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Time to Use Peripheral Norepinephrine in the Operating Room

2021; Lippincott Williams & Wilkins; Volume: 133; Issue: 1 Linguagem: Inglês

10.1213/ane.0000000000005558

1526-7598

W. Brenton French, William Rothstein, Michael J. Scott,

Abdominal Surgery and Complications

Perioperative hypotension is a known risk factor for many complications including myocardial infarction, acute kidney injury (AKI), and mortality. Avoiding hypotension in the operating room (OR) and perioperative period is a key factor to preventing postoperative complications.1,2 Although, currently, there is no universal definition of hypotension, evidence suggests organ injury occurs at mean arterial pressure (MAP) thresholds <60–65 mm Hg.1,3 Injury such as AKI appears to correlate with both magnitude and duration of hypotension.1 Factors that can precipitate perioperative hypotension include fluid and blood loss, myocardial dysfunction, and the vasomotor response to positive pressure ventilation, anesthetic agents, pneumoperitoneum, patient positioning, and the systemic inflammatory response to surgery. In addition to fluid therapy to maintain intravascular volume, vasopressors are an important tool to restore vasomotor tone and maintain MAP once intravascular volume is normalized. Hypervolemia is associated with postoperative complications, and targeted use of vasopressors can avoid excessive administration of intravenous (IV) fluid.4 Increasing implementation of Enhanced-Recovery After Surgery (ERAS) principles has led to an emphasis on avoiding perioperative fluid overload and utilization of goal-directed fluid therapy (GDT) to optimize intravascular volume, particularly in high-risk patients.4,5 Once volume status is optimized and cardiac output is adequate, vasopressor use is an important component of GDT protocols. Vasopressors, especially norepinephrine, have historically been administered via a central venous catheter (CVC) for fear of peripheral extravasation and direct tissue injury. Although this belief is widely shared, there is little evidentiary support in the clinical literature. In the OR, boluses of short acting vasopressors such as phenylephrine and ephedrine are commonly administered. However, it makes more physiological sense to run a low-dose infusion to create a more stable physiological platform. In the United States, phenylephrine infusions are commonly used, not due to the ideal properties of the drug but because anesthesiologists are comfortable administering this via a peripheral vein. Norepinephrine supports cardiac contractility and causes vasoconstriction, thereby restoring the patient's physiology closer to baseline. However, health systems and providers worldwide may restrict norepinephrine infusion to central venous lines only. The desire to avoid central line placement and its potential complications may discourage providers from adhering to goal-directed therapy principles in surgical procedures, many of which involve pressor utilization at certain hemodynamic thresholds.6 Recent studies have shown the safety of peripheral administration of norepinephrine.7–10 To encourage adoption of GDT principles, we will consider the existing evidence regarding the safety of administering norepinephrine peripherally. AVOIDING HYPOTENSION IN THE OR Understanding the consequences of hypotension is critical to encouraging vasopressor use when indicated. It is well-known that intraoperative hypotension can cause organ dysfunction, AKI, myocardial injury after noncardiac surgery (MINS), and increased mortality.1–3 Lower pressure and longer duration of hypotension lead to increased patient harm. In a large analysis by Salmasi et al1 of patients having noncardiac surgery, an intraoperative MAP below an absolute threshold of 65 mm Hg was progressively related to both myocardial and renal injuries. Time spent below an MAP of 65 mm Hg for a total of 13 minutes was associated with increased risk of AKI and MINS, while an MAP of 50 mm Hg for just 1 minute also increased this risk. Sun et al2 reviewed 5127 noncardiac surgical patients and showed a significantly higher risk of AKI with exposures to an MAP of 18,000 patients in the Veterans Affairs system and showed increased 30-day mortality risk with an intraoperative MAP of <50 mm Hg or systolic blood pressure (SBP) 65 mm Hg or at a certain percentage of a patient's baseline blood pressure. A key concept in GDT is avoiding hypervolemia by administering fluids only when a patient's hemodynamic changes suggest volume depletion. Vasopressor use is, thus, a critical component of GDT and is encouraged in the cases of hypotension without signs of hypovolemia.4,6 GDT shows significant potential benefit in clinical studies and meta-analysis in appropriate patients. A recent meta-analysis studying 95 randomized trials showed lower risk of mortality, AKI, pneumonia, and hospital length of stay (LOS) compared to standard fluid management.6 The World ERAS Society guidelines also recommend routine use of GDT in enhanced-recovery protocols for high-risk patients.5 BENEFITS OF MAINTAINING MAP WITH NOREPINEPHRINE Norepinephrine is a potent α-1, β-1, and mild β-2 agonist. As a vasoconstrictor and inotrope, it increases arterial pressure, mean systemic filling pressure, cardiac contractility, and cardiac output. Current evidence increasingly supports preferential use of norepinephrine over pure α-1 agonists in the OR. Although commonly used to treat anesthesia-induced hypotension, through pure α-agonism, phenylephrine can increase cardiac afterload while decreasing stroke volume and cardiac output.12,13 Recent evidence suggests phenylephrine can increase or maintain cardiac output in preload-dependent patients.14,15 This is attributed to increased venous pressure and mean systemic filling pressures, causing increased venous return to the heart.14 However, in patients who are adequately resuscitated and preload-independent, the phenylephrine-induced increase in afterload results in a drop in cardiac output.15 In GDT, volume status is optimized via stroke volume assessment before initiation of pressors; thus, phenylephrine would be expected to reduce cardiac output in these preload-independent patients. Studies suggest norepinephrine improves cardiac output along with splanchnic and renal blood flow compared to phenylephrine,13,16 although 1 trial showed no difference in cardiac output with norepinephrine and phenylephrine in euvolemic surgical patients.17 Currently, there is a lack of high-quality evidence equating norepinephrine use with improved clinical outcomes over phenylephrine specifically in surgical patients. However, based on the physiology, norepinephrine is likely the preferred vasopressor for intraoperative therapy aimed at maintaining euvolemia while optimizing cardiac output and tissue oxygen delivery. The common practice of restricting norepinephrine administration to central lines inhibits adoption of these well-validated principles. A thorough review of published data demonstrates that norepinephrine can be safely administered peripherally. SAFETY OF PERIPHERAL ADMINISTRATION OF NOREPINEPHRINE The widespread belief that vasopressors must be given via a CVC stems from fears of peripheral infiltration and tissue injury. However, evidence shows this complication is rare and likely preventable with certain practices.8,9,18 Loubani and Green18 performed an extensive literature review of adverse effects from peripheral vasopressor use. The majority of the tissue injuries identified were limited to case reports and involved distal peripheral intravenous (PIV) administration. From 1946 to 2014, they identified 85 studies with 80 of these presenting individual data. In patients with tissue injury, 85% had PIV access distal to the antecubital or popliteal fossae, and the average duration of infusion was 55.9 hours with a median of 24 hours. They demonstrated that based on existing reports, tissue injury can result from prolonged administration of vasopressors through more distal peripheral access, and the authors concluded that vasopressor use via a proximal PIV is unlikely to cause local tissue injury when used as a temporizing measure. Recent studies have shown that vasopressors may be safely administered via peripheral venous access (Table 1).7–10 Pancaro et al7 evaluated 14,385 patients who received peripheral norepinephrine during elective surgery in the Netherlands. The institutions studied used a standardized, dilute norepinephrine concentration of 20 µg/mL. They identified only 5 cases (0.035%) of extravasation and no reported tissue injuries. A significant amount of data also exists from intensive care unit (ICU) patients. Although a different setting, these data are highly applicable to the OR, where hypotension may be transient and related to surgery, anesthesia, or mechanical ventilation. In 2015, Cardenas-Garcia et al8 published a study of ICU patients receiving vasopressors via PIV access. Their PIV access criteria required an 18- or 20-gauge IV placed in a vein proximal to the antecubital fossa that was >4 mm in diameter on ultrasound. Of their 783 patients, norepinephrine was used in 506 with a concentration of 8 or 16 mg in 250-mL normal saline. Their mean infusion rates for norepinephrine were 0.70 µg/kg/min, and sites were monitored every 2 hours by trained staff. Extravasation occurred in 2% of patients, in which case phentolamine was injected and nitroglycerin paste was administered. No tissue injuries were identified over the course of this study. Table 1. - Studies Evaluating Peripheral Administration of Norepinephrine Study Year Observations Setting No. of patients receiving norepinephrine IV sites evaluated Total extravasation events Tissue injuries Cardenas-Garcia et al8 2015 783 ICU 506 (65%)a Proximal to antecubital fossa 19 (2.4%) 0 (0%) Lewis et al9 2019 202 ICU 146 (72%) Forearm, antecubital fossa, and hand 8 (4%) 0 (0%) Medlej et al10 2018 55 ED 50 (91%) Antecubital fossa, forearm, and hand 2 (3.6%)b 0 (0%) Pancaro et al7 2020 14,385 Intraoperative 14,385 (100%) Not reported outside of extravasation events 5 (0.035%) 0 (0%) Abbreviations: ED, emergency department; ICU, intensive care unit; IV, intravenous.aAbout 783 infusions were studied in 734 patients as part of this study.bIn addition to the 2 extravasation events, 1 patient developed thrombophlebitis that resolved without intervention. Medlej et al10 evaluated 55 emergency department patients, 50 of whom received norepinephrine via peripheral access. At a concentration of 8 mg in 250 mL (32 µg/mL) and a median duration of 13 hours, 2 patients had extravasation and 1 had thrombophlebitis; 2 of these PIVs were in the hand and 1 in the antecubital fossa. All patients recovered without intervention. Lewis et al9 in a review of 202 ICU patients with no specific peripheral administration protocol in place identified peripheral extravasation rates of 4%. Out of the 8 cases identified, 7 occurred in sites at or distal to the antecubital fossa. In the cases of extravasation, 4 were norepinephrine while 4 were phenylephrine. These events occurred at a median infusion time of 21 hours, and all cases were managed conservatively with no intervention necessary. DISCUSSION AND RECOMMENDATIONS When volume status is optimized in the OR, vasopressor use may be required to temporarily maintain MAP and to avoid the negative consequences of hypotension. Norepinephrine has physiologic advantages over phenylephrine, and the recent evidence shows that dilute concentrations of norepinephrine are safe to administer peripherally when certain conditions are met (Table 2).7–10,13 While a significant amount of the published data involves ICU patients, we believe these data are applicable to the perioperative period, where hypotension is more likely a temporary result of anesthesia, positive pressure ventilation, patient positioning, and the surgery itself. In the studies that included both peripheral norepinephrine and phenylephrine infusions, no significant differences were noted in extravasation.8,9 Any risks of peripheral vasopressor administration must be balanced with the potential complications of CVC placement, which can include pneumothorax, line infection, thrombosis, arterial injury, hematoma, and venous stenosis.19 Table 2. - Suggested Conditions for Peripheral Norepinephrine Administration IV should be 18–20 gauge in size IV location should be proximal to or at the antecubital fossa Use 4–8 mg in 250-mL concentration Duration of use should likely not exceed 6–12 h but is based on clinician judgment Site should be monitored every 2 h during infusion Have a deescalation plan to wean vasopressor use Phentolamine or nitroglycerin paste available if extravasation occurs Abbreviation: IV, intravenous. Reviewing the data shows that more proximal locations of the PIV have decreased risk of extravasation and tissue injury, and the studies show the safest location for the PIV is at the antecubital fossa or more proximal.8,9 Catheter size based on existing evidence should be 20 gauge or larger. The concentration of norepinephrine administered should ideally be ≤4–8 mg in 250 mL based on protocols of the above studies. It is worth noting that most extravasation events, when reported, occur following ≥12 hours of infusion. The tissue injuries studied by Loubani and Green18 occurred at a median infusion time of 24 hours. Thus, ideally, vasopressors are only given via a peripheral infusion for a limited duration. While the data are limited, a duration of 6 to 12 hours for a low-dose infusion appears reasonable as long as the above conditions are met, the site is closely monitored, and the patient does not have escalating vasopressor requirements. Such a duration is reasonable in the OR setting where a majority of cases are a few hours in duration. If there is a longer expected duration of pressor requirement, a central line should still be placed. As with any vasopressor use, the peripheral administration of vasoactive medication should have a deescalation plan when appropriate. In the prospective studies, protocols were developed for close monitoring of the peripheral infusion site, and this should be continued.8,10 As was done in the large study by Cardenas-Garcia et al,8 ideally the site is checked every 2 hours by a provider trained in identifying extravasation injury. This may require preoperative planning with the surgeon, as this IV site will need to be accessible during the operation. As a precaution, phentolamine or nitroglycerin paste should also be readily available to treat any extravasation incidents.20 Although rare, the potential danger of extravasation and tissue necrosis cannot be ignored. However, based on the existing studies, adhering to the above recommendations for peripheral vasopressor administration is shown to be safe, and CVC insertion is not a necessity for short-term norepinephrine administration. Anesthesiologists, surgeons, pharmacists, and OR staff should work together to develop institutional protocols that incorporate these elements when vasopressors are given peripherally, and all involved staff should be aware of these safety practices. Such a protocol will avoid the placement and complications of CVCs when temporary intraoperative norepinephrine use is indicated. This, in turn, will make it possible for more institutions and providers to incorporate GDT and vasopressor therapy, avoiding the consequences of volume overload and improving patient outcomes. CONCLUSIONS Norepinephrine can be safely administered as a peripheral infusion in the OR as long as certain conditions are met. CVC placement should not be a prerequisite for administration. The duration of infusion should not be excessive, the IV should be placed proximally, and the site should be monitored. Norepinephrine has hemodynamic advantages over pure alpha agonists, and the ability to administer norepinephrine peripherally should promote the use of GDT and vasopressor therapy to improve outcomes in surgical patients. DISCLOSURES Name: W. Brenton French, MD. Contribution: This author helped with the conception and design, drafting of the manuscript, and critical revision of the manuscript for important intellectual content. Conflicts of Interest: None. Name: William B. Rothstein, MD. Contribution: This author helped with the conception and design, drafting of the manuscript, and critical revision of the manuscript for important intellectual content. Conflicts of Interest: None. Name: Michael J. Scott, MB ChB, FRCP, FRCA, FFICM. Contribution: This author helped with the conception and design, drafting of the manuscript, and critical revision of the manuscript for important intellectual content. Conflicts of Interest: M. J. Scott has received travel, consultancy, and speaker fees from Merck, Trevena, Deltex Medical Limited, Baxter International, and Edwards Lifesciences. This manuscript was handled by: Tong J. Gan, MD.