By Betty Tran, MD, MSc

Associate Professor of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago

Dr. Tran reports no financial relationships relevant to this field of study.

SYNOPSIS: In a large perioperative patient population, norepinephrine infusion through peripheral intravenous lines did not result in any significant adverse events. However, the specific patient population, limited duration of infusion, and hospital setting may limit the generalizability of these findings.

SOURCE: Pancaro C, Shah N, Pasma W, et al. Risk of major complications after perioperative norepinephrine infusion through peripheral intravenous lines in a multicenter study. Anesth Analg 2020;131:1060-1065.

This was a retrospective observational study aimed to estimate the risk of skin damage after accidental extravasation of norepinephrine through peripheral intravenous (PIV) lines. All adult patients undergoing general anesthesia were queried from January 2012 to January 2016 at two medical centers in Amsterdam and Utrecht, Netherlands, to identify patients receiving norepinephrine via peripheral infusion. The primary outcome was documentation of extravasation linked to norepinephrine peripheral infusion, 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). Standard norepinephrine PIV infusions used were 20 mcg/mL with an infusion dose range between 0.01 mcg/kg/min to 0.02 mcg/kg/min to start, titrated to blood pressure goal, resulting in a total volume per hour of 2 mL/hour to 15 mL/hour.

During the study time period, 14,385 patients received general anesthesia as well as PIV norepinephrine while undergoing surgery. Of these patients, five (0.035%) had an extravasation event, for an estimated risk of one to eight events per 10,000 patients (95% confidence interval [CI], 0% to 0.0271%). None of the patients had a severity score greater than 1; all complications were minor and resolved without further intervention or permanent skin damage. The norepinephrine infusions that extravasated were in a dose range of 0.02 mcg/kg/min to 0.05 mcg/kg/min, and the total median duration of infusion was 20 minutes (interquartile range [IQR] 20-25 minutes). The median administered dose was 40 mcg (IQR 35 mcg to 50 mcg), the total estimated dose that extravasated was 33 mcg to 80 mcg, consisting of a volume of 1.67 mL to 4 mL.

COMMENTARY

It has been documented that when peripheral norepinephrine extravasation does occur, damage can be severe, resulting in skin necrosis and potentially limb amputation.1,2 These findings, however, are mainly on the case report level. Results of this study suggest that PIV infusion of norepinephrine is safe and rarely associated with adverse events related to extravasation; in particular, short- or long-term complications were not observed.

However, a few points are worth mentioning when considering the results from this study. First, the duration of infusion was very brief, and the resultant volume of norepinephrine that extravasated was relatively small. Second, which relates to the first point, these patients were monitored in the operative setting by vigilant anesthesiologists who could provide direct surveillance and detect the complication within minutes, thereby limiting tissue exposure. Third, this cohort of perioperative surgical patients was unlikely to experience massive circulatory shock, and their vasopressor needs likely were minimal. Fourth, the authors mentioned that the study’s academic centers have been using norepinephrine peripheral infusions for a decade, and their low incidence of adverse events may be related to accumulated daily experience that has become a part of their routine practice.

Outside the perioperative setting, other studies have found that peripheral infusion of norepinephrine and other vasopressors is associated with a higher rate of extravasation, although the overall complication rates remain low. In a prospective observational study of patients in circulatory shock conducted in the emergency department, three out of 55 (6% of those receiving norepinephrine) had complications, two with local extravasation and one who developed thrombophlebitis, and none of whom required further intervention.3

Other studies focusing on intensive care unit (ICU) patients also have found a low rate of complications. Lewis et al evaluated 202 patients in the ICU receiving intravenous (IV) vasopressors for a total median of 11.5 hours.4 Most patients (72%) received norepinephrine at a concentration of 16 mcg/mL, with the median dose being 0.08 mcg/kg/min (range 0.04 mcg/kg/min to 0.13 mcg/kg/min). The extravasation rate was 4% (n = 8), all of which were either grade 1 or 2 events, and none of which required other interventions beyond removal of the PIV.

Similarly, Cardenas-Garcia et al reported 19 cases (2%) of extravasation among 734 ICU patients receiving peripheral vasopressors for a duration of 49 ± 22 hours, with the highest dose 0.70 ± 0.23 mcg/kg/min.5 There was no documented tissue damage or infections at the extravasation sites. Notably, this study developed a detailed protocol for administering vasopressor medications through a PIV, which included use of a vein > 4 mm on ultrasound, IV gauge size of 20 or 18, no hand/wrist/antecubital fossa positions, assessment of peripheral IV access every two hours by nursing, and a maximum duration of 72 hours for peripheral IV use. In addition, they formulated a protocol for treatment of extravasation, which included the administration of phentolamine injection and the application of nitroglycerin paste to the area.

Taken together, the data suggest that short-term PIV infusion of norepinephrine likely is safe, with the incidence of extravasation being rare and unlikely to cause significant tissue damage when it does occur. However, it is important to keep in mind that vigilant surveillance of the PIV site, as well as other best clinical practices that may include ensuring the PIV is within the vein through ultrasound and/or blood return, and appropriate PIV positioning, are warranted.

REFERENCES

  1. Kim SM, et al. Well recognized but still overlooked: Norepinephrine extravasation. BMJ Case Rep 2012. doi:10.1136/bcr-2012-006836.
  2. Alexander CM, et al. Missed extravasation injury from peripheral infusion of norepinephrine resulting in forearm compartment syndrome and amputation. Am Surg 2016;82:e162-e163.
  3. Medlej K, et al. Complications from administration of vasopressors through peripheral venous catheters: An observational study. J Emerg Med 2018;54:47-53.
  4. Lewis T, et al. Safety of the peripheral administration of vasopressor agents. J Intensive Care Med 2019;34:26-33.
  5. Cardenas-Garcia J, et al. Safety of peripheral intravenous administration of vasoactive medication. J Hosp Med 2015;10:581-585.