In this prospective dose-finding study, we have shown that, in women receiving 0.5 µg/kg/min phenylephrine to prevent post-spinal hypotension during elective cesarean delivery, the ED90 of oxytocin to prevent uterine atony was 9.3 IU/h. This value is significantly higher than the recommended dose by an international consensus statement.1 The trend of increasing oxytocin infusion dose demand in patients with prophylaxis phenylephrine is consistent with our prior study using oxytocin bolus. In which, women receiving prophylactic phenylephrine required larger doses of oxytocin bolus than women without prophylactic phenylephrine treatment. 8
Oxytocin is widely used for the prevention of PPH. Various organizations have suggested different protocols for the use of oxytocin during the third stage of labor in cesarean delivery. The Royal College of Obstetricians and Gynaecologists of the UK has recommended 5 IU of oxytocin slowly infused as an i.v. bolus12. In contrast, the American College of Obstetricians and Gynecologists of the USA recommends 10 IU of oxytocin administered either as a dilute infusion or as an intramuscular injection13. For elective cesarean delivery, in 2019, an international consensus statement recommended the use of oxytocin as an initial 1 IU bolus in 15 seconds upon neonatal delivery, followed by an infusion (2.5–7.5 IU/h). Then, after UT assessment, an additional bolus of oxytocin or second-line uterotonics should be delivered. 1
However, many factors could influence the UT. In Lavoie’s study, it was found that women with prior exposure to exogenous oxytocin required higher infusion doses of oxytocin to maintain UT, in comparison with women without prior exposure (44.2 IU/h vs. 16.2 IU/h)2. Peska et al. conducted a clinical trial to compare the dose requirement of an initial bolus of oxytocin in patients with or without obesity. They found that women with a BMI ≥ 40 kg.m− 2 required more than twice the oxytocin dose than women with a BMI < 40 kg.m− 2 (0.78 vs. 0.35 IU)3. Tyagi et al. 4 compared the ED90 of prophylactic oxytocin infusion in patients with pre-eclampsia (who received magnesium therapy) and normotensive pregnant women. They found that the ED90 was significantly higher in patients who received magnesium sulfate than in patients who did not (24.9 IU/h vs. 13.9 IU/h). Prior studies demonstrated that a prophylactic phenylephrine infusion during cesarean delivery was another potential factor that could influence uterine contraction8. Nevertheless, under this condition, the ideal oxytocin infusion dose for preventing uterine atony was still unknown.
The strength of the present study is in providing full dose-response information on the oxytocin infusion dose for the prevention of uterine atony. In this study, the calculated ED90 (9.3 IU/h) of the oxytocin infusion dose was higher than the results of Qian’s study. In Qian’s study, it was found, using a very similar probit regression design to ours, that after a bolus of 1 IU oxytocin the ED95 infusion dose of oxytocin was 7.72 IU/h15. Although a direct comparison is lacking, our results concerning the oxytocin infusion dose are numerically higher than those of previous studies. They are also higher than the dose recommended by the international consensus statement,1 which indicates that the oxytocin infusion dose needs to be increased when phenylephrine is infused, to prevent post-spinal hypotension in cesarean delivery.
The exact mechanism through which prophylactic phenylephrine increases the oxytocin dose requirement to prevent uterine atony is still unclear. Nevertheless, there are two potential explanations. First, phenylephrine suppressed uterine contraction in non-pregnant mice, through cyclic adenosine monophosphate (cAMP) signaling via β2-receptor activation.14 Similarly, increased cAMP levels were induced by phenylephrine in human uterine smooth muscle cells (HUSMCs), suggesting that phenylephrine would also exhibit antagonistic effects against contractions in the human uterus.14 Second, phenylephrine infusion during surgery elevated blood pressure and subsequently increased uterine perfusion pressure, which could increase bleeding during the uterine incision procedure.8 Therefore, clinical interventions, such as a rescuing dose of oxytocin, could be a possibility for mitigating the cause of bleeding.
It should be kept in mind that the optimum dose of the initial bolus of oxytocin is still unknown in patients with prophylactic phenylephrine treatment after neonatal delivery. We chose an initial dose regimen of 3 IU rather than 1 IU, (3-fold the dose suggested by the international consensus statement),1 to reduce the potential higher risk of PPH in patients receiving prophylactic phenylephrine to manage post-spinal blood pressure. In this framework, further studies are needed to determine the optimal initial dose of oxytocin. Notably, we would like to interpret that the estimated blood loss was similar among the four fixed infusion doses of oxytocin, due to the close observation and timely treatment with rescued oxytocin and the second line uterine agent. Hence, the data in this study suggested that the management of oxytocin infusion should be based on patient’s response, because not all patients respond to oxytocin in the same way.
It should be noted that oxytocin use is associated with major cardiovascular side effects, including hypotension, ST depression, and tachycardia. Despite seemingly less serious, nausea, vomiting, chest pain, headache, and flushing are additional commonly experienced and unpleasant side effects. After careful literature revision, we found that these side effects are dependent on the dose and the administration rate. A randomized clinical trial has shown that ST depression occurred in 8% of women after a 5 IU oxytocin bolus vs. 22% after 10 IU, which was proved to be related to the occurrence of severe hypotension16. Thomas et al. 17 observed that a slow administration of 5 IU oxytocin for 5 minutes led to decreased effects on the decrement in mean arterial pressure and in the increase in the heart rate, than the administration of the same dose as a bolus. We found no differences in the incidence of side effects among the groups in our study. Besides the factors mentioned above, the small sample size of the current study does not have sufficient power to determine the differences in the secondary outcomes among groups, which may be a reasonable explanation for this finding.
There were several limitations in the current study. First, the assessment of UT was subjective. Different obstetricians could have different evaluation criteria for the UT. Second, because of the critical criteria used for patient inclusion and exclusion, the results of the current may not apply to all kinds of patients. In addition, this study only enrolled patients for elective cesarean delivery; therefore, the ED90 value determined might not be applicable to patients under emergency cesarean delivery. Finally, the initial oxytocin dose in this study was 3 IU. Different institutions may use different initial bolus administration doses, which could influence the dose requirement for the subsequent infusion. Thus, further studies are needed to evaluate whether the ED90s of oxytocin infusion are changed when different initial boluses of oxytocin are used.