- Email: [email protected]
Comparison of two oxytocin regimens to prevent uterine atony at cesarean delivery: a randomized controlled trial
Comparison of Two Oxytocin Regimens to Prevent Uterine Atony at Cesarean Delivery: A Randomized Controlled Trial Mary B. Munn, MD, John Owen, MD, Robert Vincent, MD, Marsha Wakefield, MD, David H. Chestnut, MD, and John C. Hauth, MD OBJECTIVE: To determine if high-dose oxytocin reduces the need for additional uterotonic agents at cesarean. METHODS: A randomized, double-masked trial of two oxytocin regimens was performed to prevent postpartum uterine atony in laboring women. The pharmacy prepared sequentially numbered oxytocin solutions containing either 10 U/500 mL or 80 U/500 mL of lactated Ringer’s solution infused over 30 minutes after cord clamping. The need for additional uterotonic agents was determined by the surgical team. Hypotension was diagnosed and treated with crystalloid or a pressor agent. To detect a 50% decrease in the need for additional uterotonic agents and considering a  error of 0.2, 220 patients would be required in each group (␣ ⴝ 0.05, two-tailed 2 test). RESULTS: The low-dose group (n ⴝ 163) received 333 mU/ min, and the high-dose group (n ⴝ 158) received 2667 mU/min of oxytocin. The groups were similar with respect to risk factors for atony. Women in the low-dose group received additional uterotonic medication significantly more often than those in the high-dose group (39% compared with 19%, P < .001, relative risk 2.1, 95% confidence interval 1.4, 3.0). Moreover, more women in the low-dose group received methylergonovine, 15-methyl prostaglandin F2␣ or both (9% compared with 2%, relative risk 4.8, 95% confidence interval 1.4, 16) after additional oxytocin (median 20 U) had been added to the study solution. The incidence of hypotension was similar in both groups. CONCLUSION: Compared with an infusion rate of 333 mU/ min, oxytocin infused at 2667 mU/min for the first 30 minutes postpartum reduces the need for additional uterotonic agents at cesarean delivery. (Obstet Gynecol 2001; 98:386 –90. © 2001 by the American College of Obstetricians and Gynecologists.)
Oxytocin is commonly used to prevent postpartum uterine atony. Previous controlled trials support the routine From the Departments of Obstetrics and Gynecology and Anesthesiology, The University of Alabama at Birmingham, Birmingham, Alabama. Funded only by the Internal Division Resources, The University of Alabama at Birmingham, Birmingham, Alabama.
386
administration of oxytocin to reduce the risk of postpartum hemorrhage after vaginal delivery, especially when compared with either placebo or no active intervention.1–3 Various regimens have been described. Oxytocin with ergometrine,3 as well as oxytocin given alone,2 has been shown to reduce the incidence of hemorrhage. Prendiville et al1 performed a meta-analysis of nine randomized trials of oxytocics administered in the third stage of labor. They concluded that both intravenous and intramuscular oxytocin effectively reduced postpartum hemorrhage if given after delivery of the anterior shoulder, crowning of the head, delivery of the placenta, or cord clamping. Uterotonic agents may have serious side effects. Ergot derivatives may cause or aggravate hypertension and are relatively contraindicated in women with hypertensive disorders. Prostaglandin estradiol (E2) may cause hypotension, and like prostaglandin estrone (E1), has gastrointestinal effects such as nausea, vomiting, and diarrhea. Because of its vaso- and bronchoconstrictive activity, 15-methyl prostaglandin F2␣ is discouraged in patients with cardiac disease or asthma. Conversely, oxytocin has no appreciable contraindications4 but can produce hypotension. Secher et al5 found that intravenous bolus doses as small as 10 U were followed promptly by profound hypotension. However, the administration of 10 U over a (nominal) 10-second interval is equivalent to a rate of 60,000 mU/min, which is 180-fold higher than a regimen of 20 U, diluted in 1 L of crystalloid, and given over 1 hour (333 mU/min).6 We have previously shown that higher concentrations of oxytocin are well tolerated. Intravenous oxytocin, up to 300 U over 3 hours (1667 mU/min), successfully affects second-trimester pregnancy termination with no significant cardiovascular side effects.7–9 Nevertheless, the efficacy of higher infusion rates (but considerably below bolus rates) to prevent postpartum atony has not been well studied. Uterine atony is an important contributor to blood
VOL. 98, NO. 3, SEPTEMBER 2001 © 2001 by The American College of Obstetricians and Gynecologists. Published by Elsevier Science Inc.
0029-7844/01/$20.00 PII S0029-7844(01)01479-X
loss at cesarean delivery, yet much of the literature pertaining to the prevention of hemorrhage from atony has focused primarily on vaginal deliveries.1–3 However, induced or augmented labor,6 and especially protracted labor and arrest disorders,10 comprise significant risk factors for uterine atony at cesarean delivery. Because laboring women appear to be at increased risk for atony compared with women who have not labored, we conducted a trial to determine if high-dose oxytocin affects the incidence of clinically significant uterine atony and the prescribed use of additional uterotonic agents at cesarean delivery in this at-risk population. MATERIALS AND METHODS Between January, 1997, and November, 1999, we performed a randomized, double-masked trial of two oxytocin regimens to prevent uterine atony. The study was approved by the University of Alabama at Birmingham Institutional Review Board. All women admitted for labor and delivery were invited to participate in the study. Patients who had not experienced labor before cesarean delivery were excluded. Labor was defined as at least two contractions in 10 minutes and either an initial cervical dilation of at least 2 cm or progressive cervical change. Patients were randomized using a computer-generated random number sequence. At surgery, a sealed opaque envelope containing the randomization number and data sheet was opened for each consenting patient. The randomization scheme was stratified by whether the patient had been receiving parenteral magnesium sulfate for either preeclampsia or preterm labor. Pre-mixed, oxytocin solutions prepared by the pharmacy, with either 10 U/500 mL or 80 U/500 mL of lactated Ringer’s solution, were available in the labor and delivery unit. The bags were identical in appearance. Each bag was labeled only with a study identification number, from which the pharmacy could determine the administered dose. After delivery of the infant, the study mixture was infused over 30 minutes (333 mU/min versus 2667 mU/min) using a continuous infusion pump. The technique of assisted spontaneous placental delivery was used.11 Determination of the need for additional uterotonic agents was made by the obstetrician and administered and recorded by the anesthesiologist. At the discretion of the surgical team, additional oxytocin could be added to the study solution (eg, 20 U) before requesting methylergonovine, 0.2 mg IM, or 15-methyl prostaglandin F2␣ 250 g IM. The anesthesiologist continuously monitored oxygen saturation and blood pressure (BP). Clinically significant hypotension was determined by the anesthesiologist, and corrective measures were instituted for a systolic BP
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less than 100 mmHg, a mean arterial pressure less than 60 mmHg, or a 20% decrease in BP from baseline measurements. Failure of unexplained hypotension (ie, not attributable to hemorrhage) to resolve with fluid administration and pressor agents would result in discontinuation of the oxytocin solution. After surgery, patients were monitored in the postanesthesia care unit. Blood pressure, heart rate, oxygen saturation, and the need for additional uterotonic agents were also recorded. In the postanesthesia care unit, all patients received a mixture of 20 U of oxytocin in 1 L of lactated Ringer’s solution at a rate of 125 mL/h (41.7 mU/min), which was continued for 8 hours. On the first postoperative day, the hematocrit was determined and compared with the admission value. The sample size calculation for our primary outcome was based on the following assumptions: we estimated that in 20% of our laboring patients who underwent cesarean delivery, additional pharmacologic therapy for atony not controlled by our standard oxytocin dosage (333 mU/min) and uterine massage would be requested. To detect a 50% decrease (ie, a 10% rate), and considering a  error of 0.2, 220 patients in each group would be required (␣ ⫽ 0.05, two-tailed 2 test). We planned an interim masked intergroup analysis after two-thirds of our sample had been enrolled. The trial would be stopped for a significance level ⬍ 0.01 for the primary outcome. Proportional data were compared with 2. The Fisher exact test was chosen if the expected size of any cell of the contingency table was less than 5. Continuous data were compared using the Wilcoxon rank-sum test. Multiple logistic regression was used to model the relationship between group assignment and the need for additional uterotonic agents, controlling for possible confounders. P ⬍ .05 was considered significant. All patients enrolled into the trial were analyzed on an intent-to-treat basis. RESULTS A total of 163 patients were randomized to our standard prophylactic (low-dose) oxytocin regimen (333 mU/ min), and 158 were assigned to the high-dose group (2667 mU/min); however, the group assignments remained masked during the interim “A-B” analysis. The quality and completeness of all outcome data were verified and locked before unmasking the two group assignments. There were no differences between the two groups with regard to selected maternal characteristics and the indications for cesarean delivery (Table 1). Intrapartum characteristics were also similar in the two groups, including proportions of women receiving magnesium sulfate, oxytocin, and amnioinfusion, the inci-
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Table 1. Selected Characteristics and Cesarean Indications of Women Assigned to Receive 333 mU/min or 2667 mU/min of Oxytocin Postpartum at Cesarean Delivery
Mean (⫾ 1 SD) age (y) White race (%) Nulliparous (%) Mean (⫾ 1 SD) gestational age (wk) Multiple gestation (%) Cesarean indication Nonreassuring fetal heart rate tracing (%) Arrest of labor (%) Abnormal lie (%) Other (%) Anesthetic technique for surgery Epidural (%) Spinal (%) General (%) General plus regional (%)
333 mU/min
2667 mU/min
P
25 ⫾ 6.0 36 58 37 ⫾ 4.3
25 ⫾ 6.1 37 51 37 ⫾ 4.9
.38 .9 .17 .47
7.4
5.1
.39 .16
29
29
41 21 9
34 23 15
59 27 11 3
69 20 8 3
.26
SD ⫽ standard deviation.
dence of chorioamnionitis in each group, and the duration of membrane rupture (Table 2). Thirteen patients in the low-dose group compared with 18 women in the high-dose group underwent tubal ligation at cesarean (P ⫽ .18). The rates of regional anesthesia were similar in the groups: 92% of women in the low-dose group compared with 89% in the high-dose group (P ⫽ .39). The mean duration of surgery in the groups was also similar: 52 ⫾ 16 minutes in the low-dose group and 54 ⫾ 18 minutes in the high-dose group (P ⫽ .53). None of the patients in either group underwent cesarean hysterectomy or received a blood transfusion. More women in the low-dose group required an addi-
Table 2. Intrapartum Characteristics of Women Assigned to Receive 333 mU/min or 2667 mU/min of Oxytocin Postpartum at Cesarean Delivery
Intrapartum MgSO4 (%) Oxytocin None (%) Augmentation (%) Induction (%) Amnioinfusion (%) Median (range) duration of membrane rupture (h) Chorioamnionitis (%)
388
Munn et al
333 mU/min
2667 mU/min
18
20
36 23 41 19 7.9 (0–336)
46 18 36 23 5.9 (0–303)
24
18
Atony Prevention at Cesarean
P .67 .15 .15 .44 .05 .22
tional uterotonic agent compared with women in the high-dose group (39% compared with 19%, P ⬍ .001, relative risk [RR] 2.1, 95% confidence interval [CI] 1.4, 3.0). Thirty-six percent of the patients in the standard group received additional oxytocin for uterine atony, in contrast to only 19% of patients in the high-dose group (P ⫽ .006). After additional oxytocin (median 20 U) was given, 9% of patients in the low-dose group received methylergonovine or 15-methyl prostaglandin F2␣ for persistent uterine atony, whereas only 2% of patients in the high-dose group received methylergonovine or 15methyl prostaglandin F2␣ (P ⫽ .005, RR 4.8, 95% CI 1.4, 16). There was no difference in the number of women who received an intravenous bolus of crystalloid (19% in the low-dose group compared with 17% in the high-dose group, P ⫽ .55) or pressor agents (25% in the low-dose group compared with 24% in the high-dose group, P ⫽ .82), or both (13% compared with 11%, P ⫽ .56) for BP support. In no case was the study solution discontinued for unexplained hypotension. No patient required additional uterotonic agents in the postanesthesia care unit, and only one woman was treated for hypotension. The mean estimated blood loss (957 ⫾ 148 mL compared with 937 ⫾ 159 mL, P ⫽ .08) and the mean change in the hematocrit (⫺4.6 ⫾ 3.8% compared with ⫺4.1 ⫾ 3.6%, P ⫽ .46) in the two groups were also similar. We also determined whether women with specific risk factors for uterine atony had the same response from the higher infusion rate. We observed that the 120 women who had experienced labor arrest were more likely to require additional uterotonic agents than women with other cesarean indications (41% compared with 22%, P ⬍ .001). Similarly, the 68 women with the intrapartum clinical diagnosis of chorioamnionitis were more likely to require additional uterotonic agents than those who did not have this clinical diagnosis (50% compared with 24%, P ⬍ .001). However, we determined that intrapartum magnesium sulfate was not a significant risk factor for uterine atony; the 63 women who received magnesium sulfate experienced a similar need for additional uterotonic agents compared with those who did not receive this drug (32% compared with 29%, P ⫽ .57). We further analyzed the relationship between labor arrest and clinical chorioamnionitis and the need for additional uterotonic agents by including them along with group assignment in a multiple logistic regression model with the need for additional uterotonic agents as the dependent variable. After controlling for these factors, women in the high-dose group still experienced an independent and lower incidence of additionally administered uterotonic agents (odds ratio ⫽ 0.38, 95% CI 0.22, 0.64).
OBSTETRICS & GYNECOLOGY
DISCUSSION We observed a significant decrease in the number of requests for additional uterotonic agents and no adverse side effects in women who received 2667 mU/min compared with 333 mU/min of oxytocin at cesarean delivery. Because both the surgeons and anesthesiologists were masked to the group assignments, this could not have influenced their perception of atony or the request for additional uterotonic agents. Our study groups were also similar for risk factors associated with uterine atony (eg, cesarean indication, chorioamnionitis), and we found that the higher dose of oxytocin remained more effective after controlling for these confounders. Treatment for hypotension was not significantly different between the two groups; approximately 40% of the patients in each group received additional crystalloid or ephedrine. The mean estimated blood loss and the decrease in hematocrit did not differ in the two groups. This is not unexpected, as atony is quickly recognized and treated at cesarean, because the uterus is exposed and more easily evaluated than at vaginal delivery. This facilitates prompt recognition and treatment, which limits blood loss. Uterotonic agents (ie, oxytocin, prostaglandins, ergot derivatives) decrease the incidence of postpartum hemorrhage by approximately 40% when compared with placebo or no routine prophylactic agent.1–3 Compared with placebo, the need for additional uterotonic agents is also reduced when oxytocin is routinely used after vaginal delivery.2,3,12 Chou and MacKenzie13 found no difference in blood loss at cesarean delivery when comparing intramyometrial prostaglandin F2␣ (125 g) and oxytocin administered as a 5 U “slow” bolus, followed by a rate of 125 mU/min for 2 hours. Although this study of 60 women had limited power to detect clinically significant differences in the rate of additionally administered uterotonic agents, more women in the prostaglandin F2␣ group required additional pharmacologic therapy for atony. Oxytocin appears to be the drug of choice to prevent postpartum hemorrhage in the United States. It is a safe medication and has no appreciable cardiovascular side effects when administered as a continuous intravenous infusion.7–9 However, we recommend that oxytocin be administered with an isotonic solution because of its antidiuretic effect and the possibility of hyponatremia.8 Although its use is widespread, the optimal dose has not been established for either vaginal or cesarean delivery. Small intravenous bolus doses1 (less than 10 U) or dilute solutions of 10 – 40 U of oxytocin in 1000 mL of crytalloid solution,4,6 given at a rate of 200 mU/min to 1000 mU/min,14 have been recommended for the pre-
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vention of postpartum bleeding after vaginal delivery. Guidelines for oxytocin administration at cesarean delivery appear to be mostly empiric or extrapolated from vaginal delivery regimens. Sarna et al15 reported no difference in postoperative hematocrit when oxytocin was used in doses of 5–20 U at elective cesarean delivery; however, these doses were all infused at a constant rate (100 mU/min), and this study did not address the question of whether higher infusion rates would more effectively prevent atony during cesarean delivery. We hypothesize that the higher dose of oxytocin more effectively prevents uterine atony at cesarean delivery, and that prophylaxis is more effective than treatment. Even when more oxytocin was subsequently administered, second-line agents (methylergonovine and 15methyl prostaglandin F2␣) were still required more frequently in the low-dose group. Reducing the need for second-line uterotonic agents is a clinically important finding because methylergonovine or 15-methyl prostaglandin F2␣ may be contraindicated in women with hypertension or asthma. Further, the use of 15-methyl prostaglandin F2␣ for uterine atony has been associated with maternal arterial oxygen desaturation during general anesthesia.16 These findings may be particularly relevant to practitioners in less developed countries that lack the facilities to store thermally labile prostaglandin analogues. Because oxytocin is less costly than both methylergonovine and 15-methyl prostaglandin F2␣, cost savings might also be realized. REFERENCES 1. Prendiville W, Elbourne D, Chalmers I. The effects of routine oxytocin administration in the management of the third stage of labour: An overview of the evidence from controlled trials. Br J Obstet Gynaecol 1988;95:3–16. 2. Nordstrom L, Fogelstam K, Gridman G, Larsson A, Rydhstroem H. Routine oxytocin in the third stage of labour: A placebo controlled randomized trial. Br J Obstet Gynecol 1997;104:781– 6. 3. Rogers J, Wood J, McCandish R, Ayers S, Truesdale A, Elbourne D. Active versus expectant management of third stage labour: The Hinchingbrooke randomized controlled trial. Lancet 1998;351:693–9. 4. American College of Obstetricians and Gynecologists. Postpartum hemorrhage. ACOG educational bulletin no. 243. Washington, DC: American College of Obstetricians and Gynecologists, 1998. 5. Secher NJ, Arnso P, Wallin L. Haemodynamic effects of oxytocin (Synotocinon) and methylergonetrine (Methergine) on the systemic and pulmonary circulations of pregnant anaesthetized women. Acta Obstet Gynecol Scand 1978;57:97–103. 6. Cunningham FG, MacDonald PC, Gant NF, Leveno KJ,
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7.
8.
9.
10.
11.
12.
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Gilstrap LC, Hankins GDV, et al. Williams obstetrics. 20th ed. Stamford, CT: Appleton & Lange, 1997. Owen J, Hauth JC. Comparison of concentrated oxytocin plus low dose prostaglandin E2 vaginal suppositories in mid-trimester pregnancy termination. Obstet Gynecol 1996;88:110 –3. Owen J, Hauth JC, Winkler CL, Gray SE. Midtrimester pregnancy termination: A randomized trial of prostaglandin E2 versus concentrated oxytocin. Am J Obstet Gynecol 1992;167:1112– 6. Winkler CL, Gray SE, Hauth JC, Owen J, Tucker JM. Mid-second-trimester labor induction: Concentrated oxytocin compared with prostaglandin E2 vaginal suppositories. Obstet Gynecol 1991;77:297–300. Combs CA, Murphy EL, Laros RK. Factors associated with hemorrhage in cesarean deliveries. Obstet Gynecol 1991;77:77– 82. Atkinson MW, Owen J, Wren A, Hauth JC. The effect of manual removal of the placenta on post-cesarean endometritis. Obstet Gynecol 1996;87:99 –102. Thiliganathan B, Cutner A, Latimer J, Beard R. Management of the third stage of labour in women at low risk of PPH. Eur J Obstet Gynecol Reprod Biol 1993;48:19 –22.
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13. Chou MM, MacKenzie IZ. A prospective, double-blinded, randomized comparison of prophylactic intramyometrial 15-methyl prostaglandin F, 125 micrograms, and intravenous oxytocin, 20 units, for the control of blood loss at elective cesarean section. Am J Obstet Gynecol 1994;171: 1356 – 60. 14. Gabbe SG, Niebyl JR, Simpson JL. Obstetrics: Normal and problem pregnancies. 3rd ed. New York: Churchill Livingstone, 1996. 15. Sarna MC, Soni AK, Gomez M, Oriol NE. Intravenous oxytocin in patients undergoing elective cesarean section. Anesth Analg 1997;84:753– 6. 16. Hankins GDV, Berryman GK, Scott RT, Hood D. Maternal arterial desaturation with 15-methyl prostaglandin F2␣ for uterine atony. Obstet Gynecol 1988;72:367–70. Address reprint requests to: Mary B. Munn, MD, Department of Obstetrics and Gynecology, University of South Alabama, 251 Cox Street, Suite 100, Mobile, AL 36604-3302; E-mail: [email protected]. Received March 1, 2001. Received in revised form May 29, 2001. Accepted May 31, 2001.
OBSTETRICS & GYNECOLOGY
Oxytocin is commonly used to prevent postpartum uterine atony. Previous controlled trials support the routine From the Departments of Obstetrics and Gynecology and Anesthesiology, The University of Alabama at Birmingham, Birmingham, Alabama. Funded only by the Internal Division Resources, The University of Alabama at Birmingham, Birmingham, Alabama.
386
administration of oxytocin to reduce the risk of postpartum hemorrhage after vaginal delivery, especially when compared with either placebo or no active intervention.1–3 Various regimens have been described. Oxytocin with ergometrine,3 as well as oxytocin given alone,2 has been shown to reduce the incidence of hemorrhage. Prendiville et al1 performed a meta-analysis of nine randomized trials of oxytocics administered in the third stage of labor. They concluded that both intravenous and intramuscular oxytocin effectively reduced postpartum hemorrhage if given after delivery of the anterior shoulder, crowning of the head, delivery of the placenta, or cord clamping. Uterotonic agents may have serious side effects. Ergot derivatives may cause or aggravate hypertension and are relatively contraindicated in women with hypertensive disorders. Prostaglandin estradiol (E2) may cause hypotension, and like prostaglandin estrone (E1), has gastrointestinal effects such as nausea, vomiting, and diarrhea. Because of its vaso- and bronchoconstrictive activity, 15-methyl prostaglandin F2␣ is discouraged in patients with cardiac disease or asthma. Conversely, oxytocin has no appreciable contraindications4 but can produce hypotension. Secher et al5 found that intravenous bolus doses as small as 10 U were followed promptly by profound hypotension. However, the administration of 10 U over a (nominal) 10-second interval is equivalent to a rate of 60,000 mU/min, which is 180-fold higher than a regimen of 20 U, diluted in 1 L of crystalloid, and given over 1 hour (333 mU/min).6 We have previously shown that higher concentrations of oxytocin are well tolerated. Intravenous oxytocin, up to 300 U over 3 hours (1667 mU/min), successfully affects second-trimester pregnancy termination with no significant cardiovascular side effects.7–9 Nevertheless, the efficacy of higher infusion rates (but considerably below bolus rates) to prevent postpartum atony has not been well studied. Uterine atony is an important contributor to blood
VOL. 98, NO. 3, SEPTEMBER 2001 © 2001 by The American College of Obstetricians and Gynecologists. Published by Elsevier Science Inc.
0029-7844/01/$20.00 PII S0029-7844(01)01479-X
loss at cesarean delivery, yet much of the literature pertaining to the prevention of hemorrhage from atony has focused primarily on vaginal deliveries.1–3 However, induced or augmented labor,6 and especially protracted labor and arrest disorders,10 comprise significant risk factors for uterine atony at cesarean delivery. Because laboring women appear to be at increased risk for atony compared with women who have not labored, we conducted a trial to determine if high-dose oxytocin affects the incidence of clinically significant uterine atony and the prescribed use of additional uterotonic agents at cesarean delivery in this at-risk population. MATERIALS AND METHODS Between January, 1997, and November, 1999, we performed a randomized, double-masked trial of two oxytocin regimens to prevent uterine atony. The study was approved by the University of Alabama at Birmingham Institutional Review Board. All women admitted for labor and delivery were invited to participate in the study. Patients who had not experienced labor before cesarean delivery were excluded. Labor was defined as at least two contractions in 10 minutes and either an initial cervical dilation of at least 2 cm or progressive cervical change. Patients were randomized using a computer-generated random number sequence. At surgery, a sealed opaque envelope containing the randomization number and data sheet was opened for each consenting patient. The randomization scheme was stratified by whether the patient had been receiving parenteral magnesium sulfate for either preeclampsia or preterm labor. Pre-mixed, oxytocin solutions prepared by the pharmacy, with either 10 U/500 mL or 80 U/500 mL of lactated Ringer’s solution, were available in the labor and delivery unit. The bags were identical in appearance. Each bag was labeled only with a study identification number, from which the pharmacy could determine the administered dose. After delivery of the infant, the study mixture was infused over 30 minutes (333 mU/min versus 2667 mU/min) using a continuous infusion pump. The technique of assisted spontaneous placental delivery was used.11 Determination of the need for additional uterotonic agents was made by the obstetrician and administered and recorded by the anesthesiologist. At the discretion of the surgical team, additional oxytocin could be added to the study solution (eg, 20 U) before requesting methylergonovine, 0.2 mg IM, or 15-methyl prostaglandin F2␣ 250 g IM. The anesthesiologist continuously monitored oxygen saturation and blood pressure (BP). Clinically significant hypotension was determined by the anesthesiologist, and corrective measures were instituted for a systolic BP
VOL. 98, NO. 3, SEPTEMBER 2001
less than 100 mmHg, a mean arterial pressure less than 60 mmHg, or a 20% decrease in BP from baseline measurements. Failure of unexplained hypotension (ie, not attributable to hemorrhage) to resolve with fluid administration and pressor agents would result in discontinuation of the oxytocin solution. After surgery, patients were monitored in the postanesthesia care unit. Blood pressure, heart rate, oxygen saturation, and the need for additional uterotonic agents were also recorded. In the postanesthesia care unit, all patients received a mixture of 20 U of oxytocin in 1 L of lactated Ringer’s solution at a rate of 125 mL/h (41.7 mU/min), which was continued for 8 hours. On the first postoperative day, the hematocrit was determined and compared with the admission value. The sample size calculation for our primary outcome was based on the following assumptions: we estimated that in 20% of our laboring patients who underwent cesarean delivery, additional pharmacologic therapy for atony not controlled by our standard oxytocin dosage (333 mU/min) and uterine massage would be requested. To detect a 50% decrease (ie, a 10% rate), and considering a  error of 0.2, 220 patients in each group would be required (␣ ⫽ 0.05, two-tailed 2 test). We planned an interim masked intergroup analysis after two-thirds of our sample had been enrolled. The trial would be stopped for a significance level ⬍ 0.01 for the primary outcome. Proportional data were compared with 2. The Fisher exact test was chosen if the expected size of any cell of the contingency table was less than 5. Continuous data were compared using the Wilcoxon rank-sum test. Multiple logistic regression was used to model the relationship between group assignment and the need for additional uterotonic agents, controlling for possible confounders. P ⬍ .05 was considered significant. All patients enrolled into the trial were analyzed on an intent-to-treat basis. RESULTS A total of 163 patients were randomized to our standard prophylactic (low-dose) oxytocin regimen (333 mU/ min), and 158 were assigned to the high-dose group (2667 mU/min); however, the group assignments remained masked during the interim “A-B” analysis. The quality and completeness of all outcome data were verified and locked before unmasking the two group assignments. There were no differences between the two groups with regard to selected maternal characteristics and the indications for cesarean delivery (Table 1). Intrapartum characteristics were also similar in the two groups, including proportions of women receiving magnesium sulfate, oxytocin, and amnioinfusion, the inci-
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387
Table 1. Selected Characteristics and Cesarean Indications of Women Assigned to Receive 333 mU/min or 2667 mU/min of Oxytocin Postpartum at Cesarean Delivery
Mean (⫾ 1 SD) age (y) White race (%) Nulliparous (%) Mean (⫾ 1 SD) gestational age (wk) Multiple gestation (%) Cesarean indication Nonreassuring fetal heart rate tracing (%) Arrest of labor (%) Abnormal lie (%) Other (%) Anesthetic technique for surgery Epidural (%) Spinal (%) General (%) General plus regional (%)
333 mU/min
2667 mU/min
P
25 ⫾ 6.0 36 58 37 ⫾ 4.3
25 ⫾ 6.1 37 51 37 ⫾ 4.9
.38 .9 .17 .47
7.4
5.1
.39 .16
29
29
41 21 9
34 23 15
59 27 11 3
69 20 8 3
.26
SD ⫽ standard deviation.
dence of chorioamnionitis in each group, and the duration of membrane rupture (Table 2). Thirteen patients in the low-dose group compared with 18 women in the high-dose group underwent tubal ligation at cesarean (P ⫽ .18). The rates of regional anesthesia were similar in the groups: 92% of women in the low-dose group compared with 89% in the high-dose group (P ⫽ .39). The mean duration of surgery in the groups was also similar: 52 ⫾ 16 minutes in the low-dose group and 54 ⫾ 18 minutes in the high-dose group (P ⫽ .53). None of the patients in either group underwent cesarean hysterectomy or received a blood transfusion. More women in the low-dose group required an addi-
Table 2. Intrapartum Characteristics of Women Assigned to Receive 333 mU/min or 2667 mU/min of Oxytocin Postpartum at Cesarean Delivery
Intrapartum MgSO4 (%) Oxytocin None (%) Augmentation (%) Induction (%) Amnioinfusion (%) Median (range) duration of membrane rupture (h) Chorioamnionitis (%)
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333 mU/min
2667 mU/min
18
20
36 23 41 19 7.9 (0–336)
46 18 36 23 5.9 (0–303)
24
18
Atony Prevention at Cesarean
P .67 .15 .15 .44 .05 .22
tional uterotonic agent compared with women in the high-dose group (39% compared with 19%, P ⬍ .001, relative risk [RR] 2.1, 95% confidence interval [CI] 1.4, 3.0). Thirty-six percent of the patients in the standard group received additional oxytocin for uterine atony, in contrast to only 19% of patients in the high-dose group (P ⫽ .006). After additional oxytocin (median 20 U) was given, 9% of patients in the low-dose group received methylergonovine or 15-methyl prostaglandin F2␣ for persistent uterine atony, whereas only 2% of patients in the high-dose group received methylergonovine or 15methyl prostaglandin F2␣ (P ⫽ .005, RR 4.8, 95% CI 1.4, 16). There was no difference in the number of women who received an intravenous bolus of crystalloid (19% in the low-dose group compared with 17% in the high-dose group, P ⫽ .55) or pressor agents (25% in the low-dose group compared with 24% in the high-dose group, P ⫽ .82), or both (13% compared with 11%, P ⫽ .56) for BP support. In no case was the study solution discontinued for unexplained hypotension. No patient required additional uterotonic agents in the postanesthesia care unit, and only one woman was treated for hypotension. The mean estimated blood loss (957 ⫾ 148 mL compared with 937 ⫾ 159 mL, P ⫽ .08) and the mean change in the hematocrit (⫺4.6 ⫾ 3.8% compared with ⫺4.1 ⫾ 3.6%, P ⫽ .46) in the two groups were also similar. We also determined whether women with specific risk factors for uterine atony had the same response from the higher infusion rate. We observed that the 120 women who had experienced labor arrest were more likely to require additional uterotonic agents than women with other cesarean indications (41% compared with 22%, P ⬍ .001). Similarly, the 68 women with the intrapartum clinical diagnosis of chorioamnionitis were more likely to require additional uterotonic agents than those who did not have this clinical diagnosis (50% compared with 24%, P ⬍ .001). However, we determined that intrapartum magnesium sulfate was not a significant risk factor for uterine atony; the 63 women who received magnesium sulfate experienced a similar need for additional uterotonic agents compared with those who did not receive this drug (32% compared with 29%, P ⫽ .57). We further analyzed the relationship between labor arrest and clinical chorioamnionitis and the need for additional uterotonic agents by including them along with group assignment in a multiple logistic regression model with the need for additional uterotonic agents as the dependent variable. After controlling for these factors, women in the high-dose group still experienced an independent and lower incidence of additionally administered uterotonic agents (odds ratio ⫽ 0.38, 95% CI 0.22, 0.64).
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DISCUSSION We observed a significant decrease in the number of requests for additional uterotonic agents and no adverse side effects in women who received 2667 mU/min compared with 333 mU/min of oxytocin at cesarean delivery. Because both the surgeons and anesthesiologists were masked to the group assignments, this could not have influenced their perception of atony or the request for additional uterotonic agents. Our study groups were also similar for risk factors associated with uterine atony (eg, cesarean indication, chorioamnionitis), and we found that the higher dose of oxytocin remained more effective after controlling for these confounders. Treatment for hypotension was not significantly different between the two groups; approximately 40% of the patients in each group received additional crystalloid or ephedrine. The mean estimated blood loss and the decrease in hematocrit did not differ in the two groups. This is not unexpected, as atony is quickly recognized and treated at cesarean, because the uterus is exposed and more easily evaluated than at vaginal delivery. This facilitates prompt recognition and treatment, which limits blood loss. Uterotonic agents (ie, oxytocin, prostaglandins, ergot derivatives) decrease the incidence of postpartum hemorrhage by approximately 40% when compared with placebo or no routine prophylactic agent.1–3 Compared with placebo, the need for additional uterotonic agents is also reduced when oxytocin is routinely used after vaginal delivery.2,3,12 Chou and MacKenzie13 found no difference in blood loss at cesarean delivery when comparing intramyometrial prostaglandin F2␣ (125 g) and oxytocin administered as a 5 U “slow” bolus, followed by a rate of 125 mU/min for 2 hours. Although this study of 60 women had limited power to detect clinically significant differences in the rate of additionally administered uterotonic agents, more women in the prostaglandin F2␣ group required additional pharmacologic therapy for atony. Oxytocin appears to be the drug of choice to prevent postpartum hemorrhage in the United States. It is a safe medication and has no appreciable cardiovascular side effects when administered as a continuous intravenous infusion.7–9 However, we recommend that oxytocin be administered with an isotonic solution because of its antidiuretic effect and the possibility of hyponatremia.8 Although its use is widespread, the optimal dose has not been established for either vaginal or cesarean delivery. Small intravenous bolus doses1 (less than 10 U) or dilute solutions of 10 – 40 U of oxytocin in 1000 mL of crytalloid solution,4,6 given at a rate of 200 mU/min to 1000 mU/min,14 have been recommended for the pre-
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vention of postpartum bleeding after vaginal delivery. Guidelines for oxytocin administration at cesarean delivery appear to be mostly empiric or extrapolated from vaginal delivery regimens. Sarna et al15 reported no difference in postoperative hematocrit when oxytocin was used in doses of 5–20 U at elective cesarean delivery; however, these doses were all infused at a constant rate (100 mU/min), and this study did not address the question of whether higher infusion rates would more effectively prevent atony during cesarean delivery. We hypothesize that the higher dose of oxytocin more effectively prevents uterine atony at cesarean delivery, and that prophylaxis is more effective than treatment. Even when more oxytocin was subsequently administered, second-line agents (methylergonovine and 15methyl prostaglandin F2␣) were still required more frequently in the low-dose group. Reducing the need for second-line uterotonic agents is a clinically important finding because methylergonovine or 15-methyl prostaglandin F2␣ may be contraindicated in women with hypertension or asthma. Further, the use of 15-methyl prostaglandin F2␣ for uterine atony has been associated with maternal arterial oxygen desaturation during general anesthesia.16 These findings may be particularly relevant to practitioners in less developed countries that lack the facilities to store thermally labile prostaglandin analogues. Because oxytocin is less costly than both methylergonovine and 15-methyl prostaglandin F2␣, cost savings might also be realized. REFERENCES 1. Prendiville W, Elbourne D, Chalmers I. The effects of routine oxytocin administration in the management of the third stage of labour: An overview of the evidence from controlled trials. Br J Obstet Gynaecol 1988;95:3–16. 2. Nordstrom L, Fogelstam K, Gridman G, Larsson A, Rydhstroem H. Routine oxytocin in the third stage of labour: A placebo controlled randomized trial. Br J Obstet Gynecol 1997;104:781– 6. 3. Rogers J, Wood J, McCandish R, Ayers S, Truesdale A, Elbourne D. Active versus expectant management of third stage labour: The Hinchingbrooke randomized controlled trial. Lancet 1998;351:693–9. 4. American College of Obstetricians and Gynecologists. Postpartum hemorrhage. ACOG educational bulletin no. 243. Washington, DC: American College of Obstetricians and Gynecologists, 1998. 5. Secher NJ, Arnso P, Wallin L. Haemodynamic effects of oxytocin (Synotocinon) and methylergonetrine (Methergine) on the systemic and pulmonary circulations of pregnant anaesthetized women. Acta Obstet Gynecol Scand 1978;57:97–103. 6. Cunningham FG, MacDonald PC, Gant NF, Leveno KJ,
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Gilstrap LC, Hankins GDV, et al. Williams obstetrics. 20th ed. Stamford, CT: Appleton & Lange, 1997. Owen J, Hauth JC. Comparison of concentrated oxytocin plus low dose prostaglandin E2 vaginal suppositories in mid-trimester pregnancy termination. Obstet Gynecol 1996;88:110 –3. Owen J, Hauth JC, Winkler CL, Gray SE. Midtrimester pregnancy termination: A randomized trial of prostaglandin E2 versus concentrated oxytocin. Am J Obstet Gynecol 1992;167:1112– 6. Winkler CL, Gray SE, Hauth JC, Owen J, Tucker JM. Mid-second-trimester labor induction: Concentrated oxytocin compared with prostaglandin E2 vaginal suppositories. Obstet Gynecol 1991;77:297–300. Combs CA, Murphy EL, Laros RK. Factors associated with hemorrhage in cesarean deliveries. Obstet Gynecol 1991;77:77– 82. Atkinson MW, Owen J, Wren A, Hauth JC. The effect of manual removal of the placenta on post-cesarean endometritis. Obstet Gynecol 1996;87:99 –102. Thiliganathan B, Cutner A, Latimer J, Beard R. Management of the third stage of labour in women at low risk of PPH. Eur J Obstet Gynecol Reprod Biol 1993;48:19 –22.
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13. Chou MM, MacKenzie IZ. A prospective, double-blinded, randomized comparison of prophylactic intramyometrial 15-methyl prostaglandin F, 125 micrograms, and intravenous oxytocin, 20 units, for the control of blood loss at elective cesarean section. Am J Obstet Gynecol 1994;171: 1356 – 60. 14. Gabbe SG, Niebyl JR, Simpson JL. Obstetrics: Normal and problem pregnancies. 3rd ed. New York: Churchill Livingstone, 1996. 15. Sarna MC, Soni AK, Gomez M, Oriol NE. Intravenous oxytocin in patients undergoing elective cesarean section. Anesth Analg 1997;84:753– 6. 16. Hankins GDV, Berryman GK, Scott RT, Hood D. Maternal arterial desaturation with 15-methyl prostaglandin F2␣ for uterine atony. Obstet Gynecol 1988;72:367–70. Address reprint requests to: Mary B. Munn, MD, Department of Obstetrics and Gynecology, University of South Alabama, 251 Cox Street, Suite 100, Mobile, AL 36604-3302; E-mail: [email protected]. Received March 1, 2001. Received in revised form May 29, 2001. Accepted May 31, 2001.
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