Oxytocin Dosing and Uterotonic Escalation

Postpartum hemorrhage causes a quarter of global maternal deaths. The World Health Organization recommends oxytocin as the first line agent to prevent hemorrhage during cesarean delivery. However, some randomized controlled trials suggest that other uterotonics are superior. We conducted a network meta-analysis comparing the ability of pharmacologic agents to reduce blood loss and minimize the need for additional uterotonics during cesarean delivery. We searched the Cochrane Central Register of Controlled Trials, Embase, and MEDLINE databases from inception to May 2020. We included randomized controlled trials that compared oxytocin, carbetocin, misoprostol, ergometrine, carboprost, or combinations of these in the prevention of postpartum hemorrhage during cesarean delivery. We performed a systematic review followed by an NMA in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Quality of the evidence was assessed with the Confidence in Network Meta-Analysis approach and Grading of Recommendations, Assessment, Development and Evaluations tool within the summary of findings table. Our primary outcomes were the estimated blood loss and need for additional uterotonics. Secondary outcomes included nausea and postpartum hemorrhage of >1000 mL. We performed sensitivity analyses to explore the influence of surgical context and oxytocin administration strategy. A total of 46 studies with 7368 participants were included. Of those, 21 trials (6 agents and 3665 participants) formed the "estimated blood loss" network and, considering the treatment effects, certainty in the evidence, and surface under the cumulative ranking curve scores, carbetocin was assessed to probably be superior to oxytocin, but only in reducing the estimated blood loss by a clinically insignificant volume (54.83 mL; 95% confidence interval, 26.48-143.78). Misoprostol, ergometrine, and the combination of oxytocin and ergometrine were assessed to probably be inferior, whereas the combination of oxytocin and misoprostol was assessed to definitely be inferior to oxytocin. A total of 37 trials (8 agents and 6193 participants) formed the "additional uterotonic" network and, again, carbetocin was assessed to probably be superior to oxytocin, requiring additional uterotonics 185 (95% confidence interval, 130-218) fewer times per 1000 cases. Oxytocin plus misoprostol, oxytocin plus ergometrine, and misoprostol were assessed to probably be inferior, whereas carboprost, ergometrine, and the placebo were definitely inferior to oxytocin. For both primary outcomes, oxytocin administration strategies had a higher probability of being the best uterotonic, if initiated as a bolus. Carbetocin is probably the most effective agent in reducing blood loss and the need for additional uterotonics. Oxytocin appears to be more effective when initiated as a bolus.

This study sought to compare postpartum blood loss and maternal outcomes after 3IU and 5IU oxytocin at elective caesarean delivery. In a prospective observational study, 73 women undergoing elective caesarean delivery under spinal anaesthetic received a slow I.V. injection of either 3IU (n = 35) or 5IU (n = 38) oxytocin after delivery. The main outcome was gravimetrically measured 24-hour postpartum blood loss with a non-inferiority margin of 300 mL. Uterine tone, phenylephrine dose, emesis and hypotension after oxytocin administration were secondary outcomes. Gravimetric postpartum blood loss was lower in the 3IU group (-58.8 mL [95% CI: -212.1, 94.3]) after adjusting for BMI, pre-delivery vasopressor dose, parity, and risk of uterine atony, with the upper confidence limit below the 300 mL margin in support of non-inferiority. Patients receiving 3IU had a higher (non-significant) rate of having post-delivery phenylephrine to treat hypotension (RR = 1.59 [95% CI: 0.97, 2.63]), but of those treated, the 3IU group required significantly less (-427 mcg [95% CI: -740, -114]). The 3IU group had a lower prevalence of vomiting compared to those receiving 5IU (6% versus 24%; P = 0.047). Administration of 3IU oxytocin was non-inferior compared to standard 5IU with respect to blood loss in women undergoing elective caesarean delivery.

The implications of the obstetric use of oxytocin for obstetric anaesthesia practice are summarised. The review focuses on recent research on the uterotonic effects of oxytocin for prophylaxis and management of uterine atony during caesarean delivery. Oxytocin remains the first-line agent in the prevention and management of uterine atony. In-vitro and in-vivo studies show that prior exposure to oxytocin induces uterine muscle oxytocin receptor desensitization. This may influence oxytocin dosing for adequate uterine tone following delivery. Oxytocin has important cardiovascular side-effects (hypotension, tachycardia and myocardial ischaemia). Recent studies suggest that the effective dose of oxytocin for prophylaxis against uterine atony during caesarean delivery is significantly lower than the 5-10 IU historically used by anaesthesiologists. Slow administration of small bolus doses of oxytocin minimises maternal haemodynamic disturbance. Continuous oxytocin infusions are recommended for maintaining uterine tone after bolus administration, although ideal infusion rates are still to be established. The efficacy of the long-acting oxytocin analogue carbetocin requires further investigation. Recommendations are presented for oxytocin dosing during caesarean delivery. Oxytocin remains the first-line uterotonic after vaginal and caesarean delivery. Recent research elucidates the therapeutic range of oxytocin during caesarean delivery, as well as receptor desensitization. Evidenced-based protocols for the prevention and treatment of uterine atony during caesarean delivery are recommended.

It is routine to give a uterotonic drug following delivery of the neonate during caesarean section. However, there is much heterogeneity in the relevant research, which has largely been performed in low-risk elective cases or women with uncomplicated labour. This is reflected in considerable variation in clinical practice. There are significant differences between dose requirements during elective and intrapartum caesarean section. Standard recommended doses are higher than required, with the potential for acute cardiovascular adverse effects. We recommend a small initial bolus dose of oxytocin, followed by a titrated infusion. The recommended doses of oxytocin may have to be increased in women with risk factors for uterine atony. Carbetocin at equipotent doses to oxytocin has similar actions, while avoiding the requirement for a continuous infusion after the initial dose and reducing the need for additional uterotonics. As with oxytocin, carbetocin dose requirements are higher for intrapartum caesarean sections. A second-line agent should be considered early if oxytocin/carbetocin fails to produce good uterine tone. Women with cardiac disease may be very sensitive to the adverse effects of oxytocin and other uterotonics, and their management needs to be individualised.

To compare the available evidence on intravenous oxytocin dosing regimens for the prevention of postpartum hemorrhage following cesarean delivery. We searched Ovid MEDLINE, Embase, Global Index Medicus, Cumulative Index of Nursing and Allied Health Literature, Cochrane Controlled Register of Trials, ClinicalTrials.gov, and the International Clinical Trials Registry Platform for eligible studies published until February&#xa0;2020. We included any randomized or nonrandomized study published in peer-reviewed journals that compared at least 2 different dosing regimens of intravenous oxytocin for postpartum hemorrhage prevention in women undergoing cesarean delivery. Two authors independently assessed the eligibility of studies, extracted the data, and assessed the risk of bias. The primary outcome was incidence of postpartum hemorrhage &#x2265;1000 mL. Other review outcomes included use of additional uterotonics, blood loss, and adverse maternal events. Data were analyzed according to the type of intravenous administration (bolus only, infusion only, or bolus plus infusion) and total oxytocin dose. A meta-analysis was performed on randomized trials and the results were reported as risk ratios or mean differences with 95% confidence intervals. The Grading of Recommendations, Assessment, Development, and Evaluations scale was used to rate the certainty of evidence. Findings from dose-finding trials and nonrandomized studies were reported narratively. A total of 35 studies (7333 women) met our inclusion criteria and included 30 randomized trials and 5 nonrandomized studies. There were limited data available from the trials for most outcomes, and the results were not conclusive. Compared with bolus plus infusion regimens, bolus only regimens probably result in slightly higher mean blood loss (mean difference, 52 mL; 95% confidence interval, 0.4-104 mL; moderate certainty). Among the bolus plus infusion regimens, initial bolus doses <5 IU may reduce nausea (risk ratio, 0.26; 95% confidence interval, 0.11-0.63; low certainty) when compared with doses of 5-9 IU. Total oxytocin doses of 5-9 IU vs total doses of 10-19 IU may increase the use of additional uterotonics (risk ratio, 13.00; 95% confidence interval, 1.75-96.37; low certainty). Effects on other outcomes were generally inconclusive. There are limited data available for comparisons of IV oxytocin regimens for postpartum hemorrhage prevention following cesarean delivery. Bolus plus infusion regimens may lead to minor reductions in mean blood loss and initial bolus doses of <5 IU may minimize nausea. Bolus only regimens of 10 IU vs bolus only regimens of 5 IU may decrease the need for additional uterotonics, however, further comparative trials are required to understand the effects on other key outcomes, particularly hypotension.

Oxytocin is frequently used by intravenous bolus and infusion to minimize blood loss and prevent postpartum hemorrhage at cesarean delivery. Current dosing regimens are arbitrary whereas large doses may pose a serious risk to the mother. The purpose of this study was to estimate the minimum effective intravenous bolus dose of oxytocin (ED90) required for adequate uterine contraction at elective cesarean in nonlaboring women. A randomized, single-blinded study was undertaken in 40 healthy term pregnant women presenting for elective cesarean under spinal anesthesia. Oxytocin was administered by bolus according to a biased coin up-and-down sequential allocation scheme with increments or decrements of 0.5 IU. Uterine contraction was assessed by the obstetrician, who was blinded to the dose of oxytocin, as either satisfactory or unsatisfactory. After achieving sustained uterine contraction, an infusion of 40 mU/min of oxytocin was started. Oxytocin-induced adverse effects and intraoperative complications were recorded and blood loss was estimated. Data were interpreted by parametric analysis based on logistic regression model and nonparametric analyses at 95% confidence intervals (CIs). The ED90 of oxytocin as determined by logistic regression model fitted to the data was estimated to be 0.35 IU (95% CI 0.18-0.52 IU), with nonparametric estimates of 97.1% (95% CI 84.9-99.8%) response rate at 0.5 IU, and 100% (95% CI 92.2-100%) at 1.0 IU. The estimated blood loss was 693 +/- 487 mL (mean +/- standard deviation). The bolus dose of oxytocin used at elective cesarean deliveries in nonlaboring women can be significantly reduced while maintaining effective uterine contraction. Alteration in practice will likely reduce the potential adverse effects of this drug when given in large bolus doses, but may require modification of the techniques to remove the placenta.