Norepinephrine vs. phenylephrine for spinal hypotension in cesarean section: a network meta-analysis

The Takeaway

Continuous vasopressor infusion is superior to rescue boluses in preventing post spinal hypotension and subsequent intraoperative nausea and vomiting. In addition, continuous norepinephrine infusion is superior to phenylephrine, with an effective dose of 0.07 μg/kg/min.

Study Design

• Inclusion Criteria: published and unpublished studies, conference abstracts, and letters were included. No restrictions were applied based on language or country, only randomized controlled trials
• Primary outcomes: intraoperative nausea and vomiting, postspinal hypotension
• Secondary outcomes: Apgar scores at 1 and 5 min, umbilical artery pH, the number of rescue vasopressor boluses, and all adverse events
• Included 74 studies (7798 patients) comparing PE and NE administered either via bolus or infusion

Abstract

Purpose: Postspinal hypotension (PSH) during cesarean section (CS) often causes maternal intraoperative nausea and vomiting (IONV) and fetal acidosis. Phenylephrine (PE) and norepinephrine (NE) are commonly used for management; however, the optimal agent and method (bolus vs. infusion) remains uncertain. This review assessed bolus and infusion of PE and NE for IONV and PSH during CS.

Methods: Systematic searches of MEDLINE, Embase, CENTRAL, and unpublished studies identified randomized controlled trials (RCTs) on PE and NE administration during CS under spinal anesthesia. Primary outcomes included IONV and PSH, whereas secondary outcomes encompassed Apgar scores, umbilical artery pH, rescue vasopressor bolus requirements, and adverse events. A random-effects meta-analysis and the Confidence in Network Meta-Analysis tool were utilized.

Results: Among 74 RCTs (7798 patients), NE and PE infusion reduced IONV compared with PE bolus (risk ratio [RR]: 0.47; 95% confidence interval [CI] 0.34-0.66; RR: 0.54; 95% CI 0.42-0.69, high confidence). Similarly, these approaches reduced PSH (NE infusion: RR: 0.25; 95% CI 0.21-0.31, high confidence; PE infusion: RR: 0.29; 95% CI 0.24-0.34, moderate confidence). Rescue vasopressor bolus requirements showed a similar trend. Apgar scores and umbilical artery pH were comparable across all groups. Adverse event varied, with bradycardia more common with PE, tachycardia with boluses, and dizziness with PE bolus. Hypertension was more frequent with infusions. In prophylactic studies, hypotension trends persisted, but no differences were observed in IONV.

Conclusion: Prophylactic continuous infusion appears to be a favorable strategy for managing PSH and IONV during CS. No significant difference was observed between PE and NE infusions in preventing PSH and IONV.

Physiology Refresh

When we perform spinal anesthesia, we're injecting local anesthetic into the subarachnoid space, where it mixes with cerebrospinal fluid and blocks nerve transmission. The key to understanding the resulting hypotension lies in what nerve fibers are affected.

Spinal anesthesia doesn't just block sensory and motor nerves—it also blocks autonomic sympathetic fibers, particularly the preganglionic sympathetic fibers that exit the spinal cord from T1 to L2.

Here's what happens next:

1. Sympathetic Blockade: The most immediate and significant effect is vasodilation due to the blockade of sympathetic tone to the arterioles and venules, especially in the lower extremities and splanchnic circulation. The arterioles lose their vasoconstrictive tone, which causes a drop in systemic vascular resistance (SVR) and venous pooling, decreasing venous return to the heart (preload).
2. Decreased Cardiac Output: The decreased preload means the heart has less volume to pump, so cardiac output drops. This effect is magnified if the sympathetic block extends up to or above T4, where the cardioaccelerator fibers are located. If these are blocked, you can also lose sympathetic input to the heart, leading to bradycardia, which further lowers cardiac output.
3. Resulting Hypotension: The hypotension after spinal anesthesia is primarily due to vasodilation and decreased venous return, leading to reduced cardiac output, and in some cases, compounded by bradycardia from cardioaccelerator fiber blockade.

You’ll often see this drop in blood pressure within minutes after the block is initiated, especially in volume-depleted patients or those with high levels of spinal blockade.

Excerpts

Hypotension following spinal anesthesia during cesarean section (CS) occurs in 62.1–89.7% of cases due to sympathetic blockade and vasodilation.

Persistent hypotension induces maternal intraoperative nausea and vomiting (IONV) and disrupts placental circulation, leading to fetal acidosis

Recent network meta-analyses (NMAs) have demonstrated the superiority of PE and NE over colloid and crystalloid fluids and ephedrine, leading to recommendations for their use

Current guidelines recommend PE as the most suitable agent, but its pure α-adrenergic stimulation can cause bradycardia and decreased cardiac output during both bolus and continuous infusion forms. In contrast, NE, which exhibits both α- and β-adrenergic activity, helps maintain maternal heart rate and has gained attention over the past decade, as its potential as an alternative to PE is suggested in current blood pressure management guidelines

consensus has not been achieved on the optimal vasopressor for managing spinal hypotension during CS

Previous systematic reviews (SRs) and NMAs have primarily focused on comparing different vasopressors, but have not addressed two critical clinical questions: the optimal administration method (bolus vs. continuous infusion) and timing (prophylactic vs. therapeutic)

infusion consistently resulted in lower RRs for IONV and postspinal hypotension compared with bolus administration for both PE and NE, with moderate to high confidence

findings suggest that prophylactic continuous infusion of vasopressors—whether NE or PE—is probably the most effective choice for improving maternal outcomes.

Continuous infusion was found preferable; however, current evidence remains insufficient to determine whether NE or PE is more favorable when administered by infusion.

Both NE and PE boluses yielded similar primary outcomes, with NE performing slightly better in reducing the need for rescue boluses and improving 1 min Apgar scores

PE infusion often required more interventions for bradycardia, and symptoms such as dizziness can be problematic with spinal anesthesia under consciousness.

Following spinal anesthesia, a rapid sympathetic block often causes sudden blood pressure changes, leading to nausea and vomiting

In clinical settings where continuous infusion is not feasible such as in medical institutions in low-resource or low- and middle-income countries, prophylactic bolus administration of either NE or PE is preferable, and continuous infusion could be prioritized, if feasible. However, continuous infusion is impractical in certain countries because of the limited availability of drugs and syringe pumps

In resource-rich settings, NE infusion could be prioritized, with dose–response meta-analysis indicating an effective dose of 0.07 μg/kg/min

Article Link

Citation

Imai E, Kataoka Y, Watanabe J, Okano H, Kamimura Y, Tsuji T, Ogura Y, Kodaira A, Yamazaki T. Norepinephrine vs. phenylephrine for spinal hypotension in cesarean section: a network meta-analysis. J Anesth. 2025 Jun 16. doi: 10.1007/s00540-025-03528-4. Epub ahead of print. PMID: 40522505.