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Year : 2023  |  Volume : 2  |  Issue : 1  |  Page : 1-4

Norepinephrine – Can it replace phenylephrine as the vasopressor of choice in obstetric anesthesia?

Department of Anaesthesiology and Critical Care, University College of Medical Sciences and GTB Hospital, Delhi, India

Date of Submission01-May-2023
Date of Decision03-May-2023
Date of Acceptance04-May-2023
Date of Web Publication25-May-2023

Correspondence Address:
Dr. Medha Mohta
28-B, Pocket-C, SFS Flats, Mayur Vihar Phase III, Delhi - 110 096
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jica.jica_11_23

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How to cite this article:
Mohta M. Norepinephrine – Can it replace phenylephrine as the vasopressor of choice in obstetric anesthesia?. J Ind Coll Anesth 2023;2:1-4

How to cite this URL:
Mohta M. Norepinephrine – Can it replace phenylephrine as the vasopressor of choice in obstetric anesthesia?. J Ind Coll Anesth [serial online] 2023 [cited 2023 Oct 1];2:1-4. Available from: https://www.jicajournal.in//text.asp?2023/2/1/1/377592

Maintenance of stable hemodynamic parameters during cesarean section is extremely important for an optimal maternal and neonatal outcome. Due to spinal anesthesia being the recommended anesthetic technique in majority of cases and a very high incidence of postspinal hypotension, vasopressors have become an integral part of patient management during cesarean section. Many vasopressors are in common use, but the search for the ideal one is still going on.

In this issue, Gupta et al. have compared the effects of phenylephrine and norepinephrine on maternal and neonatal outcomes, when administered as boluses for the prevention of postspinal hypotension in patients undergoing elective cesarean section.[1] They reported a higher mean maternal heart rate at the 2nd–4th min following norepinephrine compared to phenylephrine administration. However, the incidence of bradycardia was not significantly different between the groups. The incidence of hypotension, maternal complications such as nausea, and neonatal outcome in terms of Apgar scores and umbilical cord blood gases were also not different.

Phenylephrine is a pure α-agonist in clinical doses. It effectively prevents and treats hypotension and also maintains good fetal acid − base status.[2] However, it is known to cause baroreceptor-mediated reflex bradycardia with an associated decrease in cardiac output in higher doses.[3],[4] The International Consensus Statement on the management of hypotension with vasopressors during cesarean section recommends phenylephrine as the vasopressor of choice due to the availability of enough supporting evidence of its advantages.[5] At the same time, this consensus statement also mentions that the vasopressors with a small amount of β-agonist activity in addition to α-agonism may have the best profile. Norepinephrine is one such agent having potent α-1 and modest β-agonist action, and therefore, is expected to have, at least theoretically, some advantage over phenylephrine.

Ngan Kee et al., in 2015, compared computer-controlled infusions of norepinephrine and phenylephrine in healthy mothers undergoing cesarean section under spinal anesthesia.[6] They were able to maintain blood pressure with good neonatal outcome in both groups. Since then, a very large number of researchers have compared these two vasopressors to find out if norepinephrine could be an alternative to phenylephrine.

The major points of concern while comparing different vasopressors include their efficacy to prevent and/or treat hypotension, the effect on heart rate with the incidence of bradycardia, maternal complications, their relative potencies, and neonatal safety.

Most of the studies have found similar efficacy of phenylephrine and norepinephrine for prevention as well as the treatment of postspinal hypotension.[6],[7],[8],[9],[10],[11],[12] The reports on the incidence of bradycardia have shown variable results. Some workers have reported a lower incidence with norepinephrine,[6],[8],[12],[13] others had similar incidence,[7],[11] whereas some others found only statistically insignificant difference.[9],[10]

The heart rate is considered a surrogate marker of cardiac output, a fall in which may have an adverse impact on uteroplacental perfusion.[14] In Ngan Kee et al.'s study, norepinephrine infusion was associated with greater cardiac output and heart rate with a lower incidence of bradycardia compared to phenylephrine infusion.[6] Belin et al., while administering manually controlled infusions of phenylephrine or norepinephrine, measured cardiac index using thoracic bioreactance.[15] The cardiac index was maintained at higher values with norepinephrine infusion than with phenylephrine infusion. Wang et al. gave norepinephrine 8 μg or phenylephrine 100 μg immediately after spinal anesthesia for the prevention of hypotension.[13] These doses were repeated if the patient developed hypotension. The patients receiving norepinephrine had a lower incidence of bradycardia and higher cardiac output than those receiving phenylephrine boluses.

Most of the researchers have not found any significant difference in the occurrence of maternal complications such as nausea or vomiting with phenylephrine and norepinephrine.[6],[8],[10],[12],[13]

To accurately compare the efficacy of two different agents, an important prerequisite is to use their equipotent doses. In a random allocation graded dose-response study, Ngan Kee calculated relative potency ratio of norepinephrine and phenylephrine as 13.1, with phenylephrine 100 μg estimated equivalent to norepinephrine 7.6 μg.[16] Another dose-finding study, using up-down sequential allocation method, found norepinephrine to be 11.3 times more potent than phenylephrine when used as bolus doses for the treatment of postspinal hypotension.[17] The norepinephrine dose equivalent to phenylephrine 100 μg was estimated as 8.8 μg. Thus, it is reasonable to consider phenylephrine 100 μg equipotent to norepinephrine 8 μg.

Initially, some concerns were raised regarding neonatal safety with norepinephrine.[10],[18] Heesen et al. in their systematic review commented that the possibility of effect of norepinephrine on the occurrence of fetal acidosis could not be ruled out.[18] However, many other studies have now demonstrated the safety of norepinephrine in terms of neonatal outcome.[6],[7],[8],[9] To further examine this issue, a randomized, double-blind noninferiority trial comparing norepinephrine and phenylephrine during cesarean section was carried out.[19] It was a pragmatic study including elective and nonelective cases being performed under spinal or combined spinal-epidural anesthesia and using norepinephrine or phenylephrine as infusion or bolus for prophylaxis or treatment of spinal hypotension. The primary outcome measure was the umbilical arterial pH. This study concluded that norepinephrine was noninferior to phenylephrine for this primary outcome.

After the selection of the vasopressor agent, it is important to decide on the mode of administration. The vasopressor drugs have been extensively used as bolus or infusion and for prophylaxis or treatment of postspinal hypotension. Variable rate infusions using syringe pumps are recommended by the consensus statement.[5] However, bolus administration is practically easier and is not dependent on the availability of a syringe infusion pump. Thus, this method is preferred in setups with high volume of patients and resource constraints. In most of the studies using boluses, these have been administered for the treatment of postspinal hypotension. As it is preferable to avoid the development of hypotension in the first place, the prophylactic administration of vasopressors is recommended. Thus, prophylactic bolus administration appears to be an attractive option.

The consensus statement recommends starting phenylephrine infusion at a rate of 25–50 μg/min and then titrate it according to blood pressure response.[5] The top-up bolus doses may be administered if required. The aim should be to maintain systolic blood pressure at or above 90% of baseline values and avoid a fall below 80% of baseline. The most commonly used bolus dose of phenylephrine is 100 μg.[20],[21] If equipotent doses of norepinephrine are considered, an infusion beginning at 2–4 μg/min or bolus dose of 8 μg should be used. Recently, many workers have used weight-based doses of both these agents.

Siddik-Sayyid et al. used a prophylactic variable rate infusion of phenylephrine beginning at 0.75 μg/kg/min;[22] whereas some other researchers have used infusions at 0.25 μg/kg/min.[11],[23] Xiao et al. used different infusion rates of prophylactic phenylephrine, i.e., 0.25, 0.375, 0.5, and 0.625 μg/kg/min and calculated ED90 as 0.54 (95% confidence interval [CI]: 0.46–0.76) μg/kg/min.[24] This value was projected as 32.4–43.2 μg/min for patients weighing 60–80 kg.

Norepinephrine has often been used in weight-based doses. Hasanin et al. compared three different infusion doses and concluded that 0.050 μg/kg/min and 0.075 μg/kg/min infusions reduced postspinal hypotension more effectively than 0.025 μg/kg/min.[25] These doses were also found to be effective for prophylaxis of hypotension by Chen et al.[26] Xu et al., using norepinephrine doses of 0, 0.025, 0.05, 0.075, and 0.1 μg/kg/min, calculated ED50 as 0.042 (95% CI: 0.025–0.053) μg/kg/min and ED95 as 0.097 (95% CI: 0.081–0.134) μg/kg/min.[27]

Irrespective of the mode of administration, no significant difference in neonatal outcome could be demonstrated with phenylephrine or norepinephrine in healthy mothers undergoing elective cesarean sections. However, even trivial differences may have some significance in patients with compromised uteroplacental circulation. Therefore, a need to compare these two vasopressors in patients with preeclampsia or fetal compromise was expressed.[6]

In a randomized, double-blind study conducted in pre-eclamptic patients undergoing cesarean section under spinal anesthesia, the patients received either phenylephrine 50 μg or norepinephrine 4 μg for the treatment of hypotension.[28] The heart rate was lower in the phenylephrine group; however, no significant difference was seen in the incidence of bradycardia, umbilical artery pH, Apgar scores, vasopressor requirement, and incidence of maternal complications. In this study, smaller bolus doses of vasopressors were used compared to those in normotensives as pre-eclamptic patients are more sensitive to vasopressors and have reduced requirements of exogenous vasopressors.

Another study compared bolus doses of phenylephrine 50 μg, norepinephrine 4 μg, and ephedrine 4 mg for the treatment of postspinal hypotension in patients with pre-eclampsia.[29] The authors reported a higher heart rate and lower incidence of bradycardia in norepinephrine group compared to the phenylephrine group. No difference was seen in umbilical artery blood gases and Apgar scores between the groups.

Recently, phenylephrine 100 μg and norepinephrine 8 μg have also been studied for the treatment of postspinal hypotension in mothers undergoing cesarean section for fetal compromise.[30] No statistically significant difference was found in mean heart rate values, incidence of bradycardia, umbilical artery pH, number of hypotensive episodes, vasopressor requirements, and incidence of nausea/vomiting between the groups. The lack of any difference in heart rate trends between the two groups was explained by most of the patients being in labor and anxious due to compromised state of the fetus, and also a short spinal to delivery interval resulting in very small vasopressor requirements till the delivery of the baby.

Cost is another factor in the selection of a drug in resource-constrained setups. Phenylephrine preparation containing 10 mg/ml is considered to be more expensive than norepinephrine, although it can be diluted in 100 ml solution and used for a large number of patients being operated on the same day. Recently, another preparation containing 50 μg/ml in 10 ml vial has become available, reducing the cost difference between the two vasopressors.

Norepinephrine has been in regular use in critically ill patients. It was introduced to obstetric practice to overcome phenylephrine's limitations and thus explore the possibility of replacing phenylephrine with norepinephrine as the vasopressor of choice. The main aim was to maintain better uteroplacental perfusion by maintaining higher heart rate and cardiac output. However, whether the maintenance of higher cardiac output results in better neonatal outcome is not clear, so far, no study has demonstrated superior neonatal outcome with the use of norepinephrine versus phenylephrine. Wang et al., while using prophylactic boluses of norepinephrine and phenylephrine, observed higher heart rate and cardiac output in patients receiving norepinephrine but commented that there were no maternal or neonatal clinical advantages of using norepinephrine.[13] Recently, Ikeda et al. studied the association between low maternal cardiac output and fetal acidosis.[31] They did not find any such association and therefore suggested that routine cardiac output measurement during elective cesarean delivery is not indicated.

In conclusion, both phenylephrine and norepinephrine are safe and effective for the prevention and treatment of postspinal hypotension during cesarean delivery. Although norepinephrine maintains higher maternal heart rate and cardiac output, no additional advantage of this vasopressor in terms of maternal and neonatal outcomes has been demonstrated. Thus, the evidence available at present does not support the replacement of phenylephrine with norepinephrine as the vasopressor of choice.

  References Top

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Langesaeter E, Rosseland LA, Stubhaug A. Continuous invasive blood pressure and cardiac output monitoring during cesarean delivery: A randomized, double-blind comparison of low-dose versus high-dose spinal anesthesia with intravenous phenylephrine or placebo infusion. Anesthesiology 2008;109:856-63.  Back to cited text no. 3
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Kinsella SM, Carvalho B, Dyer RA, Fernando R, McDonnell N, Mercier FJ, et al. International consensus statement on the management of hypotension with vasopressors during caesarean section under spinal anaesthesia. Anaesthesia 2018;73:71-92.  Back to cited text no. 5
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Hasanin A, Amin S, Refaat S, Habib S, Zayed M, Abdelwahab Y, et al. Norepinephrine versus phenylephrine infusion for prophylaxis against post-spinal anaesthesia hypotension during elective caesarean delivery: A randomised controlled trial. Anaesth Crit Care Pain Med 2019;38:601-7.  Back to cited text no. 9
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  [Full text]  
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Dyer RA, Reed AR, van Dyk D, Arcache MJ, Hodges O, Lombard CJ, et al. Hemodynamic effects of ephedrine, phenylephrine, and the coadministration of phenylephrine with oxytocin during spinal anesthesia for elective cesarean delivery. Anesthesiology 2009;111:753-65.  Back to cited text no. 14
Belin O, Casteres C, Alouini S, Le Pape M, Dupont A, Boulain T. Manually controlled, continuous infusion of phenylephrine or norepinephrine for maintenance of blood pressure and cardiac output during spinal anesthesia for cesarean delivery: A double-blinded randomized study. Anesth Analg 2023;136:540-50.  Back to cited text no. 15
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