It is formulated with a sodium citrate buffer and titrated to a pH of 3-6.5.  This appears less acidic than dopamine (pH 3.3) or norepinephrine (pH 3-4.5)(Le 2014)(3).
2. Phenylephrine is a less potent vasoconstrictor than most.

Clinical Evidence of Safety: Epinephrine

Concentrated epinephrine even seems safe when injected into fingers

There is an interesting body of literature regarding people who accidentally inject their fingertips with 1:1000 epinephrine from an auto injector.  This delivers concentrated epinephrine into the least vascularized part of the body.  However, these patients seem to do fine.  Some patients improve without any treatment at all (Fitzcharles-Bowe 2007).  It used to be feared that injection of lidocaine with epinephrine into fingers would cause skin necrosis, but this is a myth.

Putland 2006:  Adverse events associated with the use of intravenous epinephrine in emergency department patients presenting with severe asthma.

This retrospectively described the safety of epinephrine infusion used in 220 patients with severe asthma in Australia.  Epinephrine was infused via peripheral IV with an average rate of 1.5 ug/min (range 0.5-13 ug/min) and a median duration of 20 hours (range 10 minutes to 11 days).  There were eleven episodes of extravasation, all of which were mild (local pallor or mottling) and resolved without tissue necrosis.

This was a well-powered study supporting the safety of peripheral epinephrine.  One strength is that it was large enough to include several extravasation events, suggesting that these events are not severe.  A weakness is that it isn't clear how the peripheral IV lines were selected or monitored.

Clinical Evidence of Safety: Phenylephrine

Delgado 2016:  Safety of peripheral administration of phenylephrine in a neurological intensive care study: A pilot study.

This study describes the protocoled administration of peripheral phenylephrine to 20 patients in a neurocritical care unit.  The average dose was 0.53 ug/kg/min (range 0.2-1.8 ug/kg/min) with an average duration of 14 hours (range 1-54 hours).  There was one minor complication reported as pain, erythema, and swelling around the IV site, which improved after removing the IV catheter.  Several safeguards were used to prevent extravasation:

• A low concentration of phenylephrine was used (40 mcg/ml)(4)
• Infused via 18G or larger peripheral catheter.
• IV located in arm, proximal to the wrist
• IV inspected hourly

Although underpowered, this study supports the peripheral administration of phenylephrine.  Compared to Cardenas-Garcia 2015, the method that these authors used is less cumbersome.  This supports the possibility that a less demanding protocol could be used with phenylephrine, compared to norepinephrine.

Case reports of skin necrosis

Hundreds of reported cases of vasopressor extravasation were reviewed by Loubani 2015.  Perhaps most notable is the rarity of reports involving phenylephrine and epinephrine (compared to norepinephrine, dopamine, and vasopressin).

The English literature contains two reports of skin necrosis due to phenylephrine and one due to epinephrine, summarized here (5):

These cases are strikingly similar.  Skin necrosis was probably promoted by several factors:

• All cases involved the distal leg, a poorly vascularized area which may be subject to pressure ulceration and possibly also deep vein thrombosis.
• A surgical cutdown technique was used to insert the catheter in at least one of these cases.  This involves lacerating the vein, which may promote extravasation.
• Skin necrosis may have been allowed by complete lack of any initial attempt to treat the extravasation (e.g. with subcutaneous phentolamine).

Overall, I find these reports to be reassuring.  Their existence suggests that the published literature is extensive enough to detect rare cases of skin necrosis.  However, necrosis seems to occur only under the most unfavorable conditions.

Caution is still required

Peripheral phenylephrine or epinephrine aren't 100% safe.  To improve safety, the following precautions are fairly simple and should be achievable in most situations:

Balancing Risk: Cognitive de-biasing

Everything in critical care involves risk.  We can reduce risk, but we never avoid it entirely.  If we are excessively risk-averse (for example, trying to never miss a pulmonary embolism), that will paradoxically increase the actual risk that our patients are exposed to.

Based on our training, we assign different costs to various risks.  For example:

• It is accepted that many central line complications will occur occasionally (e.g. pneumothorax, line infection, arterial injury).
• It is felt that extravasation from a peripheral line is unacceptable, a sign of personal failure that reflects laziness or inability to place a central line.

It may be time to reconsider these biases.  For example:

• Pneumothorax, central line infection, or arterial hemorrhage can occasionally be life-threatening.
• Proximal arm extravasation from epinephrine or phenylephrine seems unlikely to cause serious consequences if treated appropriately.

It is possible that we are excessively risk-averse to extravasation (6).  This risk-aversion may be pushing us to insert more central lines, thereby actually increasing the risk that our patients are exposed to (7).

Examples of how peripheral epinephrine & phenylephrine may be used

Epinephrine and phenylephrine aren't the most popular drugs, but they can get you pretty far (especially in combination)(8).

Peripheral epinephrine for mild sepsis

Epinephrine is supported by two RCTs for potential use as a front-line vasopressor in septic shock (Myburgh 2008, Annane 2007).  Imagine a patient with mild urosepsis who doesn't respond to fluid resuscitation and needs a bit of vasopressor support.  A reasonable approach to this patient could be to trial them on a low-dose peripheral epinephrine infusion.  If the patient responds well, this could be continued until shock resolves (9).

Peripheral epinephrine for symptomatic bradycardia

Previously isoproterenol was my treatment for mild symptomatic bradycardia in a patient without central access, because it has minimal extravasation risk.  However, price hikes have increased the patient cost to >5000$/vial.  Peripheral epinephrine is an effective alternative.

Phenylephrine infusions may have a similar effect compared to norepinephrine

Traditionally, phenylephrine has been frowned upon in critical care due to concerns that it could reduce cardiac output and organ perfusion.  However, most evidence suggests that phenylephrine may function very similarly to norepinephrine.  Both drugs may cause venoconstriction, increasing preload and potentially increasing cardiac output (more on this here)(10).

Bottom line: Who needs a central line?

Traditional wisdom was that all patients on a vasopressor for more than a few hours require a central line.  This has been disproven by Cardenas-Garcia 2015, Delgado 2016, and Putland 2006.  However, there still isn't enough evidence to reach a universal answer.  Thus, it may be best to make this judgment on a patient-by-patient basis, weighing the following factors:

• What drug is being infused, at what rate?
• Where is the peripheral IV, how smoothly was it placed, how well is it working, and what gauge is it?
• Can the IV site be inspected Q1hr?
• Is the patient capable of calling a nurse if pain develops around the IV site? (11)
• If extravasation occurs, can this be managed immediately?
• What is the anticipated clinical course, for example:
  • Is the patient likely to crash and require better access?
  • How long is the patient expected to require vasopressor?
• Are there factors that modify the risk associated with central line insertion, for example:
  • Is the patient too agitated or dyspneic to lie still for a central line?
  • How well would the patient tolerate a pneumothorax? (12)
• If a central line becomes required, are there practitioners available who can immediately insert it?

As with most critical care conundrums, there is no simple answer.  Make your best judgment call, follow the patient carefully, and adjust strategy as appropriate.  When in doubt, it may be reasonable to continue peripheral vasopressors, because many patients will improve and only require vasopressor transiently (13).

• It has been dogmatically believed that prolonged infusion of any vasopressor mandates placement of a central line.  However, available evidence doesn't support this.
• Concentrated solutions of epinephrine and phenylephrine are safe for subcutaneous administration, suggesting that extravasation of diluted solutions into the skin should be tolerated.
• There are no reports of skin necrosis following extravasation of phenylephrine or epinephrine infused into the arm.
• It may be safe to infuse peripheral phenylephrine or epinephrine for days, with the use of a simple protocol to avoid extravasation injury.
• The risks versus benefits of central line insertion should be considered on an individual basis, rather than assuming that every patient on a vasopressor requires central access.

Related sites:

• Peripheral vasopressor infusions and extravasation – foundational source on peripheral pressors with step-by-step guide to managing extravasation (EMCrit)
• Phenylephrine: an alternative viewpoint (PulmCrit)
• Epinephrine challenge in sepsis (PulmCrit)
• Management of bradycardia:
  • BRASH syndrome (PulmCrit)
  • Is it time to ditch isoproterenol for bradycardia? (Scott Dietrich on the EM PharmD blog)

Acknowledgements: Thanks to Jeffrey Endicott, ICU pharmacist extraordinaire, for his thoughts about this.

Notes

1. A comment by Scott Weingart on my post about phenylephrine was what opened my mind to this.
2. FDA briefing document here.
3. The exact pH of these drugs seems to be some sort of trade secret, or perhaps companies just don't want to publically commit to creating a drug with a specific pH. Regardless, it appears that phenylephrine is the least acidic.
4. It's debatable whether using a lower concentration of phenylephrine would be safer. It appears that highly concentrated phenylephrine is well tolerated when administered into the skin, so the virtue of diluting it is unclear. If a lower concentration of drug is used, then the infusion must be run at a faster rate. Subsequently, if extravasation occurs, then a larger volume may enter the tissue. It is possible that extravasation of a large volume of fluid into the skin could increase local pressure within the skin, impairing perfusion.
5. References for this table as follows: Gaze 1978 and Pierce 1954.
6. In fairness, our fear of extravasation likely stems from rare cases of amputation or gangrene, which is pretty scary.  However, the risk of this should be close to zero with appropriate safety measures and safer vasopressors.
7. It's not my intention in this post to demonize central lines.  The reality is that it's unlikely to experience a serious complication from either central line placement or peripheral vasopressor infusion.  Thus, we are comparing two risks which are both very low.  Nonetheless, our job is to minimize risk.
8. Simultaneous infusion of both epinephrine and phenylephrine can achieve substantial control over hemodynamics.  For example, combining 60 mcg/min of phenylephrine and 2 mcg/min of epinephrine could probably mimic the effect of about 8 mcg/min of norepinephrine.  Generally a patient sick enough to need two vasopressors should probably get a central line, but this remains a potential strategy in a situation where central line placement isn't feasible.
9. Various approaches to front-line vasopressor selection was discussed previously here.  The concept that norepinephrine is the “first-line vasopressor” and the best drug for every patient with septic shock is dogma which isn't evidence-based.
10. The primary difference between phenylephrine and norepinephrine seems to be the effect on heart rate.  So, if you're giving a patient phenylephrine and they are bradycardia or their heart rate seems inappropriately slow, then norepinephrine might be better.  However, if you're giving a patient phenylephrine and they are appropriately tachycardic, then it seems less likely that they would benefit from a transition to norepinephrine.
11. Ischemic tissue is generally very painful.  I would imagine that a conscious patient would report pain and thereby facilitate immediate treatment of the extravasation reaction, prior to the development of frank tissue necrosis.
12. Consequence of pneumothorax may vary widely.  For example, in a patient who already has a chest tube, a pneumothorax might not matter much.  Alternatively, for a patient with ARDS or very tenuous pulmonary status, a pneumothorax could cause significant deterioration.
13. It is always a bit ironic when a patient gets a central line placed for vasopressor infusion and then is on vasopressors for only a few hours.  Sometimes it seems like the discomfort of the central line is sufficient to increase the patient's blood pressure (“therapeutic central line”).  The transiently-used central line may be a marker of low-value care: an unnecessary intervention which is expensive and places the patient at risk, with no real benefit.

Image credits: Homeopathic dilution,

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Josh Farkas

Josh is the creator of PulmCrit.org. He is an associate professor of Pulmonary and Critical Care Medicine at the University of Vermont.

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