Top

Canadian Journal of Anesthesia/Journal canadien d'anesthésie

Published in:

01-03-2014 | Reports of Original Investigations

Carbetocin at elective Cesarean delivery: a sequential allocation trial to determine the minimum effective dose

Authors: Mubeen Khan, MD, Mrinalini Balki, MD, Iram Ahmed, MD, Dan Farine, MD, Gareth Seaward, MD, Jose C. A. Carvalho, MD, PhD

Published in: Canadian Journal of Anesthesia/Journal canadien d'anesthésie | Issue 3/2014

Abstract

Purpose

The purpose of this study was to determine the intravenous dose of carbetocin required to produce effective uterine contraction in 90% of females (ED₉₀) undergoing elective Cesarean delivery (CD) under spinal anesthesia.

Methods

We conducted a double-blind dose-finding study of carbetocin. Forty females undergoing elective CD received carbetocin intravenously upon delivery of the fetus. The dose of carbetocin for each patient was determined according to a biased-coin up-and-down sequential allocation scheme designed to cluster doses close to ED₉₀. The initial dose was 10 μg, with increments/decrements of 5 μg. The anesthesiologist, obstetrician, and patient were blinded to the dose. The obstetrician assessed the uterine tone at one-minute intervals for five minutes after carbetocin administration. In case of unsatisfactory tone, additional uterotonics were administered. The primary outcome was requirement for additional intraoperative uterotonics. Secondary outcomes were postoperative requirement for additional uterotonics within 24 hr of delivery, estimated blood loss and side effects.

Results

The ED₉₀ of carbetocin was 14.8 μg (95% confidence interval 13.7 to 15.8). Thirty-seven patients (92.5%) had adequate uterine tone with no requirement of additional intraoperative uterotonics. Two patients (5%) required postoperative uterotonics within 24 hr. The overall mean (SD) estimated blood loss was 786 (403) mL and the overall incidence of hypotension (decrease in systolic blood pressure ≥ 20% baseline) was 37.5%.

Conclusion

Based on our study, the ED₉₀ of carbetocin at elective CD is less than one-fifth the currently recommended dose of 100 μg. This study was registered at clinicaltrials.gov (NCT-01651130).

Stylianou M. Sequential Analysis of Durham and Flournoy’s Biased Coin Design for Phase I Clinical Trials. Washington, DC, American University, Department of Mathematics and Statistics, College of Arts and Sciences; 2000: i-xiii, 1-178.

Joseph KS, Rouleau J, Kramer MS, et al. Investigation of an increase in postpartum haemorrhage in Canada. BJOG 2007; 114: 751-9.PubMedCrossRef

Callaghan WM, Kuklina EV, Berg CJ. Trends in postpartum hemorrhage: United States, 1994-2006. Am J Obstet Gynecol 2010; 202: 353.e1-6.

World Health Organization. WHO recommendations for the prevention and treatment of postpartum haemorrhage. Geneva: WHO; 2012 Available from: http://apps.who.int/iris/bitstream/10665/75411/1/9789241548502_eng.pdf (accessed October 2013).

Nordstrom L, Fogelstam K, Fridman G, Larsson A, Rydhstroem H. Routine oxytocin in the third stage of labour: a placebo controlled randomised trial. Br J Obstet Gynaecol 1997; 104: 781-6.PubMedCrossRef

Ryden G, Sjoholm I. Half-life of oxytocin in blood of pregnant and non-pregnant women. Acta Endocrinol (Copenh) 1969; 61: 425-31.

Chard T, Boyd NR, Forsling ML, McNeilly AS, Landon J. The development of a radioimmunoassay for oxytocin: the extraction of oxytocin from plasma, and its measurement during parturition in human and goat blood. J Endocrinol 1970; 48: 223-34.PubMedCrossRef

Dyer RA, Butwick AJ, Carvalho B. Oxytocin for labour and caesarean delivery: implications for the anaesthesiologist. Curr Opin in Anaesthesiol 2011; 24: 255-61.CrossRef

Dansereau J, Joshi AK, Helewa ME, et al. Double-blind comparison of carbetocin versus oxytocin in prevention of uterine atony after cesarean section. Am J Obstet Gynecol 1999; 180(3 Pt 1): 670-6.PubMedCrossRef

Svanstrom MC, Biber B, Hanes M, Johansson G, Naslund U, Balfors EM. Signs of myocardial ischaemia after injection of oxytocin: a randomized double-blind comparison of oxytocin and methylergometrine during caesarean section. Br J Anaesth 2008; 100: 683-9.PubMedCrossRef

10.

Engstrom T, Barth T, Melin P, Vilhardt H. Oxytocin receptor binding and uterotonic activity of carbetocin and its metabolites following enzymatic degradation. Eur J Pharmacol 1998; 355: 203-10.PubMedCrossRef

11.

Sweeney G, Holbrook AM, Levine M, et al. Pharmacokinetics of carbetocin, a long-acting oxytocin analogue, in nonpregnant women. Curr Ther Res 1990; 47: 528-40.

12.

Attilakos G, Psaroudakis D, Ash J, et al. Carbetocin versus oxytocin for the prevention of postpartum haemorrhage following caesarean section: the results of a double-blind randomised trial. BJOG 2010; 117: 929-36.PubMedCrossRef

13.

Borruto F, Treisser A, Comparetto C. Utilization of carbetocin for prevention of postpartum hemorrhage after cesarean section: a randomized clinical trial. Arch Gynecol Obstet 2009; 280: 707-12.PubMedCrossRef

14.

Su LL, Chong YS, Samuel M. Carbetocin for preventing postpartum haemorrhage. Cochrane Database Syst Rev 2012; 4: CD005457.

15.

Leduc D, Senikas V, Lalonde AB, et al. Active management of the third stage of labour: prevention and treatment of postpartum hemorrhage. J Obstet Gynaecol Can 2009; 31: 980-93.PubMed

16.

Cordovani D, Balki M, Farine D, Seaward G, Carvalho JC. Carbetocin at elective cesarean delivery: a randomized controlled trial to determine the effective dose. Can J Anesth 2012; 59: 751-7.PubMedCrossRef

17.

Anandakrishnan S, Balki M, Farine D, Seaward G, Carvalho JC. Carbetocin at elective cesarean delivery: a randomized controlled trial to determine the effective dose, part 2. Can J Anesth 2013; . DOI:10.1007/s12630-013-0028-2.PubMed

18.

Carvalho JC, Balki M, Kingdom J, Windrim R. Oxytocin requirements at elective cesarean delivery: a dose finding study. Obstet Gynecol 2004; 104: 1005-10.PubMedCrossRef

19.

Balki M, Ronayne M, Davies S, et al. Minimum oxytocin dose requirement after cesarean delivery for labor arrest. Obstet Gynecol 2006; 107: 45-50.PubMedCrossRef

20.

Shook PR, Schultz JR, Reynolds JD, Barbara P, Spahn TE, DeBalli P. Estimating blood loss for cesarean section – how accurate are we? Anesthesiology 2003; 98(Supp 1): SOAP A2 (abstract).

21.

Pace NL, Stylianou MP. Advances in and limitations of up-and-down methodology: a précis of clinical use, study design, and dose estimation in anesthesia research. Anesthesiology 2007; 107: 144-52.PubMedCrossRef

22.

Stylianou M, Flournoy N. Dose finding using the biased coin up-and-down design and isotonic regression. Biometrics 2002; 58: 171-7.PubMedCrossRef

23.

Butwick AJ, Coleman L, Cohen SE, Riley ET, Carvalho B. Minimum effective bolus dose of oxytocin during elective caesarean delivery. Br J Anaesth 2010; 104: 338-43.PubMedCrossRef

24.

Hunter DJ, Schulz P, Wassenaar W. Effect of carbetocin, a long acting oxytocin analogue on the postpartum uterus. Clin Pharmacol Ther 1992; 52: 60-7.PubMedCrossRef

25.

Atke A, Vilhardt H. Uterotonic activity and myometrial receptor affinity of 1-deamino-1-carba-2-tyrosine(O-methyl)-oxytocin. Acta Endocrinol (Copenh) 1987; 115: 155-60.

26.

Kimura T, Tanizawa O, Mori K, Brownstein MJ, Okayama H. Structure and expression of a human oxytocin receptor. Nature 1992; 356: 526-9.PubMedCrossRef

27.

Peters NC, Duvekot JJ. Carbetocin for the prevention of postpartum hemorrhage: a systematic review. Obstet Gynecol Surv 2009; 64: 129-35.PubMedCrossRef

28.

Boucher M, Horbray GL, Griffin P, et al. Double-blind, randomized comparison of the effect of carbetocin and oxytocin on intraoperative blood loss and uterine tone of patients undergoing cesarean section. J Perinatol 1998; 18: 202-7.PubMed

Title: Carbetocin at elective Cesarean delivery: a sequential allocation trial to determine the minimum effective dose
Authors: Mubeen Khan, MD
Mrinalini Balki, MD
Iram Ahmed, MD
Dan Farine, MD
Gareth Seaward, MD
Jose C. A. Carvalho, MD, PhD
Publication date: 01-03-2014
Publisher: Springer US
Published in: Canadian Journal of Anesthesia/Journal canadien d'anesthésie / Issue 3/2014
Print ISSN: 0832-610X
Electronic ISSN: 1496-8975
DOI: https://doi.org/10.1007/s12630-013-0082-9

At a glance: The STEP trials

Springer Medicine

Carbetocin at elective Cesarean delivery: a sequential allocation trial to determine the minimum effective dose

Abstract

Purpose

Methods

Results

Conclusion

At a glance: The STEP trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 3/2014

The sensory thalamus and cerebral motor cortex are affected concurrently during induction of anesthesia with propofol: a case series with intracranial electroencephalogram recordings

Pharmacology and Physiology for Anesthesia: Foundations and Clinical Application

The off-label utilization of prothrombin complex concentrate with cryoprecipitate as an alternative to plasma transfusion in bleeding patients with acute right ventricular failure

Are we meeting nutritional targets for critically ill patients?

Estimation of equivalent threshold currents using different pulse widths for the epidural stimulation test in a porcine model

Special article: Horace Nelson MD, John Webster LDS - unrecognized Canadian anesthesia pioneers