|Year : 2022 | Volume
| Issue : 1 | Page : 22-27
Comparison of intravenous infusion versus bolus dose of oxytocin in elective caesarean delivery: A prospective, randomised study
Jigisha P Badheka, Vrinda P Oza, Nitin S Manat, Mayur B Patel
Department of Anaesthesiology, Pandit Deendayal Upadhyay Medical College and Hospital, Rajkot, Gujarat, India
|Date of Submission||17-May-2021|
|Date of Acceptance||02-Sep-2021|
|Date of Web Publication||14-Mar-2022|
Vrinda P Oza
F-201, Sadguruvatika, Marutinagar-2, Airport Road, Rajkot, Gujarat
Source of Support: None, Conflict of Interest: None
Background: Oxytocin (OT) is routinely administered during caesarean delivery to prevent and treat postpartum haemorrhage (PPH). The common adverse effects of intravenous OT are tachycardia, hypotension, chest pain, Electrocardiogram (ECG) changes, nausea and vomiting. We aimed to compare the uterine contractility, haemodynamic changes, need for other uterotonics and adverse effects by comparing the intravenous bolus dose versus infusion dose of OT while retaining its benefits. Methods: Sixty patients undergoing elective caesarean delivery under spinal anaesthesia were randomised to receive OT 3 IU as a bolus (repeat 3 IU at an interval of 3 min) in group B (Bolus) or as an infusion 1 IU per minute in group I (infusion). The uterine tone was assessed by a blinded obstetrician as either adequate or inadequate. The intraoperative heart rate, blood pressure, blood loss and any other adverse events were recorded. Results: The adequacy of uterine tone was more sustained and the requirement of other uterotonics was less in group I. The heart rate increased to 20–25 beats/min at 3–5 min in group B and 8–10 beats/min at 2–4 mins and reached the baseline at 8–9 min in group B as well as in group I. Also, a significant fall in the mean blood pressure was observed at 3–5 min in group B. The ECG changes (ST-T changes) were more common in group B compared to group I. There was no significant difference in the estimated blood loss between the two groups. Conclusion: The infusion dose of OT provides more haemodynamic stability, better uterine tone and fewer adverse effects compared to the bolus dose.
Keywords: Caesarean delivery, haemodynamic changes, oxytocin, uterine tone
|How to cite this article:|
Badheka JP, Oza VP, Manat NS, Patel MB. Comparison of intravenous infusion versus bolus dose of oxytocin in elective caesarean delivery: A prospective, randomised study. J Obstet Anaesth Crit Care 2022;12:22-7
|How to cite this URL:|
Badheka JP, Oza VP, Manat NS, Patel MB. Comparison of intravenous infusion versus bolus dose of oxytocin in elective caesarean delivery: A prospective, randomised study. J Obstet Anaesth Crit Care [serial online] 2022 [cited 2022 Aug 12];12:22-7. Available from: https://www.joacc.com/text.asp?2022/12/1/22/339542
| Introduction|| |
Postpartum haemorrhage (PPH) remains a significant cause of maternal mortality and morbidity. The incidence of PPH is estimated to be 10% of all deliveries. Uterine atony is the leading cause of PPH. Amongst the other uterotonics, oxytocin (OT) is the agent of choice in the prevention and treatment of postpartum uterine atony and is used worldwide either as a bolus or infusion. Prendiville et al. in their controlled trial concluded that the prophylactic routine use of OT reduces the incidence of PPH by up to 40%, implying that in every 22 women receiving OT, one PPH can be prevented.
Rapid and larger doses of OT cause adverse effects like hypotension, tachycardia, chest pain, ECG changes, myocardial ischaemia, headache flushing, nausea, vomiting and even convulsions.
The British National Formulary and other formularies recommended 5 IU OT by slow intravenous injection after delivery; however, there is no evidence to support that 5 IU is the correct dose.
Though the use of high doses either by bolus or continuous infusion is unnecessary and even detrimental to patients due to the possibility of side effects, particularly cardiovascular, its use is still rampant in obstetric practice. In patients with hypovolemia or low cardiac reserve, the use of high bolus doses can cause significant cardiovascular changes. A high dose of OT for prolonged periods may lead to desensitisation of OT receptors in the myometrium, resulting in clinical inefficiency. However, there are no optimal dose and infusion rate of OT for the prevention of PPH, after elective caesarean delivery (CD) established in the literature. So, we decided to do this comparative study for intravenous (IV) infusion and bolus dose with the primary aim to compare the uterine contractility, haemodynamic changes (heart rate and blood pressure) and the secondary aim to assess the adverse events, requirement of other uterotonics and intraoperative blood loss intravenous (IV) infusion versus the IV bolus dose.
| Material and Methods|| |
After approval from the Institutional Ethics Committee and written informed consent from 60 healthy pregnant patients posted for elective CD, this randomised, single-blind comparative study was carried out over 6 months. Parturients of the American Society of Anaesthesiologists physical status I and II, aged between 18 and 40 years, ≥37 weeks of gestation undergoing elective CD with Pfannenstiel incision under spinal anaesthesia, were included in our study. Patients with multiple gestations, cardiovascular instability, ruptured membrane, preeclampsia, eclampsia, diabetes mellitus, abnormal placentation like placenta previa, placenta accreta, placenta percreta, history of PPH, patient with active labour pain, failed induction and previous classical uterine incision, known drug allergy, inherited and acquired coagulation disorder were excluded from the study.
Based on the previous study, the difference of the mean arterial blood pressure using 5 units OT was 13 (15). The power of the study was 90% at an alpha error of 0.05. The sample size was determined, and considering the dropouts, 30 patients in each group were enrolled.
The patients were kept nil by mouth for 6–8 h for solid food and clear oral fluid intake up to 2 h before the induction of anaesthesia as per the enhanced recovery after surgery (ERAS) protocol. All the patients were premedicated with ranitidine 50 mg and metoclopramide 10 mg IV. Standard monitoring like ECG, non-invasive blood pressure (NIBP) and pulse-oximeter were attached. The measurements of the baseline NIBP and heart rate (HR) were recorded. Spinal anaesthesia was performed at the L3-L4 or L4-L5 intervertebral space with the patients in the sitting position with 25 G pencil-point spinal needle under all aseptic precautions and 2–2.4 mL hyperbaric bupivacaine (0.5%) was administered. The patients were then made supine with left-lateral displacement using a wedge. Surgery was allowed to proceed after achieving T6 sensory level to pinprick.
The obstetrician involved in each case was blinded to the OT dose assignments. Co-loading was performed with the infusion of a crystalloid solution with a total amount of 20 mL/kg which was divided into two halves. The first part was at 10 mL/kg given before and the second half (10 mL/kg) was given after giving spinal anaesthesia. The HR, mean blood pressure (MBP) and electrocardiogram (ECG) changes were recorded. The patients having a fall in the MBP before the administration of OT were treated with an IV bolus of 5 mg ephedrine and such cases were excluded from the study. Hypotension was defined as a decrease in the mean blood pressure (BP) 20% of the baseline value and each episode of hypotension was treated with an IV bolus of ephedrine 5 mg. Tachycardia was defined as maternal HR ≥120 beats per min.
Randomisation was done following computer-generated random numbers and allocated with a sealed opaque envelope. The patients concerned as well as the obstetrician were blinded to the mode of administration of OT. The OT was administered after the delivery of the foetus and the clamping of the umbilical cord, as per the group allocated.
In group I, OT 10 IU in 60 mL normal saline (NS) was infused at the rate of 1 I U/min, that was, 6 mL/min (360 mL/h) by the infusion pump.
In group B, the OT dose was prepared by diluting 10 IU OT in 10 mL 0.9% NS and a bolus/loading dose of 3 IU was given over 15 sec; 3 min assessment intervals; and a total of 3 bolus doses (if rescue is required) as per the 'Rule of 3 regimens'.
The obstetrician manually removed the placenta and subsequently performed uterine massage. Uterine exteriorisation was conducted and the uterine tone was assessed at 2, 3, 6 and 9 min by the operating obstetrician using Likert Scale (0–4); 0—floppy, 1—soft, 2—poorly contracted, 3—well contracted and 4—hard rock. Scale 0–2 was considered inadequate uterine tone and 3–4 was considered adequate uterine tone.
In group I patients, the infusion was stopped when the uterine tone was adequate and the total millilitres of the drug used was noted. While in group B patients if the uterus was not adequately contracted after 3 min, then a bolus of 3 IU was administered as a rescue dose. A maximum of two rescue doses were given.
In both the groups, if the uterus was not contracted with this dosage, alternative uterotonics therapy was administered—methylergometrine maleate 0.2 mg, carboprost tromethamine 0.25 mg intramuscular, or tablet misoprostol 200 μg orally—as per the decision by the obstetrician. After the study duration, all the patients received 10 IU of OT infusion in 500 mL NS given at the rate of 125 mL/h.
The study period started 1 min before giving OT, and it continued for a further 7 min. The first 15 s were taken to provide the baseline data. The next 7 min allowed us to compare the haemodynamic changes between the two methods of administration of OT. The study period of 7 min was set after a small pilot study. The HR and MBP were measured at 1 min interval up to 7 min, then at 8 and 10 min. The approximate intraoperative blood loss (measured by estimating the blood collected by suction and by calculating the weight of blood on surgical swabs) during CD was recorded. Any adverse effects occurring after administering OT, such as hypotension, electrocardiography changes, nausea, vomiting, and chest pain, headache and flushing were recorded.
Patient characteristics, obstetric history and intraoperative data were represented as mean ± Standard Deviation (SD). Numerical data were analysed with Student's t-test and categorical data were analysed with the Chi-square test. A P value of <0.05 was statistically significant. The data were collected and analysed using Microsoft Excel 2007 (12.0.4518.1014).
The primary study outcome measure was the assessment of either adequate or inadequate UT at 2 min after the administration of the initial OT dose and the haemodynamic changes (HR, MBP). The secondary endpoints include intraoperative blood loss, the number of rescue doses of OT and side effects associated with OT.
| Result|| |
A total of 63 patients were enrolled and randomly allocated into two groups: Group B (n = 32) and group I (n = 31) [Figure 1]. However, five patients (group B, n = 2 and group I, n = 1) did not receive interventions as they developed hypotension after subarachnoid block (SAB) but before OT infusion, and hence, were not included in the analysis. A total of 30 patients in each group were included for the final analysis. Both the groups were comparable demographically [Table 1].
|Figure 1: Consort flow diagram of the randomisation and intervention allocation|
Click here to view
As per [Graph 1] and [Graph 2], the mean heart rate increased at 20–25 beats/min at 3–5 min in group B and 8–10 beats/min at 2–4 min and reached the baseline at nearly 8–9 min in group B as well as in group I. Also, a significant fall in the mean blood pressure was observed at 3–5 min in group B.
As per [Table 2], the total OT requirement in group I was 3.85 IU and in group B was 4.9 IU which was not significant statistically. Rescue OT doses, other uterotonics and vasopressors were required in seven, four and three patients, respectively, in group B and none of the patients required the same in group I.
As per [Graph 3], ECG changes (ST-T changes) were observed in five patients; eight patients had chest pain, two patients had facial flushing, nausea and headache were there in four patients each in group B, while in group I, only two patients had chest pain. No patient had ECG changes and facial flushing, one patient had nausea and vomiting and one had a headache.
Various studies comparing different doses of infusion and bolus doses of OT and their results are shown in [Table 3].
| Discussion|| |
OT is used prophylactically in most obstetric patients along with uterine massage in the prevention and treatment of PPH. Apart from the uterus, OT receptors (OTRs) are present in the heart and large vessels. Synthetic OT used clinically is identical to the hormone normally released from the posterior pituitary but is devoid of contamination by other polypeptide hormones and proteins. Vasodilatation is the primary cardiovascular effect after the use of OT. Tachycardia, increased stroke volume and cardiac output (CO) occur as compensatory effects to vasodilatation. These effects are more pronounced when OT is administrated as a bolus and can be harmful to patients with impaired cardiovascular reserve. The haemodynamic changes that occur during caesarean section have multifactorial causes, such as sympathetic nervous system blockade secondary to the spinal anaesthesia, supine hypotension syndrome due to aortocaval compression, maternal auto-transfusion after placental delivery and bleeding. The use of OT is just one of these causes and is directly dependent on the way it is administered (dose and rate of infusion).
In the United States, an infusion of 10–40 IU/L is recommended for the prevention of postpartum haemorrhage. Other suggested different dosages and routes are OT 10 IU intramuscular, 5–10 IU rapid intravenous bolus, 10–20 IU/L intravenous drip at the rate of 100–150 mL/h. There are various empirical regimens and studies of OT and its dosage, but to date, there is no consensus about the ideal regime of administration for the dosing and routes for effective uterine contraction in patients undergoing elective CD.
Weis and colleagues used 10 IU of OT and observed that the patients receiving an infusion were haemodynamically stable. Thomas et al. also compared the effects of the recommended dose, that is, 5 U of OT, when given as an IV bolus or as an infusion over 5 min and showed that bolus doses should be used with caution and further studies should ascertain if OT is equally effective in reducing blood loss when given in a slower rate.
Thomas et al. and Bhattacharya et al. found that bolus dosing is associated with significantly more cardiovascular side effects then administered over 5 min both for 5 and 3 IU of OT. Although it has been shown that less than 5 IU OT achieves adequate uterine tone after CD, we need more information to show that this is not associated with an increased incidence of postpartum haemorrhage outside the operating room.
In our study as per [Graph 2], the mean heart rate increased at 20–25 beats/min at 3–5 min in group B and 8–10 beats/min at 2–4 min and reached the baseline at nearly 8–9 min in group B as well as in group I. Also, a significant fall in MBP was observed at 3–5 min in group B. In contrast to our study, Bhattacharya et al. in their study showed an increase in the HR (25–30 beats/min) in the bolus group in 30 s and did not return to the baseline even after 10 min and in the infusion group, a rise of only 10 beats/min and gradually touched the baseline.
In a study by Thomas et al., marked cardiovascular changes occurred in the bolus group (5 IU); the heart rate increased by 17 beats/min compared to 10 beats/min in the infusion group (5 IU in 5 min). He also observed that the MBP decreased by 27 mmHg in the bolus group compared with 8 mmHg in the infusion group. Arshi Taj et al. showed that the MHR increased by 27 (13.9) beats/min and the MBP decreased by 27 (8.4) mmHg in the bolus group (10 IU of OT over 15 s) and increase of 7 (±4.7) in MHR and 8 (±2.7) mmHg in the infusion group (10 IU of OT over 5 min). The reduction in the MBP and the speed of recovery are dose-dependent.
OT has been associated with electrocardiographic changes that may be related to altered myocardial demand-supply ratio or coronary vasospasm. A randomised control trial by Jonsson et al. showed that OT 10 IU versus 5 IU in healthy patients undergoing elective CD showed a 13.9% absolute risk reduction for ST depression in a lower dose. In our study, the ST-T changes were observed in five patients and chest pain in eight patients in the bolus group, while no such adverse effects were seen in the infusion group. Kovacheva et al. in their study showed that electrocardiographic changes were not different between low-dose bolus (3 IU/3 mL) and wide-open infusion (30 IU in 0.9% 500 mL NS) but were seen in a few patients; one patient in the continuous infusion group experienced new-onset atrial fibrillation. In our study, facial flushing was seen in two patients in group B and none in group I, one patient in group I and four patients in group B had nausea and headache, respectively. Like our study, Sartain et al. observed more nausea and antiemetic use with OT 5 IU (32.5%) versus 2 IU (5%) administered over 5–10 s. In contrast to our study, Kovacheva et al. observed no difference in such adverse effects. Thus, a low incidence of these adverse effects may be related to the dose, frequency and rate of OT. Carvalho et al. observed nausea (38%), vomiting (13%) and flushing (63%) in their study.
In our study, no uterotonic agents were required in group I whereas four patients required other uterotonics (injection methylergometrine) in group B. Similar observations were found by Bhattacharya et al. in their study. Three patients required injection carboprost as rescue uterotonics. An effective uterine contraction can be achieved after elective CD in non-labouring women at term by administering boluses of OT, no larger than 1 IU. The minimum effective IV bolus dose of OT is 0.35 IU. Butwick et al., in a randomised controlled trial of OT doses ranging from 0 to 5 IU, indicated that doses up to 3 IU were needed to produce a high prevalence of adequate uterine tone and additional rescue doses of OT were sometimes needed in 5 IU group. Bolus dosing is associated with significantly more cardiovascular side effects if administered over 5 min, for both 5 IU and 3 IU OT.,
Various studies observed that rapidly injected large bolus doses of OT are known to produce potentially dangerous adverse effects. Butwick et al. observed that reducing the dose of the OT bolus may not be the key to reducing the side effects: even doses between 0.5 and 3 IU have been shown to produce hypotension in 20–30% of the patients when given as a bolus. Joseph et al. studied to determine the optimal bolus dose of OT for uterine contractions in elective CD under spinal anaesthesia and concluded that OT bolus doses of one and two units were inadequate while three units appeared to be effective for adequate uterine contraction and reduced blood loss, making haemodynamics stable and absent side effects.
In contrast, Tsen and Balki in their study did not mention the importance of the speed of administration of the OT bolus. In our study, in group B, 3 IU bolus was given over 15 s to avoid any adverse effects similar to the study by Bhattacharya et al. Slow injection of OT can effectively minimise the cardiovascular effects without compromising the therapeutic benefits. But these cardiovascular changes after bolus injection are usually mild (15–20%) and short-lived and well-tolerated by healthy women. Al Zirqi et al. recommended that 5 units of OT in bolus form should be used with caution compared to a slow injection of the same amount of OT.
The estimated blood loss in both groups was not statistically significant in our study as shown in [Table 1]. Similar to our study, Kovacheva et al. observed no difference in significant blood loss. Also, Thomas et al. in their study found no difference in blood loss which agrees with other OT-dosing protocol comparison by Sartain et al.
The limitations of our study were that it was designed to be single-blinded with the analysis of data being separate from their collection to prevent bias. In our study, a single obstetrician was not involved, and hence, the uterine tone measurement by the attending obstetrician was subjective and may be variable as the palpation method was used. Also, there is no other reliable objective test easily available for uterine tone measurement. An accurate estimation of blood loss was not performed as the haematocrit was not measured. We used visual assessment of blood loss in the suction chamber and on surgical swabs which are commonly utilised to estimate blood loss; though these may be inaccurate. Another limitation is that the small sample size in our study may not be adequate in data interpretation regarding the side effects between the bolus and infusion groups. We were unable to assess the minimum effective or optimal dose of OT needed to achieve the uterine tone adequately during CD in the bolus group.
Further studies are needed for evaluation in emergency, cardiovascular unstable as well as a patient at risk of developing uterine atony and high-risk CD to clarify whether there is a benefit of OT used by infusion over bolus dose and the need for other uterotonics to achieve and maintain adequate uterine tone without any adverse effects. Also, comparative studies of OT, and a future drug, carbetocin (longer-acting synthetic derivative of OT), can be studied to reduce postpartum bleeding.
| Conclusion|| |
We conclude that the maximum dose of OT for adequate uterine contraction was less than 5 IU in infusion as well as in the bolus groups. Minimal haemodynamic and other adverse effects were observed with infusion than bolus dose.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]