Comparison of the Efficacy of Low-Concentration Norepinephrine and Ephedrine in the Management of Post-Spinal Hypotension for Cesarean Section: A Prospective Analytical Study
Background: Post-spinal hypotension remains the most formidable complication of spinal anesthesia for cesarean delivery, occurring in 70% - 80% of cases and compromising maternal-fetal safety. While ephedrine has long dominated therapeutic management, growing concerns about fetal acidosis have directed research toward safer alternatives. Norepinephrine emerges as a promising candidate with balanced pharmacological properties. This study compares three approaches: bolus ephedrine, bolus norepinephrine, and prophylactic continuous norepinephrine infusion. Methods: Prospective analytical study including 170 parturients undergoing cesarean delivery under spinal anesthesia at University Hospital Mother and Child Harouchi, Ibn Rochd, Hassan II University (February to June 2025). Computer-generated block randomization with sealed envelope allocation concealment into three balanced groups: Group I (ephedrine 3 - 6 mg bolus, n = 57), Group II (norepinephrine 8 - 16 μg bolus, n = 56), Group III (prophylactic continuous norepinephrine infusion 5 μg/kg, n = 57). Sample size calculated a priori for 80% power to detect a 20% difference in efficacy with α = 0.05. Baseline blood pressure is defined as the mean of three measurements after a 10-minute rest. Hemodynamic evaluation at four operative time points. Primary endpoint: hypotension correction efficacy (restoration of SBP > 80% baseline values within 5 minutes of first vasopressor administration). Secondary endpoints: hemodynamic stability, maternal tolerance, neonatal adaptation. Results: Baseline hemodynamic parameters were equivalent among groups (p > 0.05), confirming successful randomization. Highly significant hemodynamic differences between groups during intervention. Group II: fastest blood pressure recovery (SBP 126.2 mmHg ± 1.3 mmHg at T2 vs 80.5 mmHg ± 3.8 mmHg Group I, p < 0.001), optimal cardiac stability (HR 87.5 bpm ± 4.7 bpm vs 133.7 bpm ± 6.3 bpm Group I, p < 0.001). Group III: effective prevention of severe hypotension (MAP maintained at 82.9 mmHg ± 10.6 mmHg at T1) but inter-individual variability requiring supplemental ephedrine (20% of cases). Therapeutic efficacy: 94% (Group III), 89% (Group II), 68% (Group I), p < 0.001. Comparable Apgar scores, superior maternal satisfaction with norepinephrine (p < 0.001). No catecholamine-related arrhythmias are observed during continuous cardiac monitoring. Conclusion: Norepinephrine demonstrates clear superiority over ephedrine in
References
[1]
Bier, A. (1899) Versuche über Cocainisirung des Rückenmarkes. Deutsche Zeitschrift für Chirurgie, 51, 361-369. https://doi.org/10.1007/bf02792160
[2]
Braun, H. (1905) Ueber einige neue örtliche Anaesthetica (Stovain, Alypin, Novocain). DMW—Deutsche Medizinische Wochenschrift, 31, 1667-1671. https://doi.org/10.1055/s-0029-1188398
[3]
Löfgren, N. and Lundqvist, B. (1943) Studies on Local Anesthetics II: Xylocaine, a New Synthetic Drug. Swedish Dental Journal, 36, 252-270.
[4]
af Ekenstam, B., Egnér, B. and Pettersson, G. (1957) Local Anesthetics I. N-Alkyl Pyrrolidine and N-Alkyl Piperidine Carboxylic Acid Amides. Acta Chemica Scandinavica, 11, 1183-1190. https://doi.org/10.3891/acta.chem.scand.11-1183
[5]
Afolabi, B.B., Lesi, F.E. and Merah, N.A. (2006) Regional versus General Anaesthesia for Caesarean Section. Cochrane Database of Systematic Reviews, No. 4, CD004350.
[6]
Klöhr, S., Roth, R., Hofmann, T., Rossaint, R. and Heesen, M. (2010) Definitions of Hypotension after Spinal Anaesthesia for Caesarean Section: Literature Search and Application to Parturients. Acta Anaesthesiologica Scandinavica, 54, 909-921. https://doi.org/10.1111/j.1399-6576.2010.02239.x
[7]
Ueland, K., Novy, M.J., Peterson, E.N. and Metcalfe, J. (1969) Maternal Cardiovascular Dynamics. IV. The Influence of Gestational Age on the Maternal Cardiovascular Response to Posture and Exercise. American Journal of Obstetrics and Gynecology, 104, 856-864. https://doi.org/10.1016/0002-9378(69)90637-1
[8]
Datta, S., Alper, M.H., Ohtheimer, G.W. and Weiss, J.B. (1982) Method of Ephedrine Administration and Nausea and Hypotension during Spinal Anesthesia for Cesarean Section. Anesthesiology, 56, 68-69. https://doi.org/10.1097/00000542-198201000-00019
[9]
Robson, S.C., Hunter, S., Boys, R.J. and Dunlop, W. (1989) Serial Study of Factors Influencing Changes in Cardiac Output during Human Pregnancy. American Journal of Physiology-Heart and Circulatory Physiology, 256, H1060-H1065. https://doi.org/10.1152/ajpheart.1989.256.4.h1060
[10]
Ralston, D.H., Shnider, S.M. and deLorimier, A.A. (1974) Effects of Equipotent Ephedrine, Metaraminol, Mephentermine, and Methoxamine on Uterine Blood Flow in the Pregnant Ewe. Anesthesiology, 40, 354-370. https://doi.org/10.1097/00000542-197404000-00009
[11]
Cyna, A.M., Andrew, M., Emmett, R.S., Middleton, P. and Simmons, S.W. (2006) Techniques for Preventing Hypotension during Spinal Anaesthesia for Caesarean Section. Cochrane Database of Systematic Reviews, No. 4, CD002251.
[12]
Butterworth, J.F. and Strichartz, G.R. (1990) Molecular Mechanisms of Local Anesthesia. Anesthesiology, 72, 711-734. https://doi.org/10.1097/00000542-199004000-00022
[13]
Cooper, D.W., Carpenter, M., Mowbray, P., Desira, W.R., Ryall, D.M. and Kokri, M.S. (2002) Fetal and Maternal Effects of Phenylephrine and Ephedrine during Spinal Anesthesia for Cesarean Delivery. Anesthesiology, 97, 1582-1590. https://doi.org/10.1097/00000542-200212000-00034
[14]
Lee, A., Ngan Kee, W.D. and Gin, T. (2002) A Quantitative, Systematic Review of Randomized Controlled Trials of Ephedrine versus Phenylephrine for the Management of Hypotension during Spinal Anesthesia for Cesarean Delivery. Anesthesia & Analgesia, 94, 920-926. https://doi.org/10.1097/00000539-200204000-00028
[15]
Westfall, T.C. and Westfall, D.P. (2011) Adrenergic Agonists and Antagonists. In: Brunton, L.L., Chabner, B.A. and Knollmann, B.C., Eds., Goodman & Gilman’s the Pharmacological Basis of Therapeutics (12th edition), McGraw-Hill, 277-333.
[16]
Ngan Kee, W.D., Lee, S.W.Y., Ng, F.F., Tan, P.E. and Khaw, K.S. (2015) Randomized Double-Blinded Comparison of Norepinephrine and Phenylephrine for Maintenance of Blood Pressure during Spinal Anesthesia for Cesarean Delivery. Anesthesiology, 122, 736-745. https://doi.org/10.1097/aln.0000000000000601
[17]
Mohta, M., Janani, S.S., Sethi, A.K., Agarwal, D. and Tyagi, A. (2016) Comparison of Phenylephrine Hydrochloride and Norepinephrine Bitartrate for the Management of Hypotension during Spinal Anaesthesia for Caesarean Section. Anaesthesia, 71, 780-787.
[18]
Zhang, L., Wang, Y., Chen, S., et al. (2024) Norepinephrine versus Ephedrine and Phenylephrine for the Management of Maternal Hypotension during Cesarean Delivery under Spinal Anesthesia: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials. Journal of Clinical Anesthesia, 92, Article ID: 111298.
[19]
Hasanin, A.M., Amin, S.M., Agiza, N.A., Elsayed, M.K., Refaat, S., Hussein, H.A., et al. (2019) Norepinephrine Infusion for Preventing Postspinal Anesthesia Hypotension during Cesarean Delivery: A Randomized Dose-Finding Trial. Anesthesiology, 130, 55-62. https://doi.org/10.1097/aln.0000000000002483
[20]
Wang, X., Shen, B., Zhang, A., et al. (2020) Norepinephrine versus Phenylephrine for the Management of Maternal Hypotension during Cesarean Delivery under Spinal Anesthesia: A Systematic Review and Meta-Analysis. Journal of Clinical Anesthesia, 62, Article ID: 109717.
[21]
Ngan Kee, W.D., Khaw, K.S., Ng, F.F. and Lee, B.B. (2008) Prophylactic Phenylephrine Infusion for Preventing Hypotension during Spinal Anesthesia for Cesarean Delivery. Anesthesia & Analgesia, 107, 1921-1926.
[22]
Stewart, A., Fernando, R., McDonald, S., Hignett, R., Jones, T. and Columb, M. (2010) The Dose-Dependent Effects of Phenylephrine for Elective Cesarean Delivery under Spinal Anesthesia. Anesthesia & Analgesia, 111, 1230-1237. https://doi.org/10.1213/ane.0b013e3181f2eae1
[23]
Hasanin, A.M., Amin, S.M., Agiza, N.A., et al. (2019) Norepinephrine versus Phenylephrine Infusion for Prophylaxis against Post-Spinal Anaesthesia Hypotension during Elective Caesarean Delivery: A Randomised Controlled Trial. Anaesthesia, 74, 27-33.
[24]
Wang, M., Zhuo, L., Wang, Q., et al. (2020) Efficacy of Prophylactic Norepinephrine and Phenylephrine Infusions for Preventing Maternal Hypotension during Cesarean Delivery under Spinal Anesthesia: A Randomized Clinical Trial. JAMA Network Open, 3, e1919896.
[25]
Singh, P.M., Singh, N.P., Reschke, M., Ngan Kee, W.D. and Siddik-Sayyid, S.M. (2021) Vasopressor Drugs for the Prevention and Treatment of Hypotension during Neuraxial Anaesthesia for Caesarean Delivery: A Bayesian Network Meta-Analysis of Fetal and Maternal Outcomes. British Journal of Anaesthesia, 127, 792-801.
[26]
Chen, D., Xu, J., Wang, L., et al. (2022) Comparison of Norepinephrine, Phenylephrine, and Ephedrine for Maternal Hypotension during Cesarean Section under Spinal Anesthesia: A Network Meta-Analysis. International Journal of Surgery, 104, Article ID: 106741.
[27]
Martinez, R., Garcia-Lopez, C., Sanchez-Pedrosa, G., et al. (2023) Prophylactic versus Therapeutic Administration of Norepinephrine for Spinal Hypotension during Cesarean Delivery: A Randomized Controlled Trial. European Journal of AnaesthesioLogy, 40, 245-252.
[28]
Thompson, K.J., Milligan, K.R., Quinn, A.C., et al. (2023) Multi-Center Comparison of Vasopressor Choice for Cesarean Delivery under Spinal Anesthesia: A Pragmatic Randomized Trial. Anesthesia & Analgesia, 136, 512-520.
[29]
Liu, S.S., Chen, Y.H., Wang, J.F., et al. (2024) Cost-Effectiveness Analysis of Norepinephrine versus Phenylephrine for Cesarean Delivery under Spinal Anesthesia. Health Economics Review, 14, 15.
[30]
Hoffman, B.B. (2001) Catecholamines, Sympathomimetic Drugs, and Adrenergic Receptor Antagonists. In: Hardman, J.G. and Limbird, L.E., Eds., Goodman & Gilman’s The Pharmacological Basis of Therapeutics (10th Edition), McGraw-Hill, 215-268.
[31]
Brodde, O. and Michel, M.C. (1999) Adrenergic and Muscarinic Receptors in the Human Heart. Pharmacological Reviews, 51, 651-689. https://doi.org/10.1016/s0031-6997(24)01425-x
[32]
Reynolds, F. and Seed, P.T. (2005) Anaesthesia for Caesarean Section and Neonatal Acid-Base Status: A Meta-Analysis. Anaesthesia, 60, 636-653. https://doi.org/10.1111/j.1365-2044.2005.04223.x
[33]
Mercier, F.J., Riley, E.T., Frederickson, W.L., Roger-Christoph, S., Benhamou, D. and Cohen, S.E. (2001) Phenylephrine Added to Prophylactic Ephedrine Infusion during Spinal Anesthesia for Elective Cesarean Section. Anesthesiology, 95, 668-674. https://doi.org/10.1097/00000542-200109000-00020
[34]
Langesæter, E., Rosseland, L.A. and Stubhaug, A. (2008) Continuous Invasive Blood Pressure and Cardiac Output Monitoring during Cesarean Delivery: A Randomized, Double-Blind Comparison of Low-Dose versus High-Dose Spinal Bupivacaine with Fentanyl. Anesthesiology, 109, 856-863. https://doi.org/10.1097/aln.0b013e31818a401f
[35]
Carvalho, B. and Dyer, R.A. (2015) Norepinephrine for Spinal Hypotension during Cesarean Delivery: Another Paradigm Shift? Anesthesiology, 122, 728-730. https://doi.org/10.1097/aln.0000000000000602
[36]
Sharkey, A.M., Siddik-Sayyid, S.M., Bou-Diab, M., Aouad, M.T. and Taha, S.K. (2019) Comparison of Intermittent Intravenous Boluses of Phenylephrine and Norepinephrine to Prevent Spinal Hypotension during Caesarean Section: A Randomised Controlled Trial. Anaesthesia, 74, 1553-1560.
[37]
Fu, F., Xiao, F., Chen, W., et al. (2020) A Randomised Double-Blind Dose-Response Study of Weight-Adjusted Infusions of Norepinephrine for Preventing Hypotension during Combined Spinal-Epidural Anaesthesia for Caesarean Delivery. Anaesthesia, 75, 1589-1595.
[38]
Heesen, M., Klöhr, S., Rossaint, R. and Straube, S. (2013) Prophylactic Phenylephrine for Caesarean Section under Spinal Anaesthesia: Systematic Review and Meta‐Analysis. Anaesthesia, 69, 143-165. https://doi.org/10.1111/anae.12445
