title: Carbetocin at Cesarean delivery for labour arrest: a sequential allocation trial to determine the effective dose.
abstract: OBJECTIVE
  The aim of this study was to estimate the effective dose 90% (ED90) of carbetocin to provide adequate uterine tone at Cesarean delivery (CD) for labour arrest.
  
  
  METHODS
  We conducted a double-blind dose-finding study of carbetocin using a biased-coin up-and-down design in women undergoing CD for labour arrest under epidural anesthesia. Forty healthy term pregnant women who had received at least three hours of oxytocin infusion during labour were recruited for the study. Carbetocin was administered intravenously upon delivery of the anterior shoulder of the fetus. The first patient received 20 µg, and the dose for the subsequent patient was determined according to the response of the previous patient as per the biased-coin allocation scheme using increments or decrements of 20 µg (maximum 140 µg). Uterine tone was assessed by the obstetrician and rated as satisfactory or unsatisfactory throughout the intraoperative period. The primary outcome was satisfactory uterine tone with no need for additional uterotonic drugs intraoperatively. Secondary outcomes included use of additional uterotonic drugs postoperatively in the first 24 hr, estimated blood loss, and adverse effects.
  
  
  RESULTS
  The ED90 of carbetocin to produce adequate uterine tone was estimated at 121 µg (95% confidence interval [CI]: 111 to 130; 99% CI: 108 to 133) using the truncated Dixon and Mood (DM) method. The isotonic estimator of ED90 was 140 µg; however, the observed response rate across all doses was < 90%. Also, the 95% CI of the DM estimator is likely to have lower than expected coverage, while the 99% CI may have about 90% coverage. Therefore, these results should be interpreted with caution. The overall median (range) estimated blood loss was 1,014 (104-2,436) mL. The overall incidence of hypotension and tachycardia were 45% and 57.5%, respectively. At a dose of 140 µg, the incidence of tachycardia and intraoperative arrhythmias was 76% and 14%, respectively.
  
  
  CONCLUSIONS
  The ED90 of carbetocin at CD for labour arrest, as determined in our study, should be interpreted with caution since it may be underestimated. This dose is higher than the currently recommended dose of 100 µg at elective CD and should not be used routinely given the uncertainty regarding its efficacy and the high incidence of arrhythmias at higher doses. This trial was registered at ClinicalTrials.gov, number: NCT01725243.
authors: Department of Anesthesia and Pain Management, Mount Sinai Hospital, University of Toronto, 600 University Avenue, Room 19-104, Toronto, ON, M5G 1X5, Canada.
authors: Nhathien
authors: N
authors: Nguyen-Lu
authors: Jose Carlos Almeida
authors: JC
authors: Carvalho
authors: Dan
authors: D
authors: Farine
authors: Gareth
authors: G
authors: Seaward
authors: Xiang Y
authors: XY
authors: Ye
authors: Mrinalini
authors: M
authors: Balki
mesh_terms: D000293:Adolescent; D000328:Adult; D000767:Anesthesia, Epidural; D000773:Anesthesia, Obstetrical; D002585:Cesarean Section / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007743:Labor, Obstetric / Q000187:drug effects*; D008875:Middle Aged; D009123:Muscle Hypotonia / Q000188:drug therapy; D007744:Obstetric Labor Complications / Q000188:drug therapy*; D010120:Oxytocics / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D010121:Oxytocin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011247:Pregnancy; D014599:Uterus / Q000187:drug effects; D055815:Young Adult
chemical_list: D010120:Oxytocics; D010121:Oxytocin; C020731:carbetocin