Intraoperative hypotension arises during general anesthesia with an incidence ranging from 5% to 99% (Anesthesiology 2007;107:213-20). Continuous infusions of norepinephrine to treat perioperative hypotension are generally administered through a central venous catheter (CVC) and not through a peripheral I.V. line (PIV). Although commonly used in perioperative anesthesia care in Northern Europe, peripherally administered norepinephrine is uncommon in U.S. anesthetic practice because of the perceived risk of extravasation and resulting tissue injury (Eur J Anaesthesiol 2015;32:571-80; Am Surg 2016;82:162-3).

However, the use of CVCs has been associated with additional costs, significant morbidity, and complications including infection, which has been reported in approximately 15% of patients (Intensive Care Med 2002;28:18-28). Further, the findings for PIVs are mainly on the case report level, and there is limited safety data of when peripheral norepinephrine is used to counteract anesthesia-associated hypotension in elective surgical cases.

Thus, a new study published in Anesthesia & Analgesia aimed to estimate the rate of occurrence of drug-related adverse effects, including skin necrosis requiring medical or surgical management after accidental dilute norepinephrine extravasation through PIVs during surgery (Anesth Analg 2020;131:1060-5).

The multicenter retrospective observational study used the perioperative databases of the University Hospitals in Amsterdam and Utrecht, the Netherlands, to identify surgical patients who received norepinephrine PIV infusions while undergoing elective surgery between 2012 and 2016. Norepinephrine peripheral infusions are commonly performed by the departments of anesthesiology at these two medical centers, together performing approximately 45,000 surgeries per year.

The primary endpoint chosen here was an adverse drug event (ADE) linked to peripheral norepinephrine administration, with documentation graded by severity: grade 1 (intact skin), grade 2 (blanched skin, erythema), grade 3 (necrosis/ulceration causing severe tissue damage warranting surgical intervention), grade 4 (life-threatening warranting immediate intervention), and grade 5 (death).

Of 179,811 patients who had surgery during the study period, 14,385 (8%) received PIV norepinephrine. Of these patients, only five patients (0.035%; 95% confidence interval [CI], 0.011%-0.081%) experienced extravasation. This suggests an estimated risk of 1-8 events per 10,000 patients. Of equal significance, none of the patients had a severity score greater than 1; all complications were minor and resolved without surgical or pharmacological intervention, resulting in a 95% CI of 0%-0.021% and indicating a risk of approximately 0-2 events per 10,000 patients. The norepinephrine infusions that extravasated were in a dose range of 0.02 mcg/kg/min to 0.05 mcg/kg/min, which was identified after a median of 20 minutes, with a median dose of 40 μg/mL of norepinephrine extravasated.

The current analysis has several limitations. The retrospective nature of the study is subject to an inability to validate biased or absent reporting, covariates, and potential confounders. Additionally, the analysis comes from two academic European centers with a different care model compared with the United States. Consequently, the specific patient population, limited duration of infusion, and hospital setting may limit the generalizability of these findings.

Nevertheless, the data suggest that short-term PIV of norepinephrine for hypotensive patients undergoing elective surgery is safe and rarely associated with adverse events related to extravasation, especially when closely monitored and used for a short amount of time.

The ASA Monitor caught up with Carlo Pancaro, MD, for further insights on the study. Dr. Pancaro is the lead author of the study, an obstetric anesthesiologist, physician-scientist, and Clinical Associate Professor of the Department of Anesthesiology at the University of Michigan.

Carlo Pancaro, MD

Carlo Pancaro, MD

ASA Monitor: What is one of the most compelling aspects of this study?

Dr. Pancaro: This study shows low risk of incidence of drug extravasation and tissue damage during peripheral norepinephrine extravasation when used to counteract anesthesia-induced hypotension.

ASA Monitor: The database analysis reveals there is no significant association between the use of PIV norepinephrine infusions and adverse events in patients undergoing elective, noncardiac surgery. In your opinion, what other situations would a norepinephrine infusion through peripheral venous access be useful? In what situations would you recommend avoiding it?

Dr. Pancaro: Our data come from elective surgeries and therefore would be premature to suggest in broadening the indications for its clinical use. In other clinical situations, I would keep in mind risks and benefits of using peripheral norepinephrine for select patients. For example, it is important to weigh risks and benefits in using peripheral norepinephrine in situations where the infusion sites are being covered under the drapes, arms are tucked at their sides, the OR table is turned 180 degrees away from the anesthesiologist, or the peripheral site is on the same extremity of the noninvasive blood pressure cuff. In other elective clinical situations, I would have a low threshold to use peripheral norepinephrine as part of my clinical practice.

“...the data suggest that short-term PIV of norepinephrine for hypotensive patients undergoing elective surgery is safe and rarely associated with adverse events related to extravasation, especially when closely monitored and used for a short amount of time.”

ASA Monitor: The reported incidence of norepinephrine tissue extravasation in the current study was 0.035%, which contrasts with other published rates of 3%-4%. What may explain this 100-fold difference in incidence?

Dr. Pancaro: Retrospective studies might miss important information, and that's possible that we underestimated the incidence. However, even if we underestimated the incidence of tissue extravasation, our analysis captured all serious clinical events that have led to clinical interventions. What we know is that all peripheral extravasation events were not associated with tissue injuries.

It is possible that both the long experience in using peripheral norepinephrine and having local guidelines and standard practices that are consistent with a daily routine can contribute to the low incidence of drug extravasations and tissue injuries.

ASA Monitor: The current analysis comes from two academic European centers with a different care model compared with the United States. What types of information would a future controlled clinical trial need to provide on the use of norepinephrine peripheral infusions so that findings can be generalized to U.S. hospitals?

Dr. Pancaro: A prospective randomized trial that would look at extravasation rate and tissue damage for peripheral norepinephrine and compare it to the most commonly used vasopressors, such as phenylephrine, including type of surgery and patient comorbidities, would be ideal in order to give a more thorough picture in helping to define the risk of tissue damage and the clinical benefit for each vasopressor used. However, such trials are time-consuming and, when looking at rare events such as tissue injury following drug peripheral extravasation, even large studies might not be able to give as much information as we expect. Clinicians in U.S. hospitals should be encouraged to publish their data once they start using peripheral norepinephrine while focusing on improving patients' outcomes when using different peripheral vasopressors.

Dibash Kumar Das is a science and medical writer who holds a PhD in molecular, cellular, and developmental biology from the CUNY Graduate Center and an advanced certificate in clinical and translational investigation from Weill Cornell Medicine.