This was a randomized, controlled, double-blinded trial at Cairo University Hospital in Cairo, Egypt, taking place between August 2017 and December 2017. Patients were eligible for inclusion if they were between the ages of 18 and 35 years, pregnant with full-term singletons and scheduled for elective cesarean delivery. Exclusion criteria included hypertensive disorders of pregnancy, peripartum bleeding, cardiac comorbidities, body mass index>40 kg/m2, baseline systolic blood pressure (SBP) <100 mm Hg, and failed block. After randomization using an online random number generator, patient codes were sealed into envelopes by a research assistant not involved in the study, and the study drug was prepared by an anesthesia resident who was also not involved in the study. After baseline SBP was obtained, patients were premedicated with metoclopramide (10 mg) and ranitidine (50 mg) intravenously and received subarachnoid block with rapid crystalloid coload. The L3-L4 or L4-L5 interspace was used to access the intrathecal space and 10 mg of hyperbaric bupivacaine and 20 μg fentanyl was injected. All patients received a 5 μg norepinephrine bolus and then they were divided into 1 of 3 starting doses for the norepinephrine infusion: 0.025, 0.05, or 0.075 μg/kg/min until 5 minutes following delivery. The norepinephrine was delivered via a syringe pump and prepared as a concentration of 8 μg/mL. Frequency of postspinal hypotension was the primary outcome and secondary outcomes included frequency of severe postspinal hypotension, frequency of postdelivery hypotension, frequency of intraoperative nausea and vomiting, and hemodynamic data.
Of the 290 patients who underwent randomization, 284 were included in the analysis. The 0.050 and 0.075 μg/kg/min groups had a lower frequency of postspinal hypotension compared with the 0.025 μg/kg/min group [24.7%, 26.0%, and 42.1%; odds ratios, 0.45 (95% confidence interval: 0.24-0.82) and 0.48 (95% CI: 0.26-0.89), P=0.014 and 0.022, respectively]. There was no significant difference between the 2 higher-dose groups (P=0.868). SBP was higher and heart rate was lower in the 0.050 and 0.075 μg/kg/min groups. There were no significant differences in bradycardia, nausea or vomiting, or frequency of intraoperative hypotension among the 3 groups. Neonatal outcomes were similar among the 3 groups.
Maternal hypotension was less frequent in patients receiving 0.050 and 0.075 μg/kg/min compared with a dosing of 0.025 μg/kg/min in full-term patients undergoing elective cesarean delivery. There were no advantages in the group receiving 0.075 μg/kg/min, thus it was recommended that 0.050 μg/kg/min is the ideal initial infusion rate to treat postspinal hypotension during elective cesarean delivery. Further studies are needed to explore the incidence of side effects.
This is a further study that describes the use of norepinephrine as a vasopressor for maintaining blood pressure during spinal anesthesia for cesarean delivery. Several previous “proof of concept” studies including work from myself have provided evidence for possible advantages norepinephrine may have over phenylephrine, conferred by its weak β-adrenergic agonist properties. The current study expands on the previous work by comparing 3 different fixed-rate infusions to determine the optimal regimen for preventing hypotension.
The study appears to have been well conducted and there was a clear conclusion: under the experimental conditions of the study, an infusion rate of 0.05 µg/kg/min was recommended. With an estimated potency ratio for norepinephrine:phenylephrine of 13.1:1 in obstetric patients this would be equivalent to 0.66 µg/kg/min phenylephrine, which broadly aligns with the range of doses most clinicians would choose when using phenylephrine. Therefore, I believe that most obstetric anesthesiologists who are experienced with infusions of phenylephrine would be comfortable using infusions of norepinephrine at this rate.
Interestingly, a dose-related decrease in maternal heart rate was seen in all groups although the incidence of bradycardia (defined as heart rate<55 beats/min) was relatively low. This decrease in heart rate likely relates to the same baroreceptor-mediated reflex that underlies depression of heart rate during phenylephrine use, but the assumption—and underlying rationale for choosing norepinephrine—is that the magnitude of bradycardia (and likely associated depression of cardiac output) is on average less with norepinephrine than with phenylephrine because of the counteracting β-adrenergic stimulation exhibited by norepinephrine.
A few aspects of the study design are noteworthy. The concentration of norepinephrine (8 µg/mL) used is approximately equivalent in vasoconstrictor potency to phenylephrine 100 µg/mL which is now a common solution delivered via peripheral veins in obstetric patients. However, in the current study, the authors delivered norepinephrine via a dedicated peripheral line. In my own practice, I prefer to administer phenylephrine and norepinephrine into a running intravenous which provides the reassurance of rapid distribution of the vasopressor and may reduce the risk of tissue damage in the event of extravasation. Of further note, the vasopressor regimen included a bolus dose given as soon as cerebrospinal fluid was identified. Whether this technique has advantages over simply just using an infusion is unknown. It is unclear whether the tested norepinephrine infusion rates would be as effective or whether a rate of 0.05 µg/kg/min is optimal when an initial bolus is not given.
The authors used a fixed-rate infusion regimen. It can be argued that a titrated variable-rate infusion would be more suited to accurate blood pressure control. Of note, hypotension occurred in about a quarter of patients who received norepinephrine at 0.05 µg/kg/min. Nonetheless, the results of the current study can be seen as a guide for starting an infusion of norepinephrine; those who prefer to adjust infusions can do so in response to changes in blood pressure and/or heart rate.
Comment by Warwick D. Ngan Kee, MD, MBChB