title: Norepinephrine Intermittent Intravenous Boluses to Prevent Hypotension During Spinal Anesthesia for Cesarean Delivery: A Sequential Allocation Dose-Finding Study.
abstract: The use of phenylephrine as the first-line agent for prevention and treatment of maternal hypotension during cesarean delivery (CD) may reduce cardiac output, posing a theoretical risk to mother and fetus. Norepinephrine has been suggested as a potential alternative, because its β-adrenergic effects might result in greater heart rate and cardiac output than phenylephrine. The use of norepinephrine to prevent and treat hypotension during CD is new, and its use as a bolus has not been fully determined in this context. The purpose of this study was to determine the effective norepinephrine dose, when given as intermittent intravenous (IV) boluses, to prevent postspinal hypotension in 90% of women undergoing elective CD (ED90).
  
  
  
  This was a prospective, double-blind sequential allocation dose-finding study, using the biased coin up-and-down design. Forty-term pregnant women undergoing elective CD under spinal anesthesia received a set intermittent norepinephrine bolus of either 3, 4, 5, 6, 7, or 8 µg every time their systolic blood pressure (SBP) fell to below 100% of baseline. The primary outcome was the success of the norepinephrine regimen to maintain SBP at or above 80% of baseline, from induction of spinal anesthesia to delivery of the fetus. Secondary outcomes included nausea, vomiting, hypertension (SBP > 120% of baseline), bradycardia (<50 bpm), upper sensory level of anesthesia to ice cold and umbilical artery and vein blood gases. The ED90 and 95% confidence intervals (CIs) were estimated using both truncated Dixon and Mood and isotonic regression methods.
  
  
  
  The estimated ED90 of norepinephrine was 5.49 µg (95% CI, 5.15-5.83) using the truncated Dixon and Mood method and 5.80 µg (95% CI, 5.01-6.59) using the isotonic regression method.
  
  
  
  The use of intermittent IV norepinephrine boluses to prevent spinal-induced hypotension in elective CD seems feasible and was not observed to be associated with adverse outcomes. Practically, we suggest an ED90 dose of 6 µg. Further work is warranted to elucidate the comparative effects of intermittent IV bolus doses of phenylephrine and norepinephrine, in terms of efficacy and safety.
authors.affiliation: From the *Department of Anesthesia and Pain Management, Mount Sinai Hospital, University of Toronto, Canada; †Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Shatin, Hong Kong; and ‡Maternal-Infant Care Research Centre (MiCare), Mount Sinai Hospital, University of Toronto, Canada.
authors.forename: Desire N
authors.initials: DN
authors.lastname: Onwochei
authors.forename: Warwick D
authors.initials: WD
authors.lastname: Ngan Kee
authors.forename: Lillia
authors.initials: L
authors.lastname: Fung
authors.forename: Kristi
authors.initials: K
authors.lastname: Downey
authors.forename: Xiang Y
authors.initials: XY
authors.lastname: Ye
authors.forename: Jose C A
authors.initials: JCA
authors.lastname: Carvalho
mesh_terms: D061605:Administration, Intravenous; D000328:Adult; D000773:Anesthesia, Obstetrical / Q000009:adverse effects; D000775:Anesthesia, Spinal / Q000009:adverse effects*; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D002585:Cesarean Section / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007022:Hypotension / Q000139:chemically induced / Q000517:prevention & control*; D009638:Norepinephrine / Q000008:administration & dosage*; D010656:Phenylephrine / Q000008:administration & dosage; D011247:Pregnancy; D011256:Pregnancy Outcome; D011446:Prospective Studies; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D013599:Systole / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000008:administration & dosage
chemical_list: D011943:Receptors, Adrenergic, beta; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D009638:Norepinephrine