Phenylephrine is currently the first-choice vasopressor for the prevention and treatment of maternal hypotension during spinal anesthesia for cesarean delivery (CD); it is easy to titrate, can be used either as an intravenous (IV) bolus or as an infusion, and has a better fetal acid-base profile when compared to ephedrine.1–4
However, due to its sole action as an α-adrenergic agonist, phenylephrine can increase afterload, reduce cardiac output, and cause significant bradycardia, necessitating treatment.1,5,6 The negative chronotropic response to phenylephrine that occurs as a reflex secondary to increased blood pressure from a bolus dose or infusion has been shown to be dose related,3,5 with higher doses reducing cardiac output to a greater extent than lower doses. The healthy parturient and fetus usually tolerate these hemodynamic changes well; however, concern exists regarding phenylephrine’s effect on the compromised parturient and fetus, which have not been fully elucidated.5,6
Norepinephrine has recently been described as a practical and useful alternative to phenylephrine for maintaining blood pressure during spinal anesthesia for CD.4,6,7 Unlike phenylephrine, norepinephrine has both α- and β1-adrenergic activity suitable for maintaining blood pressure with less bradycardia, and higher maternal cardiac output.4,6,7 The optimal infusion and bolus dose of norepinephrine in terms of maternal and fetal safety to prevent maternal hypotension has yet to be determined and extensively studied. Many authors recommend that more data on its use should be obtained before routine use in clinical obstetric anesthesia practice.8–10
In this issue, Ngan Kee et al11 look to address this evidence gap in part by comparing the efficacy of norepinephrine to maintain normotension when administered as a prophylactic infusion or a rescue bolus. In both groups, the authors utilized a dilute solution of norepinephrine (5 µg/mL). The study was double blind, and both groups received identical 60 mL syringes (1 group with norepinephrine and the other with saline). The infusion was manually titrated (from 0 to 60 mL/h) with the goal of maintaining blood pressure near baseline, whereas the bolus group received treatment only when systolic blood pressure was <80% of baseline. The primary aim of this study was to demonstrate the feasibility of utilizing a prophylactic norepinephrine infusion to maintain maternal blood pressure near baseline in parturients having spinal anesthesia for elective CD. The authors found maternal blood pressure was more stable, and the incidence of hypotension was reduced with the titrated prophylactic manually controlled variable-rate prophylactic infusion of norepinephrine compared to rescue bolus norepinephrine. Also, there was no difference in neonatal outcomes as assessed by Apgar scores and umbilical cord blood gas analysis between groups. Ngan Kee et al11 concluded that despite a much greater total dose of norepinephrine given to patients who received norepinephrine by infusion, a lower incidence of hypotension could be achieved with a prophylactic infusion compared to a rescue bolus dose, with no adverse effect on neonatal outcome.
The neonatal safety profile of maternal norepinephrine in pregnancy is still a potential concern, based on animal data. Salomon et al12 in a mouse model showed norepinephrine reduced placental perfusion by 40%. Rakers et al13 showed maternal stress in sheep significantly increased maternal norepinephrine levels, which led to decreased uterine blood flow (UBF) by up to 22% for 30 minutes, (P < .05 with respect to UBF). This decreased UBF resulted in the ewe fetus releasing norepinephrine, which increased fetal metabolism, fetal lactate, and anaerobic metabolism.13 Conversely, older studies have shown no major effect of norepinephrine infused at 0.3–0.6 µg/kg/min directly into the internal jugular vein of fetal sheep; the norepinephrine infusion resulted in a small increase in fetal heart rate but with no significant change in arterial blood gas values.14 Thus far, data regarding the fetal effects of norepinephrine from a few studies in humans appear to be reassuring.
Norepinephrine in 2017 raises similar concerns for fetal safety as phenylephrine did in 1997. Historically, ephedrine was considered safer than phenylephrine, based largely on evidence collected in chronically instrumented pregnant sheep.15 For years, animal and in vitro studies observed that uteroplacental blood flow was better maintained using ephedrine versus α-adrenergic agonists such as phenylephrine. This drove anesthesiologists to rely on ephedrine as the primary first-line vasopressor to treat spinal hypotension. Subsequent clinical studies showed greater umbilical arterial blood pH and base excess with the use of α-adrenergic agonists in comparison to ephedrine to maintain maternal blood pressure during spinal anesthesia for CD. In fact, beginning in 2008, Ngan Kee et al6 conducted a series of well-designed randomized clinical trials to demonstrate both the superiority and safety of phenylephrine over ephedrine. Their group is now applying the same rigorous approach to determine both the safety and efficacy of norepinephrine to preserve maternal blood pressure, cardiac output, and uteroplacental perfusion after spinal anesthesia.
Norepinephrine does not cross the placenta into the fetus, because of the placenta’s ability to break down catecholamines.16 The reported fetal circulating half-life of norepinephrine is very short (0.25–1 minute) with no evidence of maternal to fetal transfer.17 The placenta serves many active metabolic roles including reuptake of norepinephrine, accounting for almost 50% of the fetal norepinephrine clearance.18 Future studies as was previously performed on the placental transfer and fetal metabolic effects of phenylephrine and ephedrine19 would need to be replicated with norepinephrine to verify that its use does not raise fetal heart rate nor increase fetal metabolic demand.
A limitation of this study was that it was not designed to compare prophylactic infusion and prophylactic boluses doses of norepinephrine. The infusion regimen was aimed to maintain blood pressure near baseline, whereas the bolus group received treatment only when systolic blood pressure was <80% of baseline, which might account for some of the differences seen between the groups, since by design the infusion group was more aggressive in maintaining blood pressure. As such, the design really focuses on the feasibility of a manually controlled norepinephrine infusion in this clinically relevant context. Regardless, this study adds to the rapidly growing body of evidence that norepinephrine has the advantages of causing less maternal bradycardia with greater cardiac output,11 compared to phenylephrine, the clinical relevance of which has yet to be determined. It also validates that norepinephrine can both be given as an infusion and bolus dose in a diluted concentration to maintain maternal blood pressure.
Another safety concern is the risk of maternal tissue ischemia in the event of extravasation with concentrated norepinephrine. In the current study, Ngan Kee et al.11 utilized a diluted concentration (5 μg/mL) of norepinephrine, which is equivalent in potency to phenylephrine 80 μg/mL, based on a 16:1 potency ratio demonstrated in a recent dose-finding trial by Onwochei et al.7 Clinicians in the current study further diluted the norepinephrine bolus dose by flushing with running IV crystalloid; the infusion was connected directly to a 3-way stopcock at the IV cannula. Ngan Kee et al11 argues that the risk for tissue ischemia should be no different between norepinephrine 5–6 μg/mL and phenylephrine 80–100 μg/mL, given the similarity in vasoconstrictor potency. Therefore, infusion of norepinephrine via a central venous catheter and placement of an arterial line is not necessary for routine blood pressure treatment.11,20,21 While this argument is certainly logical, it should be evaluated in animal models. The drug manufacturer of Levophed recommends norepinephrine be given via a large vein, preferably antecubital, avoiding the lower extremities, and does not specifically state it needs to be given via a central line.22
Evidence is emerging that with diluted norepinephrine instead of the concentrated infusions (up to 64 µg/mL) commonly used in intensive care units (ICUs), the risk of local tissue injury should be minimized, and would not require the use of a central line. Recently, Ngan Kee et al23 reported their experience with 291 patients utilizing dilute norepinephrine and found no evidence of maternal or neonatal adverse effects. In addition, local adverse effects associated with peripheral administration of norepinephrine were not observed in several prospective trials.4,6,7 No case reports of injury from dilute norepinephrine were found using a PubMed search. Case reports typically involved peripheral infusions for several hours through small bore peripheral IVs in hypotensive, severely ill patients. In the ICU setting, with an older, sicker patient population, the rate of extravasation was 2%–4%.24,25 In these 2 ICU studies, 1 prospective (n = 734),24 and the other retrospective (n = 202),25 the patients received vasopressor infusions through a peripheral IV catheter (75% 20 ga, 25% 18 ga); most were in septic shock, and most received norepinephrine at variable concentrations up to 64 µg/mL. In both studies, no patient suffered harm.24,25 Conservative therapy was instituted for infiltration/edema <6 cm in 1 study,25 and the other routinely used phentolamine injection and nitroglycerin ointment to prophylactically treat all extravasations.24 In addition, norepinephrine (pH 3–4.5) infusion has Y-site compatibility with oxytocin and many commonly administered medications (eg, cefazolin, gentamycin, famotidine), but not sodium bicarbonate, thiopental, or phenytoin.26 Finally, vasopressor use in obstetric anesthesia is fundamentally different than in the ICU: vasopressors are administered with rapid fluid coadministration; prolonged infusion (with infiltration) is less likely to occur; and the patients are awake and likely to complain of any discomfort.
Despite the potential advantages, further research is needed to define the optimal administration regimen of norepinephrine, and to determine whether it has clinically important advantages over phenylephrine, before it can be accepted as a routine obstetric vasopressor. Although norepinephrine is associated with greater maternal cardiac output (P = .004), maternal heart rate (P = .039), and umbilical vein oxygen content (P = .047) when compared with phenylephrine,6 the magnitude of each increase is small (9.8%, 5–7 beats per minute, and 0.9 mL/dL, respectively), and may not be clinically important. Ngan Kee et al11 should be acknowledged for publishing several well-designed clinical trials since the 2000s that have demonstrated the safety and efficacy of phenylephrine in human fetuses/newborns, despite animal data to the contrary. This study in addition to 3 recent trials6,7,27 represent an early effort to do the same with norepinephrine. Judging from his record with phenylephrine, the future of norepinephrine as a standard option for use in obstetric anesthesia looks bright.
Name: Manuel C. Vallejo, MD, DMD.
Contribution: This author helped write the manuscript and subsequent draft.
Name: Mark I. Zakowski, MD.
Contribution: This author helped write the manuscript and subsequent draft.
This manuscript was handled by: Jill M. Mhyre, MD.
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