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OBJECTIVE: To estimate the minimum effective intrave- dose is 9 times more than previously reported after elective
nous dose of oxytocin required for adequate uterine cesarean delivery in nonlaboring women at term, suggest-
contraction after cesarean delivery for labor arrest. ing oxytocin receptor desensitization from exogenous oxy-
METHODS: A randomized single-blinded study was un- tocin administration during labor. Therefore, alternative
dertaken in 30 parturients undergoing cesarean deliveries uterotonic agents, rather than additional oxytocin, may
under epidural anesthesia for labor arrest despite intra- achieve superior uterine contraction and control of blood
venous oxytocin augmentation. Oxytocin was adminis- loss during cesarean delivery for labor arrest.
tered as a slow intravenous bolus immediately after (Obstet Gynecol 2006;107:4550)
delivery of the infant, according to a biased coin up- LEVEL OF EVIDENCE: I
down sequential allocation scheme. After assisted spon-
taneous delivery of the placenta, the obstetrician,
blinded to the oxytocin dose, assessed uterine contrac-
tion as either satisfactory or unsatisfactory. Additional O xytocin is the drug of choice both for induction
and augmentation of labor, as well as for achiev-
ing uterine contraction after delivery, whether spon-
boluses of oxytocin were administered as required, fol-
lowed by a maintenance infusion. Data were interpreted taneous or operative. Prophylactic oxytocin is com-
and analyzed by a logistic regression model at 95% monly administered after delivery of the infant or
confidence intervals. placenta and has been shown to reduce the incidence
RESULTS: All patients received oxytocin infusions at a of postpartum hemorrhage by up to 40 %.1,2
mean standard deviation of 9.8 6.3 hours before Several empirical regimens have been proposed
cesarean delivery (maximum infusion dose 10.3 8.2 for oxytocin administration during cesarean delivery,
mU/min). The minimum effective dose of oxytocin re- and this has led to many different practices in its
quired to produce adequate uterine response in 90% of administration worldwide.3 8 These protocols usually
women (ED90) was estimated to be 2.99 IU (95% confi- recommend a fixed dose of oxytocin, irrespective of
dence interval 2.323.67). The estimated blood loss was the indication for cesarean delivery. In a previous
1,178 716 mL. study we estimated the minimum effective dose
CONCLUSION: Women requiring cesarean delivery for (ED90) of oxytocin required to produce adequate
labor arrest after oxytocin augmentation require approx- uterine contraction after elective cesarean delivery in
imately 3 IU rapid intravenous infusion of oxytocin to nonlaboring women, noting that such women re-
achieve effective uterine contraction after delivery. This
quired much lower doses than those commonly ad-
ministered in many centers.9
From the Departments of Anesthesia and Pain Management, Obstetrics and Laboring women requiring cesarean delivery
Gynaecology, and Paediatrics, Mount Sinai Hospital, University of Toronto,
constitute a subset of patients that may exhibit an
Toronto, Ontario, Canada.
unpredictable response to oxytocin, because either
Presented at the American Society of Regional Anesthesia and Pain Medicine,
Spring Meeting, April 2124, 2005, Canadian Anesthesiology Society Meeting, prolonged labor or use of intravenous oxytocin to
June 1721, 2005, and Society of Obstetric Anesthesia and Perinatology augment labor may desensitize the uterus and render
Meeting, May 4 7, 2005. it less responsive to the same drug during cesarean
Corresponding author: Mrinalini Balki, MD, Department of Anesthesia and delivery. Therefore, the purpose of this study was to
Pain Management, Mount Sinai Hospital, 600 University Avenue, Toronto,
Ontario, Canada, M5G 1X5; e-mail: mrinalini.balki@uhn.on.ca.
estimate the minimum effective dose (ED90) of oxyto-
2005 by The American College of Obstetricians and Gynecologists. Published
cin to produce adequate uterine contraction after
by Lippincott Williams & Wilkins. cesarean delivery for labor arrest in women who had
ISSN: 0029-7844/05 received oxytocin during labor.
46 Balki et al Labor Arrest, Cesarean Delivery, and Oxytocin OBSTETRICS & GYNECOLOGY
loss and oxytocin-related side effects. For the purpose Table 1. Demographics and Labor Details
of this study, the minimum effective dose of oxytocin Measure Value
was defined to be that at which adequate response
Number of patients 30
would occur in 90% of patients, ie, ED90.
Age (y) 32.7 4.4
Sample size was calculated by computer simula- Weight (kg) 79.2 16.5
tion using 10,000 replications. Based on clinical ex- Height (cm) 161.4 6.8
perience, it was expected that 50% of patients would Gestational age (wk) 39.9 1.1
respond to an initial oxytocin dose of 2.5 IU and 90% Primigravida 20
Multigravida 10
to 5 IU. Assuming that the actual response was
Duration of first stage (h) 15.7 6.3
described by a 2-parameter logistic curve with these Oxytocin infusion duration during labor (h) 9.8 6.3
properties, a simulation of the proposed sequential Maximum oxytocin dose during labor (mU/min) 10.3 8.2
allocation scheme determined that 80% of the time Cervical dilation at the time of diagnosis (cm) 6.3 2.5
the minimum effective dose (ED90) could be estimated Arrest of cervical dilation 26
Arrest of descent 4
with a standard error of less than 1.27 IU if a sample
Maximum temperature during labor (C) 37.4 0.61
of 30 patients was used. Primary cesarean delivery 28
A logistic regression model was used to estimate Repeat cesarean delivery 2
the ED90. Evidence of an association between the Estimated blood loss (mL) 1,178.2 716.7
initial oxytocin dose and response time was assessed Values are n or mean standard deviation.
using the Jonckheere-Terpstra test, which is a non-
parametric test for ordered differences between class- patients. Five patients had a temperature 38.0C or
es.11 It tests the null hypothesis of no difference more. For cesarean delivery, all patients received
between classes. Patients who did not respond to the epidural 2% CO2 lidocaine with 1:200,000 epineph-
initial oxytocin bolus were treated as being interval- rine (mean 17.1 3.1 mL standard deviation) and
censored between the first and second dose. Exact attained a median dermatomal block height of T4.
2-tailed P values were used. The linear association Based on the logistic regression model fitted to
between continuous variables was measured using the the data, it was estimated that the dose at which 90%
parametric Pearson correlation coefficient and the of the women would respond with adequate uterine
nonparametric Spearman correlation coefficient, as contraction (ED90) was 2.99 IU (standard error 0.34
appropriate. The Shapiro-Wilk test was used to test IU). The 95% confidence interval for ED90 was 2.32
for normality.12 All of the analyses were done in Splus 3.67 IU. Figure 1 represents the fitted response curve
6.1 and SAS 8.2 (SAS Institute Inc., Cary, NC). with the corresponding 95% confidence interval. Ta-
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 he-
matocrit postoperative hematocrit)/preoperative he-
matocrit, where estimated blood volume in milliliters
is measured as the patients 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.
Fig. 1. Doseresponse curve for oxytocin: logistic response
RESULTS curve (solid curve) with predicted probabilities and 95%
Thirty pregnant women at 37 to 41 weeks gestation of confidence bands (dashed curves) for probability of the
mixed parity, requiring primary or repeat cesarean response as a function of the initial oxytocin dose. Hori-
zontal reference line at 0.9 probability identifies ED90 of
deliveries for arrest of labor, were studied (Table 1).
oxytocin at 2.99 IU (standard error 0.34 IU,95% confidence
All patients received oxytocin for either induction or interval 2.323.67 IU).
augmentation of labor. Arrest of cervical dilation was Balki. Labor Arrest, Cesarean Delivery, and Oxytocin. Obstet
recognized in 26 patients and arrest of descent in 4 Gynecol 2006.
VOL. 107, NO. 1, JANUARY 2006 Balki et al Labor Arrest, Cesarean Delivery, and Oxytocin 47
ble 2 shows the uterine response time in minutes after and ergonovine 250 g). These patients were consid-
the initial oxytocin bolus dose. There is strong evi- ered nonresponsive to the initial oxytocin bolus.
dence of a trend in decreasing uterine response time The mean estimated blood loss was 1,178 716
with increasing initial oxytocin dose (P .001), based mL (range 2012,576 mL) as calculated from the
on the Jonckheere-Terpstra test. If the actual response preoperative and postoperative hematocrit values.
time is treated as censored for the 7 patients who did There was no correlation between the initial oxytocin
not respond to the initial dose, then the association dose after cesarean delivery and estimated blood loss
between the initial dose and the response time be- (P .82, correlation coefficient 0.04). The adverse
comes weak (P .03). effects in both the predelivery and postdelivery peri-
Most patients (22 of 30) had effective uterine ods recorded during the study are shown in Table 3.
contraction within 3 minutes at 23.5 IU of initial Hypotension occurred in 10% and 30% of patients
oxytocin dose, whereas patients who received less before and after delivery, respectively. The mean
than 2 IU did not respond within 3 minutes and dose of phenylephrine required was 0.06 0.15 mg
required additional oxytocin boluses. All patients predelivery and 0.22 0.28 mg postdelivery.
receiving 3.5 IU initial oxytocin dose showed ade-
quate uterine response within 1 to 2 minutes (Table DISCUSSION
2). Oxytocin is used daily, worldwide, with the intention
The mean duration of oxytocin exposure during of reducing the risk or severity of immediate postpar-
labor was 9.8 6.3 hours, and the mean maximum tum hemorrhage. However, the standard practice of
dose of oxytocin infusion was 10.3 8.2 mU/min oxytocin administration during cesarean delivery var-
(Table 1). We found no significant correlations be- ies widely.3 8,13 The British National Formulary and
tween 1) duration of oxytocin infusion during labor other formularies presently recommend 5 IU oxyto-
and the time for effective uterine contraction after cin by slow intravenous injection after delivery; how-
cesarean delivery (P .74, correlation coefficient ever, there is no evidence to support the assumption
0.07), 2) duration of oxytocin infusion during labor that 5 IU is the correct dose.3,4 In the United States, an
and the total oxytocin bolus dose after cesarean infusion of 10 40 IU/L is recommended for preven-
delivery (P .49, correlation coefficient 0.14), 3) tion of postpartum hemorrhage.7 Other suggested
maximum dose of oxytocin infusion during labor and protocols include oxytocin 10 IU intramuscular, 510
the time for effective uterine contraction after cesar- IU rapid intravenous bolus, and 10 20 IU/L intrave-
ean delivery (P .87, correlation coefficient 0.03), nous drip at the rate of 100 150 mL/h.8 The literature
and 4) maximum dose of oxytocin infusion during lacks true doseresponse studies on oxytocin for
labor and the total oxytocin bolus after cesarean prevention of postpartum hemorrhage after cesarean
delivery (P .81, correlation coefficient 0.05). Two delivery. Therefore, all these regimens have been
cases were excluded from the analysis due to the obste- used empirically.
tricians request for higher doses of oxytocin before the In a previous study, we demonstrated that effec-
3-minute response time (oxytocin 10 IU, oxytocin 7 IU tive uterine contraction can be achieved after elective
cesarean delivery in nonlaboring women with an
oxytocin bolus dose no larger than 1 IU, the ED90
Table 2. Frequency of Patients by Uterine
being 0.35 IU.9 The current study used the same
Response Time and Initial Oxytocin Dose
design with administration of oxytocin in an up-down
Initial Oxytocin Dose
Minutes for
Response 0.5 IU 1 IU 1.5 IU 2 IU 2.5 IU 3 IU 3.5 IU Table 3. Adverse Effects Encountered During
1 0 0 0 0 0 5 3 Cesarean Delivery (N 30)
2 0 0 0 2 2 2 2 Adverse Effect Predelivery Postdelivery
3 0 0 1* 0 2 4 0
4 0 0 0 1 1* 0 0 Hypotension 3 (10) 9 (30)
6 0 1* 0 0 0 0 0 Tachycardia 7 (23) 9 (30)
7 0 0 0 0 0 1* 0 Nausea 6 (20) 18 (60)
8 0 0 0 1* 0 0 0 Vomiting 3 (10) 12 (40)
9 1* 0 0 0 0 0 0 Chest pain 0 (0) 2 (7)
12 0 0 0 0 0 1* 0 Shortness of breath 1 (3) 2 (7)
Total 1 1 1 4 5 13 5 Headache 0 (0) 2 (7)
Flushing 0 (0) 12 (40)
Values are number of patients.
* Indicates the 7 patients who did not respond to the initial dose. Values are n (%).
48 Balki et al Labor Arrest, Cesarean Delivery, and Oxytocin OBSTETRICS & GYNECOLOGY
sequential allocation fashion. However, the subject 1,178 716 mL, approximately 2 times that of
population consisted of laboring women who had elective cesarean delivery requiring low-dose oxyto-
received oxytocin for either induction or augmenta- cin (693 487 mL).9 It is usual practice to increase
tion of labor before cesarean delivery. We found the the dose of oxytocin, assuming higher doses will result
ED90 of oxytocin in these circumstances to be 2.99 IU, in more effective uterine contraction. We advocate
about 9 times higher than in nonlaboring women at that higher doses of oxytocin are unlikely to improve
term. uterine contraction further and thus prevent postpar-
Molecular characterization of myometrial oxyto- tum hemorrhage, because the population of oxytocin
cin receptor expression and density may clarify these receptors will not only be reduced but also be desen-
differences. The uterus becomes markedly sensitive to sitized. Sarna et al20 found no advantage in increasing
the effects of oxytocin while preparing for parturi- oxytocin dose above 5 IU during elective cesarean
tion.14,15 Oxytocin, a nonpeptide hormone, is known delivery. Munn et al21 used extremely high doses of
to act both directly by binding with uterine oxytocin oxytocin at the rate of 2,667 mU/min and 333
receptors and indirectly by paracrine mechanisms.16 mU/min for 30 minutes after cesarean delivery in
Due to the effects of estrogen, the uterine oxytocin laboring women. These patients still required addi-
receptor population density increases progressively tional uterotonic agents in 19% and 39% of cases,
during pregnancy to reach a peak at term.17 In late respectively. Further, if a larger dose of oxytocin is
pregnancy, before the onset of labor, uterine oxytocin rapidly infused, its side effects may outweigh its
receptor concentrations are, on average, 12 times uterotonic action.13,2227 Hence, we suggest that, espe-
higher than in early pregnancy, and about 80 times cially in laboring patients, consideration should be
higher than the nonpregnant values.14 Messenger given to the alternate pathway uterotonic medica-
RNA expression of oxytocin receptors rises with
tions, such as ergot derivatives, carboprost, or miso-
gestation to a 300-fold increase at parturition, com-
prostol. We would predict that the response to these
pared with that of the nonpregnant myometrium.15
agonists is unaltered, because the oxytocin-induced
This could explain the uterine response to low doses
desensitization is homologous.18
of oxytocin at term elective cesarean deliveries, as
Our study indicates that women undergoing ce-
observed in our previous study.9
sarean delivery for labor arrest require approximately
Labor induces further changes in oxytocin recep-
3 IU of oxytocin as a loading dose to achieve
tor population. In early labor, the oxytocin receptor
adequate uterine contraction, before a maintenance
population is significantly higher than in term nonla-
boring patients, on the average of 2.5 times. However, oxytocin infusion (20 IU/L at 120 mL/h) is continued.
in active labor with the cervix more than 7 cm dilated, We recommend that this dose be administered as a
oxytocin receptor concentrations are reduced, on rapid diluted intravenous oxytocin infusion to avoid
average approximately twice those found in early the well-known potential complications of rapid intra-
pregnancy.14 Phaneuf et al18 compared spontaneous venous bolus, such as hypotension.13,2227 We recog-
with oxytocin-induced labor and demonstrated signif- nize and suggest that oxytocin infusion is preferable to
icant reduction in the oxytocin binding sites in the bolus injection for safety reasons; however, such
induced labor group. Continuous exposure of human infusion will have to be initially administered at a rate
myometrial cells to oxytocin leads to a significant loss that will ensure appropriate drug levels.
in their capacity to respond to oxytocin, believed to The doses of oxytocin required in both our
be due to oxytocin receptor desensitization. Robinson studies are lower than those usually recommended.
et al19 observed oxytocin receptor desensitization These doses could reflect the method of assisted
starting at 3 hours of exposure of human myometrial delivery of the placenta, allowing a longer fetus-to-
cells to oxytocin in vitro. Our study provides further placenta delivery interval, during which time the
clinical evidence that oxytocin receptor signaling is lower dose of oxytocin may have had sufficient time
attenuated in laboring women at the time of cesarean to cause effective uterine contraction. Therefore, im-
delivery. We did not find any correlation of the dose plementation of these lower dosage regimens after
and duration of oxytocin infusion administered dur- cesarean delivery may require reevaluation of the
ing labor with the time required for effective uterine surgical practice surrounding delivery of the placenta.
contraction or the total dose of oxytocin required at
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50 Balki et al Labor Arrest, Cesarean Delivery, and Oxytocin OBSTETRICS & GYNECOLOGY