Prophylactic intravenous norepinephrine for the prevention of hypotension during spinal anesthesia for elective cesarean section: a systematic review and dose-response meta-analysis of randomized controlled trials

Abstract

Introduction: In this study, we aimed to evaluate the potential dose-response relationship between prophylactic norepinephrine (NE) infusion rates and the risks of hypotension during cesarean section following spinal anesthesia. Methods: Randomized controlled trials with two or more NE doses for post-spinal hypotension prophylaxis during cesarean section were systematically searched in the MEDLINE, Embase, Web of Science, Cochrane Central Register of Controlled Trials, and US Clinical Trials Registry databases until 31 July 2022. The primary outcome was the relative risk of maternal hypotension with different NE regimens (infusion rates or bolus doses). Secondary outcomes included the relative risks of maternal and fetal adverse events with different NE regimens. Results: Ten studies with 1,144 parturients were included for final analysis using restricted cubic splines and random-effects dose-response meta-analysis models. A significant dose-response relationship existed between NE infusion rates and the relative risks of maternal hypotension. Every 0.01 μg/kg/min increment in the NE infusion rate was associated with a 14% decrease in the incidence of post-spinal hypotension. ED₅₀ and ED₉₅ of NE infusion rates for post-spinal hypotension prophylaxis were estimated to be 0.046 (95% CI from 0.032 to 0.085) and 0.2 (95% CI from 0.14 to 0.37) μg/kg/min, respectively. However, a higher NE infusion rate was associated with a higher incidence of maternal hypertension. Conclusion: An increased NE infusion rate was associated with a decreased incidence of post-spinal hypotension but an increased incidence of hypertension. Therefore, 0.07 μg/kg/min was recommended as the initial NE infusion rate for clinical practice, as it was associated with the lowest risk of physician intervention for unstable hemodynamics after spinal anesthesia for cesarean delivery. Systematic Review Registration: (https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=349934), identifier (CRD42022349934).

Keywords: cesarean section; dose–response meta-analysis; hypotension; norepinephrine; spinal anesthesia.

FIGURE 1

Flow diagram of included studies.

FIGURE 2

(A) Risk of bias graph. (B) Risk of bias summary.

FIGURE 3

Summary of relative risk of maternal hypotension in different regimens, the highest vs. the lowest dose category.

FIGURE 4

Dose–response relationship between the NE infusion rate and relative risk of maternal hypotension, showing point estimates and 95% CI for linear and non-linear meta-analysis models.

FIGURE 5

Sensitivity analysis of individual studies influenced the pooled relative risk of maternal hypotension per 0.01 μg/kg/min increase in the NE infusion rate.

FIGURE 6

After imputation, the contour-enhanced funnel plot of maternal hypotension.

FIGURE 7

Trial sequential analysis on the incidence of maternal hypotension in studies comparing NE with the saline control.

FIGURE 8

Dose–response relationship between the NE infusion rate and relative risk of maternal hypertension, showing point estimates and 95% CI for non-linear meta-analysis.

FIGURE 9

Benefit (hypotension) compared with harm (hypertension) for the NE infusion rate between 0 and 0.05 μg/kg/min. The threshold at which the benefit equaled the damage was 0.025 μg/kg/min.

FIGURE 10

Dose–response relationship between the NE infusion rate and relative risk of unstable maternal hemodynamics, showing point estimates and 95% CI for linear and non-linear meta-analysis models.

FIGURE 11

Dose–response relationship between the NE infusion rate and relative risk of maternal nausea or vomiting, showing point estimates and 95% CI for linear and non-linear meta-analysis models.

FIGURE 12

Sensitivity analysis of individual studies influenced the pooled relative risk of maternal nausea or vomiting per 0.01 μg/kg/min increase in the NE infusion rate.

FIGURE 13

After imputation, the contour-enhanced funnel plot of maternal nausea or vomiting.