Determination of the Relative Potency of Norepinephrine and Phenylephrine Given as Infusions for Preventing Hypotension During Combined Spinal-Epidural Anesthesia for Cesarean Delivery: A Randomized Up-And-Down Sequential Allocation Study

Abstract

Purpose: The relative potency of norepinephrine and phenylephrine given as boluses to treat hypotension during spinal anesthesia for cesarean delivery has been reported but few data are available for infusions. This study aimed to determine the relative potency of norepinephrine and phenylephrine when given by infusion for preventing hypotension during combined spinal-epidural anesthesia for cesarean delivery. Methods: This was a prospective, randomized, double-blind, up-and-down sequential allocation study. Patients were randomly allocated to receive a prophylactic infusion of norepinephrine or phenylephrine started immediately after induction of anesthesia. The first patients received either norepinephrine 0.1 μg/kg/min or phenylephrine 0.5 μg/kg/min. An effective infusion rate was defined when no hypotension occurred before delivery. For each subsequent patient, the norepinephrine infusion rate was decreased or increased by 0.01 μg/kg/min or the phenylephrine infusion rate was decreased or increased by 0.05 μg/kg/min according to whether the infusion was effective or ineffective respectively in the previous patient. Values for the infusion rate that was effective in preventing hypotension in 50% of patients (ED50) for norepinephrine and phenylephrine were estimated using up-and-down sequential analysis and relative potency was estimated. Probit regression was used as a backup and sensitivity analysis. Results: The ED50 values for norepinephrine and phenylephrine calculated by the up-and-down method were 0.061 (95% CI 0.054-0.068) μg/kg/min and 0.368 (95% CI 0.343-0.393) μg/kg/min respectively. The estimated relative potency ratio for ED50 for norepinephrine to phenylephrine was 6.03:1 (95% CI 5.26:1 to 6.98:1). Conclusion: Under the conditions of this study, norepinephrine given by infusion was about 6 times more potent than phenylephrine. This information is useful for clinical practice and further comparative studies of norepinephrine versus phenylephrine. Clinical Trial Registration: http://www.chictr.org.cn/showproj.aspx, identifier [ChiCTR2200056237].

Keywords: anaesthesia; cesarean section; infusions; intravenous; norepinephrine; phenylephrine; spinal.

FIGURE 1

CONSORT diagram showing patient recruitment and flow.

FIGURE 2

Observed proportions of subjects with effective or ineffective responses to different infusion rates of norepinephrine or phenylephrine.

FIGURE 3

Dose–response curves of phenylephrine and norepinephrine infusions for preventing hypotension calculated using probit analysis. Values for dose represent infusion rates. The horizontal axis is on a logarithmic scale. Antilog values for dose are shown below log (dose) values to aid interpretation.