An update on peripheral vasopressors

We have new evidence looking at the use of vasopressors through a peripheral IV. I have covered this topic before, and after reviewing the available literature in 2018, my conclusion was “I think it is clear that the administration of peripheral vasopressors is not only acceptable, but will occasionally be the best option for our patients.” (However, there is evidence of harm, so we shouldn’t be cavalier.) Subsequently, in the CENSER trial (an RCT of early norepinephrine in septic shock), about 60% of patients received their treatment through a peripheral IV, and there was no difference in complications between norepinephrine and placebo (1 case of skin necrosis in both groups). In this post, I look at 2 new papers examining the use of peripheral vasopressors.

Paper #1

Tian DH, Smyth C, Keijzers G, et al. Safety of peripheral administration of vasopressor medications: A systematic review. Emergency medicine Australasia. 2019; PMID: 31698544

Summary

As a reminder of the evidence to date, I will start with a brief summary of this systematic review. These authors were looking at any clinical publications (including case series as long as there were at least 20 patients) that looked at continuous infusions of peripheral vasopressors and reported adverse events. There were 7 relevant papers, with about 1400 patients in total. Norepinephrine was the vasopressor in about half the cases, phenylephrine in ⅓, and the remainder were dopamine, metaraminol, vasopressin, and adrenaline. Extravasation was relatively common (3.4%) but there were no cases of limb ischemia or skin necrosis. (As I discussed previously, a number of the extravasation events were treated with phentolamine, although it isn’t clear if treatment was necessary.) The numbers are too small to say anything meaningful about IV size or location. These results need to be interpreted cautiously, as the peripheral infusions were often only used briefly or very closely monitored. 

Bottom line: The evidence to date is quite limited. Extravasation occurs, but true adverse events are very rare (actually nonexistent in this review). Overall, the rate of adverse events from peripheral vasopressors appears to be lower than the rate of adverse events from central lines, so there is no reason to ban their use, but we should remain cautious.

Paper #2

Pancaro C, Shah N, Pasma W, et al. Risk of Major Complications After Perioperative Norepinephrine Infusion Through Peripheral Intravenous Lines in a Multicenter Study. Anesthesia and analgesia. 2019; PMID: 31569163

The Methods

This is a multi-center retrospective observational study.

Patients and exposure

Any patient that received a norepinephrine infusion through a peripheral IV during surgery at 1 of 2 hospitals in the Netherlands. Patients were identified using a text based query of the electronic health record.

At these institutions, when used peripherally, norepinephrine is given at a low concentration (20 ug/mL as compared to the standard 80-160 ug/mL). When peripheral extravasation of norepinephrine occurred, it was the hospitals’ current practice to stop the infusion, observe the site of extravasation for several hours post-operatively, and consult plastic surgery for additional recommendations, if necessary.

Comparison

None.

Outcome

The incidence of skin damage requiring medical or surgical intervention.

The Results

Of 179,811 patients who had surgery during the study period, 14,385 (8%) received peripheral norepinephrine.

There were only 5 patients (0.035%) with an extravasation event (95% confidence interval of 1-8 per 10,000 patients). The extravasation was identified after a median of 20 minutes, with a median dose of 40 ug of norepinephrine extravasated. All 5 patients were undergoing elective surgery.

There were no complications requiring surgery or medical intervention (with an estimated 95% CI 0-3 events per 10,000).

My thoughts

The rate of extravasation in this study is unbelievable low. In other studies, the rate of extravasation has been in the 3-6% range. That being said, the rate of true adverse events is consistently around zero. (Cardenas-Garcia 2015; Tian 2019; Medlej 2018; Lewis 2019)

The use of peripheral norepinephrine is incredibly high at these two institutions. Despite not including push dose pressors, vasopressors other than norepinephrine, or norepinephrine given through a central line, 8% of all surgical patients were given peripheral norepinephrine! That seems incredibly high to me, and will impact the generalizability of these results, as these clinicians obviously have a tremendous amount of experience using and monitoring these infusions. 

This is a chart review, which introduces significant limitations. The incidence of adverse events requires an accurate understanding of both the number of adverse events and the number of patients exposed to peripheral vasopressors. Both were found using text based queries of electronic databases, and although the databases sound better than the EHRs I have used, there is a significant chance of both over and under calling the risk based on this data. Furthermore, there is a chance that adverse events were simply not recorded, as the system relies on voluntary reporting.

These IVs are likely to be different from emergency department IVs. Sick patients rolling into the emergency department without vascular access are different than patients sitting in a preoperative assessment room. The indications for vasopressors, their dosing, and the total time required are also likely to be different in this population. Furthermore, because the anesthesiologist is providing 1 to 1 care, the IV site is likely to be much more closely monitored than it would be in the ED. This is pretty clear, because they identified extravasation within 20 minutes, and only 2-4 mL had extravasated at that point.

The fact that there were 0 cases of skin damage in more than 14,000 uses of peripheral norepinephrine is reassuring. However, every case of extravasation in this series occurred in a healthy patient undergoing elective surgery. We might expect different outcomes in patients with significant shock. Indeed, there are multiple prior case reports of significant adverse events after extravasation of peripheral vasopressors in other settings. (Loubani 2015)

Bottom line

In this retrospective look at patients in the operating room, extravasation of peripheral norepinephrine was extraordinarily rare (0.035%) and there were no true adverse events. However, there are multiple reasons that this data may not extrapolate to sick emergency department patients.

I expect that the true incidence of extravasation in the emergency department will be closer to the 3.5% quoted elsewhere. (Tian 2019) However, even with the higher rate of extravasation, very few patients end up with skin necrosis or limb ischemia.

It is reasonable to consider using the lower norepinephrine concentration used here, although I worry about dosing errors and so will stick with the standard dose that my nurses are used to. Many have advocated for using large IVs in proximal locations, but I don’t think there is actually good evidence for that recommendation. I think you want to use an IV that you are confident in (didn’t require multiple attempts to place and flushes well), that is easy to monitor, and is in a location where skin necrosis would be tolerated in the rare event that it did occur. It is also important to monitor the IV frequently to catch extravasation early.

Considering that central lines also have an adverse event rate of around 2%, and those adverse events are frequently more consequential than an extravasation, there is clearly a role for the use of peripheral vasopressors in emergency medicine. In fact, for some patients, peripheral vasopressors are probably preferable to a central line.

Other FOAMed about peripheral vasopressors

My original peripheral vasopressor review

REBEL EM: Peripheral Vasopressors: Safe or Dangerous?

EMCrit: Podcast 107 – Peripheral Vasopressor Infusions and Extravasation

References

Cardenas-Garcia J, Schaub KF, Belchikov YG, Narasimhan M, Koenig SJ, Mayo PH. Safety of peripheral intravenous administration of vasoactive medication. Journal of hospital medicine. 2015; 10(9):581-5. PMID: 26014852

Lewis T, Merchan C, Altshuler D, Papadopoulos J. Safety of the peripheral administration of vasopressor agents. J Intensive Care Med. 2019;34:26–33

Loubani OM, Green RS. A systematic review of extravasation and local tissue injury from administration of vasopressors through peripheral intravenous catheters and central venous catheters. Journal of critical care. 2015; 30(3):653.e9-17. PMID: 25669592

Medlej K, Kazzi AA, El Hajj Chehade A, et al. Complications from administration of vasopressors through peripheral venous catheters: an Observational Study. J Emerg Med. 2018;54:47–53.

Pancaro C, Shah N, Pasma W, et al. Risk of Major Complications After Perioperative Norepinephrine Infusion Through Peripheral Intravenous Lines in a Multicenter Study. Anesthesia and analgesia. 2019; [pubmed]

Permpikul C, Tongyoo S, Viarasilpa T, Trainarongsakul T, Chakorn T, Udompanturak S. Early Use of Norepinephrine in Septic Shock Resuscitation (CENSER) : A Randomized Trial. Am J Respir Crit Care Med. 2019;

Tian DH, Smyth C, Keijzers G, et al. Safety of peripheral administration of vasopressor medications: A systematic review. Emergency medicine Australasia : EMA. 2019; [pubmed]