Determination of the 90% Effective Dose of the Initial Bolus of Norepinephrine Followed by a Continuous Infusion to Prevent Hypotension in Elective Cesarean Delivery: A Randomized, Double-Blind, Up-Down Study

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Abstract

BACKGROUND: Postspinal arterial hypotension is frequent during cesarean delivery and may compromise uteroplacental perfusion, leading to adverse maternal and fetal outcomes. Norepinephrine has a favorable hemodynamic and safety profile and is increasingly used, especially in women with limited cardiovascular reserve. Although effective infusion regimens have been described, there is limited literature describing the optimal initial prophylactic bolus dose. This study aimed to determine the effective dose in 90% of patients (ED90) for a norepinephrine bolus followed by infusion to prevent hypotension during elective cesarean delivery under spinal anesthesia. METHODS: In this randomized, double-blind trial, full-term women (American Society of Anesthesiologists [ASA] physical status II-III, 18-40 years, singleton pregnancies) undergoing elective cesarean delivery received standardized spinal anesthesia and monitoring. Patients were randomized to starting bolus doses of 0.13 or 0.15 µg kg-1 norepinephrine, followed by a continuous infusion at 0.05 µg kg-1 min-1 titrated to hemodynamic response. Blood pressure and heart rate were recorded every minute until delivery. The primary endpoint was systolic hypotension, defined as systolic blood pressure <80% of baseline within 10 minutes of spinal anesthesia. The ED90 was determined using the up-and-down k-in-a-row method, with dose adjustments based on patient response. Secondary outcomes included Apgar scores, blood gases, neonatal glycemia, adverse maternal events, and hemodynamic changes. Sequence and norepinephrine dose effects were analyzed using exact logistic regression. ED90 was estimated using Firth logistic regression with a sensitivity analysis using centered isotonic regression. RESULTS: Sixty-one patients were enrolled; one was excluded due to a protocol violation.. Dose-dependency was significant (P = .034) with no effect of randomized sequence (P = 1.00). Dosing was effective in n = 54 (90.0%; 95% confidence interval [CI], 79.9-95.3), consistent with the k-in-a-row method. Effective rates for dosing at 0.13, 0.15, 0.17 and 0.19 µg kg-1 were monotonic at 60.0%, 87.0%, 96.0%, and 100.0%, respectively (P = .019, chi-square trend). The ED90 for prophylactic norepinephrine bolus was 0.157 μg kg-1 (95% CI, 0.142-0.172) using Firth logistic regression and 0.157 μg kg-1 (95% CI, 0.130-0.173) using centered isotonic regression. There were six cases of hypotension (12.2%), 10 cases of transient hypertension (8.2%), six cases of nausea (10%), two cases of vomiting (3.3%), and one case of severe neonatal hypoglycemia (1.7%) without clinical manifestations. CONCLUSIONS: An initial norepinephrine bolus of approximately 0.16 µg kg-1, followed by an infusion, appears effective in preventing postspinal hypotension during elective cesarean delivery and is associated with a low incidence of adverse events.

Abstract as published, via PubMed.