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Purpose: The purpose of our study was to determine the minimum effective dose of oxytocin maintenance infusion required to maintain adequate uterine tone in 90% of patients (ED 90 ) after administration of the initial bolus at elective Cesarean delivery (CD) under spinal anesthesia., Methods: We conducted a prospective, double-blind dose-finding study with biased coin up-down design. Immediately after delivery, a 1-IU oxytocin bolus was administered, followed by a maintenance infusion. The obstetrician assessed the uterine tone by palpation as satisfactory or unsatisfactory. In case of unsatisfactory response, the dose for the next patient was increased by 2 IU·hr -1 . For satisfactory response, the dose for the next patient was either decreased by 2 IU·hr -1 with a probability of 1/9, or remained unchanged. The primary outcome was a satisfactory uterine tone from five minutes after delivery until discharge from postanesthesia care unit. The secondary outcomes were blood loss, need for additional uterotonics, and side effects., Results: We analyzed data for 40 patients. The ED 90 of oxytocin maintenance infusion was 4.5 IU·hr -1 (95% confidence interval, 3.3 to 5.5) based on the isotonic regression estimator. The median [interquartile range] blood loss was 861 [553-1,181] mL; 18% received additional uterotonics, and 38% developed hypotension post delivery., Conclusion: Based on the results of this dose-finding study, we recommend a maintenance infusion rate of 4.5 IU·hr -1 following an oxytocin bolus of 1 IU for adequate uterine tone in pregnant patients undergoing elective CDs. This infusion rate is four-fold lower than that required without an initial bolus., Study Registration: ClinicalTrials.gov ( NCT04946006 ); first submitted 25 June 2021., (© 2024. Canadian Anesthesiologists' Society.)

Background: Multiple pregnancy is associated with higher risk of uterine atony, postpartum hemorrhage (PPH), blood transfusion, hysterectomy, and death. The optimal dose of oxytocin at cesarean delivery in people with twin pregnancy is unknown. We sought to determine the effective bolus dose of oxytocin required to initiate adequate uterine tone in 90% of people (ED90) with twin pregnancy undergoing elective cesarean delivery. Our hypothesis was that the dose of oxytocin would be higher than 0.5 international units (IU) but lower than 5 IU., Methods: A double-blind dose-finding study using the biased coin up-down method was undertaken in people with twin pregnancy ≥36 weeks gestational age undergoing elective cesarean delivery under neuraxial anesthesia. Those with additional risk factors for PPH, apart from twin pregnancy, were excluded. Oxytocin was administered as an intravenous bolus over 1 minute on delivery of the second fetus. The first patient received 0.5 IU, and subsequent oxytocin doses were administered according to a sequential allocation scheme. The actual doses administered were 0.5, 1, 2, 3, 4, and 5 IU of oxytocin. The primary outcome was the response defined as the satisfactory uterine tone at 2 minutes after completion of administration of the oxytocin bolus, as assessed by the operating obstetrician. Secondary outcomes included need for rescue uterotonic drugs, adverse effects, and estimated blood loss. The ED90 was estimated using the Dixon-Mood and the isotonic regression methods., Results: Thirty patients were included in study. The estimated ED90 of oxytocin was 4.38 IU (95% confidence interval [CI], 3.68-4.86 IU) and 3.41 IU (95% CI, 2.83-3.98 IU) by the isotonic regression and Dixon-Mood methods, respectively. Seven patients had inadequate tone at the 2-minute evaluation point and required rescue uterotonic drugs. The median (interquartile range [IQR]) estimated blood loss was 1031 mL (732-1462 mL) calculated by the change in 24-hour hematocrit. Incidence of hypotension after oxytocin administration was 27%, nausea 30%, and vomiting 17%., Conclusions: Our results demonstrated that people with twin pregnancy require a much higher dose of oxytocin than those with singleton pregnancies. We recommended people with twin pregnancies should receive an initial 5 IU bolus over at least 1 minute when undergoing elective cesarean delivery under neuraxial anesthesia., Competing Interests: Conflicts of Interest: See Disclosures at the end of the article., (Copyright © 2022 International Anesthesia Research Society.)

Objective: To evaluate whether prophylactic administration of oxytocin plus ergonovine or oxytocin plus carboprost is more effective than oxytocin alone in reducing the need for additional uterotonics among women undergoing cesarean delivery for labor arrest., Methods: In this double-blind, three-arm randomized controlled trial, participants were assigned to receive either oxytocin 5 units intravenous alone, or with ergonovine 0.25 mg intravenous or carboprost 0.25 mg intramuscular immediately after delivery, followed with maintenance infusion of oxytocin 40 milliunits/minute in all groups. Uterine tone was assessed at 3, 5, and 10 minutes after delivery, and additional uterotonics were administered if deemed necessary. The primary outcome was intraoperative need for additional uterotonics. Secondary outcomes included uterine tone, calculated blood loss, and side effects. A sample size of 34 per group (n=102), based on the null hypothesis that there is no association between treatment assignment and the need for additional uterotonics, permitted independent post hoc pairwise comparisons between oxytocin plus ergonovine, oxytocin plus carboprost, and oxytocin alone using an adjusted P-value of .025. The association between the need for additional uterotonics and treatment group was assessed using the χ2 test., Results: From June 2013 through July 2019, 105 participants were randomized (35 per group) and data from 100 participants were analyzed: oxytocin (n=35), oxytocin plus ergonovine (n=33), and oxytocin plus carboprost (n=32). There was no difference in the requirement of additional intraoperative uterotonics across groups (oxytocin [37%] vs oxytocin plus ergonovine [33%] vs oxytocin plus carboprost [34%], P=.932). Uterine tone and calculated blood loss were similar across groups. Incidence of nausea or vomiting was higher in oxytocin plus ergonovine (85%; odds ratio [OR] 5.3, 95% CI 1.7-16.9, P=.003) and oxytocin plus carboprost (72%; OR 2.4, 95% CI 0.9-6.7, P=.086) compared with the oxytocin (51%) group., Conclusion: Compared with oxytocin alone, prophylactic use of a combination of uterotonic drugs did not reduce the need for additional uterotonics at cesarean delivery for labor arrest., Clinical Trial Registration: ClinicalTrials.gov, NCT01869556., Competing Interests: Financial Disclosure The author did not report any potential conflicts of interest., (Copyright © 2021 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Pharmacotherapy with uterotonics remains the mainstay of the management for post-partum haemorrhage. Clinical studies evaluating the efficacy of these drugs are fraught with confounders, which may influence uterine contractility and blood loss. For this reason, a range of techniques have been developed to study myometrial function in vitro, allowing for the comparison of various drugs in a controlled-simulated physiological environment. In this review, we focus on the main classes of uterotonic drugs and outline their molecular and physiological basis of action. We explore the evidence related to appropriate drug dosing and relative efficacy, and compare the evidence gleaned from clinical and in vitro studies. We discuss the mechanism of oxytocin desensitisation and how basic science has helped us understand this phenomenon. We also discuss the in vitro research findings for each of the main classes of uterotonic drugs that have contributed to an improved understanding of the management of post-partum haemorrhage and, ultimately, better care for mothers., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Prolonged continuous oxytocin administration during labor may induce oxytocin receptor desensitization, which attenuates the response of the myometrium to further oxytocin, increasing the risk of postpartum hemorrhage. The literature comparing pulsatile (intermittent) versus continuous oxytocin administration for induction and augmentation of labor is inconsistent with regard to maternal outcomes. We aimed to determine the effect of intermittent versus continuous oxytocin preexposure on myometrial responsiveness to subsequent oxytocin. We hypothesized that intermittent oxytocin pretreatment would result in superior subsequent oxytocin-induced contractility than continuous oxytocin pretreatment., Methods: This in vitro study was undertaken using myometrium obtained from women undergoing elective cesarean deliveries. Each myometrial strip was mounted in an individual organ bath with physiological salt solution under homeostatic conditions and allocated to one of 3 groups: (1) control (no pretreatment); (2) continuous (pretreatment with oxytocin 10(-5) M for 2 hours); or (3) intermittent (pretreatment with alternating oxytocin 10 M and physiological salt solution every 15 minutes, for 2 hours). After pretreatment, dose-response testing to oxytocin 10(-5) to 10(-5) M was performed and contractile parameters were measured. The primary outcome was motility index (MI, amplitude × frequency) of contractions., Results: Eighteen women were recruited, and 86 successful experiments were performed (control n = 29, continuous n = 28, intermittent n = 29). The means (standard errors) of MI (√g·contractions/10 min) in the control, continuous, and intermittent groups were 2.34 (0.09), 1.78 (0.09), and 2.13 (0.11), respectively. The MI was significantly reduced in the continuous group when compared to the control (estimated difference [95% confidence interval {CI}], -0.56 [-0.81 to -0.31]; P < .01) and intermittent group (estimated difference [95% CI], -0.35 [-0.62 to -0.08]; P = .01). There was no significant difference in MI between the intermittent and control group (estimated difference [95% CI], -0.21 [-0.51 to 0.09]; P = .17)., Conclusions: Human myometrium remains more responsive to subsequent oxytocin after intermittent compared to continuous exposure to oxytocin, most likely due to reduction in oxytocin receptor desensitization, or facilitation of receptor resensitization in the intermittent group. Hence, intermittent oxytocin administration during labor warrants further investigation as a technique to preserve uterine oxytocin responsiveness.

Purpose: Prolonged exposure to oxytocin during augmentation of labour is associated with uterine atony and an increased risk of postpartum hemorrhage (PPH) due to oxytocin receptor desensitization. Cessation of oxytocin infusion during labour may facilitate recovery of oxytocin receptor function, which then helps to restore myometrial contractility and decrease postpartum blood loss. We examined the association between oxytocin recovery interval, i.e., the time from discontinuing oxytocin to Cesarean delivery (CD) for labour arrest, and blood loss., Methods: This retrospective cohort study included women who underwent CD for labour arrest following oxytocin-augmented labour from July 1, 2013 to July 19, 2015 at our institution. Data were collected on patient demographics, labour and delivery characteristics, oxytocin induction and augmentation, recovery interval, and PPH risk factors. The primary outcome was estimated blood loss (EBL), calculated using the hematocrit variation method., Results: Data on 490 women were analyzed. The mean (standard deviation) EBL was 1,341 (577) mL; the amount of oxytocin administered during labour was 6,447 (6,868) mU, and the oxytocin recovery interval was 99 (65) min. Every ten-minute increase in the recovery interval was associated with a 10-mL decrease in EBL (95% confidence interval [CI], -18 to -3; P = 0.009). Morbidly obese women had a significantly higher EBL than those with a body mass index < 40 kg·m -2 (mean difference, 572 mL; 95% CI, 382 to 762; P < 0.001). The amount and duration of oxytocin administered during labour, but not the oxytocin recovery interval, was associated with the use of additional interventions to control PPH (P = 0.005)., Conclusion: Our study shows that an increase in the oxytocin recovery interval is associated with a decrease in blood loss at CD in women with oxytocin augmented labour. These data support discontinuing the oxytocin infusion as soon as the decision is made to proceed with CD for labour arrest, particularly in morbidly obese women.

Purpose: The purpose of this study was to determine the contractile patterns induced by oxytocin in myometrium exposed to magnesium sulfate (MgSO 4 ). We hypothesized that MgSO 4 pretreatment would reduce oxytocin-induced myometrial contractions in both oxytocin-naïve and oxytocin-desensitized myometrium., Methods: In this prospective in vitro study, myometrial samples were obtained from 26 women undergoing elective Cesarean deliveries. Samples were divided into six groups. Four groups were apportioned to no pretreatment (control group), oxytocin 10 -5 M pretreatment (desensitization group), MgSO 4 3.5 mM pretreatment, and MgSO 4 3.5 mM + oxytocin 10 -5 M pretreatment. This was followed by dose-response testing to oxytocin 10 -10 to 10 -5 M in all four groups. Two additional groups included MgSO 4 3.5 mM pretreatment and MgSO 4 3.5 mM + oxytocin 10 -5 M pretreatment, followed by dose-response testing to oxytocin along with MgSO 4 3.5 mM. The outcomes were motility index (MI), as defined by the amplitude (g) × frequency of myometrial contractions (c) over ten minutes, and area under the curve (AUC)., Results: In oxytocin-naïve myometrium, the mean (standard error [SE]) MI was not affected by MgSO 4 pretreatment [3.31 (0.20) √g⋅c/10 min] as compared with control (P = 0.88), even when MgSO 4 was continued during dose-response testing [2.50 (0.19) √g⋅c/10 min; P = 0.41]. In the oxytocin-desensitized model, mean (SE) MI was not affected by MgSO 4 pretreatment [2.60 (0.21) √g⋅c/10 min; P = 0.68], but when MgSO 4 was continued during the dose-response period, the MI was significantly reduced compared with control [1.89 (0.13) √g⋅c/10 min; P < 0.001]. The results for AUC were similar to MI, except for a significant reduction in oxytocin-naïve myometrium when MgSO 4 was continued during dose-response testing (P = 0.02)., Conclusion: Magnesium sulfate pretreatment does not impair oxytocin-induced myometrial contractility in oxytocin-naïve or desensitized myometrium unless it is continued during oxytocin dose-response testing. These results suggest that its tocolytic effect is likely dependent on an extracellular mechanism. The study was registered with ClinicalTrials.gov, number NCT02647268.

Background: Prolonged exposure to oxytocin during augmentation of labor is a significant risk factor for uterine atony, resulting in the desensitization phenomenon, a decrease in the responsiveness of myometrium to further oxytocin. The importance of extracellular calcium is well established in spontaneous myometrial contractility; however, its significance is unknown in the context of desensitized myometrium. We aimed to investigate the effect of low, normal, and high extracellular calcium concentration on oxytocin-induced contractility in oxytocin-pretreated human myometrium in vitro. We hypothesized that extracellular normocalcemia would provide superior oxytocin-induced contractility in both naive and oxytocin-pretreated myometrium compared with hypocalcemia and hypercalcemia., Methods: Myometrial tissue was obtained from women undergoing elective cesarean deliveries and was dissected into longitudinal strips. Each strip was mounted in a single organ bath with physiological salt solution (PSS) under homeostatic conditions and then pretreated for 2 hours with either oxytocin 10 M or PSS (control). The tissue was then washed with PSS, and calcium concentrations were altered to reflect low (1.25 mM), normal (2.5 mM), or high (3.75 mM) levels, thereby providing 6 study groups. After equilibration in the desired calcium concentration, a dose-response testing to oxytocin 10 M to 10 M was performed. Contractile parameters were measured and compared among groups after square root transformation. The primary outcome was motility index (frequency × amplitude), and secondary outcomes included frequency, amplitude, and area under the curve., Results: One hundred seventy-four experiments were conducted from samples obtained from 36 women. In the control group, the mean motility index (√g·contractions/10 min) was significantly lower in the hypocalcemic group than in the normocalcemic group (estimated difference, -0.43; 95% confidence interval [CI], -0.82 to -0.04; P = 0.03). In addition, the mean frequency of contractions (√contractions/10 min) was significantly lower in the hypocalcemic (estimated difference, -0.27; 95% CI, -0.46 to -0.09; P = 0.002) and hypercalcemic groups (estimated difference, -0.18; 95% CI, -0.34 to -0.02; P = 0.03) compared with the normocalcemic group. In the oxytocin-pretreated group, there were no significant differences in the values of any of the contractility parameters of the hypocalcemic or hypercalcemic groups compared with the normocalcemic group (mean motility index [√g·contractions/10 min] estimated difference, 0.10; 95% CI, -0.23 to 0.43; P = 0.74 and -0.39; 95% CI, -1.10 to 0.32; P = 0.39, respectively)., Conclusions: In oxytocin-naive myometrium, normocalcemia provides superior oxytocin-induced contractility compared with hypocalcemic and hypercalcemic conditions. We were unable to draw conclusions regarding oxytocin-pretreated myometrium because of the small sample size relative to the large variability of the data. These observations warrant further investigations in laboratory and clinical settings.

Background: Postpartum hemorrhage secondary to uterine atony is a leading cause of maternal morbidity. Prolonged exposure to oxytocin for labor augmentation can result in the desensitization phenomenon, a decrease in the responsiveness of myometrium to further oxytocin. It is currently not known whether waiting for a specific time interval after the cessation of oxytocin allows the oxytocin receptors to resensitize and recover, thereby improving subsequent oxytocin-induced myometrial contractility. We aimed to investigate the effect of a rest period of 30, 60, and 90 minutes after oxytocin administration on the recovery of oxytocin-desensitized human myometrium in vitro. We hypothesized that the longer the rest period, the better the responsiveness and subsequent oxytocin-induced contractility of the myometrium., Methods: Myometrial tissue was obtained from women undergoing elective cesarean deliveries. The myometrial sample was dissected into 4 strips, and each strip was mounted in a single organ bath with physiological salt solution (PSS) under homeostatic conditions and then pretreated for 2 hours with oxytocin 10 M. After pretreatment, each strip was washed with PSS and allowed to rest in PSS solution for 30, 60, or 90 minutes. At the end of the rest period, dose-response testing to oxytocin 10 to 10 M was performed. A control group consisted of oxytocin dose-response testing without any oxytocin pretreatment. Contractile parameters were measured and compared among the groups after square root transformation. The primary outcome was motility index (frequency × amplitude), and secondary outcomes included frequency, amplitude, and area under the curve., Results: Fifty-five experiments were conducted from samples obtained from 16 women. The mean motility index (√g·contractions/10 min) during the dose-response curve (oxytocin 10 to 10 M) in the control group was significantly greater than all the experimental groups; the mean estimated differences (95% confidence intervals) were -1.33 (-2.50 to -0.15, P = 0.02), -1.59 (-2.68 to -0.50, P = 0.004), and -1.88 (-2.97 to -0.80, P = 0.001) for the 30-, 60-, and 90-minute groups, respectively. When the experimental groups were compared, there were no significant differences in any of the contractility parameters; however, confidence intervals were wide., Conclusions: Our study shows that oxytocin pretreatment attenuates oxytocin-induced contractility in human myometrium despite a rest period of up to 90 minutes after oxytocin administration. However, we were unable to determine whether increasing the rest period from 30 to 90 minutes results in improvement in myometrial contractility because of our small sample size relative to the variability in the contractile parameters. Further laboratory and clinical in vivo studies are necessary to determine whether a rest period up to 90 minutes results in improvement in myometrial contractility. In addition, further experimental studies are necessary to determine the key mechanisms of oxytocin receptor resensitization.

Background: The purpose of this study was to compare in vitro contractile effects of oxytocin and carbetocin on human term pregnant myometrium with and without oxytocin pretreatment., Methods: This laboratory investigation was conducted on myometrial samples from women undergoing elective cesarean deliveries. The samples were dissected into four strips and suspended in individual organ bath chambers containing physiologic salt solution. After equilibration, they were pretreated with oxytocin 10 M (experimental group) or physiologic salt solution (control group) for 2 h and then subjected to dose-response testing with increasing concentrations of oxytocin or carbetocin (10 to 10 M). The amplitude, frequency, motility index (amplitude × frequency), and area under the curve of contractions were recorded and analyzed during the equilibration and dose-response periods. Comparisons were made between oxytocin-induced and carbetocin-induced contractions in control and oxytocin-pretreated groups. Motility index was the primary outcome measure., Results: Sixty-three experiments were performed (carbetocin, n = 31; oxytocin, n = 32) on samples from 18 women. The motility index of contractions (√g.contractions/10 min) produced by oxytocin was significantly higher than carbetocin in both control (regression-estimated difference, 0.857; 95% CI, 0.290 to 1.425; P = 0.003) and oxytocin-pretreated (0.813; 0.328 to 1.299; P = 0.001) groups. The motility index was significantly lower in oxytocin-pretreated groups than their respective controls for both oxytocin (-1.040; -1.998 to -0.082; P = 0.03) and carbetocin (-0.996; -1.392 to -0.560; P < 0.001)., Conclusions: In vitro contractions produced by oxytocin are superior to carbetocin in human myometrium with or without oxytocin pretreatment. Oxytocin pretreatment results in attenuation of contractions induced by both oxytocin and carbetocin.

Purpose: 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., Conclusion: 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.

Background: The objective of this study was to compare the in vitro contractile effects of the combination of oxytocin (low dose and high dose) with either ergonovine or carboprost in myometrial strips from women undergoing cesarean delivery (CD), and to study the effect of oxytocin pretreatment on these contractions. We hypothesized that the use of ergonovine or carboprost in combination with oxytocin would improve contractility compared with oxytocin alone., Methods: Myometrial samples obtained from women undergoing elective CD were pretreated in organ bath chambers with either oxytocin 10 M (experimental) or physiological salt solution (control) for 2 hours. They were then washed and subjected to dose-response testing with oxytocin, ergonovine, or carboprost (10 to 10 M), either alone or in combination with a fixed low-dose (10 M) (LDOx) or high-dose (10 M) (HDOx) oxytocin. The amplitude, frequency, area under the curve, and motility index (amplitude × frequency) of contractions during the dose-response period were analyzed with linear regression models, and compared among the groups. The primary outcome was the motility index across the study groups., Results: One hundred sixty-nine experiments were done in samples obtained from 56 women. The mean square root of the motility index [standard error] (√g·contractions/10 min) of oxytocin was significantly higher in the control (3.40 [0.24]) versus experimental group (2.02 [0.15]) (P < 0.001). When all control groups were compared, the motility index of oxytocin (3.21 [0.25]) was higher than that of ergonovine (2.13 [0.30], P < 0.001 [multiple comparisons adjusted P value, P < 0.001]), carboprost (1.88 [0.10], P < 0.001 [P < 0.001]), ergonovine + LDOx (2.07 [0.15], P < 0.001 [P < 0.001]), and carboprost + LDOx (1.82 [0.15], P < 0.001 [P < 0.001]) and was not different than that of ergonovine + HDOx (3.39 [0.32], P = 0.68 [P = 0.99]) and carboprost + HDOx (2.68 [0.30], P = 0.20 [P = 0.60]). However, in oxytocin-pretreated groups, carboprost + LDOx (motility index: 2.53 [0.08], P = 0.001 [multiple comparisons adjusted P value, P = 0.002]) and ergonovine + HDOx (2.82 [0.15], P < 0.001 [P < 0.001]) exhibited significantly superior contractility response compared with oxytocin alone, while ergonovine + LDOx (2.47 [0.13], P = 0.01 [P = 0.08]) and carboprost + HDOx (2.51 [0.20], P = 0.05 [P = 0.24]) showed higher mean contractility response compared with oxytocin alone but failed to reach statistical significance in adjusted analyses., Conclusions: The attenuation of oxytocin-induced contractility in oxytocin-pretreated myometrial strips is in keeping with the previously established oxytocin-receptor desensitization phenomenon. Oxytocin is the most effective of the uterotonics tested if the myometrium is not preexposed to oxytocin. However, in the oxytocin-pretreated myometrium, a synergistic response is evident, and the combination of oxytocin with either ergonovine or carboprost produces superior response compared with oxytocin alone. Further in vivo studies in humans are necessary to determine whether these differences identified in vitro are clinically significant.

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).

Purpose: The aim of this study was to determine the intravenous dose of carbetocin required to produce effective uterine contraction in 95% of women (ED95) undergoing elective Cesarean delivery under spinal anesthesia., Methods: One hundred and twenty term pregnant women at low risk for postpartum hemorrhage (PPH) undergoing elective Cesarean delivery under spinal anesthesia were randomly allocated to receive carbetocin in doses of 20, 40, 60, 80, or 100 μg iv upon delivery of the fetus. The obstetrician evaluated the efficacy of uterine tone as satisfactory or unsatisfactory, and in case of unsatisfactory tone, additional uterotonics were administered as per routine institutional practice. The primary outcome measure was satisfactory uterine tone at two minutes after carbetocin administration, and the secondary outcomes were the estimated blood loss, need for additional uterotonic agents within 24 hr, and side effects., Results: Overall satisfactory uterine tone at two minutes was observed in 94.2% (113/120) of the women, and there was no difference across the different study groups. It was not possible to calculate the ED95 of carbetocin due to the even distribution of women with unsatisfactory uterine tone at two minutes across all dose groups (P = 0.60). Additional uterotonics within 24 hr were required in 13% (16/120) of the women. Side effects were similar across all dose groups, with an overall 42.5% incidence of hypotension following the administration of carbetocin., Conclusions: In women at low risk for PPH undergoing elective Cesarean delivery under spinal anesthesia, carbetocin is similarly effective in doses of 20-100 μg. There is a high incidence of hypotension associated with carbetocin in these doses. Further dose-finding studies are warranted, including doses lower than 20 μg. This trial was registered at www.clinicaltrials.gov (NCT01428817).

Background: Oxytocin receptor desensitization has been shown to occur in humans at biomolecular level and in isolated rat myometrium; however, its effect on human myometrial contractility has not been demonstrated. The objective of this in vitro study was to investigate the contractile response of human pregnant myometrium to oxytocin after pretreatment with different concentrations of oxytocin for variable durations., Methods: Myometrial samples were obtained from 62 women undergoing elective cesarean deliveries under regional anesthesia. The strips were pretreated with oxytocin 10, 10, 10 M, or physiological salt solution (control) for 2, 4, 6, or 12 h, followed by a dose-response testing with oxytocin 10 to 10 M. Amplitude and frequency of contractions, motility index, and area under the curve during the dose-response period were recorded, analyzed with linear regression models, and compared among groups., Results: Pretreatment with oxytocin 10 and 10 M significantly reduced motility index (estimate [standard error]: -0.771 [0.270] square root units, P = 0.005 and -0.697 [0.293], P = 0.02, respectively) and area under the curve (-3.947 [1.909], P = 0.04 and -4.241 [2.189], P = 0.05, respectively) compared with control group, whereas pretreatment with oxytocin 10 M did not significantly attenuate contractions. Increase in duration of oxytocin pretreatment from 2 to 12 h significantly decreased amplitude (type 3 generalized estimating equation analysis: chi-square = 14.0; df = 3; P = 0.003), motility index (chi-square = 9.3; df = 3; P = 0.03), and area under the curve (chi-square = 10.5; df = 3; P = 0.02), but not the frequency of oxytocin-induced contractions., Conclusion: Pretreatment with oxytocin decreases oxytocin-induced myometrial contractions in a concentration and time-dependent manner, likely as a function of the oxytocin receptor desensitization phenomenon.

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 μg, 90 μg, 100 μg, 110 μg, or 120 μg 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 μg 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 μg are similarly effective. There is a high incidence of hypotension associated with carbetocin in these doses, and further studies with doses lower than 80 μg are warranted to assess the balance of efficacy and side effects. This trial was registered at www.clinicaltrials.gov (NCT01262742).

Oxytocin receptors (OTRs) in both human and rat myometrial cells are desensitized by exposure to oxytocin, thereby reducing the ability of the cells to respond to the subsequent administration of oxytocin. However, it is unclear if this desensitization phenomenon is confined to oxytocin, or extends to other uterotonic agents such as ergonovine or prostaglandin F(2 alpha) (PGF(2 alpha)). We compared the in vitro contractile responses of myometrial samples from pregnant Wistar rats at 20 to 22 days of gestation. Longitudinal myometrial strips isolated from each animal were pretreated with either oxytocin 10(-8) mol/L (experimental groups) or physiological salt solution (control groups) for 1 hour in organ bath chambers, and then subjected to a dose-response study with oxytocin (n = 28), ergonovine (n = 16), or PGF(2 alpha) (n = 16), with cumulative increases in the organ bath concentrations from 10(- 10) to 10(-5) mol/L. The amplitude and frequency of the contractions during the dose-response period were analyzed using mixed linear modeling and compared between the groups. Oxytocin pretreatment significantly suppressed the mean amplitude of the myometrial contractions as compared to the controls when the strips were further subjected to oxytocin (1.02 vs 1.74 g; P < .0001), but not with further exposure to ergonovine (0.77 vs. 0.58 g; P = .11) or PGF(2 alpha) (0.83 vs 0.94 g; P = .4). However, oxytocin produced superior contractions in the control and oxytocin-pretreated myometrium compared to either ergonovine or PGF(2 alpha). Our study shows that the uterotonic effects of ergonovine and PGF(2 alpha) are not affected by the phenomenon of oxytocin desensitization in pregnant rat myometrium. However, oxytocin, despite the phenomenon of desensitization, provides superior uterine contractions when compared to ergonovine or PGF(2 alpha).

Objective: 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., Methods: 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)., Results: 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)., Conclusion: 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.

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Copyright of Canadian Journal of Anaesthesia / Journal Canadien d'Anesthésie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Canadian Journal of Anaesthesia / Journal Canadien d'Anesthésie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)