Carbetocin at elective Cesarean delivery: a randomized controlled trial to determine the effective dose

Abstract

Purpose The primary objective of our study was to determine the minimum intravenous dose of carbetocin required to produce adequate uterine contraction in 95% of women (effective dose [ED] 95 ) undergoing elective Cesarean delivery (CD). Methods Eighty term pregnant women with low risk for postpartum hemorrhage (PPH) undergoing elective CD under spinal anesthesia were randomly allocated to receive carbetocin intravenously in doses of 80 lg, 90 lg, 100 lg, 110 lg, or 120 lg upon delivery. The consultant obstetrician evaluated the efficacy of the patient's uterine tone as satisfactory or unsatisfactory. In case of unsatisfactory uterine tone, additional uterotonics were administered as per routine institutional practice. Side effects were monitored during the study period. The main outcome measure was satisfactory uterine tone at two minutes after carbetocin administration. Results Satisfactory uterine tone was obtained in 70 subjects (87%) within the dose range of 80-120 lg of carbetocin. It was not possible to calculate the ED 95 of carbetocin due to the even distribution of women with satisfactory uterine tone across all dose groups (P = 0.99). Similarly, the side effects were similar across all dose groups. There was a high overall incidence of hypotension (55%) following the administration of carbetocin.Conclusions In women at low risk for PPH undergoing elective CD, carbetocin doses of 80-120 lg are similarly effective. There is a high incidence of hypotension associated with carbetocin in these doses, and further studies with doses lower than 80 lg are warranted to assess the balance of efficacy and side effects. This trial was registered at www.clinicaltrials.gov (NCT01262742). RésuméObjectif L'objectif principal de notre e´tude e´tait de de´terminer la dose intraveineuse minimum de carbe´tocine ne´cessaire pour obtenir une contraction ute´rine approprie´e chez 95 % des femmes (dose efficace [DE] 95 ) subissant une ce´sarienne programme´e. Méthodes Quatre-vingts femmes enceintes a`terme ayant un faible risque d'he´morragie du postpartum subissant une ce´sarienne programme´e sous rachianesthe´sie ont e´teŕ andomise´es pour recevoir des doses intraveineuses de 80 lg, 90 lg, 100 lg, 110 lg ou 120 lg de carbe´tocine au moment de l'accouchement. L'obste´tricien a e´valueĺ 'efficacite´du tonus ute´rin de la patiente comme satisfaisant ou non satisfaisant. En cas de tonus ute´rin non satisfaisant, des me´dicaments ute´rotoniques supple´mentaires ont e´teá dministre´s conforme´ment aux pratiques habituelles de l'e´tablissement. Les effets inde´sirables ont e´te´surveille´s pendant la dure´e de l'e´tude. Le crite`re de jugement principal a éte´un tonus ute´rin satisfaisant deux minutes apre`s l'administration de carbe´tocine.

Carbetocin at elective Cesarean delivery: a randomized controlled trial to determine the effective dose, part 2

“…The overall incidence of effective uterine contraction was 87%, and we observed no significant differences in the response rate across the studied groups. 8 Furthermore, we did not observe significant differences in blood loss across the studied groups. The overall incidence of hypotension associated with the use of carbetocin was high at 55%, and this was also similar across all groups.…”

“…The incidence of hypotension in this study (42.5%) was high and similar to that observed by Cordovani et al (55%). 8 The amount of phenylephrine used as well as the incidence of nausea and vomiting did not vary across the studied groups, suggesting that the hemodynamic consequences of carbetocin are similar in this dose range. It is unclear whether reducing the administered dose of carbetocin may further reduce the incidence of this unwanted effect; therefore, further studies are warranted.…”

“…9 Sample size was calculated based on finding the clinically effective dose-defined as the dose required to achieve effective uterine tone in 95% of treated individuals (ED 95 )-using the methods derived by Bretz et al for dose-finding studies. 10 Data on 80 subjects from our previous study 8 showing an 87.5% response with carbetocin doses from 80-120 lg were used to inform the sample size calculation. Using data from Cordovani et al 8 and from Ferring Pharmaceutics (unpublished data on 18 women undergoing elective Cesarean delivery wherein none had effective uterine contractions with doses below 60 lg, and 83% [five out of six] developed adequate uterine tone after receiving a dose of 100 lg), a simple logistic dose-response curve was deemed the most likely model out of several candidate curves.…”

“…10 Data on 80 subjects from our previous study 8 showing an 87.5% response with carbetocin doses from 80-120 lg were used to inform the sample size calculation. Using data from Cordovani et al 8 and from Ferring Pharmaceutics (unpublished data on 18 women undergoing elective Cesarean delivery wherein none had effective uterine contractions with doses below 60 lg, and 83% [five out of six] developed adequate uterine tone after receiving a dose of 100 lg), a simple logistic dose-response curve was deemed the most likely model out of several candidate curves. Additionally, a twotailed type I error of 0.05 and a type II error of 0.10 (i.e., power of 90%) were assumed.…”

Carbetocin at Cesarean delivery for labour arrest: a sequential allocation trial to determine the effective dose

“…As the current evidence for this recommended dose is weak, 11 our group conducted a series of dose-finding studies of carbetocin in women undergoing elective CD. [12][13][14] We initially conducted two randomized controlled trials using doses of 80-120 lg and 20-100 lg and found satisfactory uterine response in 87% and 94% of patients, respectively. Since successful treatment was evenly distributed across all study groups, we could not plot a dose-response curve or estimate the effective dose 90% (ED 90 ).…”