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ORIGINAL RESEARCH |
From the Departments of 1Anesthesia and Pain Management, 2Obstetrics and Gynaecology, and 3Paediatrics, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
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ABSTRACT |
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 ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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METHODS: A randomized single-blinded study was undertaken in 30 parturients undergoing cesarean deliveries under epidural anesthesia for labor arrest despite intravenous oxytocin augmentation. Oxytocin was administered as a slow intravenous bolus immediately after delivery of the infant, according to a biased coin up-down sequential allocation scheme. After assisted spontaneous delivery of the placenta, the obstetrician, blinded to the oxytocin dose, assessed uterine contraction as either satisfactory or unsatisfactory. Additional boluses of oxytocin were administered as required, followed by a maintenance infusion. Data were interpreted and analyzed by a logistic regression model at 95% confidence intervals.
RESULTS: All patients received oxytocin infusions at a mean ± standard deviation of 9.8 ± 6.3 hours before cesarean delivery (maximum infusion dose 10.3 ± 8.2 mU/min). The minimum effective dose of oxytocin required to produce adequate uterine response in 90% of women (ED90) was estimated to be 2.99 IU (95% confidence interval 2.32–3.67). The estimated blood loss was 1,178 ± 716 mL.
CONCLUSION: Women requiring cesarean delivery for labor arrest after oxytocin augmentation require approximately 3 IU rapid intravenous infusion of oxytocin to achieve effective uterine contraction after delivery. This dose is 9 times more than previously reported after elective cesarean delivery in nonlaboring women at term, suggesting oxytocin receptor desensitization from exogenous oxytocin administration during labor. Therefore, alternative uterotonic agents, rather than additional oxytocin, may achieve superior uterine contraction and control of blood loss during cesarean delivery for labor arrest.
LEVEL OF EVIDENCE: I
Several empirical regimens have been proposed for oxytocin administration during cesarean delivery, and this has led to many different practices in its administration worldwide. These protocols usually recommend a fixed dose of oxytocin, irrespective of the indication for cesarean delivery. In a previous study we estimated the minimum effective dose (ED90) of oxytocin required to produce adequate uterine contraction after elective cesarean delivery in nonlaboring women, noting that such women required much lower doses than those commonly administered in many centers.9
Laboring women requiring cesarean delivery constitute a subset of patients that may exhibit an unpredictable response to oxytocin, because either prolonged labor or use of intravenous oxytocin to augment labor may desensitize the uterus and render it less responsive to the same drug during cesarean delivery. Therefore, the purpose of this study was to estimate the minimum effective dose (ED90) of oxytocin to produce adequate uterine contraction after cesarean delivery for labor arrest in women who had received oxytocin during labor.
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MATERIALS AND METHODS |
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ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Obstetric data, including duration of first and second stage of labor and cervical dilation at the time of diagnosis of labor arrest were recorded. The maximum dose and duration of intravenous oxytocin used for augmentation of labor were also recorded. Oxytocin was stopped once the obstetrician made a decision for cesarean delivery, and the operation proceeded within 30 minutes. Baseline blood pressure (BP) and heart rate were calculated as the mean of 3 readings, 2 minutes apart, recorded in the patient’s laboring room using an automated noninvasive BP device.
On arrival in the operating room, the patient was placed in the supine position with left uterine displacement using a wedge under the right buttock. Lactated Ringer’s solution was infused through the existing intravenous line at the rate of 150 mL/h. Standard monitoring included electrocardiogram, noninvasive BP, heart rate, and SpO2. The existing epidural analgesia was extended to provide surgical anesthesia with 15–20 mL of 2% CO2 lidocaine with epinephrine 1:200,000, titrated to achieve a block height to the T4 dermatome. After delivery, 2 mg of epidural morphine was injected through the epidural catheter to provide postoperative pain relief. All patients received supplemental oxygen by nasal prongs at the rate of 4 L/min until the delivery of the infant.
Systolic BP and heart rate were recorded every minute until the end of the operation. Systolic BP was maintained within 10% of the baseline values with aliquots of phenylephrine 0.1 mg. Patients not responding to phenylephrine were treated with increments of 5 mg of ephedrine. Hypotension was defined as a decrease in systolic BP greater than 20% of the baseline value, despite the use of a vasopressor.
Oxytocin was administered as an intravenous bolus, immediately upon delivery of the anterior shoulder of the infant, using a syringe containing 0.5 IU/mL, at a rate of 1 mL over 5 seconds. The dose of oxytocin for each patient was determined by the response of the previous patient to the drug, according to a biased coin up-and-down sequential allocation scheme designed to cluster doses close to ED90.9,10
If a patient did not respond adequately to the initial bolus of oxytocin, the initial dose for the next patient was increased by 0.5 IU. If the patient responded to the initial bolus, the dose for the next patient was decreased by 0.5 IU with a probability of 1/9; otherwise it remained unchanged. The "biased coin" allocation after each successful response was implemented using a computer-generated list of random responses prepared by the biostatistician in the unit: "Maintain Previous Dose" (8/9) or "Reduce Dose by 0.5 IU (1/9)." One exception was the first patient in the study, for whom the starting dose of oxytocin was arbitrarily chosen as 0.5 IU.
The obstetrician was asked to assist spontaneous delivery of the placenta using cord traction, but without uterine massage, and to keep the uterus inside the abdominal cavity until delivery of the placenta. The uterus was then exteriorized for repair. The obstetrician, blinded to the oxytocin dose, assessed uterine tone by palpation every minute, either in situ before placental delivery, or after exteriorization after delivery of the placenta. The obstetrician then rated the degree of uterine contraction as either satisfactory or unsatisfactory. If the uterine tone remained unsatisfactory at 3 minutes after initial oxytocin bolus, the obstetrician massaged the uterus and requested additional boluses of 0.5 IU to be administered every minute until uterine contraction was satisfactory. An infusion of 40 mU/min of oxytocin (20 IU/L at the rate of 120 mL/h) was then started and continued at the same rate for up to 8 hours after delivery. Cefazolin (1g diluted in 20 mL normal saline) was administered over a 5-minute period after delivery of the infant. Hemoglobin and hematocrit levels were recorded before surgery and at 48 hours after surgery to estimate intraoperative blood loss.
The primary outcome was the uterine response to the initial intravenous bolus of oxytocin, rated by the obstetrician as satisfactory or unsatisfactory. Response time was determined as the time interval between the administration of the initial oxytocin dose and satisfactory uterine contraction, as assessed by the obstetrician. Secondary outcomes were estimated blood loss and oxytocin-related side effects. For the purpose of this study, the minimum effective dose of oxytocin was defined to be that at which adequate response would occur in 90% of patients, ie, ED90.
Sample size was calculated by computer simulation using 10,000 replications. Based on clinical experience, it was expected that 50% of patients would respond to an initial oxytocin dose of 2.5 IU and 90% to 5 IU. Assuming that the actual response was described by a 2-parameter logistic curve with these properties, a simulation of the proposed sequential allocation scheme determined that 80% of the time the minimum effective dose (ED90) could be estimated with a standard error of less than 1.27 IU if a sample of 30 patients was used.
A logistic regression model was used to estimate the ED90. Evidence of an association between the initial oxytocin dose and response time was assessed using the Jonckheere-Terpstra test, which is a nonparametric test for ordered differences between classes.11 It tests the null hypothesis of no difference between classes. Patients who did not respond to the initial oxytocin bolus were treated as being interval-censored between the first and second dose. Exact 2-tailed P values were used. The linear association between continuous variables was measured using the parametric Pearson correlation coefficient and the nonparametric Spearman correlation coefficient, as appropriate. The Shapiro-Wilk test was used to test for normality.12 All of the analyses were done in Splus 6.1 and SAS 8.2 (SAS Institute Inc., Cary, NC).
Blood loss was estimated by the difference in hematocrit values assessed before and at 48 hours after cesarean delivery according to the following formula: estimated blood volume (preoperative hematocrit – postoperative hematocrit)/preoperative hematocrit, where estimated blood volume in milliliters is measured as the patient’s weight in kilograms x 85 (Shook PR, Schultz JR, Reynolds JD, Spahn TE, DeBalli P. Estimating blood loss for cesarean section: how accurate are we? Anesthesiology 2003; 98 supp:A1). Any adverse effects occurring before and after delivery, such as hypotension, dysrhythmias, nausea, vomiting, chest pain, shortness of breath, headache, flushing, and shivering were recorded.
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RESULTS |
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Based on the logistic regression model fitted to the data, it was estimated that the dose at which 90% of the women would respond with adequate uterine contraction (ED90) was 2.99 IU (standard error 0.34 IU). The 95% confidence interval for ED90 was 2.32–3.67 IU. Figure 1 represents the fitted response curve with the corresponding 95% confidence interval. Table 2 shows the uterine response time in minutes after the initial oxytocin bolus dose. There is strong evidence of a trend in decreasing uterine response time with increasing initial oxytocin dose (P = .001), based on the Jonckheere-Terpstra test. If the actual response time is treated as censored for the 7 patients who did not respond to the initial dose, then the association between the initial dose and the response time becomes weak (P = .03).
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Most patients (22 of 30) had effective uterine contraction within 3 minutes at 2–3.5 IU of initial oxytocin dose, whereas patients who received less than 2 IU did not respond within 3 minutes and required additional oxytocin boluses. All patients receiving 3.5 IU initial oxytocin dose showed adequate uterine response within 1 to 2 minutes (Table 2).
The mean duration of oxytocin exposure during labor was 9.8 ± 6.3 hours, and the mean maximum dose of oxytocin infusion was 10.3 ± 8.2 mU/min (Table 1). We found no significant correlations between 1) duration of oxytocin infusion during labor and the time for effective uterine contraction after cesarean delivery (P = .74, correlation coefficient 0.07), 2) duration of oxytocin infusion during labor and the total oxytocin bolus dose after cesarean delivery (P = .49, correlation coefficient 0.14), 3) maximum dose of oxytocin infusion during labor and the time for effective uterine contraction after cesarean delivery (P = .87, correlation coefficient 0.03), and 4) maximum dose of oxytocin infusion during labor and the total oxytocin bolus after cesarean delivery (P = .81, correlation coefficient 0.05). Two cases were excluded from the analysis due to the obstetricians’ request for higher doses of oxytocin before the 3-minute response time (oxytocin 10 IU, oxytocin 7 IU and ergonovine 250 µg). These patients were considered nonresponsive to the initial oxytocin bolus.
The mean estimated blood loss was 1,178 ± 716 mL (range 201–2,576 mL) as calculated from the preoperative and postoperative hematocrit values. There was no correlation between the initial oxytocin dose after cesarean delivery and estimated blood loss (P = .82, correlation coefficient –0.04). The adverse effects in both the predelivery and postdelivery periods recorded during the study are shown in Table 3. Hypotension occurred in 10% and 30% of patients before and after delivery, respectively. The mean dose of phenylephrine required was 0.06 ± 0.15 mg predelivery and 0.22 ± 0.28 mg postdelivery.
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DISCUSSION |
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In a previous study, we demonstrated that effective uterine contraction can be achieved after elective cesarean delivery in nonlaboring women with an oxytocin bolus dose no larger than 1 IU, the ED90 being 0.35 IU.9 The current study used the same design with administration of oxytocin in an up-down sequential allocation fashion. However, the subject population consisted of laboring women who had received oxytocin for either induction or augmentation of labor before cesarean delivery. We found the ED90 of oxytocin in these circumstances to be 2.99 IU, about 9 times higher than in nonlaboring women at term.
Molecular characterization of myometrial oxytocin receptor expression and density may clarify these differences. The uterus becomes markedly sensitive to the effects of oxytocin while preparing for parturition.14,15 Oxytocin, a nonpeptide hormone, is known to act both directly by binding with uterine oxytocin receptors and indirectly by paracrine mechanisms.16 Due to the effects of estrogen, the uterine oxytocin receptor population density increases progressively during pregnancy to reach a peak at term.17 In late pregnancy, before the onset of labor, uterine oxytocin receptor concentrations are, on average, 12 times higher than in early pregnancy, and about 80 times higher than the nonpregnant values.14 Messenger RNA expression of oxytocin receptors rises with gestation to a 300-fold increase at parturition, compared with that of the nonpregnant myometrium.15 This could explain the uterine response to low doses of oxytocin at term elective cesarean deliveries, as observed in our previous study.9
Labor induces further changes in oxytocin receptor population. In early labor, the oxytocin receptor population is significantly higher than in term nonlaboring patients, on the average of 2.5 times. However, in active labor with the cervix more than 7 cm dilated, oxytocin receptor concentrations are reduced, on average approximately twice those found in early pregnancy.14 Phaneuf et al18 compared spontaneous with oxytocin-induced labor and demonstrated significant reduction in the oxytocin binding sites in the induced labor group. Continuous exposure of human myometrial cells to oxytocin leads to a significant loss in their capacity to respond to oxytocin, believed to be due to oxytocin receptor desensitization. Robinson et al19 observed oxytocin receptor desensitization starting at 3 hours of exposure of human myometrial cells to oxytocin in vitro. Our study provides further clinical evidence that oxytocin receptor signaling is attenuated in laboring women at the time of cesarean delivery. We did not find any correlation of the dose and duration of oxytocin infusion administered during labor with the time required for effective uterine contraction or the total dose of oxytocin required at cesarean delivery. Our study, however, was not powered to determine these correlations.
The mean calculated blood loss in our study was 1,178 ± 716 mL, approximately 2 times that of elective cesarean delivery requiring low-dose oxytocin (693 ± 487 mL).9 It is usual practice to increase the dose of oxytocin, assuming higher doses will result in more effective uterine contraction. We advocate that higher doses of oxytocin are unlikely to improve uterine contraction further and thus prevent postpartum hemorrhage, because the population of oxytocin receptors will not only be reduced but also be desensitized. Sarna et al20 found no advantage in increasing oxytocin dose above 5 IU during elective cesarean delivery. Munn et al21 used extremely high doses of oxytocin at the rate of 2,667 mU/min and 333 mU/min for 30 minutes after cesarean delivery in laboring women. These patients still required additional uterotonic agents in 19% and 39% of cases, respectively. Further, if a larger dose of oxytocin is rapidly infused, its side effects may outweigh its uterotonic action.13,22–27 Hence, we suggest that, especially in laboring patients, consideration should be given to the alternate pathway uterotonic medications, such as ergot derivatives, carboprost, or misoprostol. We would predict that the response to these agonists is unaltered, because the oxytocin-induced desensitization is homologous.18
Our study indicates that women undergoing cesarean delivery for labor arrest require approximately 3 IU of oxytocin as a "loading dose" to achieve adequate uterine contraction, before a maintenance oxytocin infusion (20 IU/L at 120 mL/h) is continued. We recommend that this dose be administered as a rapid diluted intravenous oxytocin infusion to avoid the well-known potential complications of rapid intravenous bolus, such as hypotension.13,22–27 We recognize and suggest that oxytocin infusion is preferable to bolus injection for safety reasons; however, such infusion will have to be initially administered at a rate that will ensure appropriate drug levels.
The doses of oxytocin required in both our studies are lower than those usually recommended. These doses could reflect the method of assisted delivery of the placenta, allowing a longer fetus-to-placenta delivery interval, during which time the lower dose of oxytocin may have had sufficient time to cause effective uterine contraction. Therefore, implementation of these lower dosage regimens after cesarean delivery may require reevaluation of the surgical practice surrounding delivery of the placenta.
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Footnotes |
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Corresponding author: Mrinalini Balki, MD, Department of Anesthesia and Pain Management, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, Canada, M5G 1X5; e-mail: mrinalini.balki{at}uhn.on.ca.
doi:10.1097/01.AOG.0000191529.52596.c0
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REFERENCES |
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