Yes You Can—Cautiously—Infuse Norepinephrine Intraoperatively Through a Peripheral Intravenous Catheter

See Article, p 1060 In 2019, the operating room is ostensibly one of the safest areas of a hospital. While it is with exception that patients die during surgery, evidence suggests that complications soon after surgery are an important cause of morbidity and mortality. Among inpatients having noncardiac surgery in high-performing medical centers, 30-day mortality is as high as 2%–4%.1 How can this be? While there are multiple contributing factors, there is increasing evidence that perioperative hypotension is associated with untoward short- and long-term outcomes. As an accepted definition of intraoperative hypotension remains elusive, recent evidence—and conventional wisdom—suggest that maintaining an intraoperative mean arterial pressure (MAP) >55 mm Hg is prudent in the majority of patients.2 In a published statement from the Perioperative Quality Initiative (POQI) conference held in 2017, there was agreement that intraoperative MAP <60–70 mm Hg in patients undergoing noncardiac surgery is associated with an increasing incidence and extent of postoperative myocardial injury (POMI) and acute kidney injury (AKI), both of which are associated with higher 30-day mortality.3 But the clinical reality in the operative room may fall short of these recommendations, as intraoperative hypotension remains common during surgery. Definitions of intraoperative hypotension remain variable; Bijker et al4 found 140 definitions of hypotension with an incidence that ranged from 5% to 99%. Wesselink et al5 reported a strong association between POMI and AKI in patients undergoing noncardiac surgery and exposure to decreasing MAPs ranging from 80 to 50 mm Hg, suggesting that a single absolute threshold for defining hypotension may not be in the best interest of our patients. Vernooij et al6 corroborated these findings in a large multi-institutional trial in which investigators demonstrated an increasing incidence of POMI and AKI as intraoperative blood pressure decreased. Having the awareness, clinical expertise, and access to adequate hemodynamic monitoring options are important prerequisites for effectively identifying and treating low intraoperative blood pressure. But, clinicians must also have ready availability to the right drug(s) and access to an appropriate route of administration if interventions to treat intraoperative hypotension are to be meaningful. While clinicians will debate the “best vasopressor” during any given hypotensive circumstance, it is not uncommon for a patient to need a potent alpha-vasoconstrictor, such as norepinephrine, administered either in divided doses or as a continuous infusion. While convention in the United States is to infuse potent vasoactive agents directly into the central circulation, this route is seldom available for routine, elective surgical patients. But is the alternative of infusing potent vasopressors through a peripheral venous catheter a safe option? And if not, are we forced to choose between using a less potent vasoconstrictor, such as phenylephrine, and placing central access in otherwise healthy surgical patients undergoing elective surgery? These concerns are real, as clinicians continue to debate the potential dangers of infusing potent alpha-agonists via a peripheral catheter.7 In this issue of the Journal, Pancaro et al8 provide details of their substantive experience with the routine practice of infusing dilute (20 µg/mL) norepinephrine via a peripheral intravenous catheter to treat intraoperative hypotension. In this retrospective cohort study, the authors report that 8% (n = 14,385) of the 179,811 patients undergoing noncardiac surgery over a 4-year period in 2 institutions in Europe received a norepinephrine infusion administered via a peripheral intravenous catheter. Of the more than 14,000 patients who received peripheral norepinephrine, the reported incidence of extravasation was only 0.035% (n = 5 patients; 95% confidence interval [CI] for extravasation, 0.011%–0.081%, or 1–8 complications per 10,000 patients treated). Of equal importance, the extent and severity of tissue injury due to extravasation was minor in all 5 patients, and no patient required additional medical or surgical intervention or suffered permanent tissue damage because of the infiltration. Readers should recognize that this method of norepinephrine administration is common in many regions of Europe, and therefore, the extensive experience of these clinicians and comfort with this route of administration likely contributed to this remarkable safety record.9 Notably, the authors highlight that their reported incidence of norepinephrine tissue extravasation contrasts with other published rates of 3%–4%.10 What might explain this 100-fold difference in incidence? First, there are marked differences in patient acuity between the elective surgical patients highlighted by Pancaro et al8 and the intensive care unit patients described by others. The authors also suggest that “anesthesiologists can provide hypervigilant surveillance of the patient position and the infusion site more regularly” (in the elective surgical patient), “while it may be more difficult to adhere to these practices in emergent surgical cases or in the intensive care unit setting” (over prolonged periods of time). The authors hypothesize that the limited tissue injury after extravasation reported in their study is attributable to early detection and relatively small extravasation volumes. They note that compared with more intensely ill patients in whom circulatory shock, tissue hypoperfusion, and acidosis may be more common, patients undergoing elective surgery usually have adequate perfusion to their extremities helping to mitigate the impact of norepinephrine extravasation, should it occur. However, clinicians must remain cautious when interpreting these data. First, every retrospective analysis is subject to an inability to validate biased or absent reporting, as well as poor investigator control over the exposure factor (norepinephrine extravasation), covariates (patient’s age, tissue pH, peripheral edema), and potential confounders (concentration and volume of norepinephrine infusion). Thus, until more definitive information becomes available, we join the authors in recommending that dilute norepinephrine infusions (20 µg/mL) via peripheral catheters be limited to patients who are undergoing elective, noncardiac surgery where “hypervigilant surveillance” is more readily maintained with patients in the operating room. We would go a step further and recommend avoiding a norepinephrine infusion through peripheral venous access where normal venous flow might be compromised (eg, on the same extremity as a blood pressure cuff). Despite our vigilance, extravasation of norepinephrine will occur. There is a paucity of information regarding the incidence, extent of tissue damage, and appropriate management of extravasation injuries in general, and from norepinephrine in particular. Indeed, we believe this is the largest study to date that addresses the incidence of norepinephrine extravasation, and the extent and severity of associated tissue injury. While extravasation injury has been most commonly noted after the administration of antineoplastic agents in the oncology setting, there are a number of commonly used nonantineoplastic cytotoxic agents used routinely in the perioperative setting. These include 5.5% calcium chloride, 10% calcium gluconate, dobutamine, dopamine, epinephrine, concentrated glucose solutions, 15% mannitol, penicillin, phenytoin, concentrated potassium chloride, 4.2%–8.4% sodium bicarbonate, hypertonic sodium chloride, vancomycin, and vasopressin. Most of these drugs are commonly, but cautiously, administered via a peripheral intravenous catheter in the operating rooms. Factors that determine the extent of tissue damage following extravasation of cytotoxic agents include chemical and biologic properties that predispose to local vasoconstriction (osmolality, pH, and potency) and the volume and concentration of the vesicant (an agent that causes blistering).11 When these factors are combined with frequent cycling of a blood pressure cuff (if located on the same extremity) or use of high-pressure infusion devices, tissue injury can be quite extensive.7 Currently, phentolamine is the only pharmacologic treatment approved by the Food and Drug Administration for vasopressor extravasation. Additional pharmacologic treatment options are limited, but a recent literature review suggests that subcutaneous terbutaline (a selective β2 agonist) and topical nitroglycerin may have a role in this situation.12 Finally, the etiology of intraoperative hypotension is multifactorial, and elements of vasodilation and decreased myocardial contractility almost always contribute during the intraoperative period. We agree with Pancaro et al8 that norepinephrine may have a particularly favorable hemodynamic profile in this setting by virtue of its α1 and 2-receptor and β1-receptor agonistic properties when compared with phenylephrine, a pure α1-receptor agonist.13 Thus, norepinephrine will result in α-receptor–mediated vasoconstriction as well as a β1-receptor–mediated increase in myocardial contractility; that is, concurrent mechanisms aligned with correcting hypotension in the anesthetized patient. Indeed, 2 recent clinical trials that utilized peripheral norepinephrine infusions to maintain or restore normotension during anesthesia resulted in a lower incidence of adverse postoperative events.14,15 In summary, we applaud Pancaro et al8 for shedding additional light on an important observation regarding the implications of norepinephrine infusion via a peripheral venous catheter during the treatment of hypotension in the operating room. While practitioners must continuously assess the risk/benefit ratio of all therapeutic options, these findings should provide additional confidence that peripheral infusion of norepinephrine for hypotensive patients undergoing elective surgery, and in whom the care team can remain vigilant of the infusion site may be a viable option in select circumstances. Meanwhile, we look forward to future controlled clinical trials to provide vital information regarding the “best vasopressor” for the anesthetized but hypotensive patient. DISCLOSURES Name: Tjorvi E. Perry, MD, MMSc. Contribution: This author helped design the editorial, conduct the analysis, write the manuscript, and approved the final version. Conflicts of Interest: T. E. Perry reports consultations for Edwards LifeSciences. Name: Richard C. Prielipp, MD, MBA, FCCM. Contribution: This author helped design the editorial, conduct the analysis, write the manuscript, and approved the final version. Conflicts of Interest: R. C. Prielipp reports consultations for Merck Inc and Fresenius Kabi. This manuscript was handled by: Ken B. Johnson, MD.