Conditions: Labor Pain
Keywords: epidural analgesia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 179
Healthy volunteers: yes

Brief summary:
The aim of this prospective, doubled-blinded randomized study is to compare two modes of epidural analgesia delivery, programmed intermittent epidural boluses (PIEB) versus continuous epidural infusion (CEI) with patient controlled epidural analgesia (PCEA) dosing, for providing labor epidural analgesia. The primary outcome will be the volume of local anesthetic received through PCEA. Secondary outcomes will measure time to first PCEA bolus, labor pain scores, degree of motor blockade, mode of delivery, PCEA attempts and ratio of successful to unsuccessful attempts, frequency of hypotension, duration of first and second stages of labor and level of patient satisfaction. The investigator plans to enroll 120 nulliparous participants at 2-5 com cervical dilation, with 60 patients to each arm. The subject will be assigned to receive either delivery of epidural medication ropivacaine 0.1% with fentanyl 2mcg/mL with PIEB + PCEA dosing method or CEI + PCEA. Continuous data will be analyzed using the Kruskal-Wallis test or t-test as appropriate. Categorical data will be analyzed using Chi-square test or Fisher's exact test as appropriate.

Detailed description:
Labor pain during childbirth is regarded as one of the most painful experiences in a woman's life with the potential to cause lasting emotional and psychological effects. Childbirth has also been associated with the development of chronic pain with the prevalence of between 4-10% after cesarean section and 6-18% after vaginal delivery. Hence, effective management of labor pain is instrumental in preventing the development of life altering chronic pain in women of childbearing age. Maintaining epidural analgesia with combined local anesthetic and an opioid is considered extremely safe and leads to superior neonatal and maternal short and long-term outcomes. Historically, maintenance of epidural analgesia involved intermittent provider-administered bolus injections, patient controlled epidural analgesia (PCEA) and continuous epidural infusions (CEI) with or without PCEA for breakthrough pain or discomfort. CEI has been shown to provide consistent analgesia in addition to improved patient satisfaction and reduced workload for the anesthesia providers. However, CEI is associated with greater local anesthetic consumption and increased maternal motor blockade. Increased motor block is associated with reduced mobility, decreased pelvic muscle tone and impaired ability for the parturient to adequately Valsalva during the second stage of labor. Motor blockade is also associated with increased incidence of shoulder dystocia and instrumental deliveries, which precipitate birth trauma to the fetus and the mother. Achieving adequate analgesia during labor, without compromising motor function is critical for optimizing both short-term and long-term outcomes for the mother and the neonate.

A more novel approach to labor analgesia involves the administration of small, programmed intermittent epidural boluses (PIEB) with PCEA dosing for breakthrough pain. Preliminary studies have indicated that PIEB could be a superior method of labor analgesia compared to current standard of care, CEI. A randomized double-blind study by Wong et al. compared CEI and PIEB incorporating the use of PCEA for breakthrough pain in healthy parturients with singleton pregnancies. Results suggested that the cohort receiving PIEB required less local anesthetic use, had similar analgesia and improved patient satisfaction when compared with CEI. Additionally, a subsequent study by Wong et al found that in healthy, term, nulliparous women in spontaneous labor, extending the PIEB interval and increasing volume decreased local anesthetic consumption, PCEA requests or rescue analgesia requirements without increasing patient discomfort or compromising satisfaction. Two subsequent studies allocating women to receive either PIEB or CEI in nulliparous parturients and women terminating pregnancy suggested PIEB recipients experienced less motor blockade when compared to those receiving CEI.

The investigator has recently performed a systematic review and meta-analysis of studies comparing the effects of labor analgesia with either PIEB or CEI with or without PCEA in laboring women. The meta-analysis included 9 studies and evaluated various primary outcomes including: patient satisfaction, required manual anesthesia interventions, labor progression and mode of delivery (vaginal, instrumental or cesarean delivery). Secondary outcomes included: degree of motor blockade, degree of sensory blockade, time to first anesthetic intervention, local anesthetic dose delivered per hour, pruritus, shivering, maternal fever, nausea and vomiting, neonatal Apgar scores at 1 minute and 5 minutes, and umbilical artery and vein pH. PIEB dosing of local anesthetic was associated with reduced local anesthetic consumption, decreased required anesthetic interventions, and an improvement in maternal satisfaction in comparison to laboring women receiving CEI. Pooled results indicated that PIEB and CEI were comparable with regard to the duration of first stage labor, but there was a statistically significant 22 min reduction in the length of stage two of labor with PIEB. Similarly, this review did not suggest statistically significant differences in cesarean delivery rate or required anesthetic intervention between CEI and PIEB. There were several limitations to these preliminarily studies. While, each of the 9 studies reported at least one primary outcome listed in the systematic review, none of the studies included all primary outcomes. Additionally, most studies only involved nulliparous women, which may limit the ability to apply results to multiparous women. Furthermore, many of these studies involved the use of two pumps, one to deliver CEI or PEIB and another to deliver PCEA in a research setting, or involved the use of non-commercially available research pumps.

Currently the CADD solis v 3.0 pump system has been upgraded to allow the co-administration of epidural anesthesia with PIEB or CEI and PCEA. This new technology has been available on the labor and delivery unit of Duke University Medical Center as the standard of care since March 2015. This new pump differs from those used in the preliminary studies, which utilized a two-pump approach to administer PIEB or CEI and PCEA for labor pain relief. Preliminary studies have not identified optimal PIEB settings, bolus volumes, lock out intervals, or drug concentrations, which represents a gap in literature at the present time. The investigator performed a retrospective study to explore whether PIEB was associated with reduced LA use, PCEA use and rescue analgesia in comparison to CEI in laboring women. The investigator also assessed whether PIEB decreased the number of instrumental deliveries and reduced motor blockade, which serves as an impediment to the progression of labor. The study divided patients into three groups. The first received CEI 5mL/hour, the second received PIEB 5mL every 60 min, the third used PIEB of 3mL every 30 min. Each group had access to PCEA set to 5 mL boluses with an 8-minute lockout period and maximum of 35mL per hour. The results of the study did not suggest what was expected as the study revealed no statistically significant difference between the LA consumption, amount of motor blockade or mode of delivery for patients receiving CEI or PEIB when using the single pump system instead of two-pump system employed by prior studies. However, this study did suggest patients who received PIEB regimen of 3mL every 30 minutes used a lower PCEA volume than patients receiving CEI. Patients receiving PEIB regimens had more attempts/PCEA given than the CEI patients and the PIEB 3ml/30 minute group had more unsuccessful PCEA attempts/hour than CEI recipients.

This study, unlike prior studies comparing PIEB vs. CEI with PCEA, used more concentrated solutions consisting of double the concentration and half the volume of bupivacaine. One of the investigators speculations is that larger boluses of a more dilute LA may have improved dissemination in the epidural space and thus improved analgesia. This study interpreted PCEA attempts/given and the number of unsuccessful PCEA attempts/hour as reflections of patient pain or discomfort, as an attempt is interpreted as an effort to achieve better pain relief. Another way to interpret the aforementioned PCEA attempts is as representation of the amount of time a patient "locked out" or prevented from receiving additional boluses of PCEA. Hence, a limitation of this study is the fact that patient satisfaction scores were not collected as they could help distinguish whether attempts reflect the lockout period or inadequate analgesia. Other limitations of this retrospective study include the fact that explicit instructions about how to properly use the PCEA was not standardized, and the fact that patient satisfaction or pain scores were not garnered due to the study's retrospective nature. Probably one of the most significant limitations of this study was the fact that patients were not randomized to treatment groups. Hence, the providers chose the analgesia received. On the other hand, another retrospective study utilizing a more dilute concentration of local anesthetic reported reduced need for physician interventions with PIEB compared to CEI. The investigators have recently switched the local anesthetic in our practice from bupivacaine 0.125 % to a more dilute concentration of ropivacaine 0.1% mixed with fentanyl 2 mcg/ml. The investigator therefore aims to prospectively study if the use of PIEB with the new epidural solution would be associated with improved analgesia compared to a regimen using CEI.

Arms:
arm 1: Epidural catheters will be placed at the L3/4 or L4/5 interspace with 4 cm of catheter being left in the epidural space. Epidural analgesia will be initiated and maintained with a solution of ropivacaine 0.1% with fentanyl 2 mcg/ml. After the initial epidural loading dose of 20 mL is administered in incremental fashion, patients will receive either 6 mL every 45 minutes in the PIEB arm (first bolus 30 minutes after epidural initiation). All study participants will be provided with PCEA set to 8mL boluses with a 10-minute lockout period. The maximum amount of PCEA analgesia will be set to a 1-hour maximum of 45mL. arm 2: Epidural catheters will be placed at the L3/4 or L4/5 interspace with 4 cm of catheter being left in the epidural space. Epidural analgesia will be initiated and maintained with a solution of ropivacaine 0.1% with fentanyl 2 mcg/ml. After the initial epidural loading dose of 20 mL is administered in incremental fashion, patients will receive 8mL/hr of continuous infusion beginning immediately after the loading dose for the maintenance of analgesia in the CEI arm. All study participants will be provided with PCEA set to 8mL boluses with a10-minute lockout period. The maximum amount of PCEA analgesia will be set to a 1-hour maximum of 45mL.

Interventions: intervention 1: Programmed Intermittent Epidural Bolus intervention 2: Continuous Epidural Infusion intervention 3: Ropivacaine intervention 4: Fentanyl
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol document:
Prot_SAP_000.pdf: 
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1 
 
 
 
 
 
 
 
 
Comparison of Programmed Intermittent Epidural Boluses with Continuous Epidural 
Infusion for Maintenance of Labor Analgesia  
 
NCT02949271  
 
Document date: 09/22/2017


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Title: Comparison of Programmed Intermittent Epidural Boluses with Continuous 
Epidural Infusion for Maintenance of Labor Analgesia 
 
Background: 
Labor pain during childbirth is regarded as one of the most painful experiences in a woman’s life 
with the potential to cause lasting emotional and psychological effects. Childbirth has also been 
associated with the development of chronic pain with the prevalence of between 4-10% after 
cesarean section and 6-18% after vaginal delivery (1). Hence, effective management of labor 
pain is instrumental in preventing the development of life altering chronic pain in women of 
childbearing age. Maintaining epidural analgesia with combined local anesthetic and an opioid is 
considered extremely safe and leads to superior neonatal and maternal short and long-term 
outcomes (2). Historically, maintenance of epidural analgesia involved intermittent provider-
administered bolus injections, patient controlled epidural analgesia (PCEA) and continuous 
epidural infusions (CEI) with or without PCEA for breakthrough pain or discomfort (3). CEI has 
been shown to provide consistent analgesia in addition to improved patient satisfaction and 
reduced workload for the anesthesia providers. However, CEI is associated with greater local 
anesthetic consumption and increased maternal motor blockade (3). Increased motor block is 
associated with reduced mobility, decreased pelvic muscle tone and impaired ability for the 
parturient to adequately Valsalva during the second stage of labor (4). Motor blockade is also 
associated with increased incidence of shoulder dystocia and instrumental deliveries, which 
precipitate birth trauma to the fetus and the mother. Achieving adequate analgesia during labor, 
without compromising motor function is critical for optimizing both short-term and long-term 
outcomes for the mother and the neonate.  
 
A more novel approach to labor analgesia involves the administration of small, programmed 
intermittent epidural boluses (PIEB) with PCEA dosing for breakthrough pain. Preliminary 
studies have indicated that PIEB could be a superior method of labor analgesia compared to 
current standard of care, CEI. A randomized double-blind study by Wong et al. compared CEI 
and PIEB incorporating the use of PCEA for breakthrough pain in healthy parturients with 
singleton pregnancies. Results suggested that the cohort receiving PIEB required less local 
anesthetic use, had similar analgesia and improved patient satisfaction when compared with CEI 
(3). Additionally, a subsequent study by Wong et al found that in healthy, term, nulliparous 
women in spontaneous labor, extending the PIEB interval and increasing volume decreased local 
anesthetic consumption, PCEA requests or rescue analgesia requirements without increasing 
patient discomfort or compromising satisfaction (5). Two subsequent studies allocating women 
to receive either PIEB or CEI in nulliparous parturients and women terminating pregnancy 
suggested PIEB recipients experienced less motor blockade when compared to those receiving 
CEI (6,7). 
 


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3 
Our group has recently performed a systematic review and meta-analysis of studies comparing 
the effects of labor analgesia with either PIEB or CEI with or without PCEA in laboring women. 
The meta-analysis included 9 studies and evaluated various primary outcomes including: patient 
satisfaction, required manual anesthesia interventions, labor progression and mode of delivery 
(vaginal, instrumental or cesarean delivery). Secondary outcomes included:  degree of motor 
blockade, degree of sensory blockade, time to first anesthetic intervention, local anesthetic dose 
delivered per hour, pruritus, shivering, maternal fever, nausea and vomiting, neonatal Apgar 
scores at 1 minute and 5 minutes, and umbilical artery and vein pH (8). PIEB dosing of local 
anesthetic was associated with reduced local anesthetic consumption, decreased required 
anesthetic interventions, and an improvement in maternal satisfaction in comparison to laboring 
women receiving CEI. Pooled results indicated that PIEB and CEI were comparable with regard 
to the duration of first stage labor, but there was a statistically significant 22 min reduction in the 
length of stage two of labor with PIEB.  Similarly, this review did not suggest statistically 
significant differences in cesarean delivery rate or required anesthetic intervention between CEI 
and PIEB (8). There were several limitations to these preliminarily studies. While, each of the 9 
studies reported at least one primary outcome listed in the systematic review, none of the studies 
included all primary outcomes. Additionally, most studies only involved nulliparous women, 
which may limit the ability to apply results to multiparous women. Furthermore, many of these 
studies involved the use of two pumps, one to deliver CEI or PEIB and another to deliver PCEA 
in a research setting, or involved the use of non-commercially available research pumps (3).  
 
Currently the CADD solis v 3.0 pump system has been upgraded to allow the co-administration 
of epidural anesthesia with PIEB or CEI and PCEA. This new technology has been available on 
the labor and delivery unit of Duke University Medical Center as the standard of care since 
March 2015 (9). This new pump differs from those used in the preliminary studies, which 
utilized a two-pump approach to administer PIEB or CEI and PCEA for labor pain relief. 
Preliminary studies have not identified optimal PIEB settings, bolus volumes, lock out intervals, 
or drug concentrations, which represents a gap in literature at the present time. Our group 
performed a retrospective study to explore whether PIEB was associated with reduced LA use, 
PCEA use and rescue analgesia in comparison to CEI in laboring women. Our group also 
assessed whether PIEB decreased the number of instrumental deliveries and reduced motor 
blockade, which serves as an impediment to the progression of labor (9). The study divided 
patients into three groups. The first received CEI 5mL/hour, the second received PIEB 5mL 
every 60 min, the third used PIEB of 3mL every 30 min. Each group had access to PCEA set to 5 
mL boluses with an 8-minute lockout period and maximum of 35mL per hour (9). The results of 
the study did not suggest what we expected as the study revealed no statistically significant 
difference between the LA consumption, amount of motor blockade or mode of delivery for 
patients receiving CEI or PEIB when using the single pump system instead of two-pump system 
employed by prior studies. However, this study did suggest patients who received PIEB regimen 
of 3mL every 30 minutes used a lower PCEA volume than patients receiving CEI. Patients 


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receiving PEIB regimens had more attempts/PCEA given than the CEI patients and the PIEB 
3ml/30 minute group had more unsuccessful PCEA attempts/hour than CEI recipients.  
 
Our study, unlike prior studies comparing PIEB vs. CEI with PCEA, used more concentrated 
solutions consisting of double the concentration and half the volume of bupivacaine. One of our 
speculations is that larger boluses of a more dilute LA may have improved dissemination in the 
epidural space and thus improved analgesia (9).  Our study interpreted PCEA attempts/given and 
the number of unsuccessful PCEA attempts/hour as reflections of patient pain or discomfort, as 
an attempt is interpreted as an effort to achieve better pain relief (9). Another way to interpret the 
aforementioned PCEA attempts is as representation of the amount of time a patient “locked out” 
or prevented from receiving additional boluses of PCEA. Hence, a limitation of this study is the 
fact that patient satisfaction scores were not collected as they could help distinguish whether 
attempts reflect the lockout period or inadequate analgesia (9). Other limitations of our 
retrospective study include the fact that explicit instructions about how to properly use the PCEA 
was not standardized, and the fact that patient satisfaction or pain scores were not garnered due 
to the study’s retrospective nature (9). Probably one of the most significant limitations of our 
study was the fact that patients were not randomized to treatment groups. Hence, the providers 
chose the analgesia received (9).  On the other hand, another retrospective study utilizing a more 
dilute concentration of local anesthetic reported reduced need for physician interventions with 
PIEB compared to CEI. We have recently switched the local anesthetic in our practice from 
bupivacaine 0.125 % to a more dilute concentration of ropivacaine 0.1% mixed with fentanyl 2 
mcg/ml (10).  We therefore aim to prospectively study if the use of PIEB with the new epidural 
solution would be associated with improved analgesia compared to a regimen using CEI. 
 
Purpose of the study: 
The aim of this study is to compare two modes of epidural analgesia delivery, PIEB versus CEI 
with PCEA dosing, in the treatment of labor pain. Our primary outcome will be the volume of 
local anesthetic received through PCEA per hour. Secondary outcomes will measure the total 
required local anesthetic required per hour, time to first PCEA bolus, labor pain scores, degree of 
motor blockade, mode of delivery, PCEA attempts and ratio of successful to unsuccessful 
attempts, frequency of hypotension, duration of first and second stages of labor and level of 
patient satisfaction.  
 
Study design and recruitment:  
The study will be a blinded randomized, controlled trial comparing the two regimens for labor 
analgesia that are currently used as standard of care at our institution: a patient will be assigned 
to receive either delivery of epidural medication ropivacaine 0.1% with fentanyl 2mcg/mL with 
PIEB + PCEA dosing method or CEI + PCEA dosing method. Potential participants will be 
recruited from the Duke University Birthing Center as they are admitted for labor with intention 
for vaginal delivery. 


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Inclusion criteria:  
American Society of Anesthesiology (ASA) class 2 and 3 women  
Nulliparous and Multiparous  
Age > 18 yrs 
gestational age > 36 weeks 
singleton pregnancies 
vertex pregnancies  
In labor  
cervical dilatation 2-7 cm at time of epidural placement 
Pain score > 5 
 
Exclusion criteria: 
  
BMI > 50 kg/m2  
  
history of past or current intravenous drug or chronic opioid abuse 
  
chronic analgesic use 
  
allergy or contraindication to any study medications 
  
any maternal or fetal condition requiring planned assisted stage 2 delivery 
 
Study Method:  
After obtaining Duke University Institutional Review Board approval and informed consent, 
nulliparous or multiparous women in labor and cervical dilation between 2-7 cm desiring 
epidural for labor analgesia will be eligible to participate in this study. Subjects will be allocated 
to a study arm (CEI or PIEB) by computer-generated, random assignment placed in sealed 
opaque envelopes.  
 
Epidural catheters will be placed at the L3/4 or L4/5 interspace with 4 cm of catheter being left 
in the epidural space. If the subject experiences an inadvertent dural puncture during epidural 
placement, she will be removed from the study. Epidural analgesia will be initiated and 
maintained with a solution of ropivacaine 0.1% with fentanyl 2 mcg/ml. After the initial epidural 
loading dose of 20 mL is administered in incremental fashion, patients will receive either 6 mL 
every 45 minutes in the PIEB arm (first bolus 30 minutes after epidural initiation) or 8mL/hr of 
continuous infusion beginning immediately after the loading dose for the maintenance of 
analgesia in the CEI arm, both of which are standard of care at our institution.  All study 
participants will be provided with PCEA set to 8mL boluses with a10-minute lockout period. 
The maximum amount of PCEA analgesia will be set to a 1-hour maximum of 45mL. A script 
will be provided to anesthesia providers so that the same explanation about the use of the PCEA 
is provided to all subjects. Monitoring of patients will be with blood pressure measurements 
every 2 minutes for 15 minutes and then every 15 minutes afterwards, and with continuous heart 
rate and pulse oximetry as per standard of care. If the parturient does not achieve adequate 


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analgesia with a pain score ≤ 2 at 30 minutes, the catheter will be considered unsatisfactory, and 
the subject will be withdrawn from the study. Pain scores and Bromage scores will be collected 
at 30 minutes after epidural initiation and then every 2 hours until delivery. If the patient has 
inadequate analgesia, despite activating the PCEA twice in the last 20 minutes, physician boluses 
will be administered using 5 ml of ropivacaine 0. 2 % every 10 minutes. If the patient does not 
have adequate analgesia after 10 ml ropivacaine 0.2%, the catheter will be considered 
unsatisfactory if there is no bilateral sensory level at this stage and the patient will be removed 
from the study.  If there is bilateral sensory level to at least T10 after the ropivacaine boluses, 
and the patient complains of pressure, fentanyl 100 mcg will be given epidurally. If the patient 
does not achieve a pain score ≤ 2 after fentanyl, the patient will be removed from the study. The 
study will begin with epidural insertion and terminate with delivery. Per standard of care, each 
participant will be evaluated 24-hours post-partum to assess for any adverse effects.  
 
The primary endpoint will be the total volume of local anesthetic received through PCEA per 
hour. Secondary outcomes will include need for physician interventions per hour, volume of 
clinician boluses required per hour, PCEA attempts per hour, PCEA boluses given per hour, 
unsuccessful PCEA attempts per hour, ratio of attempts/giver per hour and motor blockade 
measured by the lowest recorded modified Bromage scale, frequency of hypotensive events, 
mode of delivery, labor pain scores and patient satisfaction. 
 
Statistical Analysis:  
Data from a pilot study suggested that the mean (SD) PCEA volume used per hour was 6 (3) ml 
with CEI and 4 (3) ml with PIEB. A sample size of 44 patients per group will have an 80 % 
power at alpha=0.05 to identify this difference. To account for drop-outs and catheter failures, 
we will aim to enroll 200 subjects to have 60 completed patients per group. Randomization will 
be stratified according to parity (nullipara or multipara).  Continuous data will be analyzed using 
kruskal wallis test or t test as appropriate. Categorical data will be analyzed using Chi-square test 
or Fisher’s exact test as appropriate. 
  
Subject identification, recruitment and compensation:  
Patients presenting for spontaneous or induced delivery will be screened. Those eligible will be 
approached to participate in the study. A member of the healthcare team known to the subject 
will introduce the study. There will be no compensation to the subjects as a result of participation 
in this study.  
 
Subject competency:  
Only competent subjects will be approached to participate in this study. 
 
Costs to Subject:  
There will be no additional cost to the subjects as a result of participation in this research study. 


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Data Storage & Confidentiality: 
Study records will remain confidential as required by law. Federal Privacy regulations ensure 
privacy, security and authorized access. Patient identifiers including but not limited to name, 
social security number, address, and telephone number will not be disclosed outside of the Duke 
University Health System (DUHS).  For records shared with parties outside of DUHS, patients 
will receive a unique code number. The key to the code will be kept in a locked file in Dr. 
Habib’s office.  
 
Data Integrity: 
The data will be housed on the Department of Anesthesia’s Parnassus server and the PI, and 
study team members will have access to the study data.  
 
Data monitoring: 
Data will be monitored closely for the occurrence of adverse events (AE) and reported to the IRB 
as needed. If unanticipated AEs or if expected events appear to be occurring more frequently 
than expected, those AEs will be explored per treatment arm. 
 
In accordance with federal regulations, the PI will monitor for, review, and promptly report to 
the IRB, appropriate institutional officials, sponsor, coordinating center and the appropriate 
regulatory agency head all unanticipated problems involving risks to subjects or others that occur 
in the course of a subject’s participation in a research study (45 CFR 46.103(b)(5)(i) and 21 CFR 
56.108(b)(1)), all AE reports will be reported per the DUHS IRB policies. 
 
Benefit / Harm Assessment:  
 
The will be no benefit to subjects from participating in the study, since standard of care regimens 
will be used in this study. The information gained from the study will help elucidate if PIEB 
offers benefits over CEI for maintenance of labor analgesia in our practice. Risks of epidural 
analgesia are the same irrespective of participation in the study. Preliminary studies to date have 
not shown any difference in risks with PIEB compared to CEI.  
 
References 
 
1. 
Vermelis JM, Wassen MM, Fiddelers AA, Nijhuis JG, Marcus MA. Prevalence and 
predictors of chronic pain after labor and delivery. Current opinion in anaesthesiology 
2010;23:295-9. 
2. 
Leighton BL, Halpern SH. The effects of epidural analgesia on labor, maternal, and 
neonatal outcomes: a systematic review. American journal of obstetrics and gynecology 
2002;186:S69-77. 


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3. 
Wong CA, Scavone BM, Peaceman AM, McCarthy RJ, Sullivan JT, Diaz NT, Yaghmour 
E, Marcus RJ, Sherwani SS, Sproviero MT, Yilmaz M, Patel R, Robles C, Grouper S. 
The risk of cesarean delivery with neuraxial analgesia given early versus late in labor. 
The New England journal of medicine 2005;352:655-65. 
4. 
Thornton JG, Capogna G. Reducing likelihood of instrumental delivery with epidural 
anaesthesia. Lancet (London, England) 2001;358:2. 
5. 
Wong CA, McCarthy RJ, Hewlett B. The effect of manipulation of the programmed 
intermittent bolus time interval and injection volume on total drug use for labor epidural 
analgesia: a randomized controlled trial. Anesthesia and analgesia 2011;112:904-11. 
6. 
Capogna G, Camorcia M, Stirparo S, Farcomeni A. Programmed intermittent epidural 
bolus versus continuous epidural infusion for labor analgesia: the effects on maternal 
motor function and labor outcome. A randomized double-blind study in nulliparous 
women. Anesthesia and analgesia 2011;113:826-31. 
7. 
Leone Roberti Maggiore U, Silanos R, Carlevaro S, Gratarola A, Venturini PL, Ferrero S, 
Pelosi P. Programmed intermittent epidural bolus versus continuous epidural infusion for 
pain relief during termination of pregnancy: a prospective, double-blind, randomized 
trial. International journal of obstetric anesthesia 2016;25:37-44. 
8. 
George RB, Allen TK, Habib AS. Intermittent epidural bolus compared with continuous 
epidural infusions for labor analgesia: a systematic review and meta-analysis. Anesthesia 
and analgesia 2013;116:133-44. 
9. 
Tien M, Allen TK, Mauritz A, Habib AS. A retrospective comparison of programmed 
intermittent epidural bolus with continuous epidural infusion for maintenance of labor 
analgesia. Current medical research and opinion 2016;32:1435-40. 
10. 
McKenzie CP, Cobb B, Riley ET, Carvalho B. Programmed intermittent epidural boluses 
for maintenance of labor analgesia: an impact study. International journal of obstetric 
anesthesia 2016;26:32-8.